MASTER 2

Molecular Chemistry – Medicinal Chemistry

Université de Rennes 1 – Vietnam National University, Hanoi

SYNTHESIS OF
COMMERCIAL DRUGS
Me CO2Me
N
O CO2Et N
H
N N S
N Cl
AcHN .H2SO4
N
NH2.H3PO4
HN
NH2 H
N O .CH3SO3H N O
O S N
MeO N Me
OH
Me OMe
Prof. Pierre van de Weghe
2011-2012
e-mail : pierre.van-de-weghe@univ-rennes1.fr
 INTRODUCTION

Chem. Rev. 2006, 106, 3002.

2
 SYNTHESIS OF LYRICA (pregabalin)

Evans diastereoselective alkylation

racemic

3
Evans diastereoselective alkylation = a very powerfull tool for asymmetric synthesis

Li
O O O O O O
R
LDA
R R1X R
O N O N O N
R1

always Z ! major

Cleavage of the chiral auxiliary

O Li O O O
carbonyl more R
O N 2 R N O
reactive than a less reactive center
R classical amide
1
R
R1 X

The addition of the enolate to the LiBH4 ou LAH R

OH
electrophile occurs on the less sterically 1
hindered face, that is to say, on the R
opposite side to the R2 group of the chiral O
LiOOH R
auxiliary. OH
1
R
O
HN(OMe)Me
R
N(OMe)Me
R1
Evans, D.A. et coll. J. Am. Chem. Soc. 1982, 104, 1737 and lecture of René Grée
SYNTHESIS OF LYRICA (pregabalin)

4
 SYNTHESIS OF LYRICA (pregabalin)

Manufacture route

CO2Et CO2Et
n-Pr2NH KCN
CHO CO2Et CO2Et
AcOH EtOH
CN recycling
EtO2C CO2Et
NaOEt, Tol
Lipolase (8 mol%) 110 °C
pH 7.0 (racemization)
150 nM Ca(OAc)2
3 M in substrate

CO2Et CO2Et CO2 Et

1- KOH - H2O reflux
CO2H CO2Na CO2Et
2- Ni sponge (H2) 80 - 85 °C
CN CN CN
NH2 >99% ee 85-90% ee
not isolated
99.5% purity
99.75% ee 40-45% overall yield after one recycle
*All reaction run in aqueous media
*Ratio of kg waste/kg pregabalin produced
Classical resolution route 86:1
Chemoenzymaticroute 17:1
*Solvent use per 1000 kg pregabalin
Classical resolution route 50,042 kg
Org. Proc. Res. Dev. 2008, 12, 392.
Chemoenzymatic route 6230 kg
5
 SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)

H
N O Astra Zeneca (1985)
S N Proton pomp inhibitor used in the treatment of gastric
MeO N Me reflux disease
Sales 2007 = $5 billion
Prilosec Me OMe
(omeprazole) Off patent in 2014

First synthesis : preparation in racemic form

NO2 OMe
Me Me Me Me HNO3 Me Me Na / MeOH Me Me

N 2 steps N Me CH2Cl2 N Me reflux N Me

O O O

Ac2O, 100 °C

S OMe OMe
H
NH2 N Me Me SOCl2 Me Me
EtO SK
SH
N base OH
MeO NH2 MeO N N
Cl

NaOH, EtOH, H2O

reflux, 2 h, 70%
H H
N N O
S N mCPBA S N
MeO N Me MeO N Me
CHCl3
J. Med. Chem. 1992, 35, 1049.
Me OMe racemic Me OMe 6
 SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)

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 the
liver so quickly to give “slow metabolizers”a chance
1989-1994 – 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. OH
O
Ph
O
H
N O 1- HCHO N O
S N 2- SOCl2 S N
MeO N Me MeO N Me
3- (R)-mandelic acid
omeprazole Me OMe NaOH, Bu4NHSO4 38% Me OMe
CHCl3, H2O, reflux
1- separation of diastereomers
(preparative HPLC)
2- NaOH, MeOH, H2O, rt
3- MgCl2, H2O
H
N O
S N
MeO N Me
esomeprazole
Me OMe

7
 SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)

Improvement : omeprazole to 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 6 14 weeks
new route 1 2 weeks

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SYNTHESIS OF LIPITOR (atorvastatin calcium)

Chiral side chain : 220 ton / year

Cholesterol: a very important biological molecule

-most cholesterol is not dietary, it is synthesized
internally.
-cholesterol is bound to lipoproteins and transported
through 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!

