reaxys_anonymous_20131108_024356_919

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1/80 2013-11-08 02:44:35

Query

Query Results Date

1. Query

N

O O

N H

O O

224 reactions inReaxys 2013-11-08 02h:39m:04s (EST)

Search as: Ignore stereo, No salts, No mixtures, No isotopes, Nocharges, No radicals


2/80 2013-11-08 02:44:35

HN

O

N

HN

O

HN

Rx-ID: 25854575 View in Reaxys 1/224Yield Conditions & References

80.4 % A.A7.c :c) Preparation of intermediate 30; A solution of intermediate 29 (0.0448 mol) in CH3OH (150 ml) was hydro-genated at 75 0C under 90 atm of pressure with Pd/C 10 percent (1 g) as a catalyst. After uptake of H2 (3 equiv), thecatalyst was filtered off and the filtrate was evaporated. The oily residue was triturated under diethyl ether, filtered off,washed, then dried (vacuum, 55 °C).Yield: 9.3 g of intermediate 30 (80.4 percent).

With hydrogen, palladium 10 on activated carbon in methanol, T= 75 °C , p= 68404.6Torr

Patent; JANSSEN PHARMACEUTICA N.V.; WO2007/90826; (2007); (A1) EnglishView in Reaxys

80 % With palladium on activated charcoal, hydrogen in methanol, T= 75 °C

Bongartz, Jean-Pierre; Buntinx, Mieke; Coesemans, Erwin; Hermans, Bart; Wauwe, Jean Van; Lommen, GuyVan; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 21; (2008); p. 5819 - 5823View in Reaxys

O

O N

O

O

H N


100 % Ethyl 2-methyl-2-(4-piperidyl)propanoate; Ethyl 2-methyl-2-pyridin-4-yl-propanoate (1.50 g, 7.77 mmol) in ethanol (100ml) and 5percent rhodium on alumina (150 mg, 0.075 mmol) were stirred under an atmosphere of hydrogen at apressure of 4 bars and a temperature of 25° C. for 12 hours.The reaction mixture was filtered through Celite to removethe catalyst. The solvent was evaporated under reduced pressure to give ethyl 2-methyl-2-(4-piperidyl)propanoate asa black oil (quantitative reaction).1H NMR (300.073 MHz, DMSO-d6) δ 1.04 (6H, s), 1.17 (3H, t), 1.25-1.33 (2H, m),1.48 (1H, d), 1.52-1.64 (2H, m), 1.80 (1H, s), 2.55-2.61 (2H, m), 3.09 (2H, d), 4.05 (2H, q)

With hydrogen, 5 Rh/Al2O3 in ethanol, Time= 12h, T= 25 °C , p= 3000.3Torr

Patent; AstraZeneca AB; US2008/269288; (2008); (A1) EnglishView in Reaxys

N

N

HO OH

N

HN OH

OH


82 % 12 : 2-[(2-hydroxy-ethyl)-(2-piperidin-4-yl-ethyl)-amino]-ethanol1.0 g activated ruthenium oxide is added to a solution of 57 g (0.27 mol) 2-[(2-hydroxy-ethyl)-(2-pyridin-4-yl-ethyl)-amino]-ethanol (Chem. Abstr. 1960, 13129) in 700 ml methanol and hydrogenated for 16 h at 100 C. and 150 barhydrogen pressure. It is filtered, concentrated by evaporation and chromatographed on silica gel. 47.9 g (82percent oftheory) of the desired compound is eluted as an oil with methanol.

With hydrogen, ruthenium(IV) oxide in methanol, Time= 16h, T= 100 °C , p= 112511Torr

https://www.reaxys.com/reaxys/secured/hopinto.do?context=R&query=RX.ID=25854575&database=RX&origin=ReaxysOutput&ln=

https://www.reaxys.com/reaxys/secured/hopinto.do?context=C&query=CNR.CNR=442041&database=RX&origin=ReaxysOutput&ln=






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Patent; Roche Diagnostics GmbH; US2003/236266; (2003); (A1) EnglishView in Reaxys

OH

OH

N

HCl

OH

OH

N H


80 % A.12.2A :A solution OF 4 N HCI in dioxane (5.06 mL) was added to a solution of the pyridine (1.41 g, 10.1 mmol) inMeOH (5 mL). The solution was stirred at room temperature for 1 hour, and solvent was removed under reducedpressure to give a white solid, 1.68 g (94percent). A mixture of the HCI salt of the pyridine (1.57 g, 8.94 MMMOL),platinum oxide (100 mg, 0.44 mmol), 1.0 N hydrochloric acid (1.4 mL) in ethanol (20 ML) was kept at 55 psi of hydrogengas at room temperature for 7.5 hours. The solvent was then removed under reduced pressure to deliver 1. 67 g of ayellow oil (composition of sample: 80percent title compound, 20percent mono-ol based on 'H NMR). MS (APCI) (M+L)/Z 145.9.

With hydrogenchloride, hydrogen, platinum(IV) oxide in ethanol, Time= 7.5h, T= 20 °C , p= 2844.39Torr

Patent; WARNER-LAMBERT COMPANY LLC; WO2005/26145; (2005); (A2) EnglishView in Reaxys

N

NH

HN

O N

N

NH

HN

O NH


62% 83 :The mixture of 9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (150 mg, 0.4 mmol),con.HCl (0.6 mL) and Platinum (IV) oxide monohydrate (40 mg) in methanol (30 mL) was purged with 50 atm of hydrogenat 50° C. for 18 h. Then the mixture was filtered. The solvent was removed in vacuum to obtain a crude oil which waspurified by prep-HPLC to give 9-phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (95 mg,yield 62percent). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.24-1.41 (m, 1H), 1.49-1.59 (m, 1H), 1.69-1.78 (m, 2H),1.98-2.01 (d, J=13.2 Hz, 1H), 2.67-2.86 (m, 2H), 3.22-3.31 (m, 3H), 4.18 (s, 1H), 7.05-7.08 (m, 3H), 7.14-7.21 (m, 2H),7.24-7.28 (m, 2H), 7.31-7.33 (d, J=7.2 Hz, 1H), 7.52-7.56 (t, J=8.0 Hz, 1H), 8.19-8.24 (m, 1H), 8.54-8.56 (m, 1H), 12.30(s, 1H); LC-MS (m/z) 347 (M+1)+.

With hydrogenchloride, hydrogen, Adam's catalyst in methanol, water, Time= 18h, T= 50 °C , p= 38002.6Torr

Patent; LEAD THERAPEUTICS, INC.; US2010/35883; (2010); (A1) EnglishView in Reaxys

62 % 83 :Example 839-Phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-.pound./e]phthalazin-3(7H)-one[00645] Themixture of 9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-.pound./e]phthalazin-3(7H)-one (150 mg, 0.4 mmol),con.HCl (0.6 mL) and Platinum (IV) oxide monohydrate (40 mg) in methanol (30 mL) was purged with 50 atm of hydrogenat 50 °C for 18 h. Then the mixture was filtered. The solvent was removed in vacuum to obtain a crude oil which waspurified by prep-HPLC to give 9-phenyl-8- (piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-.pound./e]phthalazin-3(7H)-one(95 mg, yield 62percent). ^-NMR (400 MHz, DMSO-i/6) δ (ppm): 1.24- 1.41 (m, 1H), 1.49-1.59 (m, 1H), 1.69-1.78(m,2H), 1.98-2.01 (d, J = 13.2 Hz, 1H), 2.67-2.86 (m, 2H), 3.22-3.31 (m, 3H), 4.18 (s, 1H), 7.05-7.08 (m, 3H), 7.14-7.21(m, 2H), 7.24-7.28 (m, 2H), 7.31-7.33 (d, J= 7.2 Hz, 1H), 7.52-7.56 (t, J= 8.0 Hz, 1H), 8.19-8.24 (m, 1H), 8.54-8.56 (m,1H), 12.30 (s, 1H); LC-MS (m/z) 347 (M+l)+.

With hydrogenchloride, hydrogen, Adam's catalyst in methanol, Time= 18h, T= 50 °C , p= 38002.6Torr

Patent; BIOMARIN PHARMACEUTICAL INC.; WANG, Bing; CHU, Daniel; WO2011/130661; (2011); (A1) EnglishView in Reaxys








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N

HO

H N

HO


95 % With hydrogen, palladium on activated charcoal in acetic acid, Time= 48h, p= 2585.7Torr

Egbertson, Melissa S.; Chang, Charles T.-C.; Duggan, Mark E.; Gould, Robert J.; Halczenko, Wasyl; et al.;Journal of Medicinal Chemistry; vol. 37; nb. 16; (1994); p. 2537 - 2551View in Reaxys

90 % With hydrogen, acetic acid, 10percent Pd/C, T= 20 °C , p= 2585.81Torr

He, Henry T.; Siahaan, Teruna J.; Song, Xiaoping; Organic Letters; vol. 4; nb. 4; (2002); p. 549 - 552View in Reaxys

85 % With hydrogen, Rh on carbon in ethanol, Time= 24h, T= 60 °C , p= 3102.89Torr , Catalytic hydrogenation

Bruns, Robert F.; Cantrell, Buddy E.; Chaney, Michael O.; Clay, Michael P.; Gehlert, Donald R.; Hahn, Patric J.;Hunden, David C.; Johnson, Douglas W.; Ornstein, Paul L.; Schober, Douglas A.; Siegel, Miles G.; Zarrinmayeh,Hamideh; Zimmerman, Dennis M.; Van Abbema, Anne M.; Koppel, Gary A.; Tetrahedron; vol. 55; nb. 39; (1999);p. 11619 - 11639View in Reaxys

With water, acetic acid, platinum, Hydrogenation

Schaefgen et al.; Journal of Polymer Science; vol. 40; (1959); p. 377,384View in ReaxysBurtner; Brown; Journal of the American Chemical Society; vol. 69; (1947); p. 630,631View in Reaxys

With Rh/Al2O3 in methanol

Bennani, Youssef L; Dwight, Wesley; Esbenshade, Timothy A; Faghih, Ramin; Fox, Gerard B; Gentles, Robert;Gopalakrishnan, Sujatha M; Hancock, Arthur A; Ireland, Lynne; Kang, Chae-Hee; Miller, Thomas R; Phelan,Kathleen; Bioorganic and Medicinal Chemistry Letters; vol. 12; nb. 15; (2002); p. 2031 - 2034View in Reaxys

71.a : aa3-(4-piperidinyl)propanol3-(4-piperidinyl)propanol was prepared by hydrogenation of 3-(4-pyridyl)propanol in acetic acid in the presence of Pd/C according to the method described in J. Org. Chem., 1962, 27, 2966-2967.

With palladium monocarbide in acetic acid

Patent; SANOFI; US5714497; (1998); (A1) EnglishView in Reaxys

3 :Example 31-Methyl-4-PiperidinepropanolAn Argonaut reaction vessel was charged with 4-pyridinepropanol (500.0 mg, 3.49 mmol) and 5percent Rh/C (62percentwet, 300.0 mg) in water (4.00 g).The resultant slurry was stirred at 500 RPM and the unit was pressurized with 300 psi of hydrogen.The resultant mixture was heated at 50° C. for about 4-4.5 h, during which time the hydrogen uptake ceased.The resultant mixture was then cooled to room temperature and a 37percent formaldehyde solution (340.0 mg, 4.19mmol) was added in a single portion.The Argonaut vessel was sealed and the resultant slurry was stirred at 500 RPM, the unit was repressurized with 300psi of hydrogen, and heated to 50° C.Hydrogen uptake ceased in about 1.2-1.5 h to yield the title compound, which was used in the next step without furtherpurification or isolation.HPLC-MS analysis of an aliquot showed only C9H19NO










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MS: (Cl): m/z 158 (M++1)

With hydrogen, 5 rhodium-on-charcoal in water, T= 50 °C , p= 15514.9Torr

Patent; Cesco-Cancian, Sergio; Chen, Hongfeng; Grimm, Jeffrey S.; Mani, Neelakandha S.; Mapes, ChristopherM.; Palmer, David C.; Pippel, Daniel J.; Sorgi, Kirk L.; Xiao, Tong; US2010/4450; (2010); (A1) EnglishView in Reaxys

O

O

N

O

O

H N


94 % With platinum(IV) oxide, hydrogen in acetic acid, Time= 0.333333h, T= 80 °C , p= 6205.94Torr , Microwave irradiation

Piras, Leonarda; Taddei, Maurizio; Genesio, Eva; Ghiron, Chiara; Synlett; nb. 8; (2008); p. 1125 - 1128View in Reaxys

88 % 11

With hydrogen, platinum(IV) oxide, Time= 18.5h, p= 3102.97Torr

Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS; WO2008/134474; (2008); (A2) EnglishView in Reaxys

58 % 10A

Stage 1: With hydrogenchloride, hydrogen, palladium on activated charcoal in ethanol, water, Time= 48h, T= 20 °C ,pH= 2Stage 2: With sodium hydroxide, water in ethyl acetate, pH= 13

Patent; BAYER HEALTHCARE AG; WO2005/68472; (2005); (A1) GermanView in Reaxys

58 % 4A

Stage 1: With hydrogenchloride, hydrogen, palladium on carbon in ethanol, water, Time= 48h, T= 20 °C , p=2250.23Torr , pH= 2Stage 2: With sodium hydroxide in water, ethyl acetate, pH= 13

Patent; BAYER HEALTHCARE AG; WO2005/77907; (2005); (A1) GermanView in Reaxys

5 g With hydrogen, aluminum oxide in methanol, water, Time= 20h, p= 2660Torr , Catalytic hydrogenation

Carpinelli; Colombo; Fazio; Kienle, M. Galli; Magni; Matarrese; Moresco; Simonelli; Soloviev; Todde; Kienle,M. Galli; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 43; nb. 4; (2000); p. 359 - 374View in Reaxys

With hydrogen, acetic acid, platinum(IV) oxide

Islam, Imadul; Bryant, Judi; May, Karen; Mohan, Raju; Yuan, Shendong; Kent, Lorraine; Morser, John; Zhao,Lei; Vergona, Ron; White, Kathy; Adler, Marc; et al.; Bioorganic & Medicinal Chemistry Letters; vol. 17; nb. 5; (2007);p. 1349 - 1354View in Reaxys

4 : EXAMPLE 4 STR27EXAMPLE 4 STR27Ethyl-4-pyridylacetate (5 g) is dissolved in ethanol (30 mL), treated with platinum oxide catalyst (30 mg) and hydro-genated on a Parr apparatus for 4 hr.The catalyst is filtered off and the ethyl-4-piperidinylacetate is isolated by removal of the solvent under vacuum.










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in ethanol

Patent; Neurogen Corporation; US6084098; (2000); (A1) EnglishView in Reaxys

7.a : EXAMPLE 7a)16.5 g (0.1 mol) Ethyl 4-pyridylacetate, 8.4 mL (0.1 mol) 12N hydrochloric acid and 2.5 g platinum oxide were dissolvedin absolute ethanol and hydrogenated at 40 psi hydrogen on a Parr shaker.After 1 hour, the contents of the vessel were filtered and concentrated in vacuo yielding 27.79 g of ethyl 4-piperidiny-lacetate.

With hydrogenchloride, hydrogen in ethanol

Patent; Sterling Winthrop Inc.; US5242924; (1993); (A1) EnglishView in Reaxys

13.a : EXAMPLE 13a)16.5 g (0.1 mol) Ethyl 4-pyridylacetate, 8.4 mL (0.1 mol) 12 N hydrochloric acid and 2.5 g platinum oxide were dissolvedin absolute ethanol and hydrogenated at 40 psi hydrogen on a Parr shaker.After 1 hour, the contents of the vessel were filtered and concentrated in vacuo yielding 27.79 g of ethyl 4-piperidiny-lacetate.

With hydrogenchloride, hydrogen in ethanol

Patent; Sterling Winthrop Inc.; US5364865; (1994); (A1) EnglishView in Reaxys

21.A : PREPARATIVE EXAMPLE 21; Step A[1989] Commercially available Ethyl 4-Pyridyl Acetate (4.5 g; 27.2 mmol), EtOH (70 ml) and 10percent Palladium onCharcoal (catalytic) was shaken under 55 psi hydrogen at room temperature for 94 hrs. The mixture was filtered throughCelite and the cake was washed with (4.x.40 ml) of EtOH. The filtrate was concentrated and purified by flash silicacolumn chromatography eluting with 3percent (10percent NH4OH:MeOH)/CH2Cl2.

With ethanol, hydrogen, palladium 10 on activated carbon, Time= 94h, T= 20 °C , p= 2844.39Torr

Patent; Schering Corporation; US2004/122018; (2004); (A1) EnglishView in Reaxys

18 :Ethyl 4-pyridyl acetate (4.5g, 27.24mmoles) is placed in a 500mL Parr bottle and dissolved in anhydrous EtOH(70mL). To the bottle is added 10percent Palladium on charcoal (1 0 g). The bottle is put on a hydrogenator and thecontents shaken under 55 psi hydrogen pressure at 25°C for 94h. The mixture is filtered through Celite.(R). and washedwith 4x40mL anhydrous EtOH. The filtrate is rotovapped down and the residue chromatographed on silica gel using3percent (10percent conc. NH4OH in methanol)dichloromethane as the eluant to give 2 944g of the title compound.

With hydrogen, palladium 10 on activated carbon in ethanol, Time= 94h, T= 25 °C , p= 2844.39Torr

Patent; Schering Corporation; Pharmacopeia Drug Discovery, Inc.; EP1140909; (2005); (B1) EnglishView in Reaxys

With hydrogenchloride, platinum(IV) oxide, hydrogen in water, p= 2585.81Torr , Inert atmosphere, Autoclave

Monovich, Lauren G.; Tommasi, Ruben A.; Fujimoto, Roger A.; Blancuzzi, Vincent; Clark, Kirk; Cornell, WendyD.; Doti, Robert; Doughty, John; Fang, James; Farley, David; Fitt, John; Ganu, Vishwas; Goldberg, Ronald;Goldstein, Robert; Lavoie, Stacey; Kulathila, Raviraj; Macchia, William; Parker, David T.; Melton, Richard;O'Byrne, Elizabeth; Pastor, Gary; Pellas, Theodore; Quadros, Elizabeth; Reel, Noela; Roland, Dennis M.; Sa-kane, Yumi; Singh, Hem; Skiles, Jerry; Somers, Joseph; Toscano, Karen; Wigg, Andrew; Zhou, Siyuan; Zhu,Lijuan; Shieh, Wen-Chung; Xue, Song; McQuire, Leslie W.; Journal of Medicinal Chemistry; vol. 52; nb. 11; (2009);p. 3523 - 3538View in Reaxys








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NH

N

NH

NH


73 % 8 :3-(Pyridin-4-ylmethyl)-1H-indole (5.00 g, 24.0 mmol) and acetic acid (25 mL) were added to platinum(IV) oxide (1.00g, 4.40 mmol, Johnson Matthey) in a 250 mL stainless steel pressure bottle and stirred for about 2 hr under about 30psi hydrogen at ambient temperature. The mixture was filtered and the filtrate was concentrated under reduced pres-sure. The residue was dissolved with EtOAc and then washed with saturated aqueous Na2CO3. The organic layerbecame turbid. A small amount of MeOH was added to form a clear solution. The organic layer was washed with 2 Naqueous NaOH and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solidwas triturated with Et2O and then dried to give 3-(piperidin-4-ylmethyl)-1H-indole (4.35 g, 73percent yield): LC/MS(Table 1, Method a) Rt=1.51 min; MS m/z: 215.12 (M+H)+.

