synthesis of commercial drugs 2011 - 12

SYNTHESIS OF LIPITOR atorvastatin calciumChiral side chain : 220 ton / year Cholesterol: a very important biological molecule -most cholesterol is not dietary, it is synthesizedinternall

MASTER 2 Molecular Chemistry – Medicinal Chemistry Université de Rennes 1 – Vietnam National University, Hanoi

SYNTHESIS OF COMMERCIAL DRUGS

Prof Pierre van de Weghe

CO 2 Et O

NH 2 .H 3 PO 4 AcHN

.CH 3 SO 3 H

OH O

NH 2

N S

CO 2 Me

Cl H 2 SO 4

N

H N

MeO

Me O

Chem Rev 2006, 106, 3002.

SYNTHESIS OF LYRICA (pregabalin)

Evans diastereoselective alkylation

racemic

Evans diastereoselective alkylation = a very powerfull tool for asymmetric synthesis

O

O N

O

O

O N

O R Li

always Z !

R1X

O

O N

O R

R1

major

NO

O

LiO

O carbonyl more

N

R2

R1 X

The addition of the enolate to the

electrophile occurs on the less sterically

hindered face, that is to say, on the

opposite side to the R 2 group of the chiral

auxiliary.

R1

O N

carbonyl more reactive than a classical amide less reactive center

HN(OMe)Me

R

N(OMe)Me

R1O

Evans, D.A et coll J Am Chem Soc 1982, 104, 1737 and lecture of René Grée

SYNTHESIS OF LYRICA (pregabalin)

SYNTHESIS OF LYRICA (pregabalin)

CO 2 H

1- KOH - H 2 O 2- Ni sponge (H 2 )

CO 2 Et

NH 2

40-45% overall yield after one recycle

*All reaction run in aqueous media

*Ratio of kg waste/kg pregabalin produced

Classical resolution route 86:1Chemoenzymaticroute 17:1

*Solvent use per 1000 kg pregabalin

Classical resolution route 50,042 kgChemoenzymatic route 6230 kg

99.5% purity

99.75% ee

Org Proc Res Dev 2008, 12, 392.

HNO 3

Me O

OMe

SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)

N

H N

MeO

Me O

Prilosec

(omeprazole)

Astra Zeneca (1985)Proton pomp inhibitor used in the treatment of gastricreflux disease

Sales 2007 = $5 billionOff patent in 2014

First synthesis : preparation in racemic form

H N MeO

SH MeO

N

H N MeO

Me mCPBA

H N MeO

Me O

J Med Chem 1992, 35, 1049.

Improvement : omeprazole to esomeprazole

1987 – Prilosec found to display significantly varying efficacy depending on rate of metabolism

of patient

Program launch to find a compound with increased bioavailability that won’t be cleared by theliver so quickly to give “slow metabolizers”a chance

1989-1994 – 30 scientists and several hundred compounds later…four candidates are identified

esomeprazole, the S-enantiomer of omeprazole.

O

O

Ph OH

SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)

N

H N MeO

N

N MeO

Me O

O

1- separation of diastereomers (preparative HPLC)

2- NaOH, MeOH, H 2 O, rt 3- MgCl 2 , H 2 O

N

H N MeO

Me O

esomeprazole omeprazole

Improvement : omeprazole to esomeprazole

SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)

Formation of the sulfoxide by using of the Kagan’s oxidation (Sharpless oxidation modified)

route steps from sulfur manufacture of esomeprazole

(5 kg in plant) medicinal route

new route

SYNTHESIS OF LIPITOR (atorvastatin calcium)

Chiral side chain : 220 ton / year

Cholesterol: a very important biological molecule

-most cholesterol is not dietary, it is synthesizedinternally

-cholesterol is bound to lipoproteins and transportedthrough blood

-2 kinds of lipoproteins:

-high density lipoprotein (HDL): “good”

- low density lipoprotein (LDL): “bad”

atherosclerosis

coronary heart disease & other cardiovascular diseases

One of the leading causes of death in the world today!

SYNTHESIS OF LIPITOR (atorvastatin calcium)

A solution: the suppression of the cholesterol biosynthesis

inhibition

SYNTHESIS OF LIPITOR (atorvastatin calcium)

The story of statins drugs

Potent inhibitors of HMG-CoA reductase

SYNTHESIS OF LIPITOR (atorvastatin calcium)

The synthesis of atorvastatin lactone

F

N

HO 2 C

O O

O Me

Me 1- Et 3 N, CH 2 Cl 2, 0 °C

Cl O Me Me

2- NaOH

Ph

O NHPh

Ac 2 O, 90 °C

Ph CONHPh

N Me Me

O O

F

1- HCl, EtOH, reflux 2- TsOH, acetone-H 2 O

N Me Me

CHO F

OMe

NaH then BuLi, THF N

Me Me F

HO

O

CO 2 Me

N Me Me F

HO

HO

CO 2 Me

1- Bu 3 B, NaBH 4, THF 2- NaOH, H O N

Me Me

110 °C

O

O HO

Ph CONHPh

Me then BuLi, THF

Ph CONHPh

Me

Ph CONHPh

Me 2- NaOH, H 2 O 2 racemic

Ph CONHPh

N Me

Me F

O

O HO

atorvastation lactone

racemic

Ph CONHPh

N Me Me F

HO HO

O H N Ph Me

H 2 N Me Ph

Ph CONHPh

N Me Me F

HO HO

O H N Ph Me

+

Ph CONHPh

N Me Me F

O

Ph CONHPh

N Me Me F

O

1- HPLC separation 2- NaOH 3- H 3 O + 4- Tol, 110 °C

SYNTHESIS OF LIPITOR (atorvastatin calcium)