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 SYNTHESIS OF LIPITOR (atorvastatin calcium)

A solution: the suppression of the cholesterol biosynthesis

inhibition

10
 SYNTHESIS OF LIPITOR (atorvastatin calcium)

The story of statins drugs

Potent inhibitors of HMG-CoA reductase

11
 SYNTHESIS OF LIPITOR (atorvastatin calcium)

The synthesis of atorvastatin lactone

Me O O
O O Cl O O
Me NHPh
O
F F O F Ph F Me
H2 N O 1- Et3N, CH2Cl2, 0 °C Me N
O
Br NH N Me
Et3 N, CH3CN, rt 2- NaOH Me Ac2 O, 90 °C
CO2Et CO2Et HO2C O Ph CONHPh

1- HCl, EtOH, reflux

HO O HO O
CO2Me CO2Me 2- TsOH, acetone-H2O
O HO HO
O O CHO
1- Bu3B, NaBH4, OMe
F Me F Me THF F Me F Me
N Tol N N NaH N
Me 110 °C Me 2- NaOH, H2O2 Me then BuLi, THF Me

Ph CONHPh Ph CONHPh Ph CONHPh Ph CONHPh

atorvastation lactone racemic
racemic
IC50 = 0.025 mM
Separation of enantiomers
(resolution via diastereomeric esters synthesis)
H H
O N Ph O N Ph

HO O HO Me HO Me HO O HO O

O HO HO O O
Ph
F Me H2N Me F Me F Me 1- HPLC separation F Me F Me
N N N N N
+ +
Me Me Me 2- NaOH Me Me
3- H3 O+
Ph CONHPh Ph CONHPh Ph CONHPh Ph CONHPh Ph CONHPh
4- Tol, 110 °C
atorvastation lactone (+)- atorvastatin lactone (-)- atorvastatin lactone
racemic IC50 = 0.007 µM IC50 = 0.44 µM
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 SYNTHESIS OF LIPITOR (atorvastatin calcium)

The enantioselective synthesis of atorvastatin lactone (labor approach)

Bn EtO OEt
Me N Cl
OEt
NaOH, F Me
F S F CH3OH F H2N OEt N
CO2Me HO Ph O Ph O
+ Me
i-Pr Et3 N TsOH, Tol
CHO i-Pr i-Pr
O O CO2Me O Ph
1- NBS, DMF
2- nBuLi, THF, PhNCO
HO O 3- H3O+
Ph 1- LDA, MgBr2, -78 °C
OH
O HO O O Ph O H
Ph
OLi OH
O Ph Me O
F Me 1- F Me F Me
(+)- atorvastatin lactone Ot-Bu Ph Ph
N N N
(> 99% ee)
Me 2- Et3B, NaBH4 Me 2- NaOMe, MeOH, 0 °C Me
3- H2O2 , NaOH
Ph CONHPh Ph CONHPh Ph CONHPh
4- Tol, 110 °C

12 linear steps
3 columns and 1 recrystallization
Low temperature steps
Low yields
Low yielding final purification

Poor potential for kg scale

13
 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

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 SYNTHESIS OF LIPITOR (atorvastatin calcium)

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

15
 SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

O CO2Et
structure of neuraminidase with
its substrat, the sialic acid
AcHN
NH2.H3PO4

Osetalmivir Phosphate
Tamiflu

Roche (1995)
Anti-viral drug to slow the spread of
the Influenza virus
Sales 2009 = 2.7 billion €
HO
H
Review = Chem. Rev. 2009, 109, 4398 O
OH
HO CO2H
OH
AcHN
OH
sialic acid
(N-acetylneuraminic acid)

towards the drug design

16
 SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Inhibition of the viral neuraminidase

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 SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Enzymatic mechanism of the viral neuraminidase

