SYNTHESIS OF COMMERCIAL DRUGS - Service central d...

MASTER 2

Molecular Chemistry – Medicinal Chemistry

Université de Rennes 1 – Vietnam National University, Hanoi

SYNTHESIS OF

COMMERCIAL DRUGSCOMMERCIAL DRUGS

Prof. Pierre van de Weghee-mail : [email protected] 2011-2012

CO2EtO

NH2.H3PO4

AcHN

N

N

NHN

HN

O

N

NMe

.CH3SO3H

OH

ONH2

N

S

CO2Me

Cl.H2SO4

N

HN

S NMeO

Me OMe

Me

O

INTRODUCTION

2

Chem. Rev. 2006, 106, 3002.

SYNTHESIS OF LYRICA (pregabalin)

Evans diastereoselective alkylation

3

racemic

Evans diastereoselective alkylation = a very powerful l tool for asymmetric synthesis

O

O

N

OR LDA

O

O

N

OR

Li

always Z !

R1XO

O

N

OR

R1

major

NO

OLiO

R

Cleavage of the chiral auxiliary

RO

ON

O

carbonyl moreNO RR2

R1 X

The addition of the enolate to theelectrophile occurs on the less stericallyhindered face, that is to say, on theopposite side to the R2 group of the chiralauxiliary.

R1ONcarbonyl more

reactive than aclassical amide

less reactive center

LiBH4 ou LAH ROH

R1

LiOOH ROH

R1

O

HN(OMe)MeR

N(OMe)MeR1

O

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


4


Manufacture route

CHO

EtO2C CO2Et

n-Pr2NH

AcOHCO2Et

CO2EtKCN

EtOHCO2Et

CO2Et

CN

Lipolase (8 mol%)pH 7.0150 nM Ca(OAc) 2

3 M in substrate

CO EtCO Et

recycling

NaOEt, Tol110 °C(racemization)

CO Et

5

CO2Et

CO2Et

CNCO2Na

CO2Et

CN>99% ee 85-90% ee

not isolated

reflux

80 - 85 °CCNCO2H

1- KOH - H2O

2- Ni sponge (H 2)

CO2Et

NH2

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 pregabalinClassical resolution route 50,042 kgChemoenzymatic route 6230 kg

99.5% purity99.75% ee

Org. Proc. Res. Dev. 2008, 12, 392.

N

Me Me

2 steps N

Me Me

MeO

HNO3

CH2Cl2 N

Me Me

MeO

NO2

Na / MeOH

reflux N

Me Me

MeO

OMe

SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)

N

HN

S NMeO

Me OMe

Me

O

Prilosec(omeprazole)

Astra Zeneca (1985)Proton pomp inhibitor used in the treatment of gastricreflux diseaseSales 2007 = $5 billionOff patent in 2014

First synthesis : preparation in racemic form

O O O

Ac2O, 100 °C

N

Me MeOMe

OH

SOCl2

N

Me MeOMe

Cl

baseN

HN

MeOSH

MeO

NH2

NH2

EtO SK

S

NaOH, EtOH, H2O

reflux, 2 h, 70%

N

HN

MeOS N

Me OMe

MemCPBA

CHCl3N

HN

MeOS N

Me OMe

Me

O

racemic 6

J. Med. Chem. 1992, 35, 1049.

Improvement : omeprazole to esomeprazole

1987 – Prilosec found to display significantly varying efficacy depending on rate of metabolismof patient.Program launch to find a compound with increased bioavailability that won’t be cleared by theliver so quickly to give “slow metabolizers”a chance1989-1994 – 30 scientists and several hundred compounds later…four candidates are identified

Only one compound survives pharmacokinetics, efficacy and safety assessments…esomeprazole, the S-enantiomer of omeprazole.