The enantioselective synthesis of atorvastatin lactone (labor approach)

HO

Bn

Et 3 N

Cl F

Ph

N Me Me F

OEt EtO

1- NBS, DMF 2- nBuLi, THF, PhNCO 3- H 3 O +

Me F

H O

O Ph

Ph

Ph OH

1-Ot-Bu

OLi Me

F

O

O HO

(+)- atorvastatin lactone

Ph

N Me Me F

CONHPh

Ph Ph 2- NaOMe, MeOH, 0 °C Ph

N Me Me F

CONHPh

Ot-Bu

2- Et 3 B, NaBH 4

3- H 2 O 2 , NaOH 4- Tol, 110 °C

Ph CONHPh

N Me Me

F (+)- atorvastatin lactone

Poor potential for kg scale

SYNTHESIS OF LIPITOR (atorvastatin calcium)

The enantioselective synthesis of atorvastatin calcium: the solution

Synthesis of Paal-Knorr precursor 1

Synthesis of Paal-Knorr precursor 2

SYNTHESIS OF LIPITOR (atorvastatin calcium)

The enantioselective synthesis of atorvastatin calcium : the solution (2)

SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

CO2Et O

NH2.H3PO4AcHN

OH HO

AcHN

OH

CO2H OH

sialic acid

(N-acetylneuraminic acid)

towards the drug design

Anti-viral drug to slow the spread of

the Influenza virus

Sales 2009 = 2.7 billion €

Review = Chem Rev 2009, 109, 4398

SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Inhibition of the viral neuraminidase

CO2O AcHN

HO

R1R

Enz

O H

Enz B

B Enz H

O

CO2AcHN

HO R

Enz

O H

Enz B

B Enz H

O

R1

O CO2

HO AcHN R

B Enz

HO R1

Enz

O H

Enz B

sialosyl cation

SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Enzymatic mechanism of the viral neuraminidase

O CO2AcHN

HO R

O Enz

B Enz H

O H

glycosyl-enzyme

Enz B H

O CO2

HO AcHN R

B Enz

Enz

O H

Enz B

H

O H

O

CO2O AcHN

HO

H R

Enz

O H

Enz B

B Enz

H

sialosyl cation

HO OH

OH

R = = virus R1 = O

O HO HO

OH

O HO

OH

OH O

O cell

SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Oseltamivir : structure design

O

OH N

H

O O

HO O

H N

NH2N

H O

OEt O

O

OH O

transition state

estérase

Goal of the design :

establishment of a competitive inhibitor of the sialic acid

preparation of an analogue of the transition state

OH HO

OH

DANA (1974)

HN

Zanamivir (1989)

NH

NH2

H HO

OH

OH AcHN

CO2Et O

NH2.H3PO4AcHN

Oseltamivir Phosphate

SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Oseltamivir phosphate: the first synthesis

CO2H HO

HO

OH

(-) acide shikimique

i) EtOH, SOCl2ii) pentan-3-one, TsOH iii) MsCl, Et3N

KHCO3, EtOH aq O CO2Et NaN3, NH4Cl O CO2Et O CO2Et

SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Oseltamivir phosphate: the Roche synthesis

- 21% overall yield, 10 steps

- industrial synthesis

- minor drawback : the sourcing (shikimic acid)

- major drawback : the use of azide chemistry

10 / 1

97%

PMe3 O CO2Et

HN (74% de pureté)

SYNTHESIS OF GLIVEC (imatinib)

Novartis (2001)Treatment of Chronic Myeloid Leukemia (CML)First protein kinase inhibitor to reach the marketSelective inhibitor forfor aa hybridhybrid tyrosinetyrosine kinasekinase ((BcrBcr AblAbl))Sales 2007 = $3 billion

Off patent in 2015

Cancer Res.2002, 62, 4236.

SYNTHESIS OF GLIVEC (imatinib)

The clinical development was particularly rapid, ascan be seen by comparison with the typical drugdiscovery and development times

SYNTHESIS OF GLIVEC (imatinib)

Glivec : structure design

The phenylaminopyrimidine structure identified

- as Protein Kinase C (a serine-theonine kinase) inhibitor,

- by random screening of compound libraries N

N

N H N N

HN O

inhibition of PKC inhibits Tyrosine Kinase

(IC 50 = 50 µµµµM) Conformational

Nature Review Drug Discovery.2002, 1, 493.

CH 3

N

N H N N

CH 3

N N

-increase activity vs tyrosine kinases

-no activity against threonine kinases

serine spacer inserted to avoid aniline structure -piperazine increases activity, selectivity and water solubility

SYNTHESIS OF GLIVEC (imatinib)

Glivec : Zimmermann’s route (1993)

Glivec : Loiseleur’s route (2003) – use cross-coupling reaction

SYNTHESIS OF GLIVEC (imatinib)

imatinib base

Buchwald-Hartwig cross-coupling reaction