classics in process chemistry alleva copy...phenacetin (bayer) n ohme 1880's germany: could not...

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




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




Bayer, ICI


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




Bayer, ICI



1932: Bayer launches firstcommercial antibiotic

NN

NH2

NH2

O2S

H2N

prontosil




Bayer, ICI



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

ClF3CN

O

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


O

HO

OHOH

H2N Me


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



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




Paul Reider



OMe

OH

H

O

vanillin

O

HO

OHOH

H2N Memethyldopa

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


NH

O

O

ClF3CN

O

S

HNNH2O

O

OH

Me

O

HO

OHOH

H2N Me



HN

OHN

SO2

Me Me NH2

O

OO

O

OH

O

HO

Me

CO2H

The Merck Synthesis of Imipenem


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, NH4ClNH

O

HO

NaBH4MeOH

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%

NO 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

CO2BzTBS-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

CO2BzTBS-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


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


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


NH

O

O

ClF3CN

O

S

HNNH2O

O

OH

Me

O

HO

OHOH

H2N Me



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


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


NH2

OCl

CF3

H

NH2

ClOH

F3C


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


NH2

OCl

CF3

H

NH2

ClOH

F3C


OH

PhN

Me


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


NH2

OCl

CF3

NHPMB

ClOH

F3C


OLi

PhN

Me


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


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


Edward Grabowski, Ph.D. Prof. David Collum


NH

O

O

ClF3CN

O

S

HNNH2O

O

OH

Me

O

HO

OHOH

H2N Me



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


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


Ghosh, A. K.; Kincaid, J. F.; et. al. J. Med. Chem, 1996, 39, 3278


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


Ghosh, A. K.; Leschenko, S.; Noetzel, M. J. Org. Chem, 2004, 69, 7822


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


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


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


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


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


O

HO

O

End-Game adopted from Ghosh's early synthesis


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 NH21. H2, Pd/C (10 mol%)

2. TFA, CH2Cl2

The Tibotec Synthesis of DarunavirEnd-Game adopted from Ghosh's early synthesis


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


NH

O

O

ClF3CN

O

S

HNNH2O

O

OH

Me

O

HO

OHOH

H2N Me



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.


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


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


PGE1

OH

O

HO

Me

CO2H


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


PGE1

OH

O

HO

Me

CO2H




[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%


PGE1

OH

O

HO

Me

CO2H




[EtO3P]2CuCN

CuI (0.5 equiv)none


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%


PGE1

OH

O

HO

Me

CO2H




[EtO3P]2CuCN

CuI (0.5 equiv)none


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


AcOCO2Me


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


AcOCO2Me


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



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


NH

O

O

ClF3CN

O

S

HNNH2O

O

OH

Me

O

HO

OHOH

H2N Me



HN

OHN

SO2

Me Me NH2

O

OO

O

OH

O

HO

Me

CO2H

classics in process chemistry alleva copy...phenacetin (bayer) n ohme 1880's germany: could not...

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