GB2070005A - Processes for preparing proline derivatives and analogous compounds - Google Patents
Processes for preparing proline derivatives and analogous compounds Download PDFInfo
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- GB2070005A GB2070005A GB8104412A GB8104412A GB2070005A GB 2070005 A GB2070005 A GB 2070005A GB 8104412 A GB8104412 A GB 8104412A GB 8104412 A GB8104412 A GB 8104412A GB 2070005 A GB2070005 A GB 2070005A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Description
1 GB 2 070 005 A 1
SPECIFICATION Novel Processes for Preparing Proline Derivatives and Analogous Compounds
This invention relates to novel processes for preparing L-proline derivatives useful as chemical intermediates and to the preparation of pharmaceutically active L-proline derivatives.
5- United States Patent No. 4,105,776 published 8th August, 1978 discloses proline derivatives 5 which are stated to inhibit the conversion of the decapeptide angiotensin I to angiotensin 11 and are therefore useful in reducing or relieving angiotensin related hypertension. The proline derivatives are disclosed as having general formula (A) i3 H C -(CH), 4 R1 2 w i 1 R2-S-(C -CH-LU-N-CH-COR M (A) wherein R is hydroxy, NH2 or lower alkoxy; R, and R4 each is hydrogen, lower alkyl, phenyl or phenyllower alkyl; R2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkyithiomethy], phenyHower alkyithiomethyi, lower alkanoyi-amidomethyi, 0 m m 11 11 11 R6-S- or R7; R3 is hydrogen, hydroxy or lower alkyl; R. is lower alky], phenyl or phenyl-lower alkyl; R. is lower alkyl, 15 phenyl, substituted phenyl, (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy lower alkyl or a mino(carboxy) lower alkyi; I,(HC)-CH R 4 1 1 1 1 R -,, H-uL-hL-iN-Lu--H- H)-SO- n p M is 0 or S; m is 1 to 3; n and p each is 0 to 2 and processes for preparing them. The asterisks indicate asymmetric carbon atoms.
The preferred isomeric form is stated to be the L-Isomer with respect to the carbon of the amino acid, and the D-isomer with respect to the carbon bearing R,. For the purposes of the present application such a preferred arrangement of asymmetric centres is termed 'D, L configuration'.
A compound failing within the above mentioned formula and described therein, namely 1-(3 mercapto-2-D-methylpropanoyi)-L-proline having the generic name captopril, has been extensively 25 investigated and found to be a potent antihypertensive agent (see for example, D. W Cushman et al, Biochemistry, Vol. 16, 5484 (1977); D. W. Cushman et al, Prog. in Cardiovascular Diseases, Vol. XXI, No. 3,183 (1978). Chemistry andEngineering, April 4,21 (1977);andH. Gavrasetal.,NewEng.J.
Med., Vol. 298, No. 18, 991 (1978). This compound has the preferred D, L configuration.
U.S. Patent No. 4,105,776 also describes a route for the preparation of captopril and related 30 compounds using as intemediates compound of formula (B) 3 1 R, R H C-CH) 14 1 2 rn 1 1 1 1 X-(CH)-CH - CO - N - CH - n (DI \,LY wherein R, R,, R3, R4, m and n are as defined above and X is halogen. Such compounds of formula (B) are prepared by reacting an activated form of an acid of formula (C) 2 GB 2 070 005 A 2 R4 R, 1 1 X-WH2)6-CH-COOH with an acid of formula (D) (C) 2 1 CHj-(CH).n 1 1 HN-CHCOR (D) We have now surprisingly found a process for preparing intermediate compounds failing within the scope of formula (B), which employs mixtures of stereolsomers failing within formula (C) and which provides increased proportions of intermediates having the same D, L configuration of asymmetric centres as for captopril. Thus the process of this invention is particularly useful for increasing the proportion of D, L intermediates when a racemic acid within formula 0- is used as precursor, thereby giving increased yields of the desired diastereoisomer.
The process of this invention is also useful for preparing other intermediates with the disclosure 10 of South African Patent Application No. 80/4946 and European Patent Application No. 80302784.6, Publication No. EP24852, having the formula (E) X Br-CH -LH-LO-L-N 2 C02 R2 (E) wherein R' is a carboxy p - rotecting group, X is hydrogen or a substituent selected from hydroxy, lower alkyl, lower alkoxy and halogen, and R-is alkyl of 1 to 4 carbon atoms. Such compounds (E) fall within a class of intermediates disclosed in South African Patent Application No. 80/4946 as useful for preparing finffl products useful for treating anglotensin related to hypertension. Some of these final products may be represented by the general formula X-1N R' 1 1 O=C-CH-CH - H where X and R' are as defined above.
Accordingly this invention provides a process for preparing a compound of formula (1) R' R 11 D-BrCH 2 CH-CO-L-N CO-R 2 1.1 (F) (1) in excess of the corresponding L, L diastereoisomer wherein R' is lower alkyl, R 2 is a carboxy protecting group, 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 25 and halogen, which comprises reacting an enantiomeric mixture of an acid of formula (11) R' 1 Brutl2U11COOH with the carbodUmide or carbonyl diimidazole coupling agent and a compound of formula (111) (11) 3 GB 2 070 005 A 3 4 5 R R L7 H-N CO2R2 (HI) in which formulae R1, R2, R4 and R5 are as defined above.
