Process for the preparation of HPB esters

Details Process for the preparation of HPB esters Process for the preparation of HPB esters

2000-09-25

2002-07-09

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S123000, C560S124000, C560S180000, C562S463000, C562S505000, C562S506000, C562S508000, C562S577000

Reexamination Certificate

active

06417389

ABSTRACT:

The present invention relates to a novel, inventive process for the stereoselective preparation of 2-hydroxybutyrates, in particular of 2-hydroxy-4-phenylbutyrates (HPB ester), and of their precursors.
HPB esters of formula
wherein A is substituents, m is an integer from 0 to 5 and R is an ester group and wherein the symbol * indicates a chiral centre, are important intermediates for the preparation of pharmacologically effective ACE inhibitors (ACE: angiotensin converting enzyme) which have the following shared structural feature:
ACE inhibitors belong to the active ingredient group of the antihypertensives and effect after oral administration a competitive inhibition of the so-called angiotensin converting enzyme and thus a lowering of the blood pressure. A particularly preferred HPB ester has the R-configuration.
An important active ingredient is 3-[(1-(ethoxycarbonyl)-3-phenyl-(1 S)-propyl)amino]-2,3,4,5-tetrahydro2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride which is known under the INN name benazepril HCl and which is commercially available in diverse oral forms of presentation, e.g. tablets, under the registered trademark Cibacen® (trademark of Novartis AG, Basel Switzerland). HPB esters can furthermore be used as intermediates for the preparation of other known ACE inhibitors, for example enalapril, cilazapril, spirapril, quinapril, ramipril or lisinopril (INN names). HPB esters can also be used for the synthesis of different types of insecticides.
Many different methods are known for preparing R-configurated HPB esters, for example reductions with micro-organisms or enzymes, enantioselective hydrogenations with homogeneous or heterogeneous catalysts, diastereoselective hydrogenations, reduction with hydrides, reactions with so-called chiral building blocks, enzymatic racemate resolution or racemate resolutions on chiral substrates, or inversion of the S-HPB ester.
These methods are disadvantageous for various reasons, such as
use of costly educts, e.g. 2-oxo-4-phenylbutyric acid
reaction at low concentrations (general problem in the case of biological or enzymatic processes)
high process costs in the case of homogeneous catalysis
maximum yield of only 50% in the case of racemate resolutions.
This invention has for its object to enantioselectively synthesise 2-hydroxybutyrates of the desired configuration, in particular HPB esters, starting from starting materials which are obtainable by simple synthesis. In the narrower meaning, this invention has for its object to enantioselectively synthesise HPB esters having the desired R-configuration without the losses necessitated by racemate resolution.
European patent application No. 206 993 describes the preparation of HPB esters through heterogeneous catalytic reduction with platinum catalysts of &agr;-keto esters of formula
The hydrogenation can be carried out enantioselectively in the presence of a chiral modifier, e.g. cinchonidine, so that the desired R-form is predominantly obtained. In spite of this possibility, this process is disadvantageous because the &agr;-keto ester must be prepared before-hand, the synthesis of which over several process steps is complicated.
Surprisingly, it has been found that starting from the &agr;,&ggr;-diketo esters of formula
(R
1
e.g. phenyl) which are accessible by simple Claisen condensation, or from their tautomeric &agr;-unsaturated &agr;-hydroxy-&ggr;-keto esters;
an &agr;-hydroxy-&ggr;-keto ester is obtained by enantioselective hydrogenation in the presence of a suitable chiral modifier, which &agr;-hydroxy-&ggr;-keto ester can be crystallised in enantiomerically pure form, for example in the desired R-configuration, in high optical yield and which can be converted to 2-hydroxybutyrate in a subsequent catalytic hydrogenation.
This invention relates to a process for the preparation of compounds of formulae
