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Classics in Pharmaceutical Process Chemistry
Jen Alleva, 11 December 2014
MacMillan Group Meeting
Pharmaceutical Process Research and DevelopmentWhat is process chemistry?
Process Chemistry: the branch of pharmaceutical chemistry whose task is defined as the design and
implementation of practical organic syntheses to support drug development and develop synthetic methods
to support these process chemistry campaigns.
■ design practical syntheses for and manufacturing procedures
■ prepare bulk quantities of drug API to support early development
■ operate within a myriad of growing regulatory requirements
analysis of low-level impurities/parameters and kinetics, when/what process changes will be, compressed timelines
Discovery PreclinicalDevelopment
ExploratoryDevelopment
Development/Life Cycle Management
Launch
Phase I Phase IIa Phase IIb Phase III Phase IVearly scale-up multi-kilo delivery
Involvement of Process R&D in Drug Development Timeline
Evolution of Pharmaceutical Process Research and DevelopmentA Historical Perspective
1688, foundingof Merck
"18th Century"founding of Geigy, Hoescht
Bayer, ICI
Evolution of Pharmaceutical Process Research and DevelopmentA Historical Perspective
1688, foundingof Merck
"18th Century"founding of Geigy, Hoescht
Bayer, ICI
1880's Bayer and Hoechst launch firstpharmaceuticals
Kairin (Hoechst)
EtO
HN Me
O
phenacetin (Bayer)
NOH Me
1880's Germany: Could not patent pharmaceuticalproducts, only the process for producing them
The birth of Process R&D
Evolution of Pharmaceutical Process Research and DevelopmentA Historical Perspective
1688, foundingof Merck
"18th Century"founding of Geigy, Hoescht
Bayer, ICI
1880's Bayer and Hoechst launch firstpharmaceuticals
1914: Eli Lilly implements first writteninternal regulations: SOP's
" No changes in details of manufacture or packaging shall be made except by written memoranda. No writtenmemoranda seeking to effect changes in manufacturing or packaging shall be authority for such changes
unless it bears the following stamp " Memo to Supervisors in 1914, composed by Eli Lilly
Evolution of Pharmaceutical Process Research and DevelopmentA Historical Perspective
1688, foundingof Merck
"18th Century"founding of Geigy, Hoescht
Bayer, ICI
1880's Bayer and Hoechst launch firstpharmaceuticals
1914: Eli Lilly implements first writteninternal regulations: SOP's
1932: Bayer launches firstcommercial antibiotic
NN
NH2
NH2
O2S
H2N
prontosil
Evolution of Pharmaceutical Process Research and DevelopmentA Historical Perspective
1688, foundingof Merck
"18th Century"founding of Geigy, Hoescht
Bayer, ICI
1880's Bayer and Hoechst launch firstpharmaceuticals
1914: Eli Lilly implements first writteninternal regulations: SOP's
1932: Bayer launches firstcommercial antibiotic
1950–1953: Merck'ssynthesis of Cortisone
HO
OH
Me
MeMe
CO2H
HH
H
HO
Me
Me
HH
HO
OH
OOAc
Desoxycholic acid Cortisone
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H
The Merck Synthesis of L-Methyldopa
"Give 'em L boys!"
O
HO
OHOH
H2N Me
■ selective α-adrenergic receptor agonist
■ psychoactive drug used to treat hypertension
■ WHO list of essential medications
■ safe for gestational hypertension
(S)-Methyldopa
- Max Tishler, presidentof Merck & Co.