By the term 'lower alkyl' as used herein is meant an alkyl group containing 1 to 4 carbon atoms and includes both straight and branched chains. A preferred lower alkyl group for R1 is methyl.
Carboxy protecting groups used for R 2 include any protecting group known in the peptide art for protecting a carboxy function of an amino acid, for example alkyl esters of 1 to 6 carbon atoms, preferably the t-butyl ester. Methods for protecting and conditions for removing specific carboxy protecting groups are described in the literature-see for example Schroder Et Lubke, The Peptides, Vol. 1 (Academic Press 1965).
The process for this invention employs a carbodilmide coupling agent of carbonyl diimidazole to 10 effect reaction of the compounds of formulae I and 11. Such coupling agents and methods for coupling using them are extensively described in the literature-see for example the aforementioned textbook by Schroder & Lubke. Examples of carbodilmide coupling agents are dicyclohexylcarbodiimide (DCC), diisopropy1carbodlimide and 1-(3-dimethylamino)propyl-3-ethylcarbodiimide.
Preferably and for convenience the enantiomeric mixture of the acid of formula II is racemic., The reaction is conveniently carried out using standard conditions for carbodilmide and car-bonyl diimidazole couplings, e.g. using a solvent such as dichloromethane at about 01C, and proceeds in high yield. Other solvents include CC14 and DMF.
Using the process of this invention it has been possible to prepare essentially quantitatively, a ca.
80:20 mixture of D, L and L, L diastereoisomers of formula I respectively using a racemic compound of 20 formula 11 as starting material.
This result is contrary to the expectation that a racemic starting material would give equimolar quantities of diastereoisomers of formula 1, should coupling be effected.
Compounds of formula I prepared by the process of this invention may be used to prepare captopril and analogous compounds, as described in U.S. Patent No. 4,105, 776 and 2,3-dihydro-lH- 25 indole derivatives as described in South African Patent Application No. 80/4946 (E.P. Publication No.
24852), by reaction with an anion of a thloacid of formula (IV) R3COSH to give a compound of formula (V) (IV) R' R R 5 3 D-R COSCH.LHLU-L-N C02 R 2 (V) in excess of the corresponding L,L-diastereoisomer, in which formulae W, R2, R4 and R5 are as defined above and R3 is lower alkyl, phenyl, or phenyl-lower alky]. The product is then converted by ammonoiysis and deprotection, in either order, into the desired final product (V1) 4 5 R' R R 1 D-H5LH 2 -LHCO--L-N (V1) wherein R' is lower alkyl, which can be separated from the corresponding L,L-isomer by fractional 35 crystallisation or other conventional means.
Compounds of formula 11 used as starting materials for the process of this invention may be prepared by reacting a lower alkyl acrylic acid with hydrogen bromide. From this reaction preferred racemic starting materials are obtained.
Determination of the proportions of DL and L,L diastereoisomers in the mixtures obtained in the. 40 process of this invention may be readily achieved by deprotecting to give the corresponding acids followed by observation of the relative intensities of the 'Hnmr signals for the R' group, especially 4 GB 2 070 005 A 4 when R' is methyl. Of course a deprotection route should be chosen which does not alter the relative proportions.
Deprotection of the compounds of formula 1 when R 2 is tert-butyl can lead to such a change in proportions of isomers, vide infra. However, when R 2 is Bul it is possible to observe the relative proportions of isomer directly by observation of the Bul resonances in the H nmr spectrum. High performance liquid chromatography may also be used.
The intermediates of formula 1 may also be employed in the preparation of captoprit and analogous compounds via other routes using a deprotected acid intermediate. In particular the intermediates of formula 1 may be used to prepare Captopril and analogous compounds as shown in 10 the following reaction scheme.
4 R R R BrCH 2 HCONV 2 deproLecE CO R 2 (1) D, -L confijuraLon 1 4- 5 R R R 1 - Hb(-h 2(-HCONP/ CO H 2 (1x) captopril (RI=Me, R4--RS=H) and analogous compounds 1 4 5 R R R I BrCH 2 CHC017N (VII) H 3R COSH W R3 Lwer 1 4 R5 R R R 3 SCH2 I HCON'V (Vill) CO, H 2 It has surprisingly been found that when R 2 is tert-butyl, deprotection using trifluoroacetic acid (TFA) under standard conditions results in substantial racemisation of the propanoyl a-carbon, such that a 4:1 mixture of the compound of formula 1 and its.L,L-diastereolsomer, can give a 3:2 15 mixture of the compound of formula VII and its L,L- diastereoisomer after a 1 hour reaction.
We have found that modification of the usual deprotection condition, but still using TFA, enables the excess of the preferred stereoisomer to be retained.