Stage 1: With hydrogen, acetic acid, platinum(IV) oxide, Time= 2h, T= 20 °C , p= 1551.49TorrStage 2: With sodium carbonate in water, ethyl acetate

Patent; ABBOTT LABORATORIES; US2011/152243; (2011); (A1) EnglishView in Reaxys

O

O

N

O

O

H N

Cl H


With hydrogenchloride, hydrogen, platinum(IV) oxide in ethanol, Time= 16h, T= 20 °C , Catalytic hydrogenation

Brundish, Derek; Bull, Alice; Donovan, Vera; Fullerton, Joseph D.; Garman, Sheila M.; Hayler, Judy F.; Janus,Diana; Kane, Peter D.; McDonnell, Mark; Smith, Garrick P.; Wakeford, Robert; Walker, Clive V.; Ambler, John;Butler, Keith; Talbot, Mark D.; Allen, Mark C.; Howarth, Graham; Hoyle, William; Kane, Peter D.; Journal of Me-dicinal Chemistry; vol. 42; nb. 22; (1999); p. 4584 - 4603View in Reaxys

124 : Reference Example 124: Ethyl (piperidin-4-yl) acetate hydrochlorideEthyl (pyridin-4-yl)acetate (50.00 g) is dissolved in acetic acid (500 ml), thereto is added platinum oxide (3.44 g) andthe mixture is shaken under 55 psi hydrogen atmosphere at room temperature for 20 hours. The insoluble materialsare removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved indioxane (200 ml), thereto is added 4 N hydrogen chloride-dioxane (400 ml), and then the mixture is evaporated toremove the solvent under reduced pressure. The resulting residue is suspended in diethyl ether-diisopropyl ether, andthe precipitates are collected by filtration, washed with diisopropyl ether, and then dried to give the title compound(61.80 g). APCI-MS M/Z:17-2[M+H]+.

Stage 1: With hydrogen, acetic acid, platinum(IV) oxide, Time= 20h, T= 20 °C , p= 2844.39TorrStage 2: With hydrogenchloride in 1,4-dioxane

Patent; Tanabe Seiyaku Co., Ltd.; EP1489078; (2004); (A1) EnglishView in Reaxys

14 : Reference Example 14:Reference Example 14:Ethyl piperidin-4-ylacetate hydrochlorideEthyl (pyridin-4-yl)acetate (50.00 g) is dissolved in acetic acid (500 ml), and thereto is added platinum oxide (3.44 g).The mixture is shaken at room temperature for 20 hours under 55 psi hydrogen atmosphere.The insoluble materials are removed by filtration and the filtrate is concentrated under reduced pressure.The resulting residue is dissolved in dioxane (200 ml), and thereto is added 4 N hydrogen chloride/dioxane (400 ml).The mixture is then evaporated to remove the solvent under reduced pressure.







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The resulting residue is suspended in diethyl ether/diisopropyl ether, and the precipitates are collected by filtration.The resultant is washed with diisopropyl ether, and dried to give the title compound (61.80 g).APCI-MS M/Z:172[M+H]+.

Stage 1: With hydrogen, acetic acid, platinum(IV) oxide, Time= 20h, T= 20 °C , p= 2844.39TorrStage 2: With hydrogenchloride in 1,4-dioxane

Patent; TANABE SEIYAKU CO., LTD.; EP1582521; (2005); (A1) EnglishView in Reaxys

1.C.1 :To a solution of ethyl 4-pyridylacetate (0.121 mol) in EtOH (100 mL) is added concentrated hydrochloric acid(11 mL), followed by the addition of platinum oxide (8.8 mmol). The resulting mixture is hydrogenated under hydrogenatmosphere (50 psi) till no more hydrogen absorption occurs. The catalyst is filtered off and washed with EtOH (20 mLx 2). The filtrate is concentrated to dryness in vacuo to give the title compound as the hydrochloric acid salt.

With hydrogenchloride, hydrogen, platinum(IV) oxide in ethanol, water, p= 2585.81Torr

Patent; NEUROGEN CORPORATION; WO2007/16496; (2007); (A2) EnglishView in Reaxys

N H N


99 % With hydrogen, rhodium on alumina

Meyers, A. I.; Shawe, Thomas T.; Gottlieb, Levi; Tetrahedron Letters; vol. 33; nb. 7; (1992); p. 867 - 870View in Reaxys

86 % With hydrogen, acetic acid, Rh/Al2O3, [RhCl(η2:η2-cycloocta-1,5-diene)]2 in ethanol, Time= 24h, T= 50 °C , p=76000.1Torr

Hayashi, Tamio; Sawamura, Masaya; Ito, Yoshihiko; Tetrahedron; vol. 48; nb. 11; (1992); p. 1999 - 2012View in Reaxys

80.5 % With hydrogen, platinum(IV) oxide in ethanol, chloroform, Time= 48h, p= 2585.81Torr , Hydrogenation

Chambournier; Gawley; Organic letters; vol. 2; nb. 11; (2000); p. 1561 - 1564View in Reaxys

80.5 % With hydrogen, platinum(IV) oxide in ethanol, chloroform, Time= 48h, p= 2585.81Torr

Chambournier; Gawley; Low; Organic letters; vol. 1; nb. 4; (1999); p. 653 - 655View in Reaxys

Reaction Steps: 21: HCl, gas / ethanol; diethyl ether / 1 h2: 81.5 percent / H2 / PtO2 / ethanol / 24 h / 2280 TorrWith hydrogenchloride, hydrogen, platinum(IV) oxide in diethyl ether, ethanol

Goessinger,E.; Monatshefte fuer Chemie; vol. 113; (1982); p. 339View in Reaxys

Reaction Steps: 21: 2) 6 N HCl / diethyl ether; toluene / 14 h / Heating2: 1) tert-butyl-pyridine, aq. NaOH; 2) Ru(OH)3, LiOH*H2O, 10 percent HCl / 1) Raney-nickel, aluminum / 1) tert-butylalcohol, 60-70 deg C, 1 h; 2) H2O, 4053 kPa, 80-120 deg C,With hydrogenchloride, ruthenium trihydroxide, lithium hydroxide, sodium hydroxide, nickel, aluminium in diethyl ether,toluene










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Ogawa, Keiichiro; Takeuchi, Yoshito; Suzuki, Hiroshi; Nomura, Yujiro; Journal of the American Chemical Society;vol. 106; nb. 4; (1984); p. 831 - 840View in Reaxys

N

N

N

H N


43.9 % 2.47.b :2.47.b4-piperidin-1-ylmethyl-piperidineA solution of 106 g (0.6 mol) of 4-piperidin-1-ylmethyl-pyridine in 1.0 L glacial acetic acid is combined with 7 g platinumdioxide and shaken in the autoclave at ambient temperature and 3 bar hydrogen.After the catalyst has been suction filtered the solvent is eliminated using the rotary evaporator.The crude product is further reacted without purification.Yield: 48 g (43.9percent of theory).

With hydrogen, platinum(IV) oxide in hydrogen, acetic acid, T= 20 °C , p= 2250.23Torr

Patent; Boehringer Ingelheim International GmbH; US2004/242572; (2004); (A1) EnglishView in Reaxys

O

N

O

HN


98 % 3.32 : 3.32 4-(2-Ethoxyethyl)piperidine (56NK129)3.32 4-(2-Ethoxyethyl)piperidine (56NK129)4-(2-Ethoxyethyl)pyridine (0.151 g, 1.0 mmol) was dissolved in EtOH (4 ml) and acetic acid (0.5 ml) and the flask wasevacuated, flooded with hydrogen and this procedure was repeated twice.Platinium oxide (0.040 g) was added and the reaction was stirred vigorously at r.t. for 18 h.The reaction mixture was filtered through Celite eluding with EtOAc and the solute concentrated in vacuo.Ether (20 ml) was added and the reaction concentrated in vacuo.Sodium hydroxide (2 ml, 2 M) was added and the product was extracted into ether (2*20 ml).The organic phases were dried (K2CO3), filtered and carefully concentrated in vacuo to give the crude title compound(56NK129) as a yellow oil (0.154 g, 98percent).1H NMR (CDCl3) δ 3.45 (m, 4H), 3.03 (m, 2H), 2.58 (m, 2H), 1.76 (br. S, 1H), 1.66 (m, 2H), 1.51 (m, 3H), 1.18 (t, J=7.5Hz, 3H), 1.11 (m, 2H); HPLC-MS (ammonium acetate) [M+H]+=158.2 (calc. 158.2).

Stage 1: With hydrogen, acetic acid, platinum(IV) oxide in ethanol, Time= 18h, T= 20 °CStage 2: With sodium hydroxide in water

Patent; Kelly, Nicholas Michael; Koch, Kristian Norup; Tolf, Bo-Ragnar; US2004/67931; (2004); (A1) EnglishView in Reaxys

NH 2

N

O

OH

N

Cl H

racemate

2

NH 2

N

O

OH

HN

Cl H

racemate

2

Rx-ID: 27873873 View in Reaxys 13/224








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Yield Conditions & References

88.2 % (+/-)-f/7reo-2-Amino-3-hydroxy-3-(pyridin-4-yl)-1 -(pyrrolidin-1 -yl)propan-1- one dihydrochloride Compound 22 (500mg, 1.61 mmol) was stirred in AcOH (10 ml_) with PtO2 hydrate typical (Pt content 79-84percent, 100 mg) underhydrogen at atmospheric pressure for 24 h at RT. After filtration on Celite.(R). 545, the filtrate was evaporated and theresidue was dried under vacuum to give a beige solid (450 mg, 88.2 percent yield). The crude product was stirred in<n="30"/>Docket 18175 PCT (AP)MeOH (50 ml_) with Amberlite (Cl-) IRA-400 (9 ml_, 12.7 mmol washed beforehandby NaOH 0.5 N then water and MeOH) at RT for 15 min. The mixture was filtered off, the filtrate was evaporated andthe free base form was purified by column chromatography (SiO2, CH2CI2:MeOH:20 percent NH3 in H2O = 70:30:8)to give (+/-)-tf7reo-2-amino-3-hydroxy-3-(piperidin-4-yl)-1- (pyrrolidin-1-yl)propan-1-one TTA 08144A (226 mg, 58per-cent yield). HCI Treatment in MeOH gave (+/-)-f/7reo-2-amino-3-hydroxy-3-(piperidin-4-yl)-1- (pyrrolidin-1-yl)propan-1-one dihydrochloride Compound 302 (190 mg, 28 percent yield) as a white solid.2.HCI (+/-)-threoCompound 302MW:314.25; Yield: 28.0 percent; White Solid; Mp (0C): 197.5Rf : 0.20 (CH2CI2:MeOH:20 percent NH3 in H2O = 70:30:8,free base). 1 H-NMR (CD3OD, δ): 1.57-2.00 (m, 9H, 4xCH2 CH), 2.94-3.08 (m, 2H, CH&2-N), 3.46-3.77 (m, 7H, 3xCH2-N, CH-N), 4.33 (s, 1 H, CH-O).13C-NMR (CD3OD, δ): 22.5, 23.4, 24.1 , 24.7, 35.2, 42.2, 42.5, 45.4, 45.5,52.0, 69.8, 164.6.MS-ESI m/z (percent rel. Int.): 242.2 ([MH]+, 45), 129.1 (100). HPLC: Method A, detection UV 214 nm, RT = 0.70 min, peakarea 98.0 percent.

With hydrogen, platinum(IV) oxide in acetic acid, Time= 24h, T= 20 °C

Patent; ALLERGAN, INC.; WO2008/109285; (2008); (A1) EnglishView in Reaxys

N

NH

HN

N

O N

N

NH

HN

NH

O N


16 % 15 :A mixture of 8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.35 mmol), plati-num (IV) oxide (60 mg) and concentrate hydrochloric acid (0.3 mL) in methanol (20 mL) was stirred at 50° C. under 20atm of hydrogen. The mixture was filtered out and the filtrate was concentrated to give crude product. The crude productwas purified by prep-HPLC to give 9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (17.6 mg, yield: 16percent) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ 1.25-1.39 (m, 1H), 1.40-1.52 (m,1H), 1.60-1.70 (m, 1H), 1.75-1.84 (m, 1H), 1.89-1.98 (m, 1H), 2.50-2.57 (m, 1H), 2.60-2.66 (m, 1H), 3.09-3.21 (m, 2H),3.34-3.37 (dd, J1=8 Hz, J2=2.4 Hz, 1H), 4.24 (d, J=2 Hz, 1H), 7.02-7.04 (dd, J1=8 Hz, J2=0.8 Hz, 1H), 7.09-7.11 (dd,J1=4.8 Hz, J2=1.2 Hz, 2H), 7.41-7.43 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 7.50-7.54 (t, J=8 Hz, 1H), 8.30-8.32 (dd, J1=4.4Hz, J2=1.6 Hz, 2H); LC-MS (ESI) m/z: 348(M+1)+

With hydrogenchloride, hydrogen, Adam's catalyst in methanol, T= 50 °C , p= 15201Torr

Patent; LEAD THERAPEUTICS, INC.; US2010/35883; (2010); (A1) EnglishView in Reaxys

16 % 15 :Example 159-(Piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-<ie]phthalazin-3(7H)-one[00518] A mix-ture of 8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-i/e]phthalazin-3(7H)-one (120 mg, 0.35 mmol), platinum (IV) ox-ide (60 mg) and concentrate hydrochloric acid (0.3 mL) in methanol (20 mL) was stirred at 50°C under 20 atm ofhydrogen. The mixture was filtered out and the filtrate was concentrated to give crude product. The crude product waspurified by prep-HPLC to give 9-(piperidin-4- yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-<ie]phthalazin-3(7H)-one(17.6 mg, yield: 16percent) as a light yellow solid. ^-NMR (400 MHz, CD3OD) δ 1.25- 1.39 (m, 1H), 1.40-1.52 (m, 1H),1.60-1.70 (m, 1H), 1.75-1.84 (m, 1H), 1.89-1.98 (m, 1Η),2.50-2.57 (m, 1H), 2.60-2.66 (m, 1H), 3.09-3.21 (m, 2H),3.34-3.37 (dd, J, = 8 Hz, J2 = 2.4 Hz, 1H), 4.24 (d, J= 2 Hz , 1H), 7.02-7.04 (dd, J, = 8 Hz, J2 = 0.8 Hz, 1H), 7.09-7.1 1(dd, J, = 4.8 Hz, J2= 1.2 Hz, 2H), 7.41-7.43 (dd, J, = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.50-7.54 (t, J= 8 Hz, 1H), 8.30-8.32 (dd,J = 4.4 Hz, J2 = 1.6 Hz, 2H); LC-MS (ESI) m/z: 348(M+1)+.

With hydrogenchloride, platinum(IV) oxide in methanol, T= 50 °C , p= 15201Torr

Patent; BIOMARIN PHARMACEUTICAL INC.; WANG, Bing; CHU, Daniel; WO2011/130661; (2011); (A1) EnglishView in Reaxys






11/80 2013-11-08 02:44:35

N

O

N

N

O

N H

HCl


100% 12.C : C. [1,1′-Biphenyl]-4-yl-(3-(piperidin-4-yl)azetidin-1-yl)methanone, 12dCompound 12c and 10percent palladium on carbon were combined in a 1:5 mixture of 1N aqueous HCl and ethanolin a Parr pressure bottle. _;The mixture was purged with N2 and then shaken under a 55 psi H2 atmosphere at 20° C._;When the reaction was complete, the catalyst was removed by filtration through a diatomaceous earth pad. _;Thefiltrate was concentrated and lyophilized to provide compound 12d in quantitative yield as the hydrochloride salt.

With hydrogenchloride, palladium 10 on activated carbon, hydrogen in ethanol, water, T= 20 °C , p= 2844.39Torr ,Inert atmosphere

Patent; Connolly, Peter J.; Bian, Haiyan; Li, Xun; Liu, Li; Macielag, Mark J.; McDonnell, Mark E.; US2013/102584;(2013); (A1) EnglishView in Reaxys

O

O

N

O

O

NH HCl


74.b :0.115 g of methyl 2-methyl-2-pyridin-4-ylpropionate (CAS 79757-27-0) are dissolved in 5 ml of methanol in anautoclave. The solution is admixed with 0.35 ml of 1.2M HCI in methanol and 0.012 g of platinum (IV) oxide, and thereaction mixture is hydrogenated at 4 bar and 23° over 46 hours. The catalyst is filtered off through Hyflo and the filtrateis concentrated by evaporation. The title compound is obtained as a light brown solid. Rf 0. 05 (200: 20: 1 dichlorome-thane-methanol-25percent conc. ammonia).

With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol, Time= 46h, T= 23 °C , p= 3000.3Torr

Patent; SPEEDEL EXPERIMENTA AG; WO2005/70871; (2005); (A2) EnglishView in Reaxys

122.b :0.115 g of methyl 2-methyl-2-pyridin-4-ylpropionate (CAS 79757-27-0) is dissolved in an autoclave in 5 ml ofmethanol. The solution is admixed with 0.35 mi of 1.2M HCI in methanol and 0.012 g of platinum (IV) oxide, and thereaction mixture is hydrogenated at 4 bar and 23 over 46 hours. The catalyst is filtered off through Hyflo and the filtrateis concentrated by evaporation. The title compound is obtained as a light brown solid. Rf 0. 05 (200 : 20: 1 dichloro-methane-methanol-25percent conc. ammonia).


Patent; SPEEDEL EXPERIMENTA AG; WO2005/70877; (2005); (A1) EnglishView in Reaxys

a :a) Methyl 2-methyl-2-piperidin-4-ylpropionate hydrochloride; 0. 115 g of methyl 2-methyl-2-pyridin-4-ylpropionate[79757-27-0] are dissolved in 5 mi of methanol in an autoclave. The solution is admixed with 0. 35 ml of 1. 2M HCl inmethanol and 0. 012 g of platinum (IV) oxide and the reaction mixture is hydrogenated at 4 bar and 23°C over 46 hours.The catalyst is filtered off through Hyflo and the filtrate is concentrated by evaporation. The title compound is obtainedas a tight brown residue. Rf = 0. 05 (200 : 20 : 1 dichloromethane-methanol-25percent conc. ammonia)


Patent; SPEEDEL EXPERIMENTA AG; WO2005/90304; (2005); (A1) English







12/80 2013-11-08 02:44:35

View in Reaxys

OH

O

N

OH

O

H N


87 % With hydrogen, platinum(IV) oxide in water, acetic acid, Time= 72h, p= 2844.3Torr

Egbertson, Melissa S.; Chang, Charles T.-C.; Duggan, Mark E.; Gould, Robert J.; Halczenko, Wasyl; et al.;Journal of Medicinal Chemistry; vol. 37; nb. 16; (1994); p. 2537 - 2551View in Reaxys

With hydrogen, hydrogen cation, platinum(IV) oxide

Asari, Tohru; Ishikawa, Shigetaka; Sasaki, Toshiki; Katada, Jun; Hayashi, Yoshio; et al.; Bioorganic & MedicinalChemistry Letters; vol. 7; nb. 16; (1997); p. 2099 - 2104View in Reaxys

P.9.A : A.A.PIPERIDINE-4-ACETIC ACID STR474-Pyridylacetic acid (7 grams) (40.4 mmoles) was hydrogenated as described in Preparative Example 7 to give theproduct compound (Yield: 5.2 grams, 90percent, MH+

Patent; Schering Corporation; US5891872; (1999); (A1) EnglishView in Reaxys

3 : 2-(4-N-t-Butyloxycarbonylpiperidine)ethanol (1-5)EXAMPLE 3 STR202-(4-N-t-Butyloxycarbonylpiperidine)ethanol (1-5)4-pyridine acetic acid (50 g, 0.314 mole) was dissolved in H2 O (50 mL), and HOAc (100 mL), PtO2 (1 g) was addedand the mixture was hydrogenated at 55 psi for 72 h.An additional 1 g of PtO2 was added after 48 h.The solution was filtered through celite, the cake was washed with H2 O and the filtrate was evaporated, using heptaneto azeotrope off excess HOAc.The 4-piperidine acetic acid was obtained as a white solid. Rf (9:1 EtOH/H2 O) 0.11.1 H NMR (400 MHz, CD3 OD) δ3.36(bd, 2H), 330 (bt, 2H), 2.3 (d, J=7 Hz, 2H), 2.08 (m, 1H), 1.99 (bd, 2H), 1.47 (m, 2H).