Key Features of Merck's Synthesis
utilization of a continuous flow system established to resolve enantiomers
best in overall atom economy
still in use today despite major advances in asymmetric catalysis
Grabowski, E. J. J. Chirality, 2005, 17, S249
The Merck Synthesis of L-Methyldopa
O
HO
OHOH
H2N Me
Grabowski, E. J. J. Chirality, 2005, 17, S249
OMe
OH
H
O
vanillin
OMe
OH
Me
O
OMe
OH
Me
NH2NC
OMe
OH
NC
MeAcHN
OMe
OH
NC
MeAcHN
HCl hydrolysis methyldopa
resolution of
acetamidonitrile
Ac2O
1. nitroethane, K2CO3MeNH2•HCl
2. Cu, HCl aq., FeCl3
KCN, NH4Cl
Merck & Co.'s Process and Manufacturing Route to Methyldopa
The Merck Synthesis of L-Methyldopa
O
HO
OHOH
H2N Me
Grabowski, E. J. J. Chirality, 2005, 17, S249
OMe
OH
H
O
vanillin
OMe
OH
Me
O
OMe
OH
Me
NH2NC
OMe
OH
NC
MeAcHN
OMe
OH
NC
MeAcHN
HCl hydrolysis methyldopa
resolution of
acetamidonitrile
Ac2O
1. nitroethane, K2CO3MeNH2•HCl
2. Cu, HCl aq., FeCl3
KCN, NH4Cl
Merck & Co.'s Process and Manufacturing Route to Methyldopa
The Merck Synthesis of L-Methyldopa
Grabowski, E. J. J. Chirality, 2005, 17, S249
OMe
OH
NC
MeAcHN
OMe
OH
NC
MeAcHN
resolution of
acetamidonitrile
Continuous Flow Resolution Provides both Enantiomers of Methyldopa
OMe
OH
(S)(S)NC
MeAcHN
OMe
OH
(R)(R)NC
MeAcHN
OMe
OH
NC
MeAcHN
NaCN, DMSO
resubjected to resolution
conglomerate: the racemate is a physical mixture of R and S formsi.e. a mechanical mixture of crystals
desired
A seeded, supersaturated solution of one enantiomer allows for selective crystallization of desired product
The Merck Synthesis of L-Methyldopa
Grabowski, E. J. J. Chirality, 2005, 17, S249
Continuous Flow Resolution Provides both Enantiomers of Methyldopa
Paul Reider
The Merck Synthesis of L-Methyldopa
Grabowski, E. J. J. Chirality, 2005, 17, S249
Continuous Flow Resolution Provides both Enantiomers of Methyldopa
The Merck Synthesis of L-Methyldopa
Grabowski, E. J. J. Chirality, 2005, 17, S249
OMe
OH
H
O
vanillin
O
HO
OHOH
H2N Me methyldopa
6 steps
practical synthesis still in use today for the manufacture of Methyldopa
despite recent advances in asymmetric
catalysis, continuous resolution continues
to be most robust and cost
effective method of preparation
Merck's asymmetric alkylation via PTC:
Dolling, U.-H.; David, P.; Grabowski, E. J. J. J. Am. Chem. Soc., 1984, 106, 446
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H
The Merck Synthesis of Imipenem
Grabowski, E. J. J. Chirality, 2005, 17, S249
The First Carbapenem Antibiotic
Grabowski, E. J. J. ACS Symposium Series, 2004, 870 (Chemical Process Research)
NO
S
HNNH2O
O
OH
Me
Imipenem
NO
S
NH3O
O
OH
Me
Thienamycin
NJ Pine Barrens: Apple Pie Hill
photo: Farmartin:en.wikipedia
■ first carbapenem and carbapenem antibiotic
■ Fermentation ultimately a failure (~100mg/kg)
■ 2nd order reaction of thienamycin with itself
■ multiple total syntheses by Merck process