Accordingly a further aspect of this invention provides a process for preparing a compound of formula VII 4 R' R R D-BrCH HLUL-N COOH (V11) 20 in excess of the corresponding L,L-diastereoisomer wherein R' is lower alkyl, which comprises reacting a compound of formula (X) 4 R' R 1 D-BrCH HCO-L-N 2 CO0Bue (X) with trifluoroacetic acid at a low temperature (e.g. from about -150 to + 200C, preferably about OOC, fora sufficiently short period of time to prevent substantial racemisation of the propanoyl a-carbon in 25 the product of formula VII.
TFA deprotection to remove a t-butyl protecting group can involve reacting at room temperature for one hour or longer-see for example Biochemistry, Vol. 16, p 5486 (1977). We have found that the stereochemistry of the starting materials is substantially retained when the TFA deprotection is carried GB 2 070 005 A 5 out at a low temperature, e. g. -5 to 1 50C and in a short period of time, for example, not more than 25 minutes, preferably not more than 20 minutes, most preferably not more than 15 minutes. In a typical TFA deprotection reaction complete retention of stereochemistry of starting materials was achieved by effecting reaction in about 10 minutes and at about O1C, i.e. the proportion of bL isomer of formula VII to L,L isomer was kept to about 80:20 (the same as in the starting materials of formula X). Reaction for longer periods was found to reduce the excess of the DL-isomer. The table below shows how the proportion of DL and L,L product varied as a function of time when 1 -(D-3-bromo-2- methylpropionyi)L-proline-t-butyl ester was deprotected using TFA at room temperature:
% of isomers Time (minutes) DL LL 10 2 78 22 78 22 67 33 63 37 Yet a further aspect of this invention relates to a stereospecific synthesis of 4S, 9aS cyclic L- 15 proline derivatives having formula (Xl) 0' R 01 C. 1 5 a R 10-/ 5 01, 3 cll- 0 (Xl) wherein R' is lower alkyl and R 4 and R5 are as hereinbefore defined. Compounds of formula XI are useful as chemical intermediates and also as angiotensin converting ensyme inhibitors and potential antihypertensive agents. They are disclosed in U.S. Patent No. 4192945 and South African Patent 20 Application No. 804946 (E.P. Appin. No. 80302784.6, E.P. Publication No. 24852).
We have found a particularly convenient route to such stereolsomers employing stereoisomers of formula Vil as hereinbefore defined. This route has the advantage of preparing the compounds of formula XI stereospecifically, thereby obviating the need to separate isomeric mixtures of final products. The isolation of the appropriate stereoisomer of formula Vii, especially when prepared by the 25 process hereinbefore described which provides increased proportions of the desired stereoisomer, is very easily effected. Also separation at an early stage avoids wasting reactant in preparation undesired isomers of the final product.
Accordingly this invention also provides a process for preparing a compound of formula (Xl) as defined above which comprises (i) reacting a compound of formula VII as defined above, substantially 30 free from the corresponding L,L-isomer, with and haloformate ester, e.g. an alkyl halo formate ester such as ethyl chloroformate, and a sulphide of formula (Xli) Y-SH (XII) 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. a tertiary amine, such as triethylamine, 35 and (ii) cyclising the product of step (i) by heating, e.g. at 401 to 6011C, preferably about 45"C.
Conveniently the reaction step (H) is carried out in the presence of a polar solvent, e.g. acetonitrile. This solvent may also be used for the first step of the reaction or other aprotic solvents such as methylene dichloride can be used. The method has the added advantage that a 'onepot' process can be used to gofrom VII toXi.
It is understood that the above mentioned reaction process forms as an intermediate in situ a compound of formula (XIII) 4 5 R' R R 1 (X111) D-BrLH.LHLU-L-N C cos E)B (D wherein R' is lower alkyl, B$ is a cation (derived from the base when Y is hydrogen), e.g. an alkali metal 45 or an ammonium ion such as an alkylammonium cation. The compounds of formula XIII substantially 45 6 GB 2 070 005 A 6 free of LL stereoisomers are also within the scope of this invention. Preferably R' is methyl. Preferably B@ is the triethylammonium ion.
This invention also provides a process for preparing a compound of formula XI as hereinbefore defined which comprises cyclising a compound of formula Xiii by heating, preferably in the presence of a polar solvent such as acetonitrile. Preferably the cyclisation is effected at a temperature of from 401 5 to 600C, e.g. about 451C. The starting materials of formula Vii may be prepared according to processes hereinbefore described. The desired DL,-stereoisomer may be separated from the corresponding LL-stereolsomer (the former preferably already in excess) by converting the acid to its dicyclohexylamine (DCHA) salt and crystallising from an appropriate solvent, e.g. propan-2-ol whereby the desired DL-form of the acid of formula VII is obtained as the DCHA salt. It maybe converted to the 10 acid by known means, e.g. treating with KHS04.
The compounds of formula VII and their dicyclohexylamine salts substantially free of L,L stereoisomers are within the scope of this invention.