Enz Enz Enz

Enz B Enz Enz
B B
H H H
O O O
CO2
R R O
O O R1 CO2 O CO2
AcHN AcHN R
HO HO O AcHN
R1 HO HO R1
H H
B B sialosyl cation B
Enz Enz Enz

Enz Enz
Enz B Enz B
Enz Enz
B H H
H O O
O CO2
R O CO2 R
O CO2 R O O H
AcHN AcHN
AcHN
HO HO
O H HO O H H
H H B B
glycosyl-enzyme B sialosyl cation Enz
Enz
Enz
HO
OH HO cell
OO
R = HO = virus R1 = HO O OH
O
OH O
OH
OH
18
 SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Oseltamivir : structure design

Goal of the design :

establishment of a competitive inhibitor of the sialic acid

preparation of an analogue of the transition state
O
Asp151 transition state
O
O HO O
OH NH2 estérase
N O H2N H OEt OH
H N N
O O H2N Arg371 H O O
O
HO OH
O Oseltamivir
O

Glu277 O Tyr406

HO HO OH
H H H
O CO2H O CO2H O CO2H
HO HO HO
OH OH OH
H2N H2N AcHN
NH2 OH HN NH2
(1969) DANA Zanamivir NH
(1974) (1989)

O CO2Et

AcHN
NH2.H3PO4

Oseltamivir Phosphate
(1995) 19
 SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Oseltamivir phosphate: the first synthesis

20
 SYNTHESIS OF TAMIFLU (oseltamivir phosphate)

Oseltamivir phosphate: the Roche synthesis

i) EtOH, SOCl2 TMSOTf

HO CO2H O CO2Et O CO2 Et
ii) pentan-3-one, TsOH BH3.Me2 S

HO iii) MsCl, Et3N O 63-75% HO

OH 80% OMs OMs
(-) acide shikimique

O CO2Et O CO2Et O CO2Et

KHCO3, EtOH aq NaN3, NH4Cl

96% EtOH aq HO N3
O
N3 10 / 1 OH

PMe3 O CO2Et i) NaN3, NH4Cl, DMF O CO2Et i) H2, Ra-Ni, ,EtOH O CO2Et

97% ii) Ac2 O AcHN ii) H3PO4 AcHN

HN
N3 71-75% NH2.H3 PO4
(74% de pureté)

- 21% overall yield, 10 steps

- industrial synthesis
- minor drawback : the sourcing (shikimic acid)
- major drawback : the use of azide chemistry
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 SYNTHESIS OF GLIVEC (imatinib)

Novartis (2001)
Treatment of Chronic Myeloid Leukemia (CML)
First protein kinase inhibitor to reach the market
Selective inhibitor for a hybrid tyrosine kinase (Bcr
Bcr--Abl)
Abl)
Sales 2007 = $3 billion
Off patent in 2015

Cancer Res.2002, 62, 4236.

22
SYNTHESIS OF GLIVEC (imatinib)

The clinical development was particularly rapid, as

can be seen by comparison with the typical drug
discovery and development times

23
 SYNTHESIS OF GLIVEC (imatinib)

Glivec : structure design

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

N N
H H H
N N N N N N

N N N

inhibition of PKC inhibits Tyrosine Kinase HN O

(IC 50 = 50 µM)
Conformational
blocker
N N N
CH3 CH3
H H H
N N N N N N

N N N

HN O HN O HN O
IC 50 = 50 µM IC 50 = 0.1 µM Imatinib
(Glivec)
-spacer inserted to
-increase activity vs tyrosine avoid aniline structure
kinases N -piperazine increases
-no activity against serine- activity, selectivity
N
threonine kinases H3C and water solubility

Nature Review Drug Discovery.2002, 1, 493.

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 SYNTHESIS OF GLIVEC (imatinib)

Glivec : Zimmermann’s route (1993)

25
 SYNTHESIS OF GLIVEC (imatinib)

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

imatinib base

Buchwald-Hartwig cross-coupling reaction

26