synthesis of commercial drugs 2011 - 12

MASTER 2
Molecular Chemistry – Medicinal Chemistry
Université de Rennes 1 – Vietnam National University, Hanoi
SYNTHESIS OF
COMMERCIAL DRUGS
COMMERCIAL DRUGS
Prof. Pierre van de Weghe
e-mail :
2011-2012
CO
2
EtO
N
H
2
.
H
3
P
O
4
AcHN
N
N
N
H
N
HN
O
N
N

M
e
.CH
3
SO
3
H
O
H
O
N
H
2
N
S
C
O
2
M
e
Cl
.
H
2
S
O
4
N
H
N

S N
MeO
M
e
O
M
e
Me
O
INTRODUCTION
2
Chem. Rev.
2006,
106
, 3002.
SYNTHESIS OF LYRICA (pregabalin)
Evans diastereoselective alkylation
3
racemic
Evans diastereoselective alkylation = a very powerfull tool for asymmetric synthesis
O
O
N
O
R
LDA
O
O
N
O

R
L
i
always Z !
R
1
X
O
O
N
O
R
R
1
major
N
O
O
Li
O
R
Cleavage of the chiral auxiliary
R
O
O
N
O
c
a
r

b
o
n
y
l
m
o
r
e
N
O
R
R
2
R
1
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.
R
1
O
N
c
a

r
b
o
n
y
l
m
o
r
e
reactive than a
classical amide
less reactive center
LiBH
4
ou LAH
R
OH
R
1
LiOOH
R
OH
R
1
O
HN(OMe)Me
R
N(OMe)M
e

R
1
O
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
CHO
EtO
2
C CO
2
Et
n-Pr
2
NH
AcOH
CO
2
Et
C
O
2
E
t
KCN
EtOH
CO
2

Et
C
O
2
E
t
CN
Lipolase (8 mol%)
pH 7.0
150 nM Ca(OAc)
2
3 M in substrate
C
O
E
t
C
O
E
t
recycling
NaOEt, Tol
110 °C
(racemization
)
C
O
E
t
5

CO
2
Et
C
O
2
E
t
CN
CO
2
Na
C
O
2
E
t
CN
>99% ee 85-90% ee
not isolated
reflux
80 - 85 °C
CN
CO
2
H
1- KOH - H
2
O
2- Ni sponge (H

2
)
C
O
2
E
t
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 86:1
Chemoenzymaticroute 17:1
*Solvent use per 1000 kg pregabalin
Classical resolution route 50,042 kg
Chemoenzymatic route 6230 kg
99.5% purity
99.75% ee
Org. Proc. Res. Dev.
2008,
12
, 392.
N
Me Me
2 steps
N
Me Me
Me
O

HNO
3
CH
2
Cl
2
N
Me Me
Me
O
N
O
2
Na / MeOH
reflux
N
Me Me
Me
O
O
M
e
SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)
N
H
N
S N
MeO
Me OMe
Me

O
Prilosec
(omeprazole)
Astra Zeneca (1985)
Proton pomp inhibitor used in the treatment of gastric
reflux disease
Sales 2007 = $5 billion
Off patent in 2014
First synthesis : preparation in racemic form
O
O
O
Ac
2
O, 100 °C
N
Me Me
OMe
OH
SOCl
2
N
Me Me
OMe
Cl
base
N
H
N
MeO

SH
MeO
NH
2
NH
2
EtO SK
S
NaOH, EtOH, H
2
O
reflux, 2 h, 70%
N
H
N
MeO
S N
M
e
O
M
e
Me
mCPBA
CHCl
3
N
H
N
MeO

S N
M
e
O
M
e
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 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.
O
O
Ph
O
H
SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)
7

N
H
N
MeO
S N
Me OMe
Me
O
1- HCHO
2- SOCl
2
3- (R)-mandelic acid
NaOH, Bu
4
NHSO
4
CHCl
3
, H
2
O, reflux
38%
N
N
MeO
S N
Me OMe
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
S N
M
e
O
M
e
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)
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 synthesized
internally
.
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!
9
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
F
Br
CO
2
Et
H
2
N
O
O
Et
3
N, CH
3
CN, rt
F
NH
CO
2
Et
OO
F
N
HO
2
C
OO
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
OO
F
1- HCl, EtOH, reflux
2- TsOH, acetone-H
2
O
N