O

O

Ph

OH


7

N

HN

MeOS N

Me OMe

Me

O 1- HCHO

2- SOCl2

3- (R)-mandelic acidNaOH, Bu4NHSO4CHCl3, H2O, reflux

38%

N

N

MeOS N

Me OMe

Me

O

O

1- separation of diastereomers(preparative HPLC)2- NaOH, MeOH, H2O, rt3- MgCl2, H2O

N

HN

MeOS N

Me OMe

Me

O

esomeprazole

omeprazole

Improvement : omeprazole to esomeprazole


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

8

route steps from sulfur manufacture of esomeprazole(5 kg in plant)

medicinal route

new route

6 14 weeks

1 2 weeks

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.internally.-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!9


A solution: the suppression of the cholesterol biosynthesis

inhibition

10


The story of statins drugs

Potent inhibitors of HMG-CoA reductase

11


The synthesis of atorvastatin lactone

F

Br

CO2Et

H2N O

O

Et3N, CH3CN, rt

F

NH

CO2Et

OO

F

N

HO2C

OO

OMe

Me1- Et3N, CH2Cl2, 0 °C

Cl

OMe

Me

2- NaOH

PhO

NHPh

Ac2O, 90 °CPh CONHPh

NMe

Me

OO

F

1- HCl, EtOH, reflux

2- TsOH, acetone-H 2O

NMe

Me

CHO

FOMe

O O

NaH

then BuLi, THF

NMe

Me

F

HO

OCO2Me

NMe

Me

F

HO

HOCO2Me

1- Bu3B, NaBH4,THF

2- NaOH, H O

NMe

Me

F Tol

110 °C

O

OHO

Ph CONHPh

Methen BuLi, THF

Ph CONHPh

Me

Ph CONHPh

Me 2- NaOH, H2O2

racemic

Ph CONHPh

Me 110 °C

atorvastation lactoneracemic

IC50 = 0.025 mMSeparation of enantiomers

(resolution via diastereomeric esters synthesis)

Ph CONHPh

NMe

Me

F

O

OHO

atorvastation lactoneracemic

Ph CONHPh

NMe

Me

F

HO

HO

OHN Ph

Me

H2N Me

Ph

Ph CONHPh

NMe

Me

F

HO

HO

OHN Ph

Me

+

Ph CONHPh

NMe

Me

F

O

Ph CONHPh

NMe

Me

F

O

1- HPLC separation

2- NaOH3- H3O+

4- Tol, 110 °C

+

O OHOHO

(+)- atorvastatin lactoneIC50 = 0.007 µµµµM

(-)- atorvastatin lactoneIC50 = 0.44 µµµµM

12


The enantioselective synthesis of atorvastatin lactone (labor approach)

F

CHO

CO2Mei-Pr

O

+S

NMe

HO

Bn

Et3N

Cl

F

O

Ph

CO2Mei-Pr

OF

O

Ph

i-Pr

ONaOH,CH3OH H2N

OEt

OEt

TsOH, TolPh

NMe

Me

F

OEtEtO

1- NBS, DMF2- nBuLi, THF, PhNC O3- H3O+

MeF

HO

Me O

O PhOH

Ph Ph

1- LDA, MgBr 2, -78 °C

MeF

HO O

O PhPh

PhOH

1- Ot-Bu

OLi

MeF

O

OHO

(+)- atorvastatin lactone

13

Ph

NMe

Me

F

CONHPh

Ph Ph

2- NaOMe, MeOH, 0 °C

Ph

NMe

Me

F

CONHPh

Ot-Bu

2- Et3B, NaBH4

3- H2O2, NaOH4- Tol, 110 °C

Ph CONHPh

NMe

Me

F(+)- atorvastatin lactone(> 99% ee)

12 linear steps3 columns and 1 recrystallizationLow temperature stepsLow yieldsLow yielding final purification