"To produce 40,000kg of imipenem per year, we would have to runthe thienamycin fermentation in Lake Erie and pump to Lake
Ontario for workup." - Ed Paul
The Merck Synthesis of ImipenemMerck's First Generation Process Synthesis
Karady, S.; Amato, J.; Reamer, R. A.; Weinstock, L. M. J. Am. Chem. Soc., 1980, 103, 6765
BzO2C
O
OBzNHSiMe3
protected L-aspartic acid
NHO
CO2BztBuMgCl, Et2O, 0°C
2N, HCl, NH4Cl NHO
HO
NaBH4
MeOH
1. MsCl, NEt3, CH2Cl2, 0 °C2. NaI, acetone, Δ
3. TBSCl, NEt3, DMFN
O
I
TBS
50% overall yield
SS
TMS
Li
1. THF, –78 °C, 80%
2. acetaldehyde, LDA, THF, –78 °C3. TFAA, DMSO, NEt3, CH2Cl2 –78 °C
NO TBS
Me
O
TMS
1. K-Selectride, KI, Et2O, 87%
2. HgCl2, HgO, MeOH aq., Δ3. H2O2, MeOH aq. , 76% N
O TBS
Me
OHO
OH
1. CDI, THF2. MgO2CCH2CO2PNB, THF
3. HCl, MeOHNH
O
Me
OHO
OPNB
ON2
90%4. PhSO2N3, Et3N, MeCN
S
S
The Merck Synthesis of ImipenemMerck's First Generation Process Synthesis
Karady, S.; Amato, J.; Reamer, R. A.; Weinstock, L. M. J. Am. Chem. Soc., 1980, 103, 6765
Rh2(OAc)4 (0.01 mol%)
PhH, 80 °CNH
O
Me
OHO
OPNB
ON2
NO
Me
OHH
O
CO2pNBquantitative
1. CIP-(O)(OPh)2, DMAP
Hunig's base, MeCN, 0 °C
2. Hunig's base, MeCN, –5 °CHS
NHCO2PNB
70%
H2, 40psi, Pd/C (10 mol%)
NO
Me
OHH
CO2pNB
S
NHCO2PNB
NO
Me
OHH
S
NH3
OO
thienamycin
19 chemical steps
The Merck Synthesis of ImipenemMerck's Second Generation Process Synthesis: Current Manufacturing Route
Reider, P. J.; Grabowski, E. J. J. Tet. Lett., 1982, 23, 2293
NHO
CO2Bz TBS-Cl, NEt3
then: Pd/C, H2 NO
CO2H
TBS
LDA, 0 °Cthen: CH3CHO, 0 °C
then: citric acid90%
92%N
O
CO2H
TBS
Me
OHH
Na2Cr2O7, H2SO4
H2O NO
CO2H
TBS
Me
OH
iPr2NH•BH3, MgTFA
NO
CO2H
TBS
Me
OHH
Mg
NHO
O
O
Me
O
TBS
H
H
The Merck Synthesis of ImipenemMerck's Second Generation Process Synthesis: Current Manufacturing Route
Reider, P. J.; Grabowski, E. J. J. Tet. Lett., 1982, 23, 2293
NHO
CO2Bz TBS-Cl, NEt3
then: Pd/C, H2 NO
CO2H
TBS
LDA, 0 °Cthen: CH3CHO, 0 °C
then: citric acid90%
92%N
O
CO2H
TBS
Me
OHH
Na2Cr2O7, H2SO4
H2O NO
CO2H
TBS
Me
OH
iPr2NH•BH3, MgTFA
NO
CO2H
TBS
Me
OHH
1. Pb(OAc)4, DMF-HOAc
2. ZnI2 OTMS
N2
OBn
O NO TBS
Me
OHH
O
N2
O
OBnN
O
Me
OHH
S
NH3
OO
thienamycin10 chemical steps
70%
80%
The Merck Synthesis of ImipenemThe First Carbapenem Antibiotic
Grabowski, E. J. J. ACS Symposium Series, 2004, 870 (Chemical Process Research)
NO
S
HNNH2O
O
OH
Me
Imipenem
NO
S
NH3O
O
OH
Me
Thienamycin
first carbapenem natural product antibiotic to make it to market
6+ syntheses of Thienamycin reported in this era
Reider's publication received over 100 citations in the first year
NHO
CO2H OTMS
N2
O
OPNB
Karady's synthesis from Penicillin synthesis
on-scale synthesis using Rh catalyzed transformationearly syntheses utilized Mitsunobu reaction
to set alcohol stereocenter
Total synthesis on-scale
The Merck Synthesis of ImipenemThe First Carbapenem Antibiotic
