Process for manufacture of chiral succinic acid derivatives

Details Process for manufacture of chiral succinic acid derivatives Process for manufacture of chiral succinic acid derivatives

1999-06-16

2001-03-06

Vollano, Jean F (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C560S121000

Reexamination Certificate

active

06197995

ABSTRACT:

BACKGROUND OF THE INVENTION
Hydroxamic acid derivatives with tricyclic substitution, as shown in formula (X) below, are known for their pharmacological activity as cartilage protective agents and are particularly useful in the treatment and prevention of degenerative joint diseases such as atherosclerosis (U.S. Pat. No. 5,614,625, EP 684 240 A1).
Certain chiral succinic acid derivatives, as shown in formula (I) below, are valuable intermediates in the synthesis of the above compounds (EP 816 341 A1). Since these derivatives are chiral, it is important to develop a stereoselective reaction to most efficiently obtain the desired enantiomer. It is known that lithium bases such as LDA provide synselectivity (in ratios of up to 90:10) in reactions with succinic acid derivatives with an ester group and a free acid group (R. Becket et al., Synlett. 137, Feb. 1993). However sodium bases such as NaN(TMS)
2
are not specific, providing a 1:1 mixture of syn to anti addition products.
SUMMARY OF THE INVENTION
The present invention is concerned with a process for the manufacture of chiral succinic acid derivatives of formula (I)
wherein R
1
is (C
1
-C
6
)alkyl or benzyl,
 which process comprises reacting a compound of formula (II)
 with a halohydantoin of formula (III)
wherein R
2
is halogen, in the presence of a strong enolate-forming potassium base.
By means of this reaction, the compound of formula (I) is obtained as the result of a selective anti-addition of the compounds of formulae (II) and (III). This is accomplished by use of a strong potassium base capable of forming an enolate. Surprisingly, in the case of an acid amide such strong potassium bases, such as KN(TMS)
2
, KNH
2
, KH or C
1
-C
6
alkoxy potassium bases (for example potassium tert-butylate), achieve the necessary anti-selectivity required to efficiently produce the compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, this invention is directed to a process for the manufacture of compounds of formula (I)
wherein R
1
signifies (C
1
-C
6
)alkyl or benzyl,
 which process comprises reacting a compound of formula (II)
 with a compound of formula (III)
wherein R
2
is chlorine, bromine or iodine, in the presence of a strong potassium base capable of forming an enolate.
In a preferred process KN(TMS)
2
(potassium bis-trimethylsilylamide) is the potassium base. In another preferred process R
1
is tert-butyl. In another preferred process R
2
is bromine. In a particularly preferred process, KN(TMS)
2
is the potassium base, R
1
is tert-butyl, and R
2
is bromine.
This invention is also directed to a process for the manufacture of compounds of formula (I)
wherein R
1
signifies (C
1
-C
6
)alkyl or benzyl, which process comprises: a) reacting (S)-4-benzyl-2-oxazolidone with a compound of formula (IV)
 to obtain (S)-3-(3-cyclopentyl-1-oxopropyl)-4-(phenyl)-2-oxazolidinone (V); b) reacting (S)-3-(3-cyclopentyl-1-oxopropyl)-4-(phenyl)-2-oxazolidinone (V) with a compound of formula (VI)
wherein R
1
signifies (C
1
-C
6
)alkyl or benzyl and Hal signifies chlorine, bromine or iodine, to obtain a compound of formula (VII)
 c) cleaving (S)-4-benzyl-2-oxazolidinone from the compound of formula (VII) to obtain the compound of formula (VIII)
 d) reacting the compound of formula (VIII) with piperidine to obtain a compound of formula (II)
 e) reacting the compound of formula (II) with a halo-hydantoin of formula (III)
wherein R
2
is chlorine, bromine or iodine in the presence of a strong potassium base capable of forming an enolate, to obtain a compound of formula (I).
In a preferred such process KN(TMS)
2
is the potassium base. In another preferred process R
1
is tert-butyl. In another preferred process R
2
is bromine. In a particularly preferred process, KN(TMS)
2
is the potassium base, R
1
is tert-butyl, and R
2
