CA1155443A - Processes for preparing proline derivatives and analogous compounds - Google Patents
Processes for preparing proline derivatives and analogous compoundsInfo
- Publication number
- CA1155443A CA1155443A CA000424590A CA424590A CA1155443A CA 1155443 A CA1155443 A CA 1155443A CA 000424590 A CA000424590 A CA 000424590A CA 424590 A CA424590 A CA 424590A CA 1155443 A CA1155443 A CA 1155443A
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Abstract
H-284a CAN
ABSTRACT
The invention relates to the stereospecific synthesis of angiotensin converting enzyme (ACE) inhibitors having the formula:
ABSTRACT
The invention relates to the stereospecific synthesis of angiotensin converting enzyme (ACE) inhibitors having the formula:
Description
H-284a CAN
~155~43 This invention relates to a novel process for the preparation of pharmaceutically active L-proline derivatives.
In particular this invention relates to a stereo-specific synthesis of 4s, 9as cyclic L-proline derivatives having formula (I) 4 ' 5 R~ R
o~ r~
R1 ~ ~ tI) wherein R1 is lower alkyl and R4 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. Compounds of formula I are useful as chemical intermediates and also as angiotensin converting enzyme inhibitors and potential antihypertensive agents.
, We have found a particularly convenient route to such stereoisomers employing stereoisomers of formula II
R ~
D-BrCH2CHCO-L-N ~ (II) wherein R , R and R are 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 II, especially when prepared by the process hereinbefore described-in our copending Canadian Patent ~pplication No.
370,546, which provides increased proportions of the desired stereoisomer, is very easily effected. Also separation at an early stage avoids wasting reactant in preparing undesired isomers of the final product.
~L
'' H-284a CAN
~55~3 Accordingly this invention also provides a process for preparing a compound of formula (I) as defined above which comprises (i) reacting a compound of formula 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 (III) Y-SH (III) 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 basej e.g.
a tertiary amine, such as triethylamine, and (ii) cyclising the product of step (i) by heating, e.g.
at 40 to 60C, preferably about 45C.
Conveniently the reaction step (ii) 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 "one-pot" process can be used to go from II to I.
It is understood that the above mentioned reaction process forms as an intermediate in situ a compound of ormula (IV) 1 R ~___~R5 D-BrCH2CHCO-_-N ~ (IV) COS ~3 B ~3 wherein R1 is lower alkyl, B ~3 is a cation (derived from the base when Y is hydrogen), e.g. an alkali metal or an ammonium ion such as an alkylammonium cation. The compounds of formula IV substantially free of L,L
stereoisomers are also within the scope of this invention.
H-284a CAN
55~43 Preferably R1 is methyl. Preferably B ~ is the triethylammonium ion.
This lnvention also provides a process ~or preparing a compound of formula I as hereinbe~ore defined which comprises cyclising a compound of formula IV by heating, preferably in the presence of a polar solvent such as acetonitrile. Preferably the cyclisation is effected at a temperature of from 40 to 60C, e.g.
about 45C. The starting materials of formula II may be prepared according to processes described in our copending Canadian Patent ~pplication No. 370,546. The desired D,L-stereoisomer may be separated from the corresponding L,L-stereoisomer ~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 D,L-form of the acid of formula II is obtained as the DCHA salt. It may be converted to the acid by known means, e.g. treating with KHSO4.
The following Examples further illustrate this invention in which Examples 1 and 2 illustrate the praparation of intermediates:
1-(3-bromo-2-D-methylpropanoyl)-L-proline tert-butyl ester Racemic 3-bromo-2-methylpropionic acid (50g) in methylene dichloride (50 ml) was added over a ~ hour period to a solution of dicyclohexylcarbodiimide (60 g) in methylene chloride (400 ml) kept at -5 to 0C by external cooling. L-proline tert-butyl ester (50 g) in methylene dichloride (50 ml) was then added over a ~ hour period. The mixture was allowed to slowly warm to room temperature and left overnight. The precipitate formed in the reaction, was filtered and the filtrate evaporated. The residue was dissolved in diethyl ether H-28~a CAN
(300 ml) and washed successively with 1N HCl, water, 1N NaOH and water. The ether layer was dried (MgSO4) 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, 4.35.