Me
M
e
CHO
F
OMe
O O
NaH
t
h
e
n

B
u
L
i
,

T
H
F
N
Me
M
e
F
HO
O
CO

2
Me
N
Me
M
e
F
HO
HO
CO
2
Me
1- Bu
3
B, NaBH
4,
THF
2
-

N
a
O
H
,

H
O
N
Me

M
e
F
Tol
1
1
0

°
C
O
OHO
Ph CONHPh
M
e
t
h
e
n

B
u
L
i
,

T
H
F
Ph CONHPh

M
e
Ph CONHPh
M
e
2
-

N
a
O
H
,

H
2
O
2
racemic
Ph CONHPh
M
e
1
1
0

°
C
atorvastation lactone
racemic

IC
5
0
= 0.025 mM
Separation of enantiomers
(resolution via diastereomeric esters synthesis)
Ph CONHPh
N
Me
Me
F
O
OHO
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
+
O OHOHO
(+)- atorvastatin lactone
IC
5
0
= 0.007 µ
µµ
µM
(-)- atorvastatin lactone
IC
5
0
= 0.44 µ
µµ
µM
12
SYNTHESIS OF LIPITOR (atorvastatin calcium)
The enantioselective synthesis of atorvastatin lactone (labor approach)
F
CHO
CO
2
Me
i-Pr
O
+
S
N

Me
HO
Bn
Et
3
N
Cl
F
O
Ph
CO
2
Me
i-Pr
O
F
O
Ph
i-Pr
O
NaOH,
CH
3
OH H
2
N
OEt
OEt
TsOH, Tol
Ph

N
Me
Me
F
O
E
t
E
t
O
1- NBS, DMF
2- nBuLi, THF, PhNC
O
3- H
3
O
+
M
e
F
HO
Me O
O Ph
OH
P
h
P
h
1- LDA, MgBr
2

, -78 °C
M
e
F
HO O
O Ph
Ph
Ph
OH
1-
O
t
-
B
u
OLi
M
e
F
O
OHO
(
+
)
-

a
t
o
r

v
a
s
t
a
t
i
n

l
a
c
t
o
n
e
13
Ph
N
M
e
Me
F
CONHPh
P
h
P
h
2- NaOMe, MeOH, 0 °C
Ph

N
M
e
Me
F
CONHPh
O
t
-
B
u
2- Et
3
B, NaBH
4
3- H
2
O
2
, NaOH
4
-

T
o
l
,

1
1

0

°
C
Ph CONHPh
N
M
e
Me
F
(
+
)
-

a
t
o
r
v
a
s
t
a
t
i
n

l
a

c
t
o
n
e
(> 99% ee)
12 linear steps
3 columns and 1 recrystallization
Low temperature steps
Low yields
Low yielding final purification
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
14
SYNTHESIS OF LIPITOR (atorvastatin calcium)
The enantioselective synthesis of atorvastatin calcium : the solution (2)
15
SYNTHESIS OF TAMIFLU (oseltamivir phosphate)
CO
2
EtO
NH
2
.H
3
PO
4

AcHN
Osetalmivir Phosphate
T
a
m
i
f
l
u
structure of neuraminidase with
its substrat, the sialic acid
Roche (1995)
Anti
-
viral
drug
to
slow
the
spread
of
16
O
H
HO
OH
H
O
AcHN
OH

CO
2
H
OH
sialic acid
(
N
-
a
c
e
t
y
l
n
e
u
r
a
m
i
n
i
c

a
c
i
d
)

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
17
O
CO
2
O
AcHN
HO
R
1
R
Enz