Grabowski, E. J. J. ACS Symposium Series, 2004, 870 (Chemical Process Research)
NO
S
HNNH2O
O
OH
Me
Imipenem
NO
S
NH3O
O
OH
Me
Thienamycin
first carbapenem natural product antibiotic to make it to market
6+ syntheses of Thienamycin reported in this era
Reider's publication received over 100 citations in the first year
NHO
CO2H OTMS
N2
O
OPNB
Karady's synthesis from Penicillin synthesis
"Frankenstein" synthesis highlights
level of collaboration and creativity of
Merck's process chemistry group
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H
Mechanistic and Synthetic Studies towards the Production of Efavirenz
NH
O
O
ClF3C
Efavirenz
NH
NH
O
Cl
N
L-738, 372
non-nucleoside reverse transcriptase inhibitor for HIV type 1
sold in combination with tenofovir, emtricitabine: Atripla since 2006
N
NCl
O
N
quinine, BuLi, THF, –25 °C N
NHCl
O
N
84%, 97% ee
collaboration between MerckProcess and Dave Collum at
Cornell
Development of efficient andenantioselective acetylide
addition
Mechanistic and Synthetic Studies towards the Production of Efavirenz
NH2
OCl
chiral modifier, BuLi
CF3
THF, –25 °C
H
NH2
ClOH
F3C
chiral modifier conversion (%) ee (%)
quinine
N-Me-pseudoephedrine
N-Me-ephedrine
6
29
62
72
67
72
N-protecting group: p-methoxybenzyl
amino alcohol:
Ph
OHN
Me
Key Observations
2 equivalents of ephedrine and acetylidewere required for complete conversion
Pre-equilibration Temp (° C) ee (%)
–40 °C 80 (avg)0 °C >98
Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J.F.; Collum, D. B. J. Am. Chem. Soc., 1998, 120, 2028Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tet. Lett, 1995, 36, 8937
THF
Mechanistic and Synthetic Studies towards the Production of Efavirenz
NH2
OCl
CF3
H
NH2
ClOH
F3C
Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J.F.; Collum, D. B. J. Am. Chem. Soc., 1998, 120, 2028Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tet. Lett, 1995, 36, 8937
OH
PhN
Me
BuLi, THF, –40 °C
collaboration with Dave Collum at Cornell
6Li
6Li13C acetylide
6Li15N chiral amino alcohol
Li
OOLiLi
Li
NN
Me
Ph
Me
PhTHF
proposed Li-tetramer
THF
Mechanistic and Synthetic Studies towards the Production of Efavirenz
NH2
OCl
CF3
H
NH2
ClOH
F3C
Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J.F.; Collum, D. B. J. Am. Chem. Soc., 1998, 120, 2028Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tet. Lett, 1995, 36, 8937
OH
PhN
Me
BuLi, THF, –40 °C
collaboration with Dave Collum at Cornell
6Li
6Li13C acetylide
6Li15N chiral amino alcohol
Li
OOLiLi
Li
NN
Me
Ph
Me
Ph
acetylide delivery to re-faceAr
O
CF3
as predicted by tetramer structure
Mechanistic and Synthetic Studies towards the Production of Efavirenz
NH2
OCl
CF3
NHPMB
ClOH
F3C
Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J.F.; Collum, D. B. J. Am. Chem. Soc., 1998, 120, 2028Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tet. Lett, 1995, 36, 8937
