The synthesis of atorvastatin lactone

Transcription

MASTER 2
Molecular Chemistry – Medicinal Chemistry
Université de Rennes 1 – Vietnam National University, Hanoi
SYNTHESIS OF
COMMERCIAL DRUGS
Me
N
O
H
N
N
CO2Me
N
CO2Et
S
N
Cl
AcHN
N
.H2SO4
NH2.H3PO4
HN
N
O
.CH3SO3H
H
N
NH2
O
OH
Prof. Pierre van de Weghe
e-mail : [email protected]
MeO
O
S
N
N
Me
Me
OMe
2011-2012
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
O
O
O
O
R
N
Li
LDA
O
N
O
O
R
O
R1X
O
R
N
R1
always Z !
O Li O
O
N 2
R
major
Cleavage of the chiral auxiliary
O
O
R
R1 X
carbonyl more
reactive than a
classical amide
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 R2 group of the chiral
auxiliary.
R
N
1
R
O
less reactive center
LiBH4 ou LAH
R
OH
1
R
O
LiOOH
R
OH
1
R
HN(OMe)Me
Evans, D.A. et coll. J. Am. Chem. Soc. 1982, 104, 1737 and lecture of René Grée
O
R
N(OMe)Me
R1
4
Manufacture route
n-Pr2NH
CHO
EtO2C
CO2Et
AcOH
KCN
CO2Et
EtOH
CO2Et
CO2Et
CO2Et
recycling
CN
NaOEt, Tol
110 °C
(racemization)
Lipolase (8 mol%)
pH 7.0
150 nM Ca(OAc)2
3 M in substrate
CO2H
NH2
99.5% purity
99.75% ee
Org. Proc. Res. Dev. 2008, 12, 392.
1- KOH - H2O
2- Ni sponge (H2)
CO2Et
reflux
CN
80 - 85 °C
CO2Et
CO2 Et
CO2Na
CN
>99% ee
not isolated
CO2Et
CN
85-90% 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
Chemoenzymatic route 6230 kg
5
SYNTHESIS OF PRILOSEC-NEXIUM (omeprazole-esomeprazole)
H
N
O
S
N
N
MeO
Astra Zeneca (1985)
Proton pomp inhibitor used in the treatment of gastric
reflux disease
Sales 2007 = $5 billion
Off patent in 2014
Me
Prilosec
(omeprazole)
Me
OMe
First synthesis : preparation in racemic form
NO2
Me
Me
N
Me
2 steps
N
O
Me
HNO3
Me
CH2Cl2
OMe
Me
Me Na / MeOH
N
O
Me
Me
reflux
Me
N
O
Me
Ac2O, 100 °C
S
NH2
MeO
EtO
NH2
OMe
H
N
SK
Me
OMe
Me
SH
N
MeO
SOCl2
Me
Me
base
N
OH
N
Cl
NaOH, EtOH, H2O
reflux, 2 h, 70%
H
N
H
N
S
MeO
J. Med. Chem. 1992, 35, 1049.
N
N
mCPBA
Me
Me
OMe
CHCl3
O
S
MeO
N
N
racemic
Me
Me
OMe
6
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
one compound survives pharmacokinetics,
esomeprazole, the S-enantiomer of omeprazole.
Only
O
S
safety
Ph
Me
Me
OMe
3- (R)-mandelic acid
NaOH, Bu4NHSO4
CHCl3, H2O, reflux
O
N
S
2- SOCl2
N
N
MeO
assessments…
OH
O
1- HCHO
N
N
omeprazole
and
O
H
N
MeO
efficacy
Me
38%
Me
OMe
1- separation of diastereomers
(preparative HPLC)
2- NaOH, MeOH, H2O, rt
3- MgCl2, H2O
H
N
O
S
MeO
N
N
esomeprazole
Me
Me
OMe
7
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
8
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!
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
Me
O
O Cl
O
F
Br
O
NH
Et3 N, CH3CN, rt
CO2Et
O
HO
O
N
Tol
N
2- NaOH
HO2C
1- Bu3B, NaBH4,
F
THF
Me
N
Me 110 °C
CONHPh
Me
Ph
Me
Ph
1- HCl, EtOH, reflux
2- TsOH, acetone-H2O
O
Me
2- NaOH, H2O2
CONHPh
CO2Me
O
CHO
OMe
Me
Ph
Me
Ac2 O, 90 °C
Me
F
NaH
N
CONHPh
N
O
O
CO2Me
Me
F
O
HO
F
atorvastation lactone
racemic
IC50 = 0.025 mM
Ph
Me
HO
Me
F
N
Me
then BuLi, THF
CONHPh
Ph
CONHPh
racemic
Separation of enantiomers
(resolution via diastereomeric esters synthesis)
H
N
O
HO
NHPh
CO2Et
HO
Ph
Me
O
O
O
F
1- Et3N, CH2Cl2, 0 °C
F
H2 N
O
O
O
HO
O
Ph
Me
HO
H
N
O
HO
Ph
Me
O
HO
HO
HO
O
O
O
Ph
Me
F
N
H2N
Me
Me F
N
Me
Ph
CONHPh
atorvastation lactone
racemic
Me
Ph
CONHPh
Me
F
N
+
Me
Ph
CONHPh
1- HPLC separation
2- NaOH
3- H3 O+
4- Tol, 110 °C
Me
F
N
Me
Ph
Me
F
N
+
CONHPh
(+)- atorvastatin lactone
IC50 = 0.007 µM
Me
Ph
CONHPh
(-)- atorvastatin lactone
IC50 = 0.44 µM
12