wherein
R is hydrogen or an ester group,
R
1
is hydroxy, etherified hydroxy, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, phenyl or phenyl which is substituted by 1 to 5 substituents, R
2
is hydrogen or C
1
-C
4
alkyl and n is 0 or 1, which process comprises enantioselectively hydrogenating an &agr;,&ggr;-diketo ester of formula
wherein R, R
1
and R
2
have the cited meanings, or the tautomer thereof, with platinum as catalyst in the presence of a cinchona alkaloid as chiral modifier and, if desired, hydrogenating for the preparation of a compound (IA) or (IB), wherein n is 0, one of the obtainable compounds of formulae
 having the desired configuration with palladium as catalyst.
A preferred embodiment of this invention relates to a process for the preparation of a compound (IA) or (IB), wherein R is e.g. hydrogen, C
1
-C
4
alkyl, preferably methyl or ethyl. R
1
is hydroxy, etherified hydroxy, for example C
1
-C
4
alkoxy, such as methoxy or ethoxy, C
1
-C
4
alkyl, for example methyl, ethyl, n-propyl, isopropyl or n-, iso- or tert-butyl, phenyl or phenyl substituted by 1-5 substituents A. R
2
is hydrogen or C
1
-C
4
alkyl, preferably methyl and n 0 or 1.
A particularly preferred embodiment of this invention relates to a process for the preparation of compounds of formulae
A is substituents,
m is an integer from 0 to 5 and
R is an ester group, which process comprises enantioselectively hydrogenating an &agr;,&ggr;-diketo ester of formula
wherein A, m and R have the cited meanings, or the tautomer thereof, with platinum as catalyst in the presence of a cinchona alkaloid as chiral modifier and hydrogenating one of the obtainable compounds of formulae
 having the desired configuration with palladium as catalyst.
The symbols, terms and denotations used in the description of this invention are preferably defined as follows:
the symbols
and
in the structural formulae mean that a predominant number of the molecules has the indicated stereochemical configuration at the chiral centre which, according to the nomenclature rules (R,S-nomenclature) of Cahn, Ingold and Prelog, has the denotation R or S.
In compounds (IA) and (IB) the ester group R is preferably a saturated hydrocarbon radical, in particular C
1
-C
20
alkyl, C
3
-C
12
cycloalkyl, C
2
-C
11
heterocycloalkyl, C
6
-C
16
aryl, C
1
-C
1
-C
15
heteroaryl or C
7
-C
16
aralkyl, which can be substituted by one or more than one substituent selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
haloalkyl, C
6
-C
16
aryl, carboxy, C
1
-C
4
alkoxycarbonyl, C
1
-C
4
alkanoyl, —SO
3
−
, ammonium and halogen.
Examples of C
1
-C
20
alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the isomers of pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. An example of aryl-substituted alkyl is benzyl.
Some examples of C
3
-C
12
cycloalkyl are cyclopropyl, cyclopentyl and cyclohexyl. Examples of substituted cycloalkyl are cyclopentyl and cyclohexyl which are substituted by methyl, dimethyl, trimethyl, methoxy, dimethoxy, trimethoxy, trifluoromethyl, bis-trifluoromethyl and tris-trifluoromethyl.
C
2
-C
11
heterocycloalkyl preferably contains one or two, and C
1
-C
15
heteroaryl one to four, heteroatoms, which are selected from the group consisting of oxygen, sulfur and nitrogen. Some examples of heierocycloalkyl are tetrahydrofuryl, pyrrolidinyl, piperazinyl and tetrahydrothienyl. Some examples of heteroaryl are furyl, thienyl, pyrrolyl, pyridyl and pyrimidinyl.
Examples of C
6
-C
16
aryl are phenyl and naphthyl. Examples of substituted aryl are phenyl substituted by methyl, dimethyl, trimethyl, methoxy, dimethoxy, trimethoxy, trifluoromethyl, bis-trifluoromethyl or tris-trifluoromethyl. One example of C
7
-C
16
aralkyl is benzyl. Examples of substituted aralkyl are benzyl substituted by methyl, dimethyl, trimethyl, methoxy, dimethoxy, trimethoxy, trifluoromethyl, bis-trifluoromethyl or tris-trifluoromethyl.
Heterocycloalkyl preferably contains one or two, and heteroaryl one to four, heteroatoms, which are selected from the group consisting of oxygen, sulfur and nitrogen. Some examples of heterocycloalkyl are tetrahydrofuryl, pyrrolidinyl, p

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