With acetic acid, PtO2 in n-heptane, water

Patent; Merck and Co., Inc.; US5646000; (1997); (A1) EnglishView in Reaxys

P.5.A : A.A.PIPERIDINE-4-ACETIC ACID) STR574-Pyridylacetic acid (7 grams) (40.4 mmoles) was hydrogensted in water (100 ml) using 10percent Pd-C at 40 psi at25° C. for 24 hours.The catalyst was filtered off and washed with water.The aqueous solution was shaken with BioRad AG1X8 resin (OH--

form) (23 ml bed) and after 5 minutes the resin was filtered off and washed with water.The aqueous solution was evaporated to give the title compound (Yield: 5.2 grams, 90percent, MH+ 144).

With Pd- C in water


P.17.A : A.A.









13/80 2013-11-08 02:44:35

Piperidine-4-Acetic Acid STR1264-Pyridylacetic acid (7 grams) (40.4 mmoles) was hydrogenated as described in Preparative Example 15 to give thetitle compound (Yield: 5.2 grams, 90percent, MH+ 144).


P.17.A : A.A.PIPERIDINE-4-ACETIC ACID STR1434-Pyridylacetic acid (7 grams) (40.4 mmoles) was hydrogenated as described in Preparative Example 15 to give thetitle compound (Yield: 5.2 grams, 90percent, MH+ 144).


N

O O

Cl H

H N

O O


95 % With hydrogen, acetic acid, platinum(IV) oxide in methanol, Time= 16h, T= 20 °C , p= 750.06Torr , Catalytic hydroge-nation


S N

O

O

NH

O

O

O

N

S N

O

O

HN

O

O

O

HN

Cl H


88% P.C : Synthesis of N-(Toluene-4-sulfonyl)sarcosyl-β-(N-benzylpiperidin-4-yl)-D,L-alanineN-(Toluene-4-sulfonyl)sarcosyl-D,L-β-(4-pyridyl)alanine methyl ester (266 mg, 0.656 mmol) was dissolved in methanol(6 mL) and 12 N HCl (273 μL) and PtO2 (25 mg) were added.The mixture was hydrogenated at 40 psi H2 for 4 hr.The mixture was filtered and the solvent was removed in vacuo to give N-(toluene-4-sulfonyl)sarcosyl-D,L-β-(4-piper-idinyl)alanine methyl ester hydrochloride (260 mg, 88percent).

With hydrogenchloride, H2, PtO2 in methanol

Patent; Athena Neurosciences, Inc.; American Home Products Corp.; US6423688; (2002); (B1) EnglishView in Reaxys








14/80 2013-11-08 02:44:35

F

N

F

N H

Cl H


93% 118.C : 4-(2-Fluorobenzyl)1-(2-(4-fluorophenoxy)ethyl)piperidine hydrochloride STR154C)4-(2-Fluorobenzyl)piperidine hydrochloride.A mixture of 4-(2-fluorobenzyl)pyridine (5.83 g, 31.1 mmol) in a solution of MeOH (100 mL) and concd HCl (5.5 mL)with PtO2 (150 mg) was hydrogenated at 20 to 30 psi to yield the title compound as a colorless powder (6.66 g, 93per-cent): mp 187-188° C. 1 H NMR (D2 O) 1.34-1.54 (m, 2H), 1.78-1.98 (m, 3H), 2.63 (d, J=6.6 Hz, 2H), 2.89 (td, J=13and 3.0 Hz, 2H), 3.32-3.43 (m, 2H), 3.78 (s, 3H), 7.06-7.17 (m, 2H), 7.23-7.31 (m, 2H).

With concd HCl, PtO2 in methanol

Patent; Warner-Lambert Company; Cocensys, Incorporated; US6124323; (2000); (A1) EnglishView in Reaxys

OH O

P O O

O

NH O

N

OH O

P O O

O

NH O

H N


100 % With hydrogen, palladium on activated charcoal in methanol, Time= 16h, T= 20 °C , p= 750.06Torr , Catalytic hydro-genation


OH

O

N

Cl H

OH

O

H N

Cl H


100 % With hydrogen, palladium on activated charcoal in ethanol, Time= 24h

Brodbeck, Robbin; He, Xiaoshu; Hodgetts, Kevin; Hutchison, Alan; Kieltyka, Andrzej; Kover, Renata X.; Pe-terson, John; Primus, Renee; Rachwal, Stanislaw; Thurkauf, Andrew; Wasley, Jan W.F.; Zhang, Xiaoyan; Zhao,He; Bioorganic and Medicinal Chemistry Letters; vol. 12; nb. 21; (2002); p. 3105 - 3109View in Reaxys

100 % With platinum(IV) oxide, hydrogen in ethanol, water, T= 20 °C , p= 2585.81Torr








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Pryde, David C.; Corless, Martin; Fenwick, David R.; Mason, Helen J.; Stammen, Blanda C.; Stephenson, PeterT.; Ellis, David; Bachelor, David; Gordon, David; Barber, Christopher G.; Wood, Anthony; Middleton, DonaldS.; Blakemore, David C.; Parsons, Gemma C.; Eastwood, Rachel; Platts, Michelle Y.; Statham, Keith; Para-dowski, Kerry A.; Burt, Catherine; Klute, Wolfgang; Bioorganic and Medicinal Chemistry Letters; vol. 19; nb. 4;(2009); p. 1084 - 1088View in Reaxys

58 % With hydrogen, rhodium on alumina in water, Time= 20h, p= 2250.2Torr

Labouta, Ibrahim M.; Falch, Erik; Hjeds, Hans; Krogsgaard-Larsen, Povl; European Journal of Medicinal Chem-istry; vol. 17; nb. 6; (1982); p. 531 - 535View in Reaxys

With hydrogen, acetic acid, platinum(IV) oxide, T= 40 - 45 °C , p= 760Torr

Ishihara, Yuji; Miyamoto, Masaomi; Nakayama, Takahiro; Goto, Giichi; Chemical & Pharmaceutical Bulletin; vol.41; nb. 3; (1993); p. 529 - 538View in Reaxys

NH

F

N

NH

F

NH


82 % With hydrogen, platinum(IV) oxide in acetic acid, Time= 20h, p= 899.8Torr , Ambient temperature

Malleron, Jean-Luc; Gueremy, Claude; Mignani, Serge; Peyronel, Jean-Francois; Truchon, Alain; et al.; Journalof Medicinal Chemistry; vol. 36; nb. 9; (1993); p. 1194 - 1202View in Reaxys

With hydrogen, acetic acid, Adam's catalyst

Andree, Terrance H.; Meagher, Kristin L.; Mewshaw, Richard E.; Scerni, Rosemary; Schechter, Lee E.; Shi,Xiaojie; Smith, Deborah; Zhou, Dahui; Zhou, Ping; Bioorganic and Medicinal Chemistry Letters; vol. 12; nb. 3;(2002); p. 307 - 310View in Reaxys

3 : Preparation of 5-Fluoro-3-(4-piperidinylmethyl)-1H-indoleEXAMPLE 3Preparation of 5-Fluoro-3-(4-piperidinylmethyl)-1H-indoleA mixture of 5-fluoro-3-(4-pyridinylmethyl)-1H-indole (4.50 g, 20 mmol) and PtO2 (0.50 g, 2.2 mmol) in ethanol andacetic acid is hydrogenated under 45 psi at room temperature for 48 hr.After filtration of the catalyst and concentration of the filtrate, the residue is taken up with water, basified to pH 11 with1N NaOH and extracted with CH2Cl2/iPrOH (3/1).The combined extracts are dried over Na2SO4 and concentrated in vacuo to give a pink solid.The solid is crystallized from EtOAc to afford the title compound as a white solid, 4.0 g (86percent) mp 155-157° C.(Lit. mp 163° C., Malleron et al, J. Med. Chem. 1193,36,1194).

With acetic acid, PtO2 in ethanol

Patent; American Home Products Corporation; US2002/128477; (2002); (A1) EnglishView in Reaxys

F

F

N

F

F

N H

Cl H











16/80 2013-11-08 02:44:35


91 % With hydrogen, palladium on activated charcoal in acetic acid, T= 60 °C , p= 7500.75Torr

Agai, Bela; Faigl, Ferenc; Proszenyak, Agnes; Vida, Laszlo; Tarkanyi, Gabor; European Journal of Organic Chem-istry; nb. 17; (2004); p. 3623 - 3632View in Reaxys

F

F

F O

N

F

F

F O

NH

Cl H




F

F

F O

HO

N

F

F

F O

HO

NH

Cl H




F F

F

F

F

F

N

F F

F

F

F

F

NH Cl H




N

F

HN

F











17/80 2013-11-08 02:44:35


55 % With hydrogenchloride, hydrogen, platinum on activated charcoal in acetic acid, Time= 16h, T= 60 °C , p= 36200.4Torr

Shanklin, James R.; Johnson, Christopher P.; Proakis, Anthony G.; Barrett, Richard J.; Journal of MedicinalChemistry; vol. 34; nb. 10; (1991); p. 3011 - 3022View in Reaxys

HO

F

F N

HO

F

F HN


85 % With hydrogen, acetic acid, platinum on activated charcoal

Walsh, David A.; Franzyshen, Stephen K.; Yanni, John M.; Journal of Medicinal Chemistry; vol. 32; nb. 1; (1989);p. 105 - 118View in Reaxys

85% 42 : α,α-Bis(4-fluorophenyl)-4-piperidineethanolPREPARATION 42α,α-Bis(4-fluorophenyl)-4-piperidineethanolA mixture of 12.25 g (0.0394 mole) of α,α-bis(4-fluorophenyl)-4-pyridineethanol and 1.3 g of 5percent platinum oncarbon catalyst in 250 ml of acetic acid was shaken under an atmosphere of hydrogen (53 psi) for 9 hr.The solution was filtered through Celite.(R)., and the solvent was removed in vacuo.The residue was partitioned between methylene chloride and dilute sodium hydroxide.The solvent was removed in vacuo to give a solid.Recrystallization from acetonitrile gave 10.62 g (85percent yield) of title compound as a white, crystalline solid, mp169°-171° C.Analysis:Calculated for C19 H21 F2 NO: C, 71.90; H, 6.67; N, 4.41. Found: C, 71.98; H, 6.75; N, 4.54.

With platinum in acetic acid

Patent; A. H. Robins Company, Incorporated; US5070087; (1991); (A1) EnglishView in Reaxys

S

NH

O

O

HO

O

O

N

S

NH

O

O

HO

O

O

NH


97 % With hydrogen, palladium on activated charcoal in acetic acid, Time= 5.5h, T= 60 °C , p= 2068.6Torr

Chung, John Y. L.; Zhao, Dalian; Hughes, David L.; Grabowski, Edward J. J.; Tetrahedron; vol. 49; nb. 26; (1993);p. 5767 - 5776View in Reaxys








18/80 2013-11-08 02:44:35

N

N

N

H N


100 % With hydrogen, acetic acid, platinum(IV) oxide, Time= 7h, T= 80 °C , p= 51714.8Torr

Binet, Jean; Thomas, Didier; Benmbarek, Abdellah; Fornel, Daniel de; Renaut, Patrice; Chemical & Pharma-ceutical Bulletin; vol. 50; nb. 3; (2002); p. 316 - 329View in Reaxys

92% VIII : Preparation of N,N,β,β-tetramethyl-4-piperidineethanaminePREPARATION VIIIPreparation of N,N,β,β-tetramethyl-4-piperidineethanamineA solution of 2 g (1.1*10-2 mole) of N,N,β,β-tetramethyl-4-pyridineethanamine in 400 ml of acetic acid was hydrogenatedin a Parr's apparatus at 50° C. at a hydrogen pressure of 3.106 Pa in the presence of platinum dioxide.After eliminating the catalyst by filtering, the solvents were evaporated off under reduced pressure.The residue obtained was taken up in an aqueous 30percent sodium hydroxide solution and extracted with methylenechloride.The organic phase was washed, dried over magnesium sulphate and filtered and the solvents were evaporated offunder reduced pressure. 1.9 g (yield: 92percent) of the desired compound was obtained as an oil. B Pt=60°-64° C.under 0.02 mm Hg (i.e. about 2.66 Pa)

With Adam's catalyst in hydrogen, acetic acid

Patent; Fournier Industrie et Sante; US5614534; (1997); (A1) EnglishView in Reaxys

F

N

F

N H

Cl H




F F

N F F

HN

HCl


6.2 :The mixture was dissolved in methanol (10 mL) and 1 M hydrochloric acid (10 mL) then catalytic platinum oxidewas added and the resulting suspension was hydrogenated in a Parr apparatus at 40 psi for 3 d. Filtration through celiteand concentration of the filtrate gave a complex mixture containing 20percent of the desired 4-(l,l-difluoroethyl)piperi-dine as the hydrochloride salt which was used without further purification.

With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol, water, Time= 72h, p= 2068.65Torr

Patent; EXELIXIS, INC.; AAY, Naing; BLAZEY, Charles, M.; BOWLES, Owen, Joseph; BUSSENIUS, Joerg; CUR-TIS, Jeffry, Kimo; DEFINA, Steven, Charles; DUBENKO, Larisa; HARRIS, Jason, R.; JACKSON-UGUETO, Eileen,








19/80 2013-11-08 02:44:35

E.; KIM, Angie, Inyoung; MANALO, Jean-claire, Limun; PACK, Michael; PETO, Csaba, J.; RICE, Kenneth, D.;TSANG, Tsze, H.; WANG, Longcheng; WO2010/138490; (2010); (A1) EnglishView in Reaxys

9.2 :The mixture was dissolved in methanol (10 mL) and 1 M hydrochloric acid (10 mL) then catalytic platinum oxidewas added and the resulting suspension was hydrogenated in a Parr apparatus at 40 psi for 3 d. Filtration through celiteand concentration of the filtrate gave a complex mixture containing 20percent of the desired 4-(l,l- difluoroethy piperidineas the hydrochloride salt which was used without further purification.

With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol, Time= 72h, p= 2068.65Torr

Patent; EXELIXIS, INC.; RICE, Kenneth; WO2012/71509; (2012); (A2) EnglishView in Reaxys

F

N

F

N H

Cl H




OH

F

F

N

OH

F

F

H N

Cl H




HN

N N

Cl

O

HN

N HN


60% 27 : 4-[2-(4,5,6,7-Tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidineEXAMPLE 274-[2-(4,5,6,7-Tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidineThe 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9 g, 0.009 M) and PtO2 (0.25 g) in ethanol (20 ml) and2 NHCl (15 ml) was reduced at 45 psig of hydrogen.After the hydrogenation, the solvent was removed and the residue was crystallized from ethanol-ether to give 1.5 g of4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (60percent yield) as dihydrochloride salt.

With hydrogen, PtO2 in ethanol

Patent; Hoffmann-La Roche Inc.; US4431653; (1984); (A1) English









20/80 2013-11-08 02:44:35

View in Reaxys

N N N NH


75% 23 : 4-(1-Benzhydrylazetidin-3-yl)piperidinePreparation 234-(1-Benzhydrylazetidin-3-yl)piperidineAqueous hydrochloric acid (1.0M, 200ml) was added to a solution of 4-(1-benzhydrylazetidin-3-yl)pyridine (Preparation22) (29.7g, 99mmol) in methanol (300ml) and methanol (100ml) and water (100ml) then added.Platinum oxide (5.0g) was added and the reaction mixture was hydrogenated for 18 hours at 50°C and a pressure of414 kPa (60 p.s.i.).After this time, the reaction mixture was filtered through Arbocel (trade mark) filter aid and the solvent was removedunder reduced pressure.A solution of sodium hydroxide (25g) in water (200ml) was added to the residue and the resultant mixture was extractedwith diethyl ether (x3).The combined organic layers were dried over Na2SO4, filtered and solvent removed under reduced pressure to producea solid.This solid was triturated with cold diisopropyl ether (50ml) to afford the title compound as a solid (22.7g, 75percent).1H-NMR (CDCl3): δ = 7.10-7.40 (10H, m), 4.30 (1H, s), 3.20-3.40 (2H, m), 2.90-3.10 (2H, m), 2.60-2.80 (2H, m),2.40-2.60 (2H, m), 2.10-2.30 (1H, m), 1.30-1.80 (4H, m), 0.80-1.00 (2H, m).

With hydrogenchloride, sodium hydroxide in methanol, water

Patent; PFIZER INC.; Pfizer Limited; EP992493; (2000); (A1) EnglishView in Reaxys

1.c : 4-(3-Azetanyl)-1-(methylsulfonyl)piperidine1c)4-(1-Benzhydryl-3-azetanyl)piperidineTo a solution of 4-(1-benzhydryl-3-azetanyl)pyridine (29.7g, 99mmol) in methanol (300ml) was added aqueous hydro-chloric acid (1.0M, 200ml), a further portion of methanol (100ml), and water (100ml).To this mixture was added platinum (IV) oxide (5.0g) and the mixture was hydrogenated overnight at 50°C and 414kPa (60 p.s.i.).After this time the reaction was carefully filtered through Arbocel.(TM). (caution - fire hazard) and the filtrate retained.The solvent was evaporated under reduced pressure to remove most of the water.A solution of sodium hydroxide (25g) in water (200ml) was added and the resultant mixture was extracted three timeswith diethyl ether.The ethereal portion was dried over sodium sulphate, filtered and concentrated under reduced pressure to produce asolid which was triturated with cold diisopropyl ether (50 ml) to provide the title compound as a solid (22.7g).LRMS m/z = 307.2 (m+1)+

1H-NMR (CDCl3): δ = 0.8-1 (m,2H), 1.3-1.8 (m,4H), 2.1-2.3 (m,1 H), 2.4-2.6 (m,2H), 2.6-2.8 (m,2H), 2.9-3.1 (m,2H),3.2-3.4 (m,2H), 4.3 (s,1H), 7.1-7.4 (m,10H).

With hydrogenchloride, sodium hydroxide in methanol, water

Patent; Pfizer Limited; PFIZER INC.; EP962457; (1999); (A1) EnglishView in Reaxys






21/80 2013-11-08 02:44:35

NH

N

O

O O

NH

H N

O

O O

Cl H


100 % With hydrogenchloride, hydrogen, platinum(IV) oxide in ethanol, Time= 16h, T= 20 °C , Catalytic hydrogenation


F

F

F

OH

N

HCl

F

F

F

OH

N H

HCl


1 :a) z-PrMgCl/THF/5°C to RT b) H2/25 psi to 35 psi/MeOH c) K2C03/Cu20/145°C to 170°C/12-20 hours e) EDCY-NaBH(O Ac)3/35°C to 4O0C/ 3-20 hours f) EDC/35°C to 5O0C/ 2-18 hours g) 80percentH2O2/MeOH/40°C to 45°C /9-44 hours; In the first step as depicted in Example 1, an appropriately substituted aryl halide, for example, the knowncompound 4-bromo-l-(trifluoromethyl)benzene (A), and pyridine-4-carbaldehyde were reacted with a Grignard reagentto form the hydrogen chloride salt of 4-pyridyl[4-(trifluoromethyl)phenyl]methan-l-ol (B). Intermediate (B) was then hy-drogenated under elevated pressure to afford the corresponding hydrogen chloride salt of 4-piperidyl[4- (trifluorometh-yl)phenyl]methan-l-ol (C). Next, an appropriately substituted phenol, for example, the known compound 4-hydroxy-benzaldehyde, was reacted with a halopyridine, for example 2-chloropyridine, in the presence of potassium carbonateand a catalytic amount of copper oxide at a temperature in the range of from 145° C to 170°C to form 4-(2-pyridy-loxy)benzaldehyde (D). Intermediate (C) was then reacted with Intermediate (D) in the presence of sodium triacetox-yborohydride at a temperature in the range of from 35 "C to 400C to form {l-[(4-(2- pyridyloxy)phenyl)methyl] (4-piper-idyl)} [4-(trifluoromethyl)phenyl]methan- 1 -ol (F). Intermediate (F) was then condensed with an appropriately substi-tuted aryl halide, for example the known compound 4-chlorobenxenisocyanate (G), at a temperature in the range offrom 35°C to 50°C to form N-(4-chlorophenyl)({l-[(4- (2-pyridyloxy)phenyl)methyl](4-piperidyi)}[4- (trifluoromethyl)phe-nyl]methoxy)carboxamide (H). Intermediate (H) was then oxidized with hydrogen peroxide at a temperature in the rangeof from 40° C to 55°C to forai N-(4-chlorophenyl)({l-oxo-l-[(4-(2-pyridyloxy)phenyl)methyl](4- piperidyl)} [4-(trifluoro-methyl)phenyl]methoxy)carboxamide (Formula I)

With hydrogen in methanol, T= 5 - 20 °C , p= 1292.9 - 1810.07Torr

Patent; FMC CORPORATION; WO2006/31764; (2006); (A2) EnglishView in Reaxys

H 2 N

N

OH O

H

H 2 N

NH

OH

O








22/80 2013-11-08 02:44:35


a; 57.B :A solution of L-4-pyridylalanine 57-A (1.0 g), 10percent Pd/C (300 mg) in EtOH (40 mL) and 1 N HCl aqueoussolution (20 mL) is shaken on Parr Shaker for 12 hours under a hydrogen atmosphere at 50 psi. The catalyst is filteredand the filtrate is concentrated to afford the piperidine 57-B.