O
H
E
n
z
B
B
Enz
H
O
CO
2
AcHN
HO
R
Enz
O
H
E
n
z
B
B
Enz
H
O
R
1
O CO
2

HO
AcHN
R
B
Enz
HO R
1
Enz
O
H
E
n
z
B
sialosyl cation
SYNTHESIS OF TAMIFLU (oseltamivir phosphate)
Enzymatic mechanism of the viral neuraminidase
O
CO
2
AcHN
HO
R
O
Enz
B
E
n
z
H

O H
glycosyl-enzyme
Enz
B
H
O CO
2
HO
AcHN
R
B
Enz
Enz
O
H
E
n
z
B
H
O H
O
CO
2
O
AcHN
HO
H
R
Enz

O
H
E
n
z
B
B
Enz
H
sialosyl cation
HO
OH
OH
R =
= virus
R
1
=
O
O
HO
HO
O
H
O
HO
OH
OH
O
O

cell
18
SYNTHESIS OF TAMIFLU (oseltamivir phosphate)
Oseltamivir : structure design
O
OH
N
H
O
O
HO
O
H
N
H
2
N
H
2
N
A
r
g
3
7
1
A
sp
151
O

O
NH
2
N
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
O
HO
OH
O
O
Glu
277
O
O
Tyr
4
0
6
H

2
N
A
r
g
3
7
1
H
O
O
Oseltamivir
O
O
H
HO
OH
H
O
H
2
N
NH
2
(
1
9
6
9
)

CO
2
H
O
H
HO
OH
H
O
H
2
N
OH
DANA
(1974)
CO
2
H
O CO
2
H
HN
Zanamivir
(
1
9
8
9
)
NH

NH
2
H
HO
O
H
OH
AcHN
CO
2
EtO
NH
2
.H
3
PO
4
AcHN
Oseltamivir Phosphate
(
1
9
9
5
)
19
SYNTHESIS OF TAMIFLU (oseltamivir phosphate)
Oseltamivir phosphate: the first synthesis
20
CO

2
HHO
HO
OH
(-) acide shikimique
i) EtOH, SOCl
2
ii) pentan-3-one, TsOH
iii) MsCl, Et
3
N
80%
CO
2
Et
OMs
O
O
63-75%
TMSOTf
BH
3
.Me
2
S
CO
2
Et
OMs
O

HO
KHCO
3
, EtOH aq
CO
2
EtO
NaN
3
, NH
4
Cl
CO
2
EtO CO
2
EtO
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
96%
O
EtOH aq
HO
N
3
N

3
OH
10 / 1
97%
PMe
3
CO
2
EtO
HN
(74% de pureté)
ii) Ac
2
O
i) NaN
3,
NH
4
Cl, DMF
CO
2
EtO
AcHN
N
3
ii) H
3
PO
4
i) H

2,
Ra-Ni, ,EtOH
CO
2
EtO
AcHN
NH
2
.H
3
PO
4
71-75%
21
SYNTHESIS OF GLIVEC (imatinib)
Novartis (2001)
Treatment of Chronic Myeloid Leukemia (CML)
First protein kinase inhibitor to reach the market
Selective inhibitor forfor aa hybridhybrid tyrosinetyrosine kinasekinase ((BcrBcr AblAbl))
Sales 2007 = $3 billion
Off patent in 2015
22
Cancer Res.2002, 62, 4236.
SYNTHESIS OF GLIVEC (imatinib)
23
The clinical development was particularly rapid, as
can be seen by comparison with the typical drug
discovery 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
H
N
N
N
H
N
N
N
H
N
N
N
N
H
N
N
HN O
inhibition of PKC inhibits Tyrosine Kinase
(IC 50 = 50 µ
µµ
µM)
Conformational
24
Nature Review Drug Discovery.2002, 1, 493.
N

N
H
N
N
HN O
N
N
H
N
N
HN O
CH
3
N
N
H
N
N
HN O
CH
3
N
N
H
3
C
IC 50 = 0.1 µ
µµ
µMIC 50 = 50 µ
µµ

µM Imatinib
(Glivec)
Conformational
blocker
-increase activity
vs
tyrosine
kinases
-no activity against serine-
threonine kinases
-spacer inserted to
avoid aniline structure
-piperazine increases
activity, selectivity
and water solubility