solid phase synthesis_1
DESCRIPTION
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Solid-‐Phase Synthesis of 1,2,5-‐Benzothiadiazepin-‐4-‐one-‐ 1,1-‐dioxides via A Cyclization/Release Strategy
A short summer project carried out by
Surendra Karwa
Department of Chemistry, IIT- Kharagpur-721302
Under the supervision of
Prof. Johan Van der Eycken
Department of Organic Chemistry
Lab. For Organic and Bioorganic synthesis
Ghent University
Abstract: Benzodiazepine/ Benzothiadiazepine based heterocycles can be prepared efficiently on solid-support by employing different approaches. In this summer project, an effort has been made to highlight academic and industrial examples of combinatorial synthesis for this type of heterocycles published in the last decade. 1,2,5-Benzothiadiazepin-4-one-1,1-dioxides were synthesized by a simple procedure utilizing polymer supported amino acids and sulfonyl chloride as building block.Cyclization of common aminoamide intermediate with concomitant release from the support(resin-bound substrates) furnished the desired 1,2,5-Benzothiadiazepin-4-one-1,1-dioxides. The products were recovered in moderate yield and exhibited excellent purities. Further, the most relevant biological properties of these heterocycles have also been incorporated.
Introduction:
Benzothiazepines are important nitrogen and sulfur containing seven member heterocyclic compounds. Which are of great interest in the area of drug discovery and development due to their broad spectrum of Pharmacological activity. Benzothiazepine and its derivatives show a wide spectrum of Pharmacological activity such as anticonvulsant, antidepressant, CNS stimulant, anticancer, Anti-HIV, antihypertensive, antiulcer, Calcium channel blocker and antimicrobial agent.
Fig. 1 Templates for Library synthesis We purpose the synthesis route for 1,2,5-‐Benzothiadiazepin-‐4-‐one-‐1,1-‐dioxides using solid support. The retro synthesis of our template is given below.
Experimental Details General Reaction Scheme:
Fig. 1 General Reaction Scheme
Herein we report the synthesis of Benzothioazapines (8 & 9) from commercially available starting materials as shown in Fig. 1 . We get the library synthesis of Benzothioazapines (8 & 9) by changing the substituent R1, R2 & R3 on it .
α -‐AMINO ACID COUPLING ON WANG RESIN
OH O
ONHFmoc
R11 2
1. Fmoc-AA-OH, DIC, DMAP, CH2Cl2, rt, 16h
2. Ac2O/DIPEA/CH2Cl2 1/1/3, rt, 2 x 2h
OH O
ONH2
R1
O
O HN
R1
SNO2
O O
NH
NSO O
O
R1
R2
O
ON
R1
SNH2
O O
R2
Wang resin
O
ONHFmoc
R1
FmocHN
R1
COOH
DIC, DMAP, CH2Cl2
20% 4-Mepiperidine
in DMF
2x 10 min collidineCH2Cl2, 2x 1 h
R2OH, DIAD
PPh3, DCE2x 1 h
O
ON
R1
SNO2
O O
R2CrCl2
DMF/MeOH 9/12x 1 h
SO2Cl
NO2
FF
N N
N
O O
O
O
ON
R1
SNO2
O O
R2
F
80°C, MW 1 h
HN O
1M LiOtBu in THF, 4 h
N
NSO O
O
R1
R2N
O
R3
(i) K2CO3, DMF
(ii) R3-X, DMF
1 2 3 4
5 6 7
8 9
GENERAL PROCEDURE :
Preswell: The Wang resin 1 (1.50 g, 1.49 mmol, 1 eq) is preswollen first by suspending it in 20 ml of CH2Cl2 and by shaking it for 20 min. After filtration, this procedure is repeated for a second time.
Preactivation: To a stirring solution of an Na-Fmoc-protected amino acid (2.97 mmol, 2 eq) in 20 ml CH2Cl2 at 0°C is added DIC (2.97 mmol, 2 eq). This reaction mixture is stirred for 20 min at 0°C.
Coupling: The preactivated reaction mixture is then added to the preswollen Wang resin together with DMAP (0.30 mmol, 0.2 eq) and shaken for 16 h at room temperature. The resin was subsequently washed 3 times with DMF, MeOH and CH2Cl2.
Capping of remaining OH: The resin is suspended in a mixture of Ac2O/DIPEA/CH2Cl2 1/1/3 (20 mLl) and the mixture is shaken for 2h. The resin is filtered and washed with CH2Cl2, after which it is suspended in Ac2O/DIPEA/CH2Cl2 1/1/3 again and shaken for 2h. The resin is filtered and washed consecutively with CH2Cl2, DMF, MeOH and CH2Cl2. The obtained resin 2 is dried under vacuum.
Determination of loading: The loading of the coupled resin was determined by Fmoc UV-quantification using 4-methylpiperidine/DMF 1/4 (calibration line: A=8.3585c).