With hydrogenchloride, hydrogen, palladium 10 on activated carbon in ethanol, water, Time= 12h, p= 2585.81Torr

Patent; IRM LLC; US2007/275906; (2007); (A1) EnglishView in Reaxys

F

F

F

OH

N

F

F

F

OH

N H

HCl


2.D :A solution of 6.4 grams (0.020 mole) of 4- (trifluoromethylphenyl)-4- pyridylmethanol in 80 mL of ethyl acetate wasstirred, and dry hydrogen chloride gas was bubbled through the solution, thereby forming the hydrochloride salt of thepyridylmethanol intermediate. The salt was collected by filtration and washed with a small amount of ethyl acetate. Thedamp solid was then dissolved in 100 mL of methanol and placed in a Parr hydrogenation bottle, along with 0.5 gram(catalyst) of platinum oxide. The mixture was then hydrogenated at 45 pounds per square inch (psi) for about 75 minutes,using a Parr Hydrogenator. An NMR taken of the reaction mixture indicated that the reaction was about 90percentcomplete. An additional 0.25 gram of platinum oxide catalyst was added to the reaction mixture, and the hydrogenationat 45 psi was continued for an additional 60 minutes. After this time, the reaction mixture was filtered through diatoma-ceous earth. The filter cake was washed with methylene chloride and the combined wash and filtrate was concentratedunder reduced pressure, yielding 5.2 grams of subject compound. The NMR spectrum was consistent with the proposedstructure. The reaction was repeated.

Stage 1: With hydrogenchloride in ethyl acetateStage 2: With hydrogen, platinum(IV) oxide in methanol, Time= 2.25h, p= 2327.23Torr , Parr Hydrogenator

Patent; FMC CORPORATION; WO2004/60371; (2004); (A1) EnglishView in Reaxys

F F

F

N

F

F

F NH

HCl


28 :Example 28 4-(trifluoromethyl)piperidine hydrochloride: Under atmosphere of argon, a solution of 4-(trifluorometh-yl)pyridine (9.33g) in methanol (80mL) was added by concentrated hydrochloric acid (16mL) and platinum oxide(510mg) and stirred for three days at room temperature under hydrogen pressure. The reaction mixture was filtratedby celite (trade name) and the filtrate was concentrated. The residue was added by saturated sodium dicarbonateaqueous solution and extracted by ethyl acetate. The organic layer was washed with saturated brine, dried over an-hydrous magnesium sulfate and then filtrated. The filtrate was added by 4N hydrogen chloride/ethyl acetate solution(50mL) and then concentrated to give the title compound (13.0g) having the following physical data. TLC: Rf 0.13(chloroform : methanol = 10 : 1); 1H NMR (CDCl3): δ 1.72 (dd, J= 13.0,4.0Hz, 1H), 1.81 (dd, J= 13.0, 4.0Hz, 1H),2.05-2.20 (m, 2H), 2.41-2.80 (m, 1H), 3.06 (dt, J= 13.0, 3.0Hz, 2H), 3.40-3.60 (m, 2H).

With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol, water, Time= 72h, T= 20 °C

Patent; ONO PHARMACEUTICAL CO., LTD.; EP1666472; (2006); (A1) EnglishView in Reaxys







23/80 2013-11-08 02:44:35

NH

N

N

NH

N

NH


89% 18 : 4-[(4,5-Dihydro-1H-Imidazol-2-yl)methyl]piperidineEXAMPLE 184-[(4,5-Dihydro-1H-Imidazol-2-yl)methyl]piperidine2-(4-pyridylmethyl)-imidazoline (3.0 g, 0.018 M) and platinum oxide (0.3 g) in ethanol (50 ml) and 2 N HCl (20 ml) washydrogenated at 45 psig for 4 hrs.The catalyst was removed by filtration and the solvent was stripped.Crystallization from ethanol gave 4.05 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]piperidine as dihydrochloride salt(89percent yield).

With hydrogenchloride in ethanol

Patent; Hoffmann-La Roche Inc.; US4431653; (1984); (A1) EnglishView in Reaxys

S O

O N

S O

O HN Cl H


72 :In a round bottom of flask was charged with 4-(3-methanesulfonyl-propyl)- pyridine (373 mg) and ethanol (5 ml_).Hydrochloric acid was added (1 ml_, 4N solution in dioxane) with stirring. The mixture was concentrated then the residuewas taken in methanol and water. Platinum oxide (21 mg, 0.09 mmol, Aldrich) was added, and the mixture was hydro-genated at 60 psi overnight using a Parr apparatus. Upon completion, the mixture was filtered through Celite andwashed thoroughly with methanol. The filtrate was concentrated to give 4-(3- methanesulfonyl-propyl)-pipehdine dihy-drochloride as a white solid (480.7 mg, 85percent pure).

Stage 1: With hydrogenchloride in 1,4-dioxane, ethanolStage 2: With hydrogen, platinum(IV) oxide in methanol, water, p= 3102.97Torr

Patent; F. HOFFMANN-LA ROCHE AG; WO2009/47161; (2009); (A1) EnglishView in Reaxys

OH

N

Cl

OH

H N

Cl


76 % With hydrogenchloride, hydrogen, platinum(IV) oxide in ethanol, Time= 0.5h, p= 2280Torr

Ablordeppey; Altundas; Fan; Li; Lyles-Eggleston; Sikazwe; Xia; Yang; Zhang; Zhu; Borne; Schmidt; Shrih-kande; Vanase-Frawley; Villalobos; Journal of Medicinal Chemistry; vol. 47; nb. 3; (2004); p. 497 - 508View in Reaxys








24/80 2013-11-08 02:44:35

F

F

F

N

F

F

F

NH

Cl H




N

N

O

O NH

N H

N

N H

O

O


86 %, 14 %Spectr.

With hydrogen, acetic acid, platinum (IV) oxide in ethanol, Time= 24h, T= 40 °C , p= 45600Torr

Kurkin, A. V.; Sumtsova, E. A.; Yurovskaya, M. A.; Chemistry of Heterocyclic Compounds (New York, NY, UnitedStates); vol. 43; nb. 1; (2007); p. 34 - 40; Khimiya Geterotsiklicheskikh Soedinenii; nb. 1; (2007); p. 41 - 48View in Reaxys

N H N


56 % With hydrogenchloride, samarium, Time= 0.166667h, Ambient temperature

Kamochi, Yasuko; Kudo, Tadahiro; Chemical & Pharmaceutical Bulletin; vol. 43; nb. 8; (1995); p. 1422 - 1424View in Reaxys

With ethanol, sodium

Ladenburg,A.; Justus Liebigs Annalen der Chemie; vol. 247; (1888); p. 70; Chemische Berichte; vol. 31; (1898); p.290View in Reaxys

With nickel, T= 210 °C , p= 110326 - 220652Torr , Hydrogenation

Adams; Leonard; Journal of the American Chemical Society; vol. 66; (1944); p. 257,260View in Reaxys

92 % Chro-mat.

With samarium diiodide in tetrahydrofuran, water, Time= 0.233333h, Ambient temperature

Kamochi, Yasuko; Kudo, Tadahiro; Heterocycles; vol. 36; nb. 10; (1993); p. 2383 - 2396View in Reaxys

With hydrogen, sodium, palladium on activated charcoal, 1.) ethanol, reflux, Multistep reaction

Adomenas, P.; Sirutkaitis, R.; Molecular Crystals and Liquid Crystals (1969-1991); vol. 124; (1985); p. 269 - 276View in Reaxys












25/80 2013-11-08 02:44:35

N

HO

OH O OH O

H N

HO


95 % With hydrogen, palladium on activated charcoal, Rh on carbon, Time= 2h, p= 76000Torr

Bakker, Remko; De Esch, Iwan J. P.; Kitbunnadaj, Ruengwit; Leurs, Rob; Menge, Wiro M. P. B.; Timmerman,Henk; Vollinga, Roeland C.; Zuiderveld, Obbe P.; Kitbunnadaj, Ruengwit; Lutz, Martin; Spek, Anthony L.; Cav-oy, Emile; Deltent, Marie-France; Journal of Medicinal Chemistry; vol. 46; nb. 25; (2003); p. 5445 - 5457View in Reaxys

3-Piperidin-4-yl-propan-1-ol:; 4-Pyridinepropanol (10.0 g, 73 mmol) was dissolved in glacial acetic acid (50 mL). 10per-cent Palladium on carbon (1.1 g) was added and the mixture hydrogenated under 50 psi hydrogen gas for 6 days. Themixture was filtered through Celite and the solvent removed by rotary evaporation. The crude product 3-piperidin-4-yl-propan-l-ol (acetic acid salt) was used as obtained. 1H NMR (500 MHz, CDCl3) No. 6.3 (br), 3.65 (2H, t), 3.36 (2H, m),2.79 (2H, dt), 2.01 (3H, s), 1.85 (2H, m), 1.7 - 1.3 (7H, m).

With hydrogen, palladium 10 on activated carbon, Time= 144h, p= 2585.81Torr

Patent; VERTEX PHARMACEUTICALS INCORPORATED; WO2005/103050; (2005); (A2) EnglishView in Reaxys

Preparation of 3-(3-(N-BOC-PIPERIDIN-4-YL)-PROPOXY)-PHENYLACETIC ACID3-PIPERIDIN-4-YL-PROPAN-1-OL : 4-PYRIDINEPROPANOL (10.0 g, 73 mmol) was dissolved in glacial acetic acid(50 mL). 10percent Palladium on carbon (1.1 g) was added and the mixture hydrogenated under 50 psi hydrogen gasfor 6 days. The mixture was filtered through Celite and the solvent removed by rotary evaporation. The crude product3-piperidin-4-yl- PROPAN-1-OL (acetic acid salt) was used as OBTAINED.APOS;H NMR (500 MHz, CDCIA) 8 6.3 (br),3.65 (2H, t), 3.36 (2H, m), 2.79 (2H, dt), 2.01 (3H, s), 1.85 (2H, m), 1.7-1. 3 (7H, m).

With hydrogen, palladium 10 on activated carbon, Time= 144h, p= 2585.81Torr


N

N

O

O

N

N H

O

O


71 % With hydrogen, palladium on activated charcoal in ethyl acetate, Time= 10h, T= 80 °C , p= 68400Torr


N

N

N

N

N

NH


70% 44 : 4-[2-(1-Ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidineEXAMPLE 44









26/80 2013-11-08 02:44:35

4-[2-(1-Ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidineThe solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.1 g, 0.0054 M) in ethanol (15 ml) and water (15ml) was added con.HCl (3 ml) and platinum oxide (0.2 g).The mixture was hydrogenated at 45 psig for 4 hrs.The catalyst was removed by filtration and the filtrate was stripped to dryness in vacuo.The residue was dissolved in methanol (25 ml) and sodium methoxide (0.011 M) was added and filtered.The filtrate was stripped to dryness and distilled at about 150° to about 175° C./0.2 mmHg to yield 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidine as an oil (0.8 g, 70percent yield).

With sodium methylate in methanol, ethanol, water


HO

N

HO

H N


With sulfuric acid, water, platinum, T= 65 °C , Hydrogenation

Rabe; Journal fuer Praktische Chemie (Leipzig); vol. <2> 151; (1938); p. 65,79View in Reaxys

45.A : Step AStep APreparation of 4-piperidylmethanol4-pyridylcarbinol (5.05 g, 45.8 mmol) dissolved in EtOH (75 ml) and concentrated HCl (3.81 ml, 45.8 mmol) was added.The starting material precipitated out and H2O was added until compound dissolved again (~10 ml), then PtO2 (1 g)was added.Stirred under H2 pressure (220 psi) overnight.The catalyst was filtered off and the solvent evaporated under reduced pressure to yield the slightly impure title com-pound (7.53 g, quantitative).This material was carried on directly to the next step without purification.

With hydrogenchloride, PtO2 in ethanol, water

Patent; Scarborough, Robert M.; Mehrotra, Mukund; Pandey, Anjali; Smyth, Mark; US2003/55244; (2003); (A1)EnglishView in Reaxys

N H N


86 % With hydrogen, Rh on carbon in ethanol, Time= 3h, p= 1500.1Torr

Sucrow, Wolfgang; Schatull, Wolfgang; Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, OrganischeChemie; vol. 37; nb. 10; (1982); p. 1336 - 1338View in Reaxys











27/80 2013-11-08 02:44:35

N

N

N

H N


89 % With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol

Cohen, Victor I.; Baumgold, Jesse; Jin, Biyun; Cruz, Rosanna De La; Rzeszotarski, Waclaw J.; Reba, RichardC.; Journal of Medicinal Chemistry; vol. 36; nb. 1; (1993); p. 162 - 165View in Reaxys


Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Martini, Elisabetta; Scapecchi,Serena; Buccioni, Michela; Marucci, Gabriella; Matucci, Rosanna; Farmaco; vol. 59; nb. 12; (2004); p. 971 - 980View in Reaxys

HN

O O

N

HN

O O

NH


With hydrogen, acetic acid, platinum(IV) oxide, p= 3102.97Torr

Klimkowski, Valentine J.; Watson, Brian M.; Wiley, Michael R.; Liebeschuetz, John; Franciskovich, Jeffry B.;Marimuthu, Jothirajah; Bastian, Jolie A.; Sall, Daniel J.; Smallwood, Jeffrey K.; Chirgadze, Nikolay Y.; Smith,Gerald F.; et al.; Bioorganic and Medicinal Chemistry Letters; vol. 17; nb. 21; (2007); p. 5801 - 5805View in Reaxys

51 : Preparation 51; N-[L-PHENYL-4-(PIPERIDINE-4-YL) BUTYL] CARBAMIC acid tert- butyl ester.Agitating N- [L-PHENYL-4- (PYRIDIN-4-YL) butyl) carbamic acid tert-butyl ester (230 mg, 0.70 mmol) and a catalyticamount of platinum oxide in 25 mL of acetic acid under an atmosphere of hydrogen at 4.1 bar (60 psig) afforded, afterfiltration through diatomaceous earth and removal of solvent under reduced pressure, the title compound as a cruderesidue that was used without further purification. 1H NMR ES-MS m/e 333 (M+1)

With hydrogen, acetic acid, platinum(IV) oxide, p= 3075.31Torr

Patent; ELI LILLY AND COMPANY; WO2004/60872; (2004); (A1) EnglishView in Reaxys

O

N

O

N H


88% 1.3 : Step 3Step 3A mixture of 4-(3-methoxybenzyl)pyridine (25 g, 126 mmol) and platinum oxide (2.4 g) in acetic acid (250 ml) washydrogenated for 2 hr.The catalyst was removed and the solution concentrated in vacuo.The residue was dissolved in water and the solution basified with sodium hydroxide.









28/80 2013-11-08 02:44:35

The basic mixture was extracted with ether.The extracts were dried and concentrated in vacuo.The residue was vacuum distilled to give 4-(3-methoxy-benzyl)piperidine as an oil (22.6 g, 88percent).A sample of the hydrochloride was prepared in ether (mp: 146°-147° C.).

in water, acetic acid

Patent; Bristol-Myers Squibb Co.; US5530012; (1996); (A1) EnglishView in Reaxys

87.6% 11.3 : Step 3Step 3A mixture of 4-(3-methoxybenzyl)pyridine (25 g, 126 mmole) and platinum oxide (2.4 g) in acetic acid (250 ml) washydrogenated for 2 hr.The catalyst was removed and the solution concentrated in vacuo.The residue was dissolved in water and the solution basified with sodium hydroxide.The basic mixture was extracted with ether.The extracts were dried and concentrated in vacuo.The residue was vacuum distilled to give 4-(3-methoxy-benzyl)piperidine as an oil (22.6 g, 87.6percent).A sample of the hydrochloride was prepared in ether (mp: 146°-147° C.). Calc'd. for C13 H19 NO.HCl: C, 64.59percent;H, 8.34percent; N, 5.80percent. Found: C, 64.38percent; H, 8.34percent; N, 5.66percent.


Patent; Briston-Myers Squibb; US5387593; (1995); (A1) EnglishView in Reaxys

N N H



Tschitschibabin; Zhurnal Russkago Fiziko-Khimicheskago Obshchestva; vol. 34; (1902); p. 511; Chem. Zentralbl.;vol. 73; nb. II; (1902); p. 597View in Reaxys

With acetic acid, platinum, Hydrogenation

Overhoff; Wibaut; Recueil des Travaux Chimiques des Pays-Bas; vol. 50; (1931); p. 957,976View in ReaxysVeer; Goldschmidt; Recueil des Travaux Chimiques des Pays-Bas; vol. 65; (1946); p. 793View in ReaxysGray et al.; Journal of the American Chemical Society; vol. 79; (1957); p. 3805,3807View in Reaxys

With nickel, T= 100 °C , p= 110326 - 220652Torr , Hydrogenation

McElvain; Vozza; Journal of the American Chemical Society; vol. 71; (1949); p. 896,898View in Reaxys










29/80 2013-11-08 02:44:35

N O

N

Cl H

N O

H N


85 % With acetic acid, platinum(IV) oxide, Time= 24h, T= 20 °C , p= 760Torr

Colibretti, Maria Luisa; Imbimbo, Bruno P.; Lamperti, Giuseppina; Mandelli, Giacomina R.; Terni, Patrizia;Maiorana, Stefano; Chemical and Pharmaceutical Bulletin; vol. 48; nb. 11; (2000); p. 1611 - 1622View in Reaxys

NH

O

N

NH

O

H N




N

N

N

H N




NH

N

N

HBr

NH

N

H N

2


52 % With hydrogen bromide, hydrogen, palladium on activated charcoal, Rh on carbon in ethanol, Time= 48h, p= 76000Torr









30/80 2013-11-08 02:44:35

Bakker, Remko; De Esch, Iwan J. P.; Kitbunnadaj, Ruengwit; Leurs, Rob; Menge, Wiro M. P. B.; Timmerman,Henk; Vollinga, Roeland C.; Zuiderveld, Obbe P.; Kitbunnadaj, Ruengwit; Lutz, Martin; Spek, Anthony L.; Cav-oy, Emile; Deltent, Marie-France; Journal of Medicinal Chemistry; vol. 46; nb. 25; (2003); p. 5445 - 5457View in Reaxys

F

O

N

F

O

N H


76% 3.3 : Step 3Step 3A mixture of 4-(2-fluoro-5-methoxybenzyl)pyridine (7.7 g, 35.5 mmole) and platinum oxide (0.7 g) in acetic acid (75 ml)was hydrogenated for 3 hr.The catalyst was removed and the acetic acid removed in vacuo.The residue was dissolved in water and the solution basified with sodium hydroxide.The basic mixture was extracted with ether.The extracts were dried and concentrated in vacuo.The residue was vacuum distilled to give the product (6g, 76percent).


Patent; Bristol-Myers Squibb Co.; US5530012; (1996); (A1) EnglishView in Reaxys

75.9% 13.3 : Step 3Step 3A mixture of 4-(2-fluoro-5-methoxybenzyl)pyridine (7.7 g, 35.5 mmole) and platinum oxide (0.7 g) in acetic acid (75 ml)was hydrogenated for 3 hr.The catalyst was removed and the acetic acid removed in vacuo.The residue was dissolved in water and the solution basified with sodium hydroxide.The basic mixture was extracted with ether.The extracts were dried and concentrated in vacuo.The residue was vacuum distilled to give the product (6 g, 75.9percent).



O

O

N

Cl

O

O

H N

Cl


With hydrogen, platinum(IV) oxide in acetic acid, Time= 20h, T= 50 °C , p= 3089.1Torr

McCaustland,D.J. et al.; Journal of Medicinal Chemistry; vol. 17; nb. 9; (1974); p. 993 - 1000View in Reaxys








31/80 2013-11-08 02:44:35

N

N

N

H N




N

N

N

H N




N

O

O

N

Cl H

N

O

O

H N

Cl H


63.4 % With hydrogen, rhodium on alumina in water, Time= 20h, p= 2250.2Torr

Labouta, Ibrahim M.; Falch, Erik; Hjeds, Hans; Krogsgaard-Larsen, Povl; European Journal of Medicinal Chem-istry; vol. 17; nb. 6; (1982); p. 531 - 535View in Reaxys

NH

O

N

NH

O

H N


With hydrogen, platinum(IV) oxide in acetic acid, T= 30 °C , p= 2585.7Torr

Alabaster, Valerie A.; Campbell, Simon F.; Danilewicz, John C.; Greengrass, Colin W.; Plews, Rhona M.; Journalof Medicinal Chemistry; vol. 30; nb. 6; (1987); p. 999 - 1003View in Reaxys










32/80 2013-11-08 02:44:35

N

N

N

H N




N

N

N

H N




N

Cl H

H N


81.5 % With hydrogen, platinum(IV) oxide in ethanol, Time= 24h, p= 2280Torr

Goessinger,E.; Monatshefte fuer Chemie; vol. 113; (1982); p. 339View in Reaxys

F

F

N

F F

F

F

H N

F F


With hydrogen, platinum on activated charcoal in acetic acid, Time= 72h, T= 60 °C , p= 2327.2Torr











33/80 2013-11-08 02:44:35

F

F

N

F F

Cl H

F

F

H N

F F


With hydrogen, platinum on activated charcoal in acetic acid, Time= 72h, T= 60 °C , p= 2327.2Torr


H N

HN

N

H N

HN

HN


91 % With hydrogen, platinum(IV) oxide in acetic acid, Time= 19h, p= 3040Torr , Ambient temperature

Mokrosz, J. L.; Dukat, Malgorzata; Misztal, S.; Chojnacka-Wojcik, Ewa; Tatarczynska, Ewa; Pharmazie; vol. 45;nb. 10; (1990); p. 765 - 767View in Reaxys

OH O

N

Cl

OH O

H N

Cl


100 % With hydrogen, platinum(IV) oxide, Time= 72h, T= 20 °C , p= 3102.89Torr

Jiang, Ji; Sane, David C.; Wang, Binghe; Wang, Wei; Bioorganic Chemistry; vol. 29; nb. 6; (2001); p. 357 - 379View in Reaxys

S N

O

O

N H O

NH O

Cl

N

S N

O

O

N H O

NH O

Cl

NH


B : GENERAL PROCEDURE B; General Procedure for the Preparation [OF CYCLOPROPYLPIPERIDINYLETHYL]acetamides[[00183]] 3- [3- (R, S)-2- (4-chloro-2, 5-dimethylbenzenesulfonyl)-4-oxo-2, 5-benzo- [DIAZEPIN-3-YL]-N- [2- (PYRID-4-YL) ETH-1-YL] ACETAMIDE,] which can be prepared by amidation of the corresponding carboxylic acid with 2- (2-aminoethyl) pyridine (TCI) in the manner described above is hydrogenated in the presence of platinum oxide [(PTO2)]in methanol to provide for 3- [3- (R, S)-2- (4-chloro-2, 5- dimethylbenzenesulfonyl)-4-oxo-2, 5- benzodiazepin-3-yl]-N-[2- (piperidin-4- yl) eth-1-yl] acetamide. Sodium cyanoborohydride (1.5 mmol) is added to a stirred solution of 3- [3- (R,









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[S)-2- (4-CHLORO-2,] 5- dimethylbenzenesulfonyl)-4-oxo-2, [5-BENZODIAZEPIN-3-YL]-N-[2-(PIPERIDIN-4-YL)ETH-1-] yl] acetamide (1 mmol), with [1-ETHOXY-L-TRIMETHYLSILOXY] cyclopropane [(1] mmol) (Aldrich) and[ACOH] (1 mmol) in [MEOH] (20 mL) at rt. After being stirred at rt, the reaction mixture is refluxed for [18H.] The excesssolvent is removed and washed with saturated [NAHC03] solution. The aqueous solution is extracted with [CH2C12](2 x 100 mL). The combined organic layers are dried and concentrated. The resulting residue is then purified by silicagel column chromatography to afford the N-cyclopropylpiperidinylethyl acetamide derivative.

With hydrogen, platinum(IV) oxide in methanol

Patent; ELIAN PHARMACEUTICALS INC; WO2004/33436; (2004); (A1) EnglishView in Reaxys

HO

OH

N

HCl

HO

OH

N H

HCl


A.10.3 :OH OH HO t t-BuOH, 92percent The title compound was prepared as provided in Tetrahedron: Asymm. 1995,6,505-518 (Reference for Sharpless asymmetric dihydroxylation); J. Org. Chem. 1965,30, 1331-1333; 1969 U. S. PatentNo. 3,464, 997 (Reference for hydrogenation

With hydrogenchloride, platinum(IV) oxide in methanol, water

Patent; WARNER-LAMBERT COMPANY LLC; WO2005/26145; (2005); (A2) EnglishView in Reaxys

N

HO

OH O

H N

HO


17.A :Example 17; 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetic acid:; Step A: 4-Pyridinepropanol (10.0 g, 73mmol) was dissolved in glacial acetic acid (50 mL). 10percent Palladium on carbon (1.1 g) was added and the mixturehydrogenated under 50 psi hydrogen gas for 6 days. The mixture was filtered through CeliteNo. and the solvent removedby rotary evaporation. The crude product 3-piperidin-4-yl- propan-1-ol (acetic acid salt) was used as obtained. 1H NMR(CDCl3) No. 6.3 (br), 3.65 (2H, t), 3.36 (2H, m), 2.79 (2H, dt), 2.01 (3H, s), 1.85 (2H, m), 1.7 - 1.3 (7H, m).

With hydrogen, acetic acid, palladium 10 on activated carbon, Time= 144h, p= 2585.81Torr


S

N

O O

N H

O

H N

O

Cl

N

S

N

O O

N H

O

H N

O

Cl

NH


L.A :2- [2- (R, S)-1- (4-chloro-2, 5-dimethylbenzenesulfonyl)-3-oxo- 1,2, 3, 4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl) eth-1-yl] acetamide, prepared by amidation of the corresponding carboxylic acid with 2- (2-aminoethyl) pyridine (TCI)in the manner described above was hydrogenated in the presence of platinum oxide (PtO2) in methanol to provide for








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2- [2- (R, S)-1- (4-chloro-2, 5- dimethylbenzenesulfonyl)-3-oxo-1, 2,3, 4-tetra-hydroquinoxalin-2-yl]-N- [2- (piperidin-4-yl) eth-1-yl] acetamide.

With hydrogen, platinum(IV) oxide in methanol

Patent; ELAN PHARMACEUTICALS, INC.; WO2003/93245; (2003); (A1) EnglishView in Reaxys

N HN HCl


141.A : 1-(2-(4-Hydroxyphenoxy)ethyl)-4-((2-naphthyl)methyl)piperidine hydrochloride STR177A)4-((2-Naphthyl)methyl)piperidine hydrochloride.A mixture of 4-((2-naphthyl) methyl)pyridine (750 mg, 3.42 mmol) and PtO2 (50 mg) in MeOH (25 mL) containing concdHCl (0.5 mL) was stirred under H2 at ambient pressure (balloon) for 19 h to yield the title compound as a pale yellowgranular solid (324 mg): mp 215-217° C.; 1 H NMR (D2 O) 1.30-1.48 (m, 2H), 1.67-1.98 (m, 3H), 2.69 (d, J=6.9 Hz, 2H),2.82 (td, J=13 and 3.0 Hz, 2H), 3.26-3.38 (m, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.45-7.56 (m, 2H), 7.65 (s, 1H), 7.80-7.92(m, 3H).

With concd HCl, PtO2 in methanol

Patent; Warner-Lambert Company; Cocensys, Incorporated; US6124323; (2000); (A1) EnglishView in Reaxys

F

F

N

F F F

F

H N

F F

Cl H


1.06 g(95.2%)

17 : 4-[Bis(2,4-difluorophenyl)methyl]piperidine hydrochloride[1:1]PREPARATION 174-[Bis(2,4-difluorophenyl)methyl]piperidine hydrochloride[1:1]A mixture of 4-[bis(2,4-difluorophenyl)methyl]pyridine (23.84 g, 0.0752 mole) and 5percent platinum on carbon (2.0 g)was subjected to hydrogenation for three days at 60° C. in 400 ml of glacial acetic acid containing 3 mL of concentratedhydrochloric acid.This reaction was carried out at a pressure of 45 psi and 13.5 pounds of hydrogen gas was consumed.The reaction mixture was cooled to room temperature and filtered.Solvent was removed by rotary evaporator.The residue obtained was dissolved in chloroform and extracted with 5percent sodium hydroxide.The chloroform layer was dried over sodium sulfate and filtered.The chloroform was removed by rotary evaporator to give a dark residue (24.4 g, quantitative yield).A one-gram sample of this material was converted to the hydrochloride and the salt was recrystallized from methanol-diethyl ether.A white solid was obtained and dried in vacuo overnight at 80° C.This provided 1.06 g (95.2percent) of the title compound as a white, crystalline solid, mp 215°-217° C.Analysis:Calculated for C18 H18 ClF4 N: C, 60.09; H, 5.04; N, 3.89. Found: C, 59.77; H, 5.02; N, 3.87.

With hydrogenchloride, platinum in chloroform, acetic acid








36/80 2013-11-08 02:44:35

OH

N

OH

NH

HCl


5 : EXAMPLE 5The mixture of 4.0 g of 4-(α-hydroxy-α-methylphenethyl)-pyridine, 100 ml of glacial acetic acid, 20 ml of water and 2.0g of 10percent palladium on charcoal is treated with hydrogen at 4.1 atm and room temperature.Following the theoretical uptake of hydrogen the reaction mixture is filtered to remove the catalyst.The filtrate is evaporated to dryness under reduced pressureand the residue treated with 50percent aqueous sodiumhydroxide.The resulting mixture is extracted with methylene chloride; the extract is dried and evaporated under reduced pressureto give an oil which is converted into the hydrochloride with ethanolic hydrogen chloride to give 4-(α-hydroxy-α-meth-ylphenethyl)-piperidine hydrochloride of melting point 162°-164°.

With sodium hydroxide, hydrogen, palladium on charcoal in water, acetic acid

Patent; Ciba-Geigy Corporation; US3992546; (1976); (A1) EnglishView in Reaxys

NH

N

NH

NH


75 % With hydrogen, Adam's catalyst in acetic acid, Ambient temperature

Gueremy, Claude; Audiau, Francois; Champseix, Alain; Uzan, Andre; Fur, Gerard Le; Rataud, Jean; Journal ofMedicinal Chemistry; vol. 23; nb. 12; (1980); p. 1306 - 1310View in Reaxys

N

N

H N

N


96 % With hydrogenchloride, hydrogen, platinum(IV) oxide, Time= 24h, p= 2280Torr

Cohen, Victor I.; Jin, Biyun; Reba, Richard C.; Liebigs Annalen der Chemie; nb. 7; (1993); p. 809 - 810View in Reaxys

With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol











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N

N

NH

N H

N

N H


89 %, 11 % With platinum (IV) oxide in ethanol, trifluoroacetic acid, T= 60 °C , p= 45600Torr


O O

O

N

O O

O

NH

Cl H


2 : Example 2The mixture of 5, 6-DIMETHOXY-2- (4-PYRIDYL) METHYL-1-INDANONE (45 gm), methanol (600 ML), concentratedhydrochloric acid (18 ml) and platinum oxide catalyst (2.5 gm) is taken into a hydrogenation flask and subjected tohydrogenation under a hydrogen gas pressure of 2 bars for 5 hours. The catalyst is filtered off and the solvents areevaporated completely under vacuum. Ethyl acetate (150 ML) is added to the residue and stirred for 15 minutes at25°C to 30°C. Then the contents are cooled to 0°C, stirred for 30 minutes and filtered to give 48 gm OF 4- [ (5, 6-DIMETHOXY-1-INDANON)-2-YL] METHYLPIPERIDINE hydrochloride.

With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol, water, Time= 5h, p= 1500.15Torr

Patent; HETERO DRUGS LIMITED; WO2005/3092; (2005); (A1) EnglishView in Reaxys

2 :Example 2 PREPRATION of 2,3-dihydro-5, 6-dimethoxy-2- (4-piperidinyl) methyl-indan-1-one, hydrochloride A mix-ture OF 5, 6-DIMETHOXY-2- (4-PYRIDYL) METHYL-INDAN-1-ONE (25g from example 1), methanol (125ML), water(125ML), conc. hydrochloric acid (12. 5G) and platinum dioxide (2. 5G) was HYDROGENATED at 15 to 20 psi hydrogenpressure for about 6 hours. The reaction mixture was filtered, the filtrate was concentrated and the residue so obtainedwas crystallized from methanol to get the title compound (24G). HPLC Purity: 99.4percent.

With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol, water, Time= 6h, p= 775.743 - 1034.32Torr

Patent; RANBAXY LABORATORIES LIMITED; WO2004/82685; (2004); (A1) EnglishView in Reaxys

6 :4-[(5,6-Dimethoxy-l-indanon-2-yl)methyl]pyridine N-oxide (1Og) in methanol (100 ml) was hydrogenated in presenceof cone, hydrochloric acid (l.lδg) and palladium on activated carbon (Ig). The reaction mixture was filtered, filtrate wasconcentrated and residue so obtained was crystallized from acetone to get the title compound (9.5g).

With hydrogenchloride, hydrogen, palladium on activated charcoal in methanol, Product distribution / selectivity

Patent; JUBILANT ORGANOSYS LIMITED; WO2006/70396; (2006); (A1) EnglishView in Reaxys









38/80 2013-11-08 02:44:35

O

OH

N OH O

OH

O O

OH

NH


8 :Shake a mixture of (S)-2-(2-isopropoxy-3-methylphenyl)-1-(4-pyridinyl)ethanol (21.1 g, 78 mmol), HOAc (400 mL)and Pt02 (370 mg) with H2 (50 psi) for 15 hr. Filter the mixture through celite and evaporate the solvent to give (S) - 2-(2-isopropoxy-3- methylphenyl)-1-(4-piperidinyl)ethanol as the acetate salt; 1H-NMR (CDCl3) No. 7.1-6.9 (m, 2H), 4.2(m, 1 H), 3.6 (m, 1 H), 3.4 (m, 2H), 2.9-2.7 (m, 4H), 2.3 (s, 3H), 2.0 (s, 3H), 2.1-1.5 (m, 5H), 1.3 (d, 6H).

With hydrogen, platinum(IV) oxide, Time= 15h, p= 2585.81Torr

Patent; AVENTIS PHARMACEUTICALS INC.; WO2005/111025; (2005); (A1) EnglishView in Reaxys

N

HO

H N

S

HO

O O

H N

HO


84.b : 3-(Piperidin-4-yl)propan-1-ol p-toluenesulfonate:EXAMPLE 84b3-(Piperidin-4-yl)propan-1-ol p-toluenesulfonate:To a solution of 3-(4-pyridyl)propan-1-ol (15.13 g, 0.1103 mol) in EtOH (100 mL) was added p-TsOH (20.98 g, 0.1103mol) and PtO2 (1.5 g, 6.6 mmol).The resulting mixture was placed on a Parr apparatus and hydrogenated at 55 p.s.i.After 6 hr, the mixture was filtered (EtOH wash) and the filtrate concentrated in vacuo, giving 36.78 g (>100percent) ofthe desired piperidine; 1 H NMR (300 MHz, CDCl3) δ 7.7 (d, 2H), 7.2 (d, 2H), 3.55 (t, 2H), 3.3 (m, 4H), 2.95 (bt, 2H),2.38 (s, 3H), 1.95 (bd, 2H), 1.58 (m, 2H), 1.3 (m, 3H).

With p-TsOH, PtO2 in ethanol

Patent; The Dupont Merck Pharmaceutical Company; US5563158; (1996); (A1) EnglishView in Reaxys

NH

N

N Cl

O NH

N

NH


87% 36 : 4-(1H-Imidazol-2-yl-methyl)-piperidineEXAMPLE 364-(1H-Imidazol-2-yl-methyl)-piperidine2-(4-pyridylmethyl)imidazole (4 g, 0.025 M) and platinum oxide (0.4 g) in ethanol (40 ml) and 2 NHCl (50 ml) washydrogenated at 45 psig for 4 hrs.The catalyst was removed by filtration and the filtrate was stripped to dryness.Crystallization from ethanol gave 4-(1H-imidazol-2-yl-methyl)piperidine as the dihydrochloride salt m.p. 251°-252° C.(5.2 g, 87percent yield).

in ethanol









39/80 2013-11-08 02:44:35

NH

N

NH

NH




N

N

H N

N






N

N

H N

N




With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol











40/80 2013-11-08 02:44:35

NH

Cl

N

NH

Cl

NH




OH

O

N

Cl H

OH

O

H N


With hydrogen, platinum(IV) oxide in acetic acid, Yield given

Chung, John Y. L.; Zhao, Dalian; Hughes, David L.; McNamara, James M.; Grabowski, Edward J. J.; Reider,Paul J.; Tetrahedron Letters; vol. 36; nb. 41; (1995); p. 7379 - 7382View in Reaxys

VI.a : aaPiperidin-4-ylacetic acid75 g of 4-pyridylacetic acid hydrochloride are treated with 750 ml of glacial acetic acid (50percent strength), 6 g ofplatinum dioxide are added and the mixture is hydrogenated at 3 bar and room temperature in the course of 3 hours.The catalyst is filtered off with suction and the mother liquor is concentrated to dryness in vacuo.The residue is triturated with acetone and filtered off with suction.It is washed twice with acetone and once with ether.Yield: 71.7 g (92percent of theory) of white substance,Melting point: 150-153° C.

With Adam's catalyst in acetic acid

Patent; Karl Thomae; US5994356; (1999); (A1) EnglishView in Reaxys

N

O

O

N

N

O

O

H N



Kassiou, Michael; Read, Roger W.; Shi, Xue-qin; Bioorganic & Medicinal Chemistry Letters; vol. 7; nb. 7; (1997); p.799 - 804View in Reaxys









41/80 2013-11-08 02:44:35

N

OH

H N

OH

Cl H


100 % With hydrogenchloride, hydrogen, platinum on activated charcoal in water, Time= 264h, Ambient temperature

Lygo; Wainwright; Crosby; Lowdon; Tetrahedron; vol. 55; nb. 9; (1999); p. 2795 - 2810View in Reaxys

HN

O O

O

N

HN

O O

O

NH


100 % With hydrogenchloride, hydrogen, palladium on activated charcoal in ethanol

Adang, Anton E. P.; De Zwart, Edwin; Gerritsma, Siene; Peters, Co A. M.; Veeneman, Gerrit; Bioorganic andMedicinal Chemistry Letters; vol. 9; nb. 9; (1999); p. 1227 - 1232View in Reaxys

NH

N

O

NH

H N

O


With hydrogenchloride, hydrogen, platinum(IV) oxide in ethanol, Time= 16h, T= 20 °C , Catalytic hydrogenation


1 : Preparation of 4-(2-Acetamidoethyl)piperidine STR20PREPARATION 1Preparation of 4-(2-Acetamidoethyl)piperidine STR204-(2-Acetamidoethyl)pyridine (33 g.) in ethanol (250 ml.) was acidified to pH 4 with hydrochloric acid and hydrogenatedat 60 p.s.i./60° C. over a platinum oxide catalyst for 18 hours, after which time the uptake of hydrogen was complete.The catalyst was then removed by filtration and the filtrate was treated with a solution of potassium hydroxide flakes inmethanol (1.1 molar equivalents) and refiltered.The solvents were distilled off in vacuo, leaving a clear oil, which on standing gave 4-(2-acetamidoethyl)piperidine (18g.) as a white solid, m.p. 60° C.The oxalate salt was also prepared, m.p. 125°-129° C.Analysis percent: Found: C, 50.9; H, 7.7; N, 10.4.Calculated for C9 H18 N2 O:C2 H2 O4: C, 50.8; H, 7.8; N, 10.8.