The following Examples further illustrate this invention:
Example 1 is 1-(3-Bromo-2-D-methylpropanoyi)-L-proline Tert-butyl Ester Racemic 3-bromo-2-methylpropionic acid (50 g) in methylene dichloride (50 m]) was added over a -1 hour period to a solution of dicyclohexylcarbodiimide (60 g) in methylene chloride (400 m[) kept at 2 -5 to OOC by external cooling. L-proline tert-butyl ester (50 g) in methylene dichloride (50 mi) was then added over a -11 hour period. The mixture was allowed to slowly warm to room temperature and 20 left overnight. The precipitate formed in the reaction, was filtered and the filtrate evaporated. The residue was dissolved in diethyl ether (300 mi) and washed successively with 1 N HCI, water, 1 N NaOH and water. The ether layer was dried (M9S04) and evaporated to give a mixture (90 g) of the title compound in excess of 1-(3-bromo-2-L-methylpropanoyl)-L-proline, tert butyl ester.
Found: C, 48.5; H, 7.1; N, 4.3 5.
C,,H2,BrNO3 requires C, 48.13; H, 6.9; N4.4% The relative isomer proportions were estimated to be 80:20 from the nmr spectrum of the tertiary butyl groups in the product, in C13C13' Example 2
1-(3-Bromo-2-D-methylpropanoyi-L-proline (a) To trIfluoroacetic acid (300 9) cooled to OIC was added 1-(3-bromo-2-methylpropanoyi)-Lproline, tbutyl ester (90 g of an 80:20 mixture of QL and L,L forms). The mixture was warmed to 251C and kept there for 1/4 hour. The trifluoroacetic acid was removed by evaporation and azeotroping with carbon tetrachloride, and twice with toluene:propan-2-ol (30:70) and then diethyl ether. The relative isomer proportions were estimated from the same spectrum of the methyl group in the product, MeOW 35 dO NaOD solution. Signals appeared at 8 1. 50 and 1.55 for DL and LL isomers respectively and were in the ratio 80:20. (b) The residue was dissolved in diethyl ether (500 mi) and treated with excess di-cyclohexyla mine (90 g). A solid formed and was filtered and recrystallised from propen-2-ol to give l-Q-brorno-2-D- methyl propanoyl)-L-prol ine di-cyclohexylamine salt (83 9, 95% QL form). (c) The di-cyclohexylamine salt was converted back into the free acid by treatment with KHS04 solution (1 N 5 volumes) and it was extracted with methylene dichloride solvent. The solvent was removed by evaporation and the residue dissolved in Na2C03 solution and this was washed with ether (3x), acidified with HQ (2N) and the acid was extracted with ether. After the ether solution had been dried (M9S04)and evaporated the residue was recrystallised from di- isopropyl ether to give l-Qbromo-2-D-methylpropanoyi)-L-proline as the monohydrate (m.p. 74-50).
Analysis:
Example 3
R 30- 1 Found: C, 3 8. 1; H, 5.7; N, 4.5 C,H14BrNO3, H20 requires C, 38.3; H, 5.7; N, 5.0%.
so (4S, 9aS)-Hexahydro-4-methyi-l H.5H-pyrrolo[2.1 -c] [1,4]thlazepine-1,5- dione. (Cyclic Captopril X1W=Me, R 4 =RI=H) 1 1 A solution of 1 -(3-bromo2-D-methylpropanoyi)-L-pro line (1.3 g) in CH2C 2 (50 mi) was coo ed to 011C and treated in turn with triethylamine (1 mi) then ethyl chloroformate (0.5 m]). After 1 hour W triethyia mine (0.5 m[) was added and H2S gas was bubbled in at 20 mi/min for 20 minutes to give a 55 mixture containing the triethylamine salt of 1-(3-bromo-2-Dmethylpropanoyl)-L-Pro-SH. The solvent was removed by evaporation, then the residue dissolved in acetonitrile (50 mi) and heated at 450C for 4 hours. The solvent was removed by evaporation and the residue was dissolved in methylene dichlorlde. This solution was washed successively with water and Na2C03 solution then dried and evaporated. The residue was extracted with diethyl ether and the solvent evaporated. The residue was.60 7 GB 2 070 005 A 7 extracted once more with diethyl ether and the solvent evaporated to give an oil (1 9) containing the title compound. The title compound was obtained on recrystallising from diethyl ether (0.2 g).
Analysis:
Found: C.1-1,3NO2S requires C, 54.7; H, 6.8; N, 6.85. C, 54.3; H, 6.6; N, 7.0%.
Example 4 1 -(3-Bro mo-2-D-methyl propionylR -pro line t-butyl tster To a solution of di-eyclohexylcarbodiimide (1.2 g) in dimethylformamide (DIVIF) (5 mi) at OOC was added racemic 3-bromo-2-methylproplonic acid (1 g) in DIVIF (5 mi) and then L-proline t-butyl ester (1 9) in DIVIF (5 mi). The mixture was stirred for 4 hours then poured onto H20 (30 mi), filtered and extracted with ether. The ether solution was washed with H20, N/1 0 HCI and Na2C03 solutions, dried (M9S04) and evaporated. The residue (1.2 g) consisted of a 2:1 mixture of the title compound and its L,L isomer.