AMINE DEPROTECTION
O
ONH2
R13
20% 4-methylpiperidine in DMF, rT, 2x10 min
O
ONHFmoc
R12
GENERAL PROCEDURE
Deprotection: The resin is suspended in a solution of 20 ml 20% 4-methylpiperidine in DMF and shaken for 10 min. The resin is subsequently washed with DMF, MeOH and CH2Cl2 and this procedure is repeated for a second time, delivering the resin-bound deprotected a-amino acid 3.
SULFONYL CHLORIDE BUILDING BLOCK COUPLING
O
ONH2
R1
O
O HN
R1
SNO2O O
3 4
sym-collidine, CH2Cl2, rt, 2x1 h
F
NO2
SO2ClF
GENERAL PROCEDURE
The solid supported a-amino acid 7 (0.500 g, 0.37 mmol, 1 eq) is suspended in 10 ml of CH2Cl2 and shaken in the presence of sulfonyl chloride building block (0.92 mmol, 2.5 eq) and sym-collidine (1,86 mmol, 5 eq). After 1 h shaking at room temperature, the resin is filtered off and washed subsequently with DMF, MeOH and CH2Cl2. This reaction is repeated for a second time, delivering the sulfonamide 4.
MITSUNOBU ALKYLATION
O
O HN
R1
SNO2O O
O
ON
R1
SNO2O O
R2
4 5
R2-OH, DIAD, PPh3, DCE, rt, 2x1h
F F
GENERAL PROCEDURE
Resin bound compound 4 (0.37 mmol, 1 eq) is suspended in 10 ml of 1,2-dichloroethane, followed by addition of respectively an alcohol (3.7 mmol, 10 eq), triphenylphosphine (0.488 g, 1.86 mmol, 5 eq) and DIAD (0.37 ml, 1.86 mmol, 5 eq). After shaking this yellow mixture for 1 h, the resin is filtered off and washed consecutively 3 times with DMF, MeOH and CH2Cl2. This procedure is repeated for a second time, yielding the desired alkylated compound 5.
ON-RESIN NUCLEOPHILIC AROMATIC SUBSTITUTION
O
ON
SNO2
F
R2
O OO
ON
SNO2
N
R2
O ONMP, 80°C MW, 60 min
5 6
O
morpholine
R1 R1
To the fluoro containing resin 5 (0.349 mmol, 1 eq), brought in a microwave tube, is added subsequently 5 ml of NMP and morpholine (6.99 mmol, 20 eq). This suspension is heated for 60 min using microwave heating with constant cooling (Powermax method), then filtered off and washed 3x with DMF, MeOH and CH2Cl2. This readily delivers the aminated compounds 6.
NITRO REDUCTION
O
ON
R1
SNO2O O
R2
6
O
ON
R1
SNH2O O
R2
7
Cr(II)Cl2, DMF/MeOH 9/1RT, 2x 1 h
N N
O O
GENERAL PROCEDURE
To the resin bound compound 9 (0.37 mmol, 1 eq) is added 6 ml of a mixture of DMF/MeOH 9/1 and chromium(II) chloride (2.96 mmol, 8 eq). This green suspension is shaken for 1 h, followed by filtration and washing 3 times with DMF, MeOH and CH2Cl2. The reduction and washing procedure is repeated for a second time, delivering the desired aniline 10.
RING CLOSURE VIA CYCLIZATION/RELEASE
O
ON
R1
SNH2O O
R2
7NH
NSO
O
O
R1
R2
8
1M LiOtBu in THFRT, 4 h
NO
GENERAL PROCEDURE
To resin 7 (0.34 mmol, 1 eq) is added 4 ml of a 1M solution of LiOtBu in THF. This suspension is shaken for 4 h at room temperature, followed by filtrating off the resin and washing with THF. The filtrate is then evaporated under reduced pressure, redissolved in 12 ml of EtOAc and washed 2 times with a 5% solution of NaHCO3 in water and 1 time with 10 ml brine. The organic phase is then dried over MgSO4 and evaporated again to yield a brownish oil. This oil is purified using column chromatography or recrystallization, yielding the desired 1,2,5-benzothiadiazepin-4-one-1,1-dioxides.
ALKYLATION OF N5-POSITION IN SOLUTION
N
NSO
O
O
R1
R2
9
(i) K2CO3, DMF NO
NH
NSO
O
O
R1
R2
8
NO
R3
(ii) R3-X, DMF
GENERAL PROCEDURE
Substance 8 (0.34 mmol, 1eq.) is dissolved in DMF and K2CO3 is added to this solution. Now a solution of R3-‐X (0.34 mmol, 1eq) in DMF is added to above prepared solution of substance 8 . Reaction mixture is stirred for 2 h at room temperature. DMF is evaporated and compound 9 is redissolved in 8 ml of EtoAC and washed with a 5% solution of NaHCO3 in water and 1 time with 10 ml brine. The organic phase is then evaporated and final product 9 is column purified.
Result:
During my summer internship , I have synthesized library of 12 (twelve) Benzothiadiazepine compound. List of synthesized compound is given below with yield and crude purity .
NMR spectra :
1.