C13H22BrNO3 requires C, 48.8; H,6.9; N, 4.4%
The relative isomer proportions were estimated to be 80:20 from the nmr spectrum of the tertiary butyl groups in the product, in CDC13.
1-(3-Bromo-2-D-methylpropanoyl-L-proline (a) To trifluoroacetic acid (300 g) cooled to 0C was added 1-(3-bromo-2-methylpropanoyl)-L-proline, t-butyl ester (90 g of an 80:20 mixture of D,L and L,L forms).
The mixture was warmed to 25C and kept there for ~
hour. The trifluoroacetic ac-id 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, MeOH-d4, NaOD
solution. Signals appeared at ~ 1.50 and 1.55 for D,L
and L,L isomers respectively and were in the ratio 80:20.
(b) The residue was dissolved in diethyl ether (500 ml) and treated with excess di-cyclohexylamine (90 g). A
solid formed and was filtered and recrystallised from propan-2-ol to give 1-(3-bromo-2-D-methylpropanoyl)-L-proline di-cyclohexylamine salt (83 g, 95~ D,L form).
(c) The di-cyclohexylamine salt was converted back into the free acid by treatment with KHSO4 solution (1N 5 volumes) and it was extracted with methylene dichloride solvent. The solvent was removed by evaporation and the residue dissolved ln Na2CO3 solution and this was washed with ether (3 x), acidified with HCl (2N) and the H-2~4a CAN
1 ~554~3 acid was extracted with ether. After the ether solution had been dried (MgS04) and evaporated the residue was recrystallised from di-isopropyl ether to give 1-(3~bromo-2-D-methylpropanoyl)-L-proline as the monohydrate (m.p. 74-5).
Analysis:
Found: C, 38.1; H, 5~7; N, 4.5 CgH14BrNO3,H2O re~uires C, 38.3; H, 5.7; N, 5.0~.
~4S, 9aS)-Hexahydro-4-methyl-1H,5H-pyrrolo[2,1-c]-[1,4]thiazepine-1,5-dione. (I :R1 = Me, R = R5 = H) ~ A solution of 1-(3-bromo-2-D-methylpropanoyl)-L-proline (1.3 g) in CH2Cl2 (50 ml) was cooled to 0C and treated in turn with triethylamine (1 ml) then ethyl chloroformate (0.5 ml). After ~ hour triethylamine (0.5 ml) was added and H2S gas was bubbled in at 20 ml/min for 20 minutes to give a mixture containing the triethyl-amine salt of 1-(3-bromo-2-D-methylpropanoyl)-L-Pro-SH.
The solvent was removed by evaporation, then the residue dissolved in acetonitrile (50 ml) and heated at 45C for 4 hours. The solvent was removed by evaporation and the residue was dissolved in methylene dichloride. 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 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).
Anal~sis:
Found: C, 54.7; H, 6.8; N, 6.B5.
CgH13NO2S requires C, 54.3; H, 6.6; N, 7.0
~155~43 This invention relates to a novel process for the preparation of pharmaceutically active L-proline derivatives.
In particular this invention relates to a stereo-specific synthesis of 4s, 9as cyclic L-proline derivatives having formula (I) 4 ' 5 R~ R
o~ r~
R1 ~ ~ tI) wherein R1 is lower alkyl and R4 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. Compounds of formula I are useful as chemical intermediates and also as angiotensin converting enzyme inhibitors and potential antihypertensive agents.
, We have found a particularly convenient route to such stereoisomers employing stereoisomers of formula II
R ~
D-BrCH2CHCO-L-N ~ (II) wherein R , R and R are 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 II, especially when prepared by the process hereinbefore described-in our copending Canadian Patent ~pplication No.
370,546, which provides increased proportions of