Example 5 15 1-(3-Bromo-2-D-methylpropionyl).-proline-t-butyl Ester To a solution of dicyclohexylcarbodiimide (3 9) in CC14 (20 mi) at OOC was added racemci 3bromo-2-methylproplonic acid (2.5 g) in CC14 (5 mi) followed by L-proline t-butyl ester (2.5 g) in CC14 (5 mi). The mixture was stirred for 5 minutes, allowed to stand at ambient temperature for 18 hours and then filtered. The filtrate was washed with 2N HCI, H20 and then Na2C03 solution, dried (M9S04) and evaporated to give 3 g of a 4:1 mixture of the title compound and its L,L isomer.
is Example 6 1-(3-Bromo-2-D-methylpropionyi)-L-prolinet-butyl Ester To a solution of 1,1 -carbonyidiimidazole (2 g) in C.(2C12 (20 mi) at OIC was added racemic 3bromo-2m ethyl proplonic acid (2 g) in CH2C12 (5 mi) followed by L-proline t-butyl ester (2 g) in CH2C12 (5 mi). The mixture was stirred at OIC for 5 minutes, then allowed to stand at ambient temperature for 25 18 hours. It was then evaporated and the residue was dissolved in hexane and washed with dilute HCI, H20 and then Na2C03 solution, dried (M9S04) and evaporated to give 2 g of a 4:1 mixture of the title compound and its L,L isomer.
Example 7
1-(3-Bromo-2-D-methylpropionyl)-L-proline t-butyl Ester To a suspension of 1,(3-dimethylamino)propyi-3-et[i-yicarbodilmide hydrochloride (2.2 g) in CH2C12 (20 mi) at OOC was added racemic 3-bromo-2-methylpropionic acid (2 g) in CH2C12 (5 m') followed by L-proline t-butyl ester (2 g) in CH2C12 (5 mi). The mixture was stirred at OOC for 5 minutes then allowed to stand at ambient temperature for 18 hours. The solvent was then removed by evaporation and the residue was dissolved in hexane and washed with dilute HCL H20 and Na2C03 solution, dried (M9S04) 35 and evaporated to give 3 g of a 4:1 mixture of the title compound and its L,L isomer.
Claims (26)
1. A process for preparing a compound of formula (1) 4 5 R' R ' R 1 D-Br(H
2 CH-CO-L-N (1) R 2 in excess of the corresponding LL diastereoisomer wherein R' is lower alkyl, R 2 is a carboxy protecting 40 group, R 4 and R 5 either are 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 or halogen, which comprises reacting an enantiomeric mixture of an acid of formula (11) R' 1 BrCH.CHCOOH with a carbodilmide or carbonyl diimidazole coupling agent and a compound of formula (111) (11) 8 GB 2 070 005 A 8 4 5 R R L- H C0) R2 2.
in which formulae W, R 2, R 4 and R5 are as defined above.
GID 2. A process as claimed in Claim 1 wherein R' is methyl.
3. A process as claimed in Claim 1 or Claim 2 wherein R 2 is an alkyl ester of 1 to 6 carbon atoms.
4. A process as claimed in any one of Claims 1 to 3 wherein the coupling agent is dicyciohexylcarbodiimide, diisopropylcarbodiimide, 1-(3dimethylamino)propyl-3-ethylcarbodiimide or carbonyl diimidazole.
5. A process for preparing a compound of formula V11 4 R' R R 1 D-BrCH 2 CHCO-L-N COOH (VII) in excess of the corresponding. LL-diastereoisomer wherein R', R4 and R' areas defined in-Clai m 1, 10 which comprises reacting a compound of formula (X) 4 R' R 1 1 D-BrCH HW-L-N 2 CO0Bub with trifluoroacetic acid at a low temperature for a sufficiently short period of time to prevent substantial racemisation of the propanoyl a- carbon.
(X)
6. A process as claimed in Claim 5 which is effected at a temperature from about -5 to 150C. 15
7. A process as claimed in Claim 6 which is effected at about OOC.
8. A process as claimed in any one of Claims 5 to 7 which is effected in a time of less than about 25 minutes.
9. A process as claimed in any one of Claims 5 to 8 in which the compound of formula X is 20 prepared by a process as claimed in any one of Claims 1 to 4.
10. A process for preparing a compound of formula XI 4 R R, R 1 1. t '%,H s,- \ 0 C (Xl) wherein R' is lower alkyl, R 4 and R5 either both represent hydrogen or together with the carbon atoms to which they are attached represent a benzene ring optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen, which comprises:
a) reacting a compound of formula A 4 5 R' R R D-BrCH 2 'HCO-L- COOH (VII) 9 GB 2 070 005 A 9 substantially free from the L,L isomer, wherein W, R4 and R5 are as defined above with a haloformate ester and a sulphide of formula X11 Y-SH wherein Y represents hydrogen or an alkali metal, with the proviso that when Y is hydrogen the 5 reaction is carried out in the presence of base, and cyclising the product by heating, or b) cyclising by heating a compound of formula (X111) R 1 1 4 5 R R D-BrLHLHLU--L- cos a (X111) substantially free of L,L stereoisomer wherein W, R 4 and Rr' are as defined above, BO is a cation.