The enantioselective synthesis of atorvastatin lactone (labor approach)
F
+
CHO
CO2Me
i-Pr
EtO
Bn
N Cl
Me
S
HO
OEt
F
Ph
Et3 N
O
O
HO
NaOH,
CH3OH
O
HO
Me
N
Me
CONHPh
1-
Ot-Bu
2- Et3B, NaBH4
3- H2O2 , NaOH
4- Tol, 110 °C
O
H2N
O
O
Me
F
N
Me
Ph
N
OEt
Me
TsOH, Tol
Ph
O
O
F
Ph
Ph
i-Pr
OLi
Me
F
F
i-Pr
CO2Me
O
(+)- atorvastatin lactone
(> 99% ee)
OEt
1- NBS, DMF
2- nBuLi, THF, PhNCO
3- H3O+
Ph
1- LDA, MgBr2, -78 °C
OH
O
Ph
Ph
OH
Ph
Me
O
F
Ph Ph
O
Me
N
2- NaOMe, MeOH, 0 °C
CONHPh
H
Me
Ph
CONHPh
12 linear steps
3 columns and 1 recrystallization
Low temperature steps
Low yields
Low yielding final purification
Poor potential for kg scale
13
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)
O
CO2Et
AcHN
structure of neuraminidase with
its substrat, the sialic acid
NH2.H3PO4
Osetalmivir Phosphate
Tamiflu
Roche (1995)
Anti-viral drug to slow the spread of
the Influenza virus
Sales 2009 = 2.7 billion €
Review = Chem. Rev. 2009, 109, 4398
HO
H
HO
OH
AcHN
O
OH
CO2H
OH
sialic acid
(N-acetylneuraminic acid)
towards the drug design
16
Inhibition of the viral neuraminidase
17
Enzymatic mechanism of the viral neuraminidase
Enz
B
Enz
O
Enz
B
Enz
H
O
Enz
B
Enz
H
O
H
CO2
R
O
AcHN
O
R
O R1
HO
HO
H
H
HO
glycosyl-enzyme
O
H
Enz
B
R
sialosyl cation
O
CO2
R
AcHN
OH
R1
=
HO
H
CO2
O H
H
Enz
B
Enz
HO
HO
= virus
O
HO
O H
H B
OH
R = HO
Enz
B
H
O
HO
B
Enz
Enz
AcHN
O H
H
B
Enz
HO R1
HO
sialosyl cation
O
CO2
CO2
AcHN
R1
B
Enz
Enz
B
O
R
Enz
O
R
O
B
Enz
Enz
AcHN
CO2
AcHN
O
O
OO
OH
cell
O
OH
OH
18
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
O
Asp151
O
transition state
HO
O
N
H
HO
O
OH
O
O
H
N
H2N
H2N
estérase
NH2
OEt
N
H O
Arg371
OH
O
O
OH
Glu277
Oseltamivir
O
O
O
Tyr406
HO
H
HO
OH
H2N
HO
O
CO2H
HO
OH
H2N
NH2
(1969)
H
O
OH
H
HO
O
CO2H
OH
AcHN
OH
DANA
(1974)
O
CO2H
HN
Zanamivir
NH2
NH
(1989)
CO2Et
AcHN
NH2.H3PO4
Oseltamivir Phosphate
(1995)
19
Oseltamivir phosphate: the first synthesis
20
Oseltamivir phosphate: the Roche synthesis
HO
CO2H
HO
i) EtOH, SOCl2
ii) pentan-3-one, TsOH
iii) MsCl, Et3N
OH
(-) acide shikimique
KHCO3, EtOH aq
CO2Et
HN
(74% de pureté)
HO
CO2Et
O
HO
O
CO2Et
N3
N3
ii) Ac2 O
CO2 Et
OMs
O
NaN3, NH4Cl
CO2Et i) NaN3, NH4Cl, DMF
97%
O
BH3.Me2 S
OMs
O
O
TMSOTf
63-75%
EtOH aq
96%
PMe3
O
80%
O
CO2Et
O
10 / 1
OH
CO2Et i) H2, Ra-Ni, ,EtOH
ii) H3PO4
AcHN
N3
71-75%
O
CO2Et
AcHN
NH2.H3 PO4
- 21% overall yield, 10 steps
- industrial synthesis
- minor drawback : the sourcing (shikimic acid)
- major drawback : the use of azide chemistry
21
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
The clinical development was particularly rapid, as
can be seen by comparison with the typical drug
discovery and development times
23
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
H
N
N
H
N
N
N
H
N
N
N
N
inhibits Tyrosine Kinase HN
inhibition of PKC
O
(IC 50 = 50 µM)
Conformational
blocker
N
N
H
N
N
H
N
N
N
N
CH3
N
HN
O
CH3
N
HN
IC 50 = 50 µM
H
N
N
O
IC 50 = 0.1 µM
-increase activity vs tyrosine
kinases
-no activity against serinethreonine kinases
HN
O
Imatinib
(Glivec)
N
H3C
N
-spacer inserted to
avoid aniline structure
-piperazine
increases
activity,
selectivity
and water solubility
Nature Review Drug Discovery.2002, 1, 493.
24
Glivec : Zimmermann’s route (1993)
25
Glivec : Loiseleur’s route (2003) – use cross-coupling reaction
imatinib base
Buchwald-Hartwig cross-coupling reaction
26

The synthesis of atorvastatin lactone

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