With potassium hydroxide in methanol, ethanol

Patent; Pfizer Inc.; US4370328; (1983); (A1) EnglishView in Reaxys









42/80 2013-11-08 02:44:35

O H N

O NH O

O

O

N

O H N

O NH O

O

O

H N


100 % With hydrogen, acetic acid, platinum(IV) oxide in ethanol, Hydrogenation

Bergum, Peter W.; Brunck, Terence K.; Cohen, Cheryl R.; Goldman, Erick A.; Ho, Jonathan Z.; Levy, Odile E.;Nutt, Ruth F.; Reiner, John E.; Semple, J. Edward; Tamura, Susan Y.; Uong, Theresa H.; Bioorganic and MedicinalChemistry Letters; vol. 10; nb. 8; (2000); p. 745 - 749View in Reaxys

H N

N N

O

O

HO O

N H N

N N

O

O

HO O

NH

Cl H


Stage 1: With hydrogen, palladium on activated charcoal in water, isopropyl alcohol, T= 75 °C , p= 3102.89TorrStage 2: With ethanol, C6H5N*HCl in dichloromethane, water, T= 40 °C

Andrews, Ian P; Atkins, Richard J; Badham, Neil F; Bellingham, Richard K; Breen, Gary F; Carey, John S;Etridge, Stephen K; Hayes, Jerome F; Hussain, Nigel; Morgan, David O; Share, Andrew C; Smith, Stephen A.C;Walsgrove, Timothy C; Wells, Andrew S; Tetrahedron Letters; vol. 42; nb. 29; (2001); p. 4915 - 4917View in Reaxys

F

F

F

HO

N

F

F

F

NH

Cl H

F

F

F

HO

NH

Cl H


With hydrogen, palladium on activated charcoal in acetic acid, T= 70 °C , p= 7500.75Torr


N H N

Cl H


59.13 g(80.3%)

23 : 4-(Diphenylmethyl)piperidine hydrochloride [1:1]PREPARATION 23









43/80 2013-11-08 02:44:35

4-(Diphenylmethyl)piperidine hydrochloride [1:1]A mixture of 62.69 g (0.256 mole) of diphenyl-4-pyridylmethane and 6.4 g of 10percent palladium on carbon (0.0060mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatusat 865° for 4 days.The reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate.The residue was partitioned between methylene chloride and dilute sodium hydroxide.The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give asolid.This was dissolved in a mixture of methanol-acetonitrile, and excess ethereal hydrogen chloride was added.A precipitate was collected to give 59.13 g (80.3percent) of slightly impure title compound as a white, crystalline solid,m.p. 273°-274° C.Part of this was recrystallized from methanol-ether to give an analytically pure sample, m.p. 275.5°-277° C.Analysis:Calculated for C18 H22 ClN: C, 75.11; H, 7.70; N, 4.87. Found: C, 75.03; H, 7.73; N, 4.93.

With palladium in acetic acid, 3-hydroxy-propionitrile


59.13 g(80.3%)

39 : 4-(Diphenylmethyl)piperidine hydrochloride [1:1]PREPARATION 394-(Diphenylmethyl)piperidine hydrochloride [1:1]A mixture of 62.69 g (0.256 mole) of 4-(diphenylmethyl)pyridine and 6.4 g of 10percent palladium on carbon (0.006mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatusat 85° for 4 days.The reaction mixture was filtered, and the solvent was removed in vacuo from the filtate.The residue was partitioned between methylene chloride and dilute sodium hydroxide.The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give asolid.This was dissolved in a mixture of methanol-acetonitrile, and excess ethereal hydrogen chloride was added.A precipitate was collected to give 59.13 g (80.3percent) of slightly impure title compound as a white, crystalline solid,mp 273°-274° C.Part of this was recrystallized from methanol-ether to give an analytically pure sample, mp 275.5°-277° C.Analysis:Calculated for C18 H22 ClN: C, 75.11; H, 7.70; N, 4.87. Found: C, 75.03; H, 7.73; N, 4.93.

With palladium in acetic acid, 3-hydroxy-propionitrile


N

N

N

NH









44/80 2013-11-08 02:44:35

NH

O

N

NH

O

NH




N

O

N

N

O

H N


With hydrogen, platinum(IV) oxide in acetic acid, T= 60 °C , p= 2280Torr

Aubert, C.; Perrio-Huard, C.; Lasne, M. C.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 40;(1997); p. 752 - 754View in Reaxys

O

O

N

Cl H

O

O

H N

Cl H


0.76 g With hydrogenchloride, hydrogen, platinum on activated charcoal in methanol, diethyl ether, Time= 15h, T= 20 °C , p=2068.59Torr

Deutsch, Howard M.; Dunn, Travis; Ye, Xiaocong; Schweri, Margaret M.; Medicinal Chemistry Research; vol. 9;nb. 4; (1999); p. 213 - 222View in Reaxys

H N

O

O N

H N

O

O NH


ii : N-2-[1-(Methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyll -N'-33-methoxy-4-(5-oxazolyl)phenyl]oxalamideii)2.1 g (8.4 mmol) of tert-butyl [1,1-dimethyl-2-(4-pyridyl)ethyl]carbamate, in 20 ml of methanol were hydrogenated with400 mg of 10percent palladium on carbon catalyst at 70° C. and 7 Bar for 6 days.The resulting suspension was filtered, evaporated to dryness and the residue triturated with diethyl ether/petrol (1:9)to give 1.2 g of tert-butyl [1,1-dimethyl-2-(4-piperidinyl)ethyl]carbamate as a white solid. 1H NMR (400 MHz DMSO) δ:









45/80 2013-11-08 02:44:35

1.18 (6H,s), 1.28-1.41 (2H,m), 1.37 (9H,s), 1.52-1.69 (3H,m), 1.75-1.83 (2H,d), 2.74-2.84 (2H,t), 3.12-3.21 (2H,d),6.40-6.48 (1H,br.s), 8.60-8.95 (1H,br.s).

With palladium in methanol

Patent; Broadhurst, Michael J.; Hill, Christopher H.; Hurst, David N.; Jones, Philip S.; Kay, Paul B.; Kilford, IanR.; McKinnell, Robert M.; US2002/52513; (2002); (A1) EnglishView in Reaxys

ii : N-[2-[1-(Methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N'-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamideii)2.1 g (8.4 mmol) of tert-butyl [1,1-dimethyl-2-(4-pyridyl)ethyl]carbamate, in 20 ml of methanol were hydrogenated with400 mg of 10percent palladium on carbon catalyst at 70° C. and 7 Bar for 6 days.The resulting suspension was filtered, evaporated to dryness and the residue triturated with diethyl ether/petrol (1:9)to give 1.2 g of tert-butyl [1,1-dimethyl-2-(4-piperidinyl)ethyl]carbamate as a white solid. 1H NMR (400 MHz DMSO) δ:1.18 (6H,s), 1.28-1.41 (2H,m), 1.37 (9H,s), 1.52-1.69 (3H,m), 1.75-1.83 (2H,d), 2.74-2.84 (2H,t), 3.12-3.21 (2H,d),6.40-6.48 (1H,br.s), 8.60-8.95 (1H,br.s).

With palladium in methanol

Patent; Broadhurst, Michael J.; Hill, Christopher H.; Hurst, David N.; Jones, Philip S.; Kay, Paul B.; Kilford, IanR.; McKinnell, Robert M.; US2002/52513; (2002); (A1) EnglishView in Reaxys

HO

N

O O F

F F

F

F

F

HCl

HO

NH

O O F

F F

F

F

F

HCl


11.C : Synthesis of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine hydrochloride as an intermedi-ateStep CSynthesis of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine hydrochloride as an intermediateA solution of 2.0 grams (0.004 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]pyridine hydrochloride and acatalytic amount of platinum oxide in 125 mL of methanol was hydrogenated at 50 psi of hydrogen in a Parr hydroge-nator.The completion of hydrogenation required about two hours.After this time, the reaction mixture was filtered to remove the catalyst.The filtrate was concentrated to about 20 mL in volume, 80 mL of diethyl ether was added, and the solution was placedin a refrigerator.The resultant solid precipitate was collected by filtration, yielding about 0.4 gram of product.The filtrate was concentrated under reduced pressure, yielding an additional 1.9 grams of product.The two solid fractions were combined, yielding 2.3 grams of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidinehydrochloride.The NMR spectrum was consistent with the proposed structure.

With hydrogen in methanol, diethyl ether

Patent; FMC Corporation; US5569664; (1996); (A1) EnglishView in ReaxysPatent; FMC Corporation; US5639763; (1997); (A1) EnglishView in Reaxys







46/80 2013-11-08 02:44:35

O

NH

O

N

O

HN

O

H N


50 % With platinum(IV) oxide, hydrogen in acetic acid, Time= 12h, T= 40 °C , p= 2585.81Torr

Blum, Charles A.; Dai, Han; Disch, Jeremy S.; Jin, Lei; Lavu, Siva; Perni, Robert B.; Schuman, Eli; Vlasuk,George P.; Belyanskaya, Svetlana L.; Chiu, Cynthia H.; Cuozzo, John W.; Evindar, Ghotas; Lind, Kenneth E.;Aquilani, Leah; Coppo, Frank; Deng, Jianghe; Graybill, Todd L.; Mao, Cheney; Journal of Medicinal Chemistry;vol. 56; nb. 9; (2013); p. 3666 - 3679View in Reaxys

N

O O

H N

O O


With hydrogen, palladium on activated charcoal in acetic acid, Time= 16h, p= 2534.03Torr , Ambient temperature


N

N

H N

N

Cl H 2


With hydrogenchloride, hydrogen, platinum(IV) oxide in ethanol, isopropyl alcohol, p= 2068.6Torr

Fabio, Paul F.; Lang, S. A.; Lin, Yang-i; Tomcufcik, Andrew S.; Journal of Medicinal Chemistry; vol. 23; nb. 2;(1980); p. 201 - 206View in Reaxys

N

F

HN

F











47/80 2013-11-08 02:44:35


N H N




F

F

N

Cl H

F

F

H N




NH

F N

NH

F NH


With hydrogen, platinum(IV) oxide in acetic acid, Time= 20h, p= 899.8Torr , Ambient temperature, Yield given


NH F

N

NH F

NH


With hydrogen, platinum(IV) oxide in acetic acid, Time= 20h, p= 899.8Torr , Ambient temperature, Yield given












48/80 2013-11-08 02:44:35

N

O

O

N

N

O

O

NH


With hydrogen, Rh/Al2O3 in ethanol, Time= 3h, p= 2585.7Torr , Ambient temperature

Abou-Gharbia, Magid; Patel, Usha R.; Webb, Michael B.; Moyer, John A.; Andree, Terrance H.; Muth, Eric A.;Journal of Medicinal Chemistry; vol. 31; nb. 7; (1988); p. 1382 - 1392View in Reaxys

NH

N

NH

NH




N

OH

O

H N

OH

O


With hydrogen, acetic acid, platinum(IV) oxide in methanol, Time= 16h, p= 2585.7Torr

Klein, Scott I.; Molino, Bruce F.; Czekaj, Mark; Gardner, Charles J.; Chu, Valeria; et al.; Journal of MedicinalChemistry; vol. 41; nb. 14; (1998); p. 2492 - 2502View in Reaxys

N

H N

N

O

N

N

H N

N

O

NH


32 : EXAMPLE 32EXAMPLE 32A mixture of 1.5 g of 10-(4-pyridylmethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 100 ml of acetic acid, 5ml of 1N hydrochloric acid and 0.19 g of platinum oxide is hydrogenated at a pressure of 56 bar for 18 hours at 50° C.After removal of the catalyst and the solvent a beige solid (1.5 g) is obtained, to which is added 100 ml of water; thesuspension obtained is washed with 50 ml of dichloromethane, basified to pH 8 with saturated sodium hydrogen car-bonate solution, washed again with twice 50 ml of dichloromethane and concentrated on a rotary evaporator.250 ml of dimethylformamide, 20 ml of water and 3 g of silica are added to the residue obtained and the mixture isconcentrated on a rotary evaporator.









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The evaporation residue is purified by chromatography on a column of silica (150 g partially deactivated with 3percentwater), eluding with a mixture of chloroform, methanol and 28percent aqueous ammonia (24/6/1 by volume).0.18 g of 10-(4-piperidylmethyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is obtained, in the form of an or-ange solid N.M.R. spectrum: (300 MHz; (CD3)2 SO d6 with a few drops of CD3 COOD d4; δ in ppm): from 1.10 to 1.50(mt, 5H: CH2 and CH of the piperidine); 2.05 to 2.35 (mt, 2H: CH2); 2.65 (mt, 2H: NCH2 of the piperidine axial H); 3.05(broad d, J=12 Hz, 2H: NCH2 of the piperidine equatorial H); 4.30 (dd, J=9 and 3 Hz, 1H: H10); 7.30 and 7.40 (2t, J=8.5Hz, 2H: H7 and H8); 7.62 and 7.88 (2d broad, J=8.5 Hz, 1H each: H6 and H9); 7.58 and 8.02 (2s broad, 1H each: --Hof the[imidazole)].

With hydrogenchloride, ammonium hydroxide, acetic acid in N-methyl-acetamide, methanol, dichloromethane, water

Patent; Rhone-Poulenc Rorer S.A.; US5753657; (1998); (A1) EnglishView in Reaxys

N

N

H N

N


42 % With hydrogenchloride, hydrogen, platinum(IV) oxide in methanol, Time= 24h, p= 2482.31Torr


N

HN

N

H N

HN

N


With hydrogenchloride, hydrogen, palladium on activated charcoal in methanol, Time= 48h, p= 76000Torr

Kitbunnadaj, Ruengwit; Hashimoto, Takeshi; Poli, Enzo; Zuiderveld, Obbe P.; Menozzi, Alessandro; Hidaka,Ryoko; Esch, Iwan J. P. de; Bakker, Remko A.; Menge, Wiro M. P. B.; Yamatodani, Atsushi; Coruzzi, Gabriella;et al.; Journal of Medicinal Chemistry; vol. 48; nb. 6; (2005); p. 2100 - 2107View in Reaxys

N

N

N

O

N

HN

N

O


X : N,N-dimethyl-2-[methyl-(2-piperidin-4-yl-ethyl)-amino]-acetamideOf the crude N,N-dimethyl-2-[methyl-(2-pyridine-4-yl-ethyl)-amino]-acetamide, 44 g are dissolved in 500 ml of glacialacetic acid and hydrogenated with 4 g of PtO2 at ambient temperature under 3 bar H2.After the catalyst has been removed by suction filtering the filtrate is evaporated down.The residue is made alkaline with 50percent potassium hydroxide solution while cooling with ice and the product ob-tained is taken up in ether.








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The ether solution is dried over sodium sulphate, filtered and the solution is evaporated down.The product is left as a yellow oil. Yield: 42 g

With potassium hydroxide in acetic acid

Patent; Boehringer Ingelheim Pharma KG; US2003/171359; (2003); (A1) EnglishView in Reaxys

HN

N

O

N H

NH

O


175.ii : (ii)(ii)N-(1-Piperidin-4-Yl-Ethyl)-FormamideN-(1-Pyridin-4-yl-ethyl)-formamide (1.86 g, 12.38 mmol) was dissolved in 50 ml of acetic acid.After addition of Rh (5percent on A1203, 307 mg) the mixture was hydrogenated with 10 bar hydrogen and 100° C. for120 hours.The mixture was evaporated and lyophilised.The crude material was used without purification.

With hydrogen in acetic acid

Patent; Nazare, Marc; Will, David William; Peyman, Anuschirwan; Matter, Hans; Zoller, Gerhard; Gerlach,Uwe; US2002/198195; (2002); (A1) EnglishView in Reaxys

N HN


7 : EXAMPLE 7This compound (12 g, 59 mmol) was subjected to hydrogenation reaction in acetic acid (200 ml) at a hydrogen pressureof 8 kg/cm2 in the presence of platinum oxide (300 ml) as a catalyst.The catalyst was filtered off, and the solvent was distilled off under reduced pressure.Then, a 10M sodium hydroxide aqueous solution (200 ml) was added thereto, and the solution was extracted withtoluene (200 ml*2).The organic layer was dried on anhydrous sodium carbonate and then filtered, and the solvent was distilled off underreduced pressure to obtain 4-(4-propyl)cyclohexylpiperidine.

With sodium hydroxide in acetic acid

Patent; Chisso Corporation; US6576303; (2003); (B1) EnglishView in Reaxys

O

O

O O

N

HCl

O

O

O O

HN

HCl


XV.b : bbDiethyl 2-[2-(4-piperidinyl)-ethyl]malonate hydrochloride








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64.5 g (0.21 mol) of diethyl 2-[2-(4-pyridyl)-ethyl]malonate hydrochloride are hydrogenated exhaustively in 400 ml ofabsolute ethanol at room temperature under a hydrogen pressure of 50 psi over platinum dioxide as the catalyst.After the catalyst has been filtered off with suction, the solution which remains is concentrated to dryness in vacuo.The residue is brought to crystallization with acetone and is filtered off with suction.Yield: 62.8 g (95.5percent of theory) of highly hygroscopic crystals which deliquesce in air, Rf value: 0.22 (silica gel;methylene chloride/methanol=9:1)

With Adam's catalyst in ethanol

Patent; Dr. Karl Thomae GmbH; US5922717; (1999); (A1) EnglishView in Reaxys

N NH 2

N HCl

N NH 2

HN Cl H


48 : 1-Amino-3-(4-piperidyl)-3,4-dihydroisoquinoline hydrochlorideEXAMPLE 481-Amino-3-(4-piperidyl)-3,4-dihydroisoquinoline hydrochlorideA slurry of platinum oxide (8 mg, 10 moll) in methanol (1 ml) was added to a solution of 1-amino-3-(4-pyridyl)-3,4-dihydroisoquinoline hydrochloride (Example 28) (150 mg, 0.578 mmol) in methanol and concentrated hydrochloric acid(0.4 ml), and stirred under 3 atmospheres of hydrogen for 16 h.The mixture was filtered through celite and evaporated.The residue was purified by RP-HPLC to yield a white hygroscope solid (126 mg).[M+H]+

230; 360 MHz 1 H n.m.r (d6 -DMSO) 10.30 (1H, s), 9.43 (1H, s), 9.03 (1H, s), 8.80 (1H, br.s), 8.56 (1H, br.s), 8.05 (1H,d, J 7.8 Hz), 7.71 (1H, t, J 7.5 Hz), 7.54-7.50 (2H, m), 3.72-3.68 (1H, m), 3.27 (2H, d, J 13.2 Hz), 3.15 (1H, dd, J 17, 4Hz), 2.99 (1H, dd, J 17.2, 6.9 Hz), 2.80-2.74 (2H, m), 1.95-1.63 (3H, m), 1.48-1.38 (2H, m).