Poor potential for kg scale


The enantioselective synthesis of atorvastatin calcium: the solution

Synthesis of Paal-Knorr precursor 1

Synthesis of Paal-Knorr precursor 2

14


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

15

SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

CO2EtO

NH2.H3PO4

AcHN

Osetalmivir Phosphate

Tamiflu

structure of neuraminidase withits substrat, the sialic acid

Roche (1995)

Anti-viral drug to slow the spread of

16

OH

HOOH

HO

AcHNOH

CO2HOH

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


Inhibition of the viral neuraminidase

17

O

CO2

OAcHN

HO

R1R

Enz

OH

EnzB

BEnz

H

OCO2AcHN

HO

R

Enz

OH

EnzB

BEnz

H

OR1

O CO2

HOAcHN

R

BEnz

HO R1

Enz

OH

EnzB

sialosyl cation


Enzymatic mechanism of the viral neuraminidase

O CO2AcHNHO

R

O

Enz

BEnz

HO H

glycosyl-enzyme

EnzB

H

O CO2

HOAcHN

R

BEnz

Enz

OH

EnzB

HO H

O

CO2

OAcHN

HO

HR

Enz

OH

EnzB

BEnz

H

sialosyl cation

HOOH

OH

R = = virus R1 = O

O

HO

HO

OH

OHO

OH

OHO

O cell

18


Oseltamivir : structure design

O

OHNH

O

O

HOO

HN

H2NH2N

Arg371

Asp151

O

O

NH2NH O

OEt

O

O

OHO

transition state

estérase

Goal of the design :

� establishment of a competitive inhibitor of the sialic acid

� preparation of an analogue of the transition state

O

HO OH

O

O

Glu277 O

O

Tyr406

H2N Arg371H O

O

Oseltamivir

O

OH

HO

OH

HO

H2NNH2

(1969)

CO2H OH

HO

OH

HO

H2NOH

DANA(1974)

CO2H O CO2H

HN

Zanamivir

(1989)NH

NH2

HHO

OH

OHAcHN

CO2EtO

NH2.H3PO4

AcHN

Oseltamivir Phosphate

(1995) 19


Oseltamivir phosphate: the first synthesis

20

CO2HHO

HOOH

(-) acide shikimique

i) EtOH, SOCl2

ii) pentan-3-one, TsOH

iii) MsCl, Et3N

80%

CO2Et

OMs

O

O 63-75%

TMSOTf

BH3.Me2SCO2Et

OMs

O

HO

KHCO3, EtOH aq CO2EtO NaN3, NH4Cl CO2EtO CO2EtO


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

96%O

EtOH aq HON3

N3

OH10 / 1

97%

PMe3 CO2EtO

HN

(74% de pureté)

ii) Ac2O

i) NaN3, NH4Cl, DMF CO2EtO

AcHNN3

ii) H3PO4

i) H2, Ra-Ni, ,EtOH CO2EtO

AcHNNH2.H3PO471-75%

21

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 billionOff patent in 2015

22

Cancer Res.2002, 62, 4236.


23

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


Glivec : structure designThe phenylaminopyrimidine structure identified

- as Protein Kinase C (a serine-theonine kinase) inhibitor,- by random screening of compound libraries. N

NHN

N

NHN

N

NHN

N

N

NHN

N

HN Oinhibition of PKC inhibits Tyrosine Kinase

(IC 50 = 50 µµµµM)

Conformational

24

Nature Review Drug Discovery.2002, 1, 493.

N

NHN

N

HN O

N

NHN

N

HN O

CH3

N

NHN

N

HN O

CH3

NN

H3C

IC 50 = 0.1 µµµµMIC 50 = 50 µµµµM Imatinib(Glivec)

Conformationalblocker

-increase activity vs tyrosinekinases-no activity against serine-threonine kinases

-spacer inserted toavoid aniline structure-piperazine increasesactivity, selectivityand water solubility


Glivec : Zimmermann’s route (1993)

25

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


26

imatinib base

Buchwald-Hartwig cross-coupling reaction

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