11. A process as claimed in Claim 10 wherein Y is hydrogen which is carried out in a tertiary aminesolvent.
12. A process as claimed in Claim 10 wherein B+ is an alkylammonium cation.
13. A process as claimed in Claim 10 wherein B+ is a triethylammonium cation.
14. A process as claimed in any one of Claims 10 to 13 which is effected at a temperature from about 400C to 600C.
15. A process as claimed in any one of Claims 10-14 in which the compound of formula V11 is 15 prepared by a process according to any one of Claims 5 to 9.
16. A process as claimed in Claim 1 substantially as hereinbefore described in any one of Examples 1, 4, 5, 6 and 7.
17. A process as claimed in Claim 5 substantially as hereinbefore described in Example 2a.
18. A process as claimed in Claim 10 substantially as hereinbefore described in Example 3.
19. A compound of formula 1 whenever prepared by a process as claimed in any one of claims 1 to 4 and 16.
20. A compound of formula V11 whenever prepared by a process as claimed in any one of Claims to 9 and 17.
21. A compound of formula Xl whenever prepared by a process as claimed in anyone of Claims 25 10to15and18.
22. A compound of formula X111 4 R R R D-BrCHLHLU-L-Ni cos (3 B e (X111) substantially free of the L,L isomer, wherein W, BO, R4 and R5 are as defined in Claim 10.
23. A compound as claimed in Claim 22 which is the triethylamine salt of 1-(3-brorno-2-D- 30 methyl propanoyl)-L-Pro-SH,
24. A compound of formula V11 4 5 R' R R D-BrLH 2 1 HCO-L- COOH substantially free from the L,L-isomer, wherein W, R4 and R5 are as defined in Claim 5 or a di35 cyclohexyla mine salt thereof.
25. 1-(3-Bromo-2-Dmethylpropanoyi)-L-proline, di-cyclohexylamine salt.
26. 1-(3-Bromo-2-D-methylpropanoyl)-L-proline.
(VID Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981. Published by the Patent Office, 25 Southampton Buildings, London, WC2A l AY, from which copies maybe obtained.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8006414 | 1980-02-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2070005A true GB2070005A (en) | 1981-09-03 |
| GB2070005B GB2070005B (en) | 1984-12-19 |
Family
ID=10511671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8104412A Expired GB2070005B (en) | 1980-02-26 | 1981-02-12 | Processes for preparing proline derivatives and analogous compounds |
Country Status (11)
| Country | Link |
|---|---|
| US (4) | US4349480A (en) |
| EP (1) | EP0035336B1 (en) |
| JP (2) | JPS56128755A (en) |
| AR (2) | AR227663A1 (en) |
| AU (2) | AU544337B2 (en) |
| CA (1) | CA1154782A (en) |
| DE (1) | DE3174292D1 (en) |
| GB (1) | GB2070005B (en) |
| IE (1) | IE50839B1 (en) |
| PH (3) | PH16751A (en) |
| ZA (1) | ZA81743B (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE50839B1 (en) * | 1980-02-26 | 1986-07-23 | Wyeth John & Brother Ltd | Novel processes for preparing proline derivatives and analogous compounds |
| NL180746C (en) * | 1983-11-18 | 1987-04-16 | Matthijs Cornelis Evers | PROCESS FOR PREPARING CAPTOPRIL. |
| JPH0662671B2 (en) * | 1986-01-17 | 1994-08-17 | 株式会社大塚製薬工場 | Proline derivative |
| HU196368B (en) * | 1986-07-04 | 1988-11-28 | Egyt Gyogyszervegyeszeti Gyar | Process for production of 1-/3-brom-/25/-methil-prophionil/-pirrolidin-/25/-carbonic acid |
| US4847384A (en) * | 1987-03-12 | 1989-07-11 | Sandoz Pharm. Corp. | Process for the preparation of certain nitrogen-containing mono- and bicyclic ace inhibitors, and novel intermediates useful therefor |
| US5237073A (en) * | 1988-08-26 | 1993-08-17 | Sepracor, Inc. | Derivatives and precursors of captopril and its analogues |
| IL91581A (en) * | 1988-09-13 | 1993-07-08 | Sepracor Inc | Methods for preparing optically active captopril and its analogues |
| US5166361A (en) * | 1988-09-13 | 1992-11-24 | Sepracor, Inc. | Methods for preparing captopril and its analogues |
| US5430145A (en) * | 1990-10-18 | 1995-07-04 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