OLi
PhN
Me
BuLi, THF, –50 °C
synthesis of Efavirenz
PMB-Cl, TsOH
MeCN, 70 °C
NHPMB
OCl
CF3
93%
Tol-Hept recrystallized93%, >99.5% ee
1. DDQ, PhMe
2. recrystallizationNH2
ClOH
F3C
90%, >99.5% ee
1. COCl2, THF-hept.
2. KOH/KHCO3, MTBE
OO2NO
Cl
NH
OCl
O
F3C
Efavirenz
94%, >99.8% ee
Mechanistic and Synthetic Studies towards the Production of Efavirenz
NH
O
O
ClF3C
Efavirenz
■ combination therapy Atripla combines Efavirenz, tenofovir, emtricitabine
sold in developing countries for about $1/day
■ expedient synthesis allows for inexpensive manufacturing process
■ productive collaboration between industry and academia
"As to our interactions with Dave Collum, I can only say that he is a prince among chemists, and he haschanged the ways in which we view all lithium anion reactions." - Ed Grabowski
Grabowski, E. J. J. ACS Symposium Series, 2004, 870 (Chemical Process Research)
Edward Grabowski, Ph.D. Prof. David Collum
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H
The Tibotec Synthesis of Darunavir
Ghosh, A. K.; Kincaid, J. F.; et. al. Bioorg. Med. Chem. Lett., 1998, 8, 687
Addressing Resistance Towards Peptide-based HIV Protease Inhibitors
Me
MeN
OHNH
O
O O
O
O2S
NH2
Darunavir
■ 1990's HIV resistance to protease inhibitors
■ eliminate peptide-like character
■ Ghosh et al. developed novel biological mimics of
■ stereochemically defined and conformationallyconstrained
peptide-like structures
Me
MeN
OHNH
O
O O
O2S
Me
Me
MeN
OHNH
O
O O
O2S
NH2
Me
MeN
OHNH
O
O O
O2S
OMe
SAR developed at Dept of Chemistry, University of Illinois at Chicago, The Chicago Medical School
The Tibotec Synthesis of Darunavir
Ghosh, A. K.; Kincaid, J. F.; et. al. Bioorg. Med. Chem. Lett., 1998, 8, 687
Early Synthetic Studies Towards the Preparation of the Hexahydrofuranol
Me
MeN
OHNH
O
O O
O
O2S
NH2
Darunavir
The Tibotec Synthesis of Darunavir
Ghosh, A. K.; Kincaid, J. F.; et. al. J. Med. Chem, 1996, 39, 3278
Early Synthetic Studies Towards the Preparation of the Hexahydrofuranol
O
O
OH
Ghosh and Merckradical cyclization approach
O O
I
O
H
NIS
propargyl alcoholCH2Cl2, 0–23 °C
cobaloxime (cat.)
NaBH4, EtOH O O
1. O3, CH2Cl2, MeOHMe2S, –78–23 °C
2. NaBH4, EtOH, 15 °C O O
HO
91%
75% 78%
chiral resolution provides 95% ee of alcohol
expensive and unscalable radical cyclization
The Tibotec Synthesis of Darunavir
Ghosh, A. K.; Leschenko, S.; Noetzel, M. J. Org. Chem, 2004, 69, 7822
Early Synthetic Studies Towards the Preparation of the Hexahydrofuranol
O
O
OH
Ghoshphotochemical conjugate
Ph3P=CHCO2Me
MeOH, 0 °C
H2SO4, MeOH
then protection
benzophenone(10–15 mol%)
[1,3]-dioxolane75%36–91%
difficult to scale photochemical reactions
reduction provides incorrect diastereomer
addition
O
H
OO
MeMe
H
OO
MeMe
CO2Me
88%
O OPGO
O OPGO
OO
Hg-lamp
1. LAH, THF
2. 1N HCl, THF/H2O
O
O
OH77%R=Bn
The Tibotec Synthesis of Darunavir
Quaedflieg, P. J. L. M.; Kesteleyn, B. R. R.; Wigerinck, P. B. T. P.; Goyvaerts, N. M. F.; Vijn, R. J.;
O
O
OH
Liebregts, C. S. M.; Kooistra, J. H. M. H.; Cusan, C. Org. Lett., 2005, 7, 5917
XOR
OO2N
OO
MeMe
O
O
O
OMe
X
O
H
OO
MeMe
OMe
O
OO
MeMe
MeO
O
OMe
O
THF, pyridine (0.5 equiv)Ac2O (3 equiv)
OMeO
77%
CH3NO2
MeOH/DBU
OMe
O
OO
MeMe OMeO