is bromine. In another preferres such process the (S)-4-benzyl-2-oxazolidinone is cleaved by H
2
O
2
and NaOH in a mixture of water and an alcohol.
Another process of this invention is a process for the manufacture of a compound of formula (X)
wherein a) in a compound of formula (I)
wherein R
1
has the significance given in formula 1, the R
1
is cleaved to obtain the compound of formula (IX)
and b) hydroxylamine is added to the compound of formula (IX)
 to obtain the compound of formula (X).
In a preferred such process R
1
is tert-butyl and is cleaved with a mineral acid in a carboxylic acid, especially where the mineral acid is HBr and the carboxylic acid is acetic acid. In another preferred process R
1
is (C
1
-C
6
)alkyl other than tert-butyl or a sterically hindered alkyl group and is cleaved with an alkali or alkaline earth metal hydroxide. In another preferred process R
1
is Bz and is cleaved hydrogenolytically. In yet another preferred process, the hydroxylamine is added: a) by means of trimethylsilyl-hydroxylamine or tetrahydropyranyl-hydroxylamine and cleavage of the trimethylsilyl or tetrahydropyranyl group, or b) by means of benzylhydroxylamine hydrochloride and hydrogenolytic cleavage of the benzyl group.
This invention is directed to another process for the manufacture of a compound of formula (X)
wherein a) a compound of formula (I)
wherein R
1
is a straight chain (C
1
-C
6
)alkyl, is reacted with benzylhydroxylamine hydrochloride activated by alkylmagnesium halide and b) the benzyl group is hydrogenolytically cleaved off the resulting compound to obtain the compound of formula (X).
In a preferred such process R
1
is cleaved with an alkali or alkaline earth metal hydroxide.
This invention is also directed to compounds which are intermediates in the above-described processes.
These include compounds of formula (VII)
wherein R
1
signifies (C
1
-C
6
)alkyl or benzyl, for example tert-butyl (R)-4-[(S)-4-benzyl-2-oxo-oxazolidon-3-yl]-3-cyclopentylmethyl-4-oxo-butanoate.
Also included are compounds of formula (VIII)
wherein R
1
signifies (C
1
-C
6
)alkyl or benzyl, for example (R)-2-cyclopentylmethyl-succinic acid-4-tert-butyl ester.
Also included are compounds of formula (II)
wherein R
1
signifies (C
1
-C
6
)alkyl or benzyl, for example tert-butyl (R)-3-cyclopentylmethyl-4-oxo-4-piperidin-1-yl-butanoate.
By halogen is meant chlorine, bromine and iodine. (C
1
-C
6
)Alkyl signifies a straight-chain or branched alkyl group with 1 to 6 C atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl or isopropyl or tert-butyl. R
1
is preferably a (C
1
-C
4
)alkyl. (C
1
-C
6
)alkoxy means alkyl as defined above bonded to oxygen. By sterically hindered alkyl group is meant a branched alkyl group like iso-propyl, sec-butyl or, preferably, tert-butyl, which are not easily accessible to base cleavage. Strong potassium bases capable of forming an enolate are e.g., t-BuOK, KH, KNH
2
or, preferably, KN (TMS)
2
. Bz stands for benzyl.
Compounds of formula (I) are described in EP 816 341 A1. Compounds of formula I are valuable intermediates in the synthesis of the pharmacologically active cartilage protecting compound (X) (U.S. Pat. No. 5,614,625, EP 684 240 A1). The compound of formula (X) has valuable pharmacological properties and can accordingly be used for the treatment and prevention of illnesses such as degenerative joint diseases, for example atherosclerosis.
The alkylation of compounds of formula II with the halomethylhydantoin (III) is effected in a presence of a strong base in a solvent such as an ether, preferably THF, at a temperature of −100° to 22°, preferably −60° C.
The stereoselectivity of the newly formed stereocentre depends to a very large extent on the nature of the cation of the base. Lithium bases such as LDA, give rise to syn-selectivity (ratio up to 90:10), as has been described in the case of succinic acid derivatives having an ester group and a free acid group (R. Becket et al. in Synlett 137, Feb. 1993). On the other hand, sodium bases such as NaN(TMS)
2
, are not specific (1:1 mixture).
Unexpectedly, it has now been found that in the case of an acid amide and the use of stro

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