| US5308841A (en) * | 1990-12-21 | 1994-05-03 | Merrell Dow Pharmaceuticals Inc. | Amino and nitro containing tricyclic compounds useful as inhibitors of ACE |
| ZA927211B (en) * | 1991-09-27 | 1993-03-24 | Merrell Dow Pharma | Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE. |
| US5455242A (en) * | 1991-09-27 | 1995-10-03 | Merrell Dow Pharmaceuticals Inc. | Carboxyalkyl tricyclic derivatives useful as inhibitors of enkephalinase and ace |
| DE69220744T2 (en) * | 1991-09-27 | 1997-11-13 | Merrell Pharma Inc | 2-Substituted indan-2-mercaptoacetylamide compounds with enkephalinase and ACE inhibitory activity |
| US5457196A (en) * | 1991-09-27 | 1995-10-10 | Merrell Dow Pharmaceuticals Inc. | 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE |
| ES2117123T3 (en) * | 1992-02-14 | 1998-08-01 | Merrell Pharma Inc | DERIVATIVES OF AMINOCETILMERCAPTOACETILAMIDA USED AS INHIBITORS OF ENCEPHALINASE AND ANGIOTENSIN CONVERSION ENZYME. |
| CA2133963C (en) * | 1992-05-15 | 1998-07-07 | Gary A. Flynn | Novel mercaptoacetylamido pyridazo[1,2]pyridazine, pyrazolo[1,2]pyridazine, pyridazo[1,2-a][1,2]diazepine and pyrazolo[1,2-a][1,2]diazepine derivatives useful as inhibitors of enkephalinase and ace |
| US5420271A (en) * | 1992-08-24 | 1995-05-30 | Merrell Dow Pharmaceuticals, Inc. | 2-substituted indane-2-mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase |
| EP0669936B1 (en) * | 1992-10-30 | 2000-11-22 | Merrell Pharmaceuticals Inc. | Mercaptoacetylamide bicyclic lactam derivatives useful as inhibitors of enkephalinase and ace |
| ES2145267T3 (en) * | 1994-02-14 | 2000-07-01 | Merrell Pharma Inc | NOVEL 1,3,4,5-TETRAHYDRO-BENZO (C) AZEPIN-3-ONA MERCAPTOACETYLAMIDE BISULFIDE DERIVATIVES USEFUL AS ENCEPHALINASE AND ANGIOTENSIN CONVERSION ENZYME INHIBITORS. |
| EP0745081B1 (en) * | 1994-02-14 | 2001-11-21 | Merrell Pharmaceuticals Inc. | indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase |
| US5750521A (en) * | 1994-02-14 | 1998-05-12 | Hoechst Marion Roussel Inc. | Mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ACE |
| WO1995021857A1 (en) * | 1994-02-14 | 1995-08-17 | Merrell Pharmaceuticals Inc. | Novel 2-substituted indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace |
| US5530013A (en) * | 1994-02-14 | 1996-06-25 | American Home Products Corporation | Venlafaxine in the inducement of cognition enhancement |
| US5484783A (en) * | 1994-03-24 | 1996-01-16 | Merrell Dow Pharmaceuticals Inc. | Hypocholesterolemic, antiatherosclerotic and hypotriglyceridemic mercaptoacetylamide and benzazapine derivatives |
| ES2201100T3 (en) * | 1994-03-24 | 2004-03-16 | Merrell Pharmaceuticals Inc. | HYPOCOLESTEROLEMIC DISULFIDE MERCAPTOACETILAMIDE DERIVATIVES. |
| CA2184696C (en) * | 1994-03-24 | 2001-01-02 | Gary A. Flynn | Hypocholesterolemic, antiatherosclerotic and hypotriglyceridemic aminoacetylmercapto derivatives |
| GB0119305D0 (en) | 2001-04-12 | 2001-10-03 | Aventis Pharma Gmbh | Mercaptoacetylamide derivatives,a process for their preparation and their use |
| US7531217B2 (en) * | 2004-12-15 | 2009-05-12 | Iowa State University Research Foundation, Inc. | Methods for making high-temperature coatings having Pt metal modified γ-Ni +γ′-Ni3Al alloy compositions and a reactive element |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT986630B (en) * | 1972-04-20 | 1975-01-30 | Pierres Holding Sa | PROCEDURE FOR PRECISION MACHINING OF PIECES BY LASER RADIATION AND DEVICE FOR EXECUTION OF THE PROCEDURE |
| US4105776A (en) * | 1976-06-21 | 1978-08-08 | E. R. Squibb & Sons, Inc. | Proline derivatives and related compounds |
| US4129566A (en) * | 1978-02-15 | 1978-12-12 | E. R. Squibb & Sons, Inc. | Derivatives of dehydrocyclicimino acids |
| US4127535A (en) * | 1977-06-16 | 1978-11-28 | Coy David Howard | Novel dipeptides, intermediates therefor, and compositions and methods employing said dipeptides |
| US4154935A (en) * | 1978-02-21 | 1979-05-15 | E. R. Squibb & Sons, Inc. | Halogen substituted mercaptoacylamino acids |