O2N
1. NaOMe/MeOH
2. H2SO4/MeOHO
O
O
OMe
OMe
O
61%
OMe
O
HOHO
OMeO
O
The Tibotec Synthesis of Darunavir
Quaedflieg, P. J. L. M.; Kesteleyn, B. R. R.; Wigerinck, P. B. T. P.; Goyvaerts, N. M. F.; Vijn, R. J.;
O
O
OH
Liebregts, C. S. M.; Kooistra, J. H. M. H.; Cusan, C. Org. Lett., 2005, 7, 5917
XOR
OO2N
OO
MeMe
O
O
O
OMe
X
O
H
OO
MeMe
OMe
O
OO
MeMe
MeO
O
OMe
O
THF, pyridine (0.5 equiv)Ac2O (3 equiv)
OMeO
77%
CH3NO2
MeOH/DBU
OMe
O
OO
MeMe OMeO
O2N
1. NaOMe/MeOH
2. H2SO4/MeOHO
O
O
OMe
OMe
O
61%
KOH/H2O
MeOH, Δ
O
HO
OMe
O
O
The Tibotec Synthesis of Darunavir
Quaedflieg, P. J. L. M.; Kesteleyn, B. R. R.; Wigerinck, P. B. T. P.; Goyvaerts, N. M. F.; Vijn, R. J.;Liebregts, C. S. M.; Kooistra, J. H. M. H.; Cusan, C. Org. Lett., 2005, 7, 5917
O
HO
OMe
O
O1. AcOH
2. iPrOH
O
O
O
OMe52%
1. LiBH4
2. conc. HCl O
HO
O
80%
6 steps, 19% overall yield produced over 100kg of material
drawbacks: Knoevenagel reaction maximum yield is 77%
decarboxylation/recyclization loses 50% of material
required large reactors due to intermediate lability
Completing the 6-step route to key pharmacophore
The Tibotec Synthesis of Darunavir
Quaedflieg, P. J. L. M.; Kesteleyn, B. R. R.; Wigerinck, P. B. T. P.; Goyvaerts, N. M. F.; Vijn, R. J.;Liebregts, C. S. M.; Kooistra, J. H. M. H.; Cusan, C. Org. Lett., 2005, 7, 5917
O
HO
OMe
O
O1. AcOH
2. iPrOH
O
O
O
OMe52%
1. LiBH4
2. conc. HCl O
HO
O
80%
6 steps, 19% overall yield produced over 100kg of material
Completing the 6-step route to key pharmacophore
O
H
OO
MeMe
OMe
O
OO
MeMe
THF, H2O
92%
TEPA
Horner-Wadsworth-Emmons
The Tibotec Synthesis of Darunavir
O
HO
O
End-Game adopted from Ghosh's early synthesis
Ghosh, A. K.; Leschenko, S.; Noetzel, M. J. Org. Chem, 2004, 69, 7822
di-succinimidyl-carbonate
NEt3, CH2Cl2O
O
O
O
ON
O
O
BocHNO
Me
MeNH2
1. iPrOH, 84 °C
2. p-NO2PhSO2Cl
NaHCO3 aq., CH2Cl2
BocHNOH
NSO2
Me Me NO2
95%
66%
BocHNOH
NSO2
Me Me NO2
H2NOH
NSO2
Me Me NH2
1. H2, Pd/C (10 mol%)
2. TFA, CH2Cl2
The Tibotec Synthesis of DarunavirEnd-Game adopted from Ghosh's early synthesis
Ghosh, A. K.; Leschenko, S.; Noetzel, M. J. Org. Chem, 2004, 69, 7822
H2NOH
NSO2
Me Me NH2
O
O
O
O
ON
O
O
NEt3, CH2Cl2
HN
OHN
SO2
Me Me NH2
O
OO
O
Darunavir, 12 chemical steps
85% yield for 3 step sequence
Approved in 2006 for multiply resistance HIV 1 infections
collaborations between U. I. Chicago, Merck, Tibotec and DSM Pharma
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H
The Syntex Synthesis of Prostaglandin PGE1
Bindra, J. S.; Bindra, R. (1977) Prostaglandin Synthesis. New York, New York: Academic Press. pp 2–6
Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
Induces childbirth or abortionerectile dysfunction
vasodilation
CO2H
OH
O
HO
Me
PGE2
treatment of infant heart defects
PGE1
OH
O
HO
Me
CO2H
PGI2 PGF2α
OHHO
Me
O
OOH
3
CO2H
OH
HO
HO
Me
uteral contraction and bronchoconstriction
The Syntex Synthesis of Prostaglandin PGE1Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.
O(CH2)3CO2H
C5H11
OH
HO
CHOC5H11
OH
TBSO
Wittig
SN2 cuprate additionPGA2
OO
Corey, E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832.
The Syntex Synthesis of Prostaglandin PGE1Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.