With hydrogenchloride in methanol

Patent; Astra Pharmaceuticals, Ltd.; US6063789; (2000); (A1) EnglishView in Reaxys

H N

N O

N

O

O O

N H N

N O

N

O

O O

NH


2.c : ccmethyl (R,S)-2,3,4,5-tetrahydro-4-isopentyl-3-oxo-8-[[[2-(4-piperidinyl)ethyl]methylamino]carbonyl]-1H-1,4-benzodia-zepine-2-acetateA solution of the compound of Example 2(b) (0.2 mmol) and 0.6N hydrochloric acid (0.6 mL) in methanol (30 mL) wastreated with platinum oxide (5 mg) and hydrogenated (45 psi) overnight.The mixture was filtered and concentrated to give the title compound. MS(ES) m/e 473 [M+H+.

With hydrogenchloride in methanol

Patent; SmithKline Beecham Corporation; US6117866; (2000); (A1) EnglishView in Reaxys







52/80 2013-11-08 02:44:35

HO

N

HO NH HCl


XX : 4-Hydroxymethyl-piperidine-hydrochlorideEXAMPLE XX4-Hydroxymethyl-piperidine-hydrochloride25 g of 4-pyridylmethanol are hydrogenated in 300 ml of 50percent acetic acid in the presence of 2 g of platinum dioxideat ambient temperature and under a hydrogen pressure of 60 psi.After the uptake of hydrogen has ceased and the catalyst has been removed, the solvent is removed under reducedpressure.The solid residue is taken up in ether and then the hydrochloride is precipitated with ethereal hydrochloric acid.The precipitate is suction filtered and dried. Yield: 28.3 g (82percent of theory), Melting point: 120°-125° C.

With Adam's catalyst in acetic acid

Patent; Dr. Karl Thomae GmbH; US5442064; (1995); (A1) EnglishView in Reaxys

N

O

O

N

HO

O N

O

O

NH

HO

O


19.e : e)e)Synthesis of [3-(piperidin-4-yl)-2,5-dioxopyrrolidin-1-yl]acetic acid2.8 g of [3-(4-pyridyl)-2,5-dioxopyrrolidin-1-yl]acetic acid are suspended in 160 ml of acetic acid and hydrogenated inan autoclave at 100° C. and a hydrogen pressure of 150 bar for 24 h using 100 mg of 5percent rhodium on carbon asa catalyst.The catalyst is then filtered off and the filtrate is concentrated to dryness in vacuo.The product thus obtained is taken up in a little water and freeze-dried.Yield: 2.3 gMS(ES): 255 [M+H]+

With rhodium in hydrogen, acetic acid

Patent; Hoechst Aktiengesellschaft; US5658935; (1997); (A1) EnglishView in Reaxys

N H N

Cl H


34 : 4-[Bis(4-methylphenyl)methyl]piperidine hydrochloride [1:1]PREPARATION 344-[Bis(4-methylphenyl)methyl]piperidine hydrochloride [1:1]The free base of the title compound was prepared by hydrogenation of 4-[(bis-4-methylphenyl)methyl]pyridine in aceticacid using palladium on carbon as catalyst and converted to the hyrochloride salt in methanoldiethyl ether.The sale was recrystallized from methanol-ethyl ether and isopropanol-ethyl ether and dried overnight in vacuo at 80°C. White solid amounting to 46percent yield, m.p. 232° C. was obtained.

With palladium in acetic acid







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O

N HN

N

O

N NH

NH


15 : Example 15A mixture of 4.5 parts of N-(4-pyridinylmethyl)-2-benzoxazolamine and 120 parts of methanol was hydrogenated atnormal pressure at about 50° C. with 2 parts of rhodium-on-charcoal catalyst 5percent.After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated,yielding 4.6 parts of N-(4-piperidinylmethyl)-2-benzoxazolamine as an oily residue (intermediate 75).

With rhodium-on-charcoal in methanol

Patent; Janssen Pharmaceutica N.V.; US4689330; (1987); (A1) EnglishView in Reaxys

O

N

O

HN


4.1 : (1)(1)Preparation of 2-[(4-piperidinyl)methyl]-2,3-dihydro-1-1H-indenone (or 2-[(4-piperidinyl)methyl]-1-indanone).60 g of 2-[(4-pyridyl)methyl]-2,3-dihydro-1-1H-indenone in solution in 600 ml of acetic acid are hydrogenated at theambient temperature, under a pressure of 1 bar of hydrogen, in the presence of 3 g of platinum oxide Adams.After 7 hours of hydrogenation, the catalyst is eliminated by filtration and the filtrate is evaporated.The residue is fixed on a column containing 1600 g of silica and eluted with a 90/10 chloroform-diethylamine mixture.30.2 g of a purified product, in the form of the free base, are thus obtained.This product is converted into the hydrochloride.

With hydrogen in acetic acid

Patent; Pharmindustrie; US4357337; (1982); (A1) EnglishView in Reaxys

N

O

H N

O


28 : Preparation of 4-(2-Methoxyethyl)piperidinePreparation 28Preparation of 4-(2-Methoxyethyl)piperidine4-(2-Methoxyethyl)pyridine (9.6 g), in a mixture of ethanol (100 ml) and 2 N hydrochloric acid (30 ml) was hydrogenatedover platinum oxide at 50°/50 p.s.i. until uptake of hydrogen ceased.The catalyst was removed by filtration and the solution evaporated in vacuo.The residue was then dissolved in water (50 ml), basified to pH 8 with dilute sodium hydroxide, and extracted withchloroform.The aqueous phase was evaporated in vacuo to give an oil which solidified on cooling.The solid was triturated with ether (60 ml), collected by filtration and dissolved in the minimum quantity of boiling ethylacetate.








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The hot solution was filtered and on cooling deposited hygroscopic crystals of 4-(2-methoxyethyl)piperidine (9.9 g),m.p. 108°-110°.The structure was verified by i.r. and n.m.r. spectroscopy.

With hydrogenchloride in ethanol, water, ethyl acetate


O

N

O

NH


R.4 : REFERENCE EXAMPLE 4REFERENCE EXAMPLE 4A solution of 4-(1,1-dimethyl-2-methoxyethyl)pyridine (10.0 g) in acetic acid (120 ml) was catalytically hydrogenatedover platinum dioxide at 40 p.s.i. for 41 hours at from ambient temperature to 43° C.After 24 hours a further quantity of platinum dioxide was added, and a final addition was made after a further 8 hours.After a total of 41 hours the solution obtained after filtration of the catalyst was evaporated in vacuo and further evapo-rated after the addition of toluene to remove acetic acid.The resultant yellow oil was dissolved in dichloromethane and brought to pH12 with dilute aqueous sodium hydroxidesolution.After saturation with sodium chloride, the organic phase was separated and the aqueous layer was re-extracted withfive portions of dichloromethane.The combined organic solution was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give 4-(1,1-dimethyl-2-methoxyethyl)piperidine (9.7 g) as a straw-coloured oil.

With Adam's catalyst in dichloromethane, acetic acid, toluene

Patent; May and Baker Limited; US4871748; (1989); (A1) EnglishView in Reaxys

S N

O O

N S N

O O

NH Cl H


20 : PREPARATION 20 STR76 (This is slight alternative to the method of Preparation 10.)PREPARATION 20 STR76 (This is slight alternative to the method of Preparation 10.)A solution of 2-[2-(4-pyridyl)ethyl)]isothiazolidine-1,1-dioxide (186 g) in acetic acid (2.5 liters) was hydrogenated overplatinum oxide catalyst (6.2 g) at 60° and 60 p.s.i. for 3 hours.The catalyst was filtered, the acetic acid solution was evaporated to small volume and the residue was dissolved inchloroform (1.5liters).The chloroform solution was washed with aqueous sodium hydroxide solution (0.62 liters, 5N) and evaporated to dry-ness to give the crude product (167.3 g), as the free base.A sample of the free base (50 g) was dissolved in ethyl acetate (450 ml) and washed with aqueous sodium hydroxidesolution (185 ml, 5N).The ethyl acetate solution was concentrated to low volume (150 ml) and a solution of HCl/isopropanol (42 ml, 5.71N)was added over 5 minutes.The resulting product, 2-[2-(4-piperidyl)ethyl]isothiazolidine-1,1-dioxide hydrochloride, was granulated at 0°-5° for 2hours, filtered and dried in vacuum at 40°-50°, yield 51.4 g, m.p. 191°-193°.Analysis percent: Found: C,44.4; H,7.9; N,10.5; Calculated for C10 H20 N2 SO2.HCl C,44.7; H,7.8; N,10.4.

With hydrogenchloride in chloroform, acetic acid, ethyl acetate, isopropyl alcohol








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N

NH O

N

F

F F

N N

NH O

N

F

F F

HN


20 : 2,3,4,4a-Tetrahydro-3-[2-(4-Piperidinyl)Ethyl]-8-(Trifluoromethyl)-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-OneEXAMPLE 202,3,4,4a-Tetrahydro-3-[2-(4-Piperidinyl)Ethyl]-8-(Trifluoromethyl)-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-OneA mixture of 5 g. (0.014 mole) of 2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-8-trifluoromethyl-1H-pyrazino[1,2-a]qui-noxalin-5(6H)-one, 60 ml. of ethanol, 120 ml. of water, 12 ml. of concentrated hydrochloric acid and 1 g. of platinumoxide catalyst was hydrogenated in a Parr apparatus for 2 hours.The catalyst was filtered and the solvents removed.The residue was crystallized two times from methanol to yield 42 g. of the title compound as the dihydrochloride salt,m.p. 279°-282° C.Analysis for: C19 H25 F3 N4 O.2HCl.CH3 OH. Calculated: C, 49.30; H, 6.41; N, 11.48; Cl, 14.54. Found: C, 49.77; H,6.50; N, 11.65; Cl, 14.64.

With hydrogenchloride in ethanol, water

Patent; American Home Products Corporation; US4203987; (1980); (A1) EnglishView in Reaxys

N

NH O

N N

N

NH O

N HN


15 : 2,3,4,4a-Tetrahydro-3-[2-(4-Piperidinyl)Ethyl]-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-OneEXAMPLE 152,3,4,4a-Tetrahydro-3-[2-(4-Piperidinyl)Ethyl]-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-OneA solution of 2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one in 120 ml. water and60 ml. ethanol containing 13 ml. conc. hydrochloric acid was placed in a Parr hydrogenation apparatus, with 1.2 g.PtO2, under 45 psi. of hydrogen and shaken till pressure drop ceased.After filtering off catalyst the solvents were removed under vacuum and the residue crystallized from hot ethanol.Product filtered off, washed (ethanol), and dried.Dissolved in hot methanol which was displaced by ethanol by boiling off lower boiling solvent. Yield:4.0 g. of the title compound as the dihydrochloride salt, m.p. 238°-240° C.Analysis for: C18 H26 N4 O.2HCl.H2 O. Calculated: C, 53.33; H, 7.45; N, 13.82; Cl, 17.49. Found: C, 53.06; H, 7.12; N,13.77; Cl, 17.43.

With hydrogenchloride, hydrogen in methanol, ethanol, water


N O

O

N

N

O O

NH


24 : Ethyl (3-(2-(Piperidin-4-yl)ethyl)-3-azaspiro[5.5]undec-9-yl)acetateEXAMPLE 24Ethyl (3-(2-(Piperidin-4-yl)ethyl)-3-azaspiro[5.5]undec-9-yl)acetate0.17 g (0.5 mmol) of the compound from Example 22 were dissolved in 25 ml 90percent acetic acid followed by additionof 30 mg platinum(IV) oxide.







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The mixture was filled into an autoclave and hydrogenated for 4 h at room temperature and a pressure of 20 atm.The catalyst was removed by filtration and the solvent evaporated under reduced pressure.The residue was treated with water and neutralized with sodium carbonate followed by extraction with dichloromethane.The organic layer was dried over sodium sulfate and concentrated in vacuo to leave the pure title compound.yield: 0.04 g (23percent), brown resin

With Adam's catalyst in water, acetic acid

Patent; Eli Lilly and Company; COR Therapeutics Inc.; US6291469; (2001); (B1) EnglishView in Reaxys

OH

N

OH

N H


With sulfuric acid, hydrogen, platinum(IV) oxide in methanol, Time= 18h, T= 20 °C

Atkinson, Peter J.; Bromidge, Steven M.; Duxon, Mark S.; Gaster, Laramie M.; Hadley, Michael S.; Hammond,Beverley; Johnson, Christopher N.; Middlemiss, Derek N.; North, Stephanie E.; Price, Gary W.; Rami, HarshadK.; et al.; Bioorganic & Medicinal Chemistry Letters; vol. 15; nb. 3; (2005); p. 737 - 742View in Reaxys

With platinum(IV) oxide, sulfuric acid, hydrogen in methanol

Armitage, Mark; Bret, Guillaume; Choudary, Bernie M.; Kingswood, Mike; Loft, Mike; Moore, Steve; Smith,Steve; Urquhart, Michael W. J.; Organic Process Research and Development; vol. 16; nb. 10; (2012); p. 1626 - 1634View in Reaxys

HO O

O

N HO O

O

HN


45 : Preparation of alpha,alpha-Bis(3-methoxyphenyl)-4-piperidineethanolEXAMPLE 45Preparation of alpha,alpha-Bis(3-methoxyphenyl)-4-piperidineethanolA solution of alpha,alpha-bis(3-methoxyphenyl)-4-pyridine-ethanol (63 g) in acetic acid (400 ml) was hydrogenated overplatinum oxide (2 g; 100 p.s.i.; 50°).The reaction was stopped after the uptake of the theoretical amount of hydrogen (0.564 mol), then it was filtered toremove the catalyst and the solvent was evaporated under reduced pressure.After the residue was taken up in water (400 ml) and toluene (200 ml), the mixture was heated to reflux and then madebasic with 10N sodium hydroxide.The mixture was cooled to 5°, and the resulting solid was collected by filtration, then was washed in turn with water,toluene, toluene-hexane (1:1) and hexane to give, after drying, 62.5 g of alpha,alpha-bis(3-methoxyphenyl)-4-piperi-dineethanol, mp 111°-113°.

With sodium hydroxide, hydrogen in hexane, water, acetic acid, toluene









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OH

N

F

F

OH

H N

F

F




OH

F F

N

F

F

OH

F F

H N

F

F




NH

O N

NH

O HN


With hydrogen, platinum(IV) oxide in methanol, p= 2068.59Torr

Huang, Wenrong; Naughton, Mary Ann; Scarborough, Robert M.; Su, Ting; Yang, Hua; Zhu, Bing-Yan; Arfsten,Ann; Dam, Suiko; Edwards, Susan; Sinha, Uma; Wong, Paul W.; Hollenbach, Stanley; Bioorganic and MedicinalChemistry Letters; vol. 13; nb. 4; (2003); p. 723 - 728View in Reaxys

O

N

O

HN


With hydrogen, platinum(IV) oxide in acetic acid, T= 50 °C

Marxer,A.; Helvetica Chimica Acta; vol. 52; nb. 25; (1969); p. 262 - 270View in Reaxys










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O

N

O

H N




O

N

Cl

O

H N

Cl




O Cl

N

O Cl

H N




O

N

O

O

H N

O




N

NH

O

N

N

NH

O

H N












59/80 2013-11-08 02:44:35


With hydrogen, Rh/Al2O3 in hydrogenchloride, Time= 48h, p= 2280Torr , Ambient temperature

Nomoto, Yuji; Obase, Hiroyuki; Takai, Haruki; Hirata, Tadashi; Teranishi, Masayuki; et al.; Chemical & Pharma-ceutical Bulletin; vol. 38; nb. 9; (1990); p. 2467 - 2471View in Reaxys

N

HN O

N

N

HN O

H N


With hydrogen, Rh/Al2O3 in hydrogenchloride, Time= 48h, p= 2280Torr , Ambient temperature

Nomoto, Yuji; Obase, Hiroyuki; Takai, Haruki; Hirata, Tadashi; Teranishi, Masayuki; et al.; Chemical & Pharma-ceutical Bulletin; vol. 38; nb. 9; (1990); p. 2467 - 2471View in Reaxys

N

OH

O

Cl H

H N

OH

O

Cl H


With hydrogen, acetic acid, platinum(IV) oxide, T= 40 - 45 °C , p= 760Torr

Ishihara, Yuji; Miyamoto, Masaomi; Nakayama, Takahiro; Goto, Giichi; Chemical & Pharmaceutical Bulletin; vol.41; nb. 3; (1993); p. 529 - 538View in Reaxys

HN

O

N

HN

O

H N


With hydrogen, platinum(IV) oxide in acetic acid, p= 2280Torr , Ambient temperature

Aubert, C.; Perrio-Huard, C.; Lasne, M. C.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 40;(1997); p. 752 - 754View in Reaxys









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F

N

F

N H


With hydrogenchloride, hydrogen, palladium on activated charcoal in methanol, water, T= 60 - 65 °C

Proszenyak, Agnes; Agai, Bela; Tarkanyi, Gabor; Vida, Laszlo; Faigl, Ferenc; Journal of Labelled Compoundsand Radiopharmaceuticals; vol. 48; nb. 6; (2005); p. 421 - 428View in Reaxys

N

N

Cl H 2

N

H N


With methanol, platinum, p= 2206.5 - 2942.03Torr , Hydrogenation

Phillips; Journal of the American Chemical Society; vol. 79; (1957); p. 2836View in Reaxys

N

N

2 H

2 H 2 H

2 H 2 H

2 H


With diclazuril, deuterium, platinum(IV) oxide in water-d2, Time= 20h, p= 2068.6Torr , Ambient temperature

Sheikh-Ali, Bashir M.; Khetrapal, C. L.; Weiss, Richard G.; Journal of Physical Chemistry; vol. 98; nb. 4; (1994); p.1213 - 1216View in Reaxys

N

N

N

NH


With hydrogen, Adam's catalyst in acetic acid, Ambient temperature











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N

N

N

NH


With hydrogen, Adam's catalyst in acetic acid, Ambient temperature


O

O

N

Cl H

O

O

H N

Cl H


With hydrogen, palladium on activated charcoal in ethanol

Dutta, Aloke K.; Coffey, Lori L.; Reith, Maarten E. A.; Journal of Medicinal Chemistry; vol. 40; nb. 1; (1997); p. 35- 43View in Reaxys

N

N

N

O

N

N

N

N

O

HN


0.180 g With hydrogen, acetic acid, platinum(IV) oxide, Time= 7h, T= 20 °C

Kakefuda, Akio; Sakamoto, Shuichi; Suzuki, Takeshi; Tahara, Atsuo; Tobe, Takahiko; Tsukada, Junko; Tsu-kamoto, Shin-ichi; Tsukada, Junko; Journal of Medicinal Chemistry; vol. 45; nb. 12; (2002); p. 2589 - 2598View in Reaxys








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N

N

H N

N




N

N

H N

N




N

N

H N

N











63/80 2013-11-08 02:44:35

F

F

N

F

F

N H


12.3 : Step 3Step 3A mixture of platinum oxide (0.5 g) and 4-(2,5-difluorobenzyl)pyridine from above in acetic acid (100 ml) was hydro-genated for 3 hr.The catalyst was removed and the solution concentrated in vacuo.The residue was dissolved in water and the solution basified with sodium hydroxide.The basic mixture was extracted with ether and the extracts concentrated in vacuo.The crude oil was vacuum distilled to give the product (5.1 g, 72.9percent, bp: 110° C.).A sample of the hydrochloride was prepared in ether (mp: 182°-183° C.). Calc'd. for C12 H15 F2 N.HCl: C, 58.19percent;H, 6.52percent; N, 5.66percent. Found: C, 58.14percent; H, 6.56percent; N, 5.59percent.



