Hydrogenation

Details Hydrogenation Hydrogenation

1996-03-07

1997-04-08

Shippen, Michael L.

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

Organic compounds

Carboxylic acid esters

560122, C07C 6974

Patent

active

056189702

DESCRIPTION:

BRIEF SUMMARY
This is the national stage under 35 U.S.C. .sctn.371(c) and 37 C.F.R. .sctn.1.491 of International Application No. PCT/EP94/03036, having the international filing date of Sep. 9, 1994, which was originally filed Sep. 22, 1993 as Great Britain Patent Application No. 93307517.8.
This invention relates to preparation of compounds which are useful as intermediates in preparation of spiro-substituted glutaramide derivatives, notably the compound having the approved non-proprietary name candoxatril and the systematic name (S)-cis-4-(1-[2-(5-indanyloxycarbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclop entane carboxamido)-1-cyclohexanecarboxylic acid. This compound is among those mentioned in U.S. Pat. No. 5,192,800 as inhibitors of the neutral endopeptidase E.C.3,4.24.11 enzyme useful in therapy as diuretic agents for the treatment of hypertension, heart failure, renal insufficiency and other disorders.
Candoxatril may be prepared by coupling the (S)-enantiomer of a compound of formula (I): ##STR3## wherein R is 5-indanyl or a carboxylic acid protecting group, with cis-4-amino-cyclohexane-carboxylic acid benzyl ester, followed by hydrogenation to remove the benzyl group. When R is a 5-indanyl group this procedure produces candoxatril; when R is another group it may be removed and replaced by a 5-indanyl group by conventional methods.
The compound of formula (I) is the (S)-enantiomer of the chiral glutaric acid derivative shown and the substantially optically pure enantiomer is required for manufacture of candoxatril which is itself an enantiomer of a chiral compound. As described in U.S. Pat. No. 5,192,800 (Example 431 et seq) the (S)-enantiomers of formula (I) may be prepared by resolution of its racemate with (1S,2S)-(+)-pseudoephedrine. This resolution process is inefficient.
The present invention is intended to provide a method of providing the (S) enantiomers of compounds of formula (I) by asymmetric hydrogenation of a corresponding (E)-allylic ether.
According to the invention, there is provided a method of preparing the (S) enantiomer of a compound of formula (I): ##STR4## or an amine salt thereof, wherein R is 5-indanyl or a carboxylic acid protecting group, which comprises hydrogenating an (E)-allylic ether of formula (II): ##STR5## or an amine salt thereof wherein R is as defined for formula (I), in the presence of a stereoselective chiral rhodium or ruthenium biphosphine catalyst capable of catalysing said hydrogenation and a protic solvent.
R may be a straight or branched C.sub.1 -C.sub.4 alkyl group such as a t-butyl group.
Several chiral biphosphine catalysts containing rhodium or ruthenium are known and are either commercially available or may be made by methods known in the art. They contain rhodium or ruthenium species complexed with chiral biphosphine ligands such as 2,2'bis(diphenylphosphino)-1,1'-binaphthyl (generally known as BINAP), t-butyl-4-(diphenyl phosphino)-2-(diphenylphosphino)-2-(diphenylphosphinomethyl)-1-pyrrolidine carboxylate (known as BPPM) and 1,2-bis(diphenylphosphino)propane (known as PROPHOS). Being chiral, these ligands exist in (R)- and (S)-forms and their complexes with metals such as rhodium and ruthenium are themselves chiral. It has been found that some, but not all, of these catalysts are capable of giving stereoselective reduction of the allylic ethers of formula (II).
These catalysts may be obtained commercially or prepared by known methods. Alternatively, they may be prepared in situ in known manner.
The hydrogenation may be carried out in known manner by exposing a solution of the allylic ether to hydrogen gas, typically at a pressure of about 60 psi, in the presence of the catalyst. A reaction temperature of up to 50.degree. C. is generally suitable, at higher temperatures decarboxylation of the acid of formula (II) may occur. The solvent used should be a protic solvent:methanol and aqueous methanol have been found suitable. Substantially no reduction took place in aprotic solvents such as toluene and dimethylformamide.
R may be a C.sub.1 -C.sub.4 alkyl group, such as

REFERENCES:
patent: 4194051 (1980-03-01), Bachmann
patent: 4962230 (1990-10-01), Takaya
patent: 5192800 (1993-03-01), Barnish
patent: 5334758 (1994-08-01), Saburi
Chemistry in Britain, Apr. 1993, p. 319.

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