O(CH2)3CO2H
C5H11
OH
HO
CHOC5H11
OH
TBSO
Wittig
SN2 cuprate additionPGA2
OO
Corey, E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832.
erectile dysfunctiontreatment of infant heart defects
PGE1
OH
O
HO
Me
CO2H■ Synthesis devised by Syntex Labs in Mexico
■ Later acquired by Roche in Palo Alto
■ Novel cuprate chemistry (heteratom-substitution)
■ Modular and convergent synthesis
The Syntex Synthesis of Prostaglandin PGE1Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
PGE1
OH
O
HO
Me
CO2H
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
organocuprate conjugateaddition
The Syntex Synthesis of Prostaglandin PGE1Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
PGE1
OH
O
HO
Me
CO2H
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
organocuprate conjugateaddition Cu(I) source solvent Temp (°C) (% d)
[EtO3P]2CuCN
CuI (0.5 equiv)
010
Et2OTHF
–70–20
I
OMe
Me Cu
OMe
Me
The Syntex Synthesis of Prostaglandin PGE1Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
PGE1
OH
O
HO
Me
CO2H
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
organocuprate conjugateaddition Cu(I) source solvent Temp (°C) (% d)
[EtO3P]2CuCN
CuI (0.5 equiv)none
CuICuI (0.5 equiv)[(Bu3P)CuI]4
01088825071
Et2O
Et2OEt2OEt2OEt2O
THF–70–20–20–20–20–70
I
OMe
Me Cu
OMe
Me
low yields: 2–5%
The Syntex Synthesis of Prostaglandin PGE1Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
PGE1
OH
O
HO
Me
CO2H
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
organocuprate conjugateaddition Cu(I) source solvent Temp (°C) (% d)
[EtO3P]2CuCN
CuI (0.5 equiv)none
CuICuI (0.5 equiv)[(Bu3P)CuI]4
none
CuICuI (0.5 equiv)
01088825071857667
Et2O
Et2OEt2OEt2OEt2OEt2OEt2O
THF
THF
–70–20–20–20–20–70–20–20–20
I
OMe
Me Cu
OMe
Me
TMEDA80%
The Syntex Synthesis of Prostaglandin PGE1Rich History of Prostaglandin Synthesis and Structure Elucidation in Organic Chemistry
PGE1
OH
O
HO
Me
CO2H
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
organocuprate conjugateaddition Cu(I) source solvent Temp (°C) (% d)
[EtO3P]2CuCN
CuI (0.5 equiv)none
CuICuI (0.5 equiv)[(Bu3P)CuI]4
none
CuICuI (0.5 equiv)
01088825071857667
Et2O
Et2OEt2OEt2OEt2OEt2OEt2O
THF
THF
–70–20–20–20–20–70–20–20–20
I
OMe
Me Cu
OMe
Me
TMEDA
O
HO
CO2H
OH
O
HO
Me
CO2H
I
OH
Me
1. BuLi, TMEDA, CuITHF, –20 °C
6
The Syntex Synthesis of Prostaglandin PGE1
AcOCO2Me
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
OH
MeI
1. NaH, phthalic anhydridePhH, DMF
then: recrystallization
Me
NH2
2. 15% NaOH OH
MeI
1. NBS, THF aq.
2. Li2CO3, pyridine, 90 °CCO2Me
O
NBS then AgClO4
acetone aq.40%
then resolution
CO2MeO
HO
The Syntex Synthesis of Prostaglandin PGE1
AcOCO2Me
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
OH
MeI
1. NaH, phthalic anhydridePhH, DMF
then: recrystallization
Me
NH2
2. 15% NaOH OH
MeI
1. NBS, THF aq.
2. Li2CO3, pyridine, 90 °CCO2Me
O
NBS then AgClO4
acetone aq.40%
then resolution
CO2MeO
HO
diastereoselective cuprateaddition developed at
Syntex
The Syntex Synthesis of Prostaglandin PGE1
Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc., 1972, 94, 7827Patterson Jr., J. W.; Fried, J. H. J. Org. Chem., 1974, 39, 2506
erectile dysfunctiontreatment of infant heart defects
PGE1
OH
O
HO
Me
CO2H
one of the shortest prostaglandin syntheses at 7 steps
elegent demonstration of atom economy in classical atom-uneconomical reaction
"green chemistry" before green chemistry was cool
Classic Syntheses in Pharmaceutical Process Research and Development
NH
O
O
ClF3C
NO
S
HNNH2O
O
OH
Me
O
HO
OHOH
H2N Me
Methyldopa Imipenem Efavirenz
Darunavir Prostaglandin E1
HN
OHN
SO2
Me Me NH2
O
OO
O
OH
O
HO
Me
CO2H