HO

N

HO

HN


XXVII : 9-(4'-piperidinyl)-9-fluorenolEXAMPLE XXVII9-(4'-piperidinyl)-9-fluorenolA solution of 13.0 g (0.05 mole) of 9-(4'-pyridyl)-9-fluorenol in 200 of glacial acetic acid was hydrogenated over 0.8 gof platinum oxide at 40 psi.The mixture was filtered, stripped, and the residue made basic affording 9-(4'-piperidinyl)-9-fluorenol.

in acetic acid

Patent; McNeilab, Inc.; US4251655; (1981); (A1) EnglishView in Reaxys

OH

HO

N

OH

HO

NH


5 : Preparation 5STR66A solution of 2-(4-pyridyl)propane-1,2-diol (2.0 g) in acetic acid (30 cm3) was hydrogenated over platinum oxide (0.10g) at 60° and 60 p.s.i. pressure for 16 hours.The catalyst was removed by filtration through "Avicel" and volatile material was removed in vacuo to afford 2-(4-piperidyl)propan-1,2-diol (2.1 g).(Crude acetate salt, oil).Also prepared by a similar method from the appropriate pyridine starting materials were:

in acetic acid

Patent; Pfizer Inc.; US4542132; (1985); (A1) English







64/80 2013-11-08 02:44:35

View in Reaxys

N

F

F F

HN

F

F F


10.B : EXAMPLE 10A solution of 15.7 parts of 4-[α-(p-trifluoromethylphenyl)benzyl]pyridine in 250 parts of acetic acid is heated, with agi-tation, at 47° C. under approximately 4 atmospheres of hydrogen and in the presence of 2 parts of platinum oxidecatalyst for 2 hours.The resultant mixture is filtered, and the filtrate is stripped of solvent by vacuum distillation.The residue is poured into 3 volumes of ice water, and the mixture thus obtained is made alkaline with sodium hydroxide.This mixture is then extracted with ether.The ether extract is dried over anhydrous potassium carbonate, filtered, and the ether removed to provide 4-[(4-tri-fluoromethylphenyl)phenylmethyl]piperidine as an oil.

in (2S)-N-methyl-1-phenylpropan-2-amine hydrate, acetic acid

Patent; G. D. Searle and Co.; US4105849; (1978); (A1) EnglishView in Reaxys

S NH

O

O

N

S NH

O

O

H N


1.B : (B)(B)Preparation of 4-(2-methanesulphonamidoethyl)piperidine STR134-(2-Methanesulphonamidoethyl)pyridine (8.4 g.) in ethanol (85 ml.) was acidified to pH 2 with 2 N HCl and hydrogen-ated at room temperature and a pressure of 50 p.s.i. over a platinum oxide catalyst until hydrogen uptake ceased.The catalyst was then removed by filtration and the filtrate was taken to dryness in vacuo to give a white solid whichwas dissolved in the minimum volume of hot ethanol, filtered quickly, and left at room temperature overnight.The resultant white crystals were collected by filtration and dried to yield 4-(2-methanesulphonamidoethyl)piperi-dine:hydrochloride (8.3 g.), m.p. 165°-167° C.Analysis percent: Found: C, 39.6; H, 7.8; N, 11.7: Calculated for C8 H18 N2 O2 S:HCl: C, 39.6; H, 7.9; N, 11.5.

in ethanol


N H N


With nickel, T= 180 °C , p= 147102Torr , Hydrogenation

Profft; Solf; ; vol. 2; (1959); p. 273,275








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View in Reaxys

With sodium, butan-1-ol, Hydrieren des Reaktionsprodukts an Palladium/Kohle in Essigsaeure

Wawzonek et al.; Journal of the American Chemical Society; vol. 74; (1952); p. 2894View in Reaxys

With hydrogen, sodium, 1.) ethanol, reflux, Multistep reaction


N

OH O OH O

H N


With hydrogen, palladium on activated charcoal, T= 100 °C

Bellamy, Francois D.; Chazan, Jean B.; Dodey, Pierre; Dutartre, Patrick; Ou, Khan; et al.; Journal of MedicinalChemistry; vol. 34; nb. 5; (1991); p. 1545 - 1552View in Reaxys

N

OH O OH O

H N


With hydrogen, palladium on activated charcoal, T= 100 °C

Bellamy, Francois D.; Chazan, Jean B.; Dodey, Pierre; Dutartre, Patrick; Ou, Khan; et al.; Journal of MedicinalChemistry; vol. 34; nb. 5; (1991); p. 1545 - 1552View in Reaxys

HO

N N

O

O HO

H N


1.i : (b)(i)The N-benzoyl-4-phenoxymethylpiperidine used as starting material is obtained as follows:4-Hydroxymethylpyridine is hydrogenated in methanol at 140° C. under 200 atmospheres of hydrogen pressure in thepresence of ruthenium oxide, producing 4-hydroxymethylpiperidine, b.p. 126°-130° C./14 mm Hg; m.p. 55°-56° C.

in methanol

Patent; Boehringer Mannheim GmbH; US4243807; (1981); (A1) EnglishView in Reaxys











66/80 2013-11-08 02:44:35

N

OH

O

OH

O HN

E

H N


XXX : 9-(4'-Piperidyl)fluorene fumarateEXAMPLE XXX9-(4'-Piperidyl)fluorene fumarateA solution of 54.75 g (0.225 mole) of 9-(4'-pyridyl)fluorene in 600 ml of acetic acid was hydrogenated over 5.0 g ofplatinum oxide at 40 psi and 25° C.The mixture was filtered, stripped and made basic, affording 9-(4'-piperidyl)fluorene, which was crystallized as thefumarate salt, m.p. 228°-230° C. (dec).

in acetic acid

Patent; McNeilab, Inc.; US4251655; (1981); (A1) EnglishView in Reaxys

N

OH

H N

OH


With sodium, butan-1-ol, und Hydrieren des vermutlich als 2-<1,2,3,6-Tetrahydro-<4>pyridyl>-aethanol C7H13NO zuformulierenden Reaktionsprodukts in Essigsaeure an Palladium

Wawzonek et al.; Journal of the American Chemical Society; vol. 74; (1952); p. 2894View in ReaxysLukes et al.; Collection of Czechoslovak Chemical Communications; vol. 22; (1957); p. 1173,1177View in Reaxys


Burtner; Brown; Journal of the American Chemical Society; vol. 69; (1947); p. 630,631View in Reaxys

N H N


With sodium, butan-1-ol, Hydrieren des Reaktionsprodukts an Palladium/Kohle in Essigsaeure

Wawzonek et al.; Journal of the American Chemical Society; vol. 74; (1952); p. 2894View in Reaxys













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O

O

N

Cl H

O

O

H N


With ethanol, platinum, Hydrogenation

Jachontow; Rubzow; Zhurnal Obshchei Khimii; vol. 27; (1957); p. 72,75; engl. Ausg. S. 83, 85View in Reaxys


Leonard et al.; Journal of the American Chemical Society; vol. 75; (1953); p. 6249,6251View in Reaxys

N

OH

H N

OH


With hydrogen, acetic acid, platinum(IV) oxide, Time= 96h, p= 3102.97Torr

Desaubry, Laurent; Riche, Stephanie; Laeuffer, Patricia; Cazenave, Jean-Pierre; Bioorganic and Medicinal Chem-istry Letters; vol. 18; nb. 6; (2008); p. 2028 - 2031View in Reaxys

F

N F

H N

2 H

2 H


Reaction Steps: 21: hydrogen; hydrochloric acid / Pd/C / methanol; H2O / 60 - 65 °C2: [2H4]-methanol; deuterium chloride / Pd/C / D2O / 6 h / 60 °C / 2250.18 TorrWith hydrogenchloride, methanol-d4, hydrogen, DCl, palladium on activated charcoal in methanol, water, water-d2

Proszenyak, Agnes; Agai, Bela; Tarkanyi, Gabor; Vida, Laszlo; Faigl, Ferenc; Journal of Labelled Compoundsand Radiopharmaceuticals; vol. 48; nb. 6; (2005); p. 421 - 428View in Reaxys

O

N

Cl

O

H N

Cl

(+)-enantiomer


Reaction Steps: 2










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1: H2 / PtO2 / acetic acid / 50 °C2: Dg-tartaric acid / ethanolWith (2S,3S)-2,3-dihydroxybutanedioic acid, hydrogen, platinum(IV) oxide in ethanol, acetic acid


O

N

Cl

O

H N

Cl

(-)-enantiomer


Reaction Steps: 21: H2 / PtO2 / acetic acid / 50 °C2: Dg-tartaric acid / ethanolWith (2S,3S)-2,3-dihydroxybutanedioic acid, hydrogen, platinum(IV) oxide in ethanol, acetic acid


N H N

H N


With sodium, butan-1-ol

Wawzonek et al.; Journal of the American Chemical Society; vol. 74; (1952); p. 2894View in ReaxysLukes; Ferles; Collection of Czechoslovak Chemical Communications; vol. 20; (1955); p. 1227,1232View in Reaxys

N H N


With nickel, Hydrogenation

McElvain; Carney; Journal of the American Chemical Society; vol. 68; (1946); p. 2592,2599View in Reaxys

N

O

H N

O













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Norton et al.; Journal of the American Chemical Society; vol. 68; (1946); p. 1572,1575View in Reaxys

N H N


With hydrogenchloride, ethanol, platinum, Hydrogenation

Harris et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 3959,3960, 3962View in Reaxys

HO

N

Cl H HO

HN


With methanol, platinum, Hydrogenation

Tilford; Van Campen; Journal of the American Chemical Society; vol. 76; (1954); p. 2431,2435, 2438; Journal of theAmerican Chemical Society; vol. 79; (1957); p. 6575View in Reaxys

O

O NH

N

O

O NH

N H


With hydrogen, palladium on activated charcoal in methanol

Scopes,D.I.C. et al.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry(1972-1999); (1977); p. 2376 - 2385View in Reaxys

NH

N

NH

N H


Reaction Steps: 21: triethylamine / tetrahydrofuran / 30 °C2: 14 percent Spectr. / acetic acid; hydrogen / platinum(II) oxide monohydrate / ethanol / 24 h / 40 °C / 45600 Torr










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With hydrogen, acetic acid, triethylamine, platinum (IV) oxide in tetrahydrofuran, ethanol


O

F

N

O

F

HN


Reaction Steps: 21: 1.) H2, glacial AcOH, 2.) NaOH / 1.) PtO2 / 1.) 1 atm, 8 h, 2.) THF, 24 h2: 31 percent / TFA / 20 h / HeatingWith sodium hydroxide, hydrogen, acetic acid, trifluoroacetic acid, platinum(IV) oxide

Cain; Christos; Cook; Drummond; Gilligan; Johnson; Kergaye; McElroy; Rohrbach; Schmidt; Tam; Journal ofMedicinal Chemistry; vol. 35; nb. 23; (1992); p. 4344 - 4361View in Reaxys

N

NH

O

N F N

N

NH

O

N F HN


17 : 8-Fluoro-2,3,4,4a-Tetrahydro-3-[2-(4-Piperidinyl)Ethyl]-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-OneEXAMPLE 178-Fluoro-2,3,4,4a-Tetrahydro-3-[2-(4-Piperidinyl)Ethyl]-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-OneFrom 3 g. of 8-fluoro-2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one treated in thesame manner as Example 16, there was obtained 2.5 g. of product, the title compound as the dihydrochloride salt, m.p.227°-230° C. (from ethanol).Analysis for: C18 H25 FN4 O.2HCl.H2 O. Calculated: C, 49.88; H, 6.74; N, 12.93; Cl, 16.36. Found: C, 49.81; H, 6.48;N, 12.73; Cl, 6.10.


N

O

N

N

O

HN


With hydrogen, platinum

Heitmeier,D.E. et al.; Journal of Organic Chemistry; vol. 36; (1971); p. 1449 - 1455View in Reaxys









71/80 2013-11-08 02:44:35

O

O

N

O

O

H N


With hydrogen, rhodium on alumina

Nielsen,A.T. et al.; Journal of Organic Chemistry; vol. 29; (1964); p. 2898 - 2903View in Reaxys

HO

N

HO

NH



Patent; Merrell Co.; US2804422; (1954)View in Reaxys

Reaction Steps: 51: acetone / 20 °C2: sodium tetrahydroborate / methanol / 4 h / 20 °C3: cyclohexanol / 2 h / Reflux4: potassium carbonate / chloroform / 20 °C5: ethanol / 24 h / Reflux; Inert atmosphere; Alkaline conditionsWith sodium tetrahydroborate, potassium carbonate, cyclohexanol in methanol, ethanol, chloroform, acetone

Benaka Prasad, S. B.; Vinaya, K.; Ananda Kumar, C. S.; Rangappa, K. S.; Swarup, Sanjay; Medicinal ChemistryResearch; vol. 19; nb. 3; (2010); p. 220 - 235View in Reaxys

S

O

O O

N

S

O

O O

NH


With hydrogen, palladium on activated charcoal










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NH

NH

O

O O

N

O O

NH

NH

O

O O

H N

O O


With platinum(IV) oxide, hydrogen in ethanol, water, acetic acid, Catalytic hydrogenation

Bergum, Peter W.; Brunck, Terence K.; Cohen, Cheryl R.; Goldman, Erick A.; Ho, Jonathan Z.; Levy, Odile E.;Nutt, Ruth F.; Reiner, John E.; Semple, J. Edward; Tamura, Susan Y.; Uong, Theresa H.; Bioorganic and MedicinalChemistry Letters; vol. 10; nb. 8; (2000); p. 745 - 749View in Reaxys

O

O

O

N

O

O

O

HN


With hydrogen, acetic acid, platinum(IV) oxide

Ishii, Noe; Kakefuda, Akio; Kubota, Hideki; Masuda, Noriyuki; Sakamoto, Shuichi; Tsukamoto, Shin-Ichi; Wada,Kouichi; Watanabe, Toshihiro; Bioorganic and Medicinal Chemistry Letters; vol. 14; nb. 12; (2004); p. 3049 - 3052View in Reaxys

F F

N

F

F F HO

O

F F

HN


Reaction Steps: 31.1: acetone / 16 h / Heating2.1: NaBH4 / methanol / 16 h / Heating2.2: H2; aq. HCl / Pd(OH)2 / ethanol2.3: NaOH / dioxaneWith sodium tetrahydroborate in methanol, acetone

Ladduwahetty, Tammy; Boase, Amanda L.; Mitchinson, Andrew; Quin, Caroline; Patel, Smita; Chapman, Kerry;MacLeod, Angus M.; Bioorganic & Medicinal Chemistry Letters; vol. 16; nb. 12; (2006); p. 3201 - 3204View in Reaxys

F

H N

F

F

O

O

N

F

NH

F

F

O O

HN










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With Adam's catalyst, hydrogen, acetic acid in ethanol

Benbow, John W.; Andrews, Kim A.; Aubrecht, Jiri; Beebe, David; Boyer, David; Doran, Shawn; Homiski, Mi-chael; Hui, Yu; McPherson, Kirk; Parker, Janice C.; Treadway, Judith; VanVolkenberg, Maria; Zembrowski,William J.; Bioorganic and Medicinal Chemistry Letters; vol. 19; nb. 8; (2009); p. 2220 - 2223View in Reaxys

OH

N

Cl H OH

H N


With ethanol, platinum, Hydrogenation

Patent; Merrell Co.; US2832786; (1956)View in ReaxysMcCarty et al.; Journal of Organic Chemistry; vol. 26; (1961); p. 4084,4086View in Reaxys

With methanol, platinum, Hydrogenation


OH

N

Cl H OH

H N


With methanol, platinum


With ethanol, platinum














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O

O HO

N

O

O HO

H N


With hydrogen, palladium on activated charcoal

Nielsen,A.T.; Platt,E.N.; Journal of Heterocyclic Chemistry; vol. 6; (1969); p. 891 - 900View in Reaxys

N

N

N

H N


With acetic acid, platinum, p= 2942.03Torr , Hydrogenation

Chough; ; vol. <C> 8; (1959); p. 335,351; ; (1960); p. 13129View in Reaxys

N

N

N

H N


With acetic acid, platinum, p= 2942.03Torr , Hydrogenation


N H N













75/80 2013-11-08 02:44:35

N H N




N H N




N H N




N H N











76/80 2013-11-08 02:44:35


O

N

O

N

O

N

O

N H


Reaction Steps: 31: acetonitrile / 1 h / 80 °C / |Inert atmosphere2: sodium tetrahydroborate; sodium hydrogencarbonate / ethanol / 1.17 h / 0 - 20 °C / |Inert atmosphere3: hydrogen; palladium(II) oxide hydrate / ethanol / 96 h / 20 °C / 2585.81 Torr / |Inert atmosphereWith sodium tetrahydroborate, hydrogen, palladium(II) oxide hydrate, sodium hydrogencarbonate in ethanol, acetoni-trile

Patent; Connolly, Peter J.; Bian, Haiyan; Li, Xun; Liu, Li; Macielag, Mark J.; McDonnell, Mark E.; US2013/102584;(2013); (A1) EnglishView in Reaxys

N H N


With sodium, butan-1-ol, Hydrierung des Reaktionsprodukts an Platin in Essigsaeure

Sury; Hoffmann; Helvetica Chimica Acta; vol. 37; (1954); p. 2133,2141; Helvetica Chimica Acta; vol. 38; (1955); p.728,735View in Reaxys

Br H

O

N

Br H

O

H N


With water, platinum, Hydration

Lukes; Galik; Collection of Czechoslovak Chemical Communications; vol. 21; (1956); p. 620,623View in Reaxys

Br H

HO HO

N

HO HO

H N


With water, platinum, Hydrogenation










77/80 2013-11-08 02:44:35

Lukes; Ernest; Collection of Czechoslovak Chemical Communications; vol. 14; (1949); p. 665,672View in Reaxys

N H N

H N


With sulfuric acid, Electrolysis

Ferles; Collection of Czechoslovak Chemical Communications; vol. 24; (1959); p. 1029,1031, 1033View in Reaxys

N H N



Ames; Bowman; Journal of the Chemical Society; (1952); p. 1057,1062View in Reaxys

N

O

N

N

O

H N




O

O

O O

N

O

O

O O

H N


With hydrogenchloride, platinum, Hydrogenation

Rubzow et al.; Zhurnal Obshchei Khimii; vol. 26; (1956); p. 445,446; engl. Ausg. S. 469, 470










78/80 2013-11-08 02:44:35

View in Reaxys

HO

N

O

HO

HN

O


With water, acetic acid, platinum, Hydrogenation

Patent; Merrell Co.; US2832786; (1956)View in Reaxys

O

O

N H

O N

O

O

N H

O NH


With ethanol, nickel, anschliessend Hydrieren an Platin unter Zusatz von Essigsaeure

Barash; Osbond; Journal of the Chemical Society; (1959); p. 2157,2163View in Reaxys

O

O

O

O

N

O

O

O

O

H N



Rubzow et al.; Zhurnal Obshchei Khimii; vol. 24; (1954); p. 2059,2061; engl. Ausg. S. 2025, 2027View in Reaxys

O

N

Cl

O

HN

Cl


(i) Raney-Ni, EtOH, (ii) H2, PtO2, AcOH, Multistep reaction

McCaustland,D.J. et al.; Journal of Medicinal Chemistry; vol. 17; nb. 9; (1974); p. 993 - 1000View in Reaxys











79/80 2013-11-08 02:44:35

N N H

N H



Veer; Goldschmidt; Recueil des Travaux Chimiques des Pays-Bas; vol. 65; (1946); p. 793View in Reaxys

N

OH sodium

H N

H N


Wawzonek et al.; Journal of the American Chemical Society; vol. 74; (1952); p. 2894View in ReaxysLukes; Ferles; Collection of Czechoslovak Chemical Communications; vol. 20; (1955); p. 1227,1232View in Reaxys

N

OH sodium

H N


Ladenburg; Justus Liebigs Annalen der Chemie; vol. 247; (1888); p. 79View in Reaxys

N

O S

OH

HO O lead-cathode

H N

H N


elektrochemische Reduktion


N

OH sodium

H N

H N


elektrochemische Reduktion














80/80 2013-11-08 02:44:35

N

OH sodium

N H

4-benzyl-piperideine


Tschitschibabin; Zhurnal Russkago Fiziko-Khimicheskago Obshchestva; vol. 34; (1902); p. 511; Chem. Zentralbl.;vol. 73; nb. II; (1902); p. 597View in Reaxys



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