500 MHz.7108.001.1r.esp
16 14 12 10 8 6 4 2 0 -2 -4Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
2.821.114.201.124.231.040.011.001.070.805.300.66
H2O
CDCl3
7.90
7.33
7.27
7.26
7.02 6.89
6.87
4.67
4.65 3.
87 3.86
3.85
3.19 3.18
3.17
3.13
3.11 1.
571.
54
2.
300 MHz.7151.001.1r.esp
9 8 7 6 5 4 3 2 1Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Nor
mal
ized
Inte
nsity
2.393.981.131.104.100.361.000.002.021.185.320.84
CDCL3
8.78
7.39 7.39
7.36 7.33
7.27
7.25
7.00 6.
996.
96 4.47 4.45
4.44
4.42
4.14
4.12
3.88 3.
863.
853.
673.
653.
353.
20 3.18 3.18
3.17
3.07
3.05
2.94 2.91
2.89
2.05
1.37
1.33 1.27
1.24
0.87
0.85
0.82
3.
10 9 8 7 6 5 4 3 2 1 0 -1Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
Inte
nsity
8.23 4.15 4.091.01 1.00
DMSO-d6
H2O
4.
300 MHz.7125.001.1r.esp
16 14 12 10 8 6 4 2 0 -2 -4Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
6.884.824.414.481.082.261.261.00
H2O
CDCL3
8.49 7.
34 7.33
7.27
6.97
6.94
4.66 4.63
4.61
3.88 3.
863.
853.
493.
192.
801.
90 1.88 1.87
1.85
1.04
1.01
0.99
5.
300 MHz.7161.001.1r.esp
10 9 8 7 6 5 4 3 2Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
Nor
mal
ized
Inte
nsity
3.044.084.042.103.081.00
DMSO
H2O
10.3
6 7.26 7.26
7.13
4.14
3.75 3.
733.
713.
343.
13 3.11
3.10
2.69
2.51 2.
502.
492.
49
6.
300 MHz.7146.001.1r.esp
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Nor
mal
ized
Inte
nsity
4.434.985.031.242.511.320.001.00
H2O
H2O
CDCL3
8.71 7.
347.
337.
277.
077.
047.
026.
99
4.65
4.64 4.
63
4.60
4.58
3.88 3.
86
3.85
3.20 3.19
3.17
2.81
2.05 1.67
1.58
1.56
7.
300 MHz.7141.001.1r.esp
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Nor
mal
ized
Inte
nsity
9.302.884.020.631.013.860.480.961.950.771.991.940.930.60
H2O
CDCL3
8.67
8.15
8.12
7.68
7.60 7.
327.
277.
257.
257.
03 6.96
6.93
6.92 4.85
4.84
4.83 4.83
4.82
4.81
4.80 4.14
4.12
4.10
3.88 3.
863.
843.
703.
673.
253.
223.
20 3.19
3.17
3.05
2.82
2.79
2.77
2.41 2.18
2.05
1.88 1.71
1.67
1.39 1.
29 1.27
8.
300 MHz.7163.001.1r.esp
10 9 8 7 6 5 4 3 2 1Chemical Shift (ppm)
0
0.05
0.10
0.15
Nor
mal
ized
Inte
nsity
9.333.091.073.711.033.700.916.760.90
DMSOH2O
10.1
6
7.15
7.12 7.
117.
097.
066.
946.
776.
75
4.45 4.44
4.42
4.40
3.62
3.60
3.59
3.23
3.20
2.99 2.
972.
962.
852.
822.
502.
392.
382.
371.
97 1.87 1.25
1.15
1.06
9.
300 MHz.7165.001.1r.esp
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
Nor
mal
ized
Inte
nsity
3.003.991.061.034.010.911.004.190.102.030.051.040.860.84
H2O
CDCL3
8.66
8.17 7.
67 7.65 7.
35 7.32 7.31
7.27
7.10
6.98
6.96
6.93
4.79 4.77
4.77
4.75
4.17
4.15
4.12
4.10
3.87
3.85
3.84
3.73
3.71
3.32
3.30
3.18
3.17
3.15
2.78
2.32
2.06
1.72
1.29
1.27
1.25
Conclusions: Ø Cyclization/release strategy is successfully developed.
Ø Model library is synthesized.
Ø Synthesized high purity of crude cyclization products
Ø large diversity possible: a- and β-amino acids
Ø N4-alkyl derivatives: steric effects are important for amide formation: practically limited to cis- and trans-aminocyclohexanecarboxylic acids
Ø Application to further libraries is under investigation
Acknowledgments: I am thankful to Ghent University and Prof. Johan Van der Eycken group for providing financial support during my summer internship.
References:
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Jonathan A. Ellman* , J. Org. Chem. 1997, 62, 1240-1256
3. Douglas A. Horton,† Gregory T. Bourne,†,‡ and Mark L. Smythe*,†,‡, Chem. Rev. 2003, 103, 893-930
4. Ahmed Kamal*, K. Laxma Reddy, V. Devaiah, N. Shankaraiah and D.
Rajasekhar Reddy, Mini-Reviews in Medicinal Chemistry, 2006, 6, 53-69