| CA1109475A (en) * | 1978-07-27 | 1981-09-22 | Miguel A. Ondetti | Thiopropanoylamino acid derivatives |
| US4192945A (en) * | 1978-12-07 | 1980-03-11 | E. R. Squibb & Sons, Inc. | Process for preparing proline and homoproline derivatives |
| EP0017390A3 (en) * | 1979-03-23 | 1981-06-24 | American Home Products Corporation | Bicyclic oxo-thiolactones, pharmaceutical compositions containing them, processes for their preparation and compounds useful as intermediates for their preparation |
| US4303583A (en) * | 1979-08-13 | 1981-12-01 | American Home Products Corporation | 1H,5H-[1,4]Thiazepino[4,3-a]indole-1,5-diones |
| US4291040A (en) * | 1979-10-22 | 1981-09-22 | E. R. Squibb & Sons, Inc. | Mercaptoacyl derivatives of 4-disubstituted prolines and 4-substituted dehydroprolines |
| GB2065643B (en) * | 1979-12-13 | 1983-08-24 | Kanegafuchi Chemical Ind | Optically active n-mercaptoalkanoylamino acids |
| HU184082B (en) * | 1979-12-29 | 1984-06-28 | Egyt Gyogyszervegyeszeti Gyar | Process for preparing 1-3-/3mercapto-/2s/-methyl-propinyl/-pyrrolidine-/2s/-carboxylic acid |
| IE50839B1 (en) * | 1980-02-26 | 1986-07-23 | Wyeth John & Brother Ltd | Novel processes for preparing proline derivatives and analogous compounds |
| US4454291A (en) * | 1981-07-20 | 1984-06-12 | American Home Products Corporation | N-(2-Substituted-1-oxoalkyl)-2,3-dihydro-1H-indole-2-carboxylic acid derivatives |
-
1981
- 1981-02-03 IE IE210/81A patent/IE50839B1/en not_active IP Right Cessation
- 1981-02-04 ZA ZA00810743A patent/ZA81743B/en unknown
- 1981-02-05 AU AU66941/81A patent/AU544337B2/en not_active Expired
- 1981-02-10 CA CA000370546A patent/CA1154782A/en not_active Expired
- 1981-02-11 AR AR284267A patent/AR227663A1/en active
- 1981-02-12 JP JP1957481A patent/JPS56128755A/en active Pending
- 1981-02-12 GB GB8104412A patent/GB2070005B/en not_active Expired
- 1981-02-12 PH PH25215A patent/PH16751A/en unknown
- 1981-02-12 EP EP81300568A patent/EP0035336B1/en not_active Expired
- 1981-02-12 DE DE8181300568T patent/DE3174292D1/en not_active Expired
- 1981-02-20 US US06/236,350 patent/US4349480A/en not_active Expired - Lifetime
-
1982
- 1982-02-19 PH PH26893A patent/PH17373A/en unknown
- 1982-02-19 PH PH26894A patent/PH17181A/en unknown
- 1982-03-26 AR AR288889A patent/AR231987A1/en active
- 1982-05-10 US US06/376,356 patent/US4391752A/en not_active Expired - Lifetime
- 1982-05-10 US US06/376,354 patent/US4578480A/en not_active Expired - Lifetime
- 1982-05-10 US US06/376,355 patent/US4506082A/en not_active Expired - Lifetime
-
1985
- 1985-02-25 AU AU39126/85A patent/AU566441B2/en not_active Expired - Fee Related
-
1987
- 1987-06-05 JP JP1987086778U patent/JPS62199283U/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP0035336A2 (en) | 1981-09-09 |
| US4506082A (en) | 1985-03-19 |
| ZA81743B (en) | 1982-09-29 |
| PH17181A (en) | 1984-06-13 |
| AU566441B2 (en) | 1987-10-22 |
| JPS56128755A (en) | 1981-10-08 |
| GB2070005B (en) | 1984-12-19 |
| PH17373A (en) | 1984-08-06 |
| US4578480A (en) | 1986-03-25 |
| AR227663A1 (en) | 1982-11-30 |
| EP0035336B1 (en) | 1986-04-09 |
| IE50839B1 (en) | 1986-07-23 |
| CA1154782A (en) | 1983-10-04 |
| IE810210L (en) | 1981-08-26 |
| JPS62199283U (en) | 1987-12-18 |
| EP0035336A3 (en) | 1981-11-25 |
| AR231987A1 (en) | 1985-04-30 |
| US4391752A (en) | 1983-07-05 |
| DE3174292D1 (en) | 1986-05-15 |
| AU6694181A (en) | 1981-09-03 |
| AU544337B2 (en) | 1985-05-23 |
| AU3912685A (en) | 1985-07-11 |
| US4349480A (en) | 1982-09-14 |
| PH16751A (en) | 1984-02-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 727 | Application made for amendment of specification (sect. 27/1977) | ||
| 727A | Application for amendment of specification now open to opposition (sect. 27/1977) | ||
| 727B | Case decided by the comptroller ** specification amended (sect. 27/1977) | ||
| SP | Amendment (slips) printed | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 20010211 |