GB2139221A

GB2139221A - Substituted proline-thiolocarboxylate salts useful as intermediates

Info

Publication number: GB2139221A
Application number: GB08408638A
Authority: GB
Inventors: Roger Crossley
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1980-02-26
Filing date: 1984-04-04
Publication date: 1984-11-07
Also published as: GB2139221B; GB8408638D0

Abstract

1-(3-Bromo-2-D-alkylpropanoyl)-L-prolyl -2-thiolocarboxylate salts of formula <IMAGE> wherein B<(+)> is a cation, R<1> is C1-4 alkyl and R<4> and R<5> are both hydrogen or together with the carbons to which they are attached represent a benzene ring optionally substituted by OH, C1-4 alkyl or alkoxy, or halogen are useful as chemical intermediates in the stereospecific synthesis of angiotensin converting enzyme inhibitors having the formula: <IMAGE> The intermediates are prepared by reacting the corresponding free carboxylic acid derivatives with a haloformate ester followed by treatment with H2S or an alkali metal hydrogensulphide.

Description

SPECIFICATION Proline derivatives useful as intermediates This invention relates to proline derivatives useful as chemical intermediates in the preparation of pharmaceutically active L-proline derivatives.

In ourcopending UKPatentApplication No.

8104412 (Publication No. 2070005) there is described a process for preparing, stereospecifically, 4S, 9aS cyclic L-proline derivatives having formula (I)

wherein R' is lower alkyl and R4 and R5 are either both hydrogen or together with the carbon atoms to which they are attached represent a fused benzene ring optionally substituted by hydroxy, lower alkyl, lower alkoxy and halogen. Compounds offormula I are useful as chemical intermediates and also as angiotensin converting enzyme inhibitors and potential antihypertensive agents. They are disclosed in U.S. Patent No.4192945 and South African Patent Application No.8014946 (E.P. Applin. No.80302784.6, E.P. Publication No.24852).

We have found a particularly convenient route to such stereoisomers employing stereoisomers of

substantiallyfree df the L,L-diastereoisomerwherein R1 is lower alkyl and R4and R5 are as hereinbefore defined. This route has the advantage of preparing the compounds of formula I stereospecifically, thereby obviating the need to separate isomeric mixtures offinal products.

In particular UK Patent Publication No.2070005 provides a process for preparing a compound of formula (I) as defined above which comprises (i) reacting a compound offormula VII as defined above, substantially free from the corresponding L,L-isomer, with an haloformate ester, e.g. an alkyl haloformate ester such as ethyl chloroformate, and a sulphide of formula (ill) Y-SH (111) wherein Y represents hydrogen or an alkali metal, e.g. sodium, with the proviso that when Y is hydrogen the heating is carried out in the presence of base, e.g.

atertiaryamine, such astriethylamine, and (ii) cyclising the product of step (i) by heating, e.g. at 40 to 60 C, preferably about 45 C.

Convenientlythe reaction step ( is carried out in the presence of a polar solvent, e.g. acetonitrile.This solvent may also be usedforthefirst step ofthe reaction or other aprotic solvents such as methylene.

dichloridecan be used. The method hasthe added advantage that a 'one-pot' process can be used to go from Ill to I.

It is understood that the above mentioned reaction process forms as an intermediate in situ a compound

wherein R1 is lower alkyl, Visa cation derived from the base when Y is hydrogen), e.g. an alkali metal or an ammonium ion such as an alkylammonium cation, and R4and R5 are as defined above. Preferably R1 is methyl. Preferably Boils the triethylammonium ion.

This invention provides the intermediates offormula IV.

The compound offormula las hereinbefore defined may be prepared by cyclising a compound of formula IV by heating, preferably in the presence ofa polar solvent such as acetonitrile. Preferably the cyclisation is effected atatemperature offrom 400 to 60 C, e.g.

about 45 C. The starting materials offormula II may be prepared according to processes disclosed in UK Patent Publication No.2070005. By theterm "lower" as used herein in connection with alkyl or alkoxy means such groups containing 1 to 4 carbon atoms and includes both straight andbranched chains. A preferred loweralkyl group is methyl.

Thefollowing Examplefurther illustratesthis invention: Example (4S, 9aS) -Hexahydro -4 - methyl - 1H, 5H -pyrrolo[2, 1 - c] - [1,4]thiazepine - 1,5 - dione. (cyclic captopril I :R1 Me, R4=R5= H) Asolution of 1 - (3 -bromo - 2 - D- methylpropanyl) L - proline t1.3 g) (prepared according to Examples 1 and 2 of UK Patent Publication No.2070005) in CH2C12 (50 ml) was cooled to 0 C and treated in turnwith triethylamine (1 ml) then ethyl chloroformate (0.5 ml).

After1/4 hourtriethylamine (0.Sml)wasadded and H2S gas was bubbled in at 20 mljmin for 20 minutes to give a mixture containing the triethylamine salt of 1 (3 - bromo -2 - D- methylpropanoyl) - L - Pro-SH.The solvent was removed byevaporation,then the residue dissolved in acetonitrile (50 ml) and heated at 45 C for 4 hours. The solvent was removed by evaporation and the residue was dissolved in methylene dichloride. This solution waswashed successively with water and Na2CO3 solution then dried and evaporated.The residue was extracted with diethyl ether and the solvent evaporated. The residue was extracted once more with diethyl ether and the solvent evaporated to give an oil (1 g) containing the title compound. The title compound was obtained on recrystallising from diethyl ether (0.2 g).

Analysis: Found: C, 54.7; H, 6.8; N, 6.85 C91113N025 requires C, 54.3; H, 6.6; N, 7.0%.

'T. Compound offormula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

SPECIFICATION Proline derivatives useful as intermediates This invention relates to proline derivatives useful as chemical intermediates in the preparation of pharmaceutically active L-proline derivatives.

In ourcopending UKPatentApplication No.

8104412 (Publication No. 2070005) there is described a process for preparing, stereospecifically, 4S, 9aS cyclic L-proline derivatives having formula (I)

wherein R' is lower alkyl and R4 and R5 are either both hydrogen or together with the carbon atoms to which they are attached represent a fused benzene ring optionally substituted by hydroxy, lower alkyl, lower alkoxy and halogen. Compounds offormula I are useful as chemical intermediates and also as angiotensin converting enzyme inhibitors and potential antihypertensive agents. They are disclosed in U.S. Patent No.4192945 and South African Patent Application No.8014946 (E.P. Applin. No.80302784.6, E.P. Publication No.24852).

We have found a particularly convenient route to such stereoisomers employing stereoisomers of

substantiallyfree df the L,L-diastereoisomerwherein R1 is lower alkyl and R4and R5 are as hereinbefore defined. This route has the advantage of preparing the compounds of formula I stereospecifically, thereby obviating the need to separate isomeric mixtures offinal products.

In particular UK Patent Publication No.2070005 provides a process for preparing a compound of formula (I) as defined above which comprises (i) reacting a compound offormula VII as defined above, substantially free from the corresponding L,L-isomer, with an haloformate ester, e.g. an alkyl haloformate ester such as ethyl chloroformate, and a sulphide of formula (ill) Y-SH (111) wherein Y represents hydrogen or an alkali metal, e.g. sodium, with the proviso that when Y is hydrogen the heating is carried out in the presence of base, e.g.

atertiaryamine, such astriethylamine, and (ii) cyclising the product of step (i) by heating, e.g. at 40 to 60 C, preferably about 45 C.

Convenientlythe reaction step ( is carried out in the presence of a polar solvent, e.g. acetonitrile.This solvent may also be usedforthefirst step ofthe reaction or other aprotic solvents such as methylene.

dichloridecan be used. The method hasthe added advantage that a 'one-pot' process can be used to go from Ill to I.

It is understood that the above mentioned reaction process forms as an intermediate in situ a compound

wherein R1 is lower alkyl, Visa cation derived from the base when Y is hydrogen), e.g. an alkali metal or an ammonium ion such as an alkylammonium cation, and R4and R5 are as defined above. Preferably R1 is methyl. Preferably Boils the triethylammonium ion.

This invention provides the intermediates offormula IV.

The compound offormula las hereinbefore defined may be prepared by cyclising a compound of formula IV by heating, preferably in the presence ofa polar solvent such as acetonitrile. Preferably the cyclisation is effected atatemperature offrom 400 to 60 C, e.g.

about 45 C. The starting materials offormula II may be prepared according to processes disclosed in UK Patent Publication No.2070005. By theterm "lower" as used herein in connection with alkyl or alkoxy means such groups containing 1 to 4 carbon atoms and includes both straight andbranched chains. A preferred loweralkyl group is methyl.

Thefollowing Examplefurther illustratesthis invention: Example (4S, 9aS) -Hexahydro -4 - methyl - 1H, 5H -pyrrolo[2, 1 - c] - [1,4]thiazepine - 1,5 - dione. (cyclic captopril I :R1 Me, R4=R5= H) Asolution of 1 - (3 -bromo - 2 - D- methylpropanyl) L - proline t1.3 g) (prepared according to Examples 1 and 2 of UK Patent Publication No.2070005) in CH2C12 (50 ml) was cooled to 0 C and treated in turnwith triethylamine (1 ml) then ethyl chloroformate (0.5 ml).

After1/4 hourtriethylamine (0.Sml)wasadded and H2S gas was bubbled in at 20 mljmin for 20 minutes to give a mixture containing the triethylamine salt of 1 (3 - bromo -2 - D- methylpropanoyl) - L - Pro-SH.The solvent was removed byevaporation,then the residue dissolved in acetonitrile (50 ml) and heated at 45 C for 4 hours. The solvent was removed by evaporation and the residue was dissolved in methylene dichloride. This solution waswashed successively with water and Na2CO3 solution then dried and evaporated.The residue was extracted with diethyl ether and the solvent evaporated.The residue was extracted once more with diethyl ether and the solvent evaporated to give an oil (1 g) containing the title compound. The title compound was obtained on recrystallising from diethyl ether (0.2 g).

Analysis: Found: C, 54.7; H, 6.8; N, 6.85 C91113N025 requires C, 54.3; H, 6.6; N, 7.0%.

'T. Compound offormula

substantially free from the L,L - isomer, wherein R' is lower alkyl, B#is a cation, R4 and R5 are either both hydrogen ortogetherwith the carbon atoms to which they are attached represent a fused benzene ring optionally substituted by hydroxy, lower alkyl, lower alkoxy and halogen.
2. A compound as claimed in Claim 1 which is the triethylamine salt of 1 - (3 - bromo - 2 - D- methyl propanoyl) - L - Pro -SH.

CLAIMS-Amendments to claims have been filed, and have the following effect: Claim 1 above has been textually amended as follows: 1. A compound offormula

su bstantiallyfree from the L,L - isomer, wherein R' is lower alkyl, B# is a a cation, R4 and R5 are either both hydrogen ortogetherwith the carbon atoms to which they are attached represent a fused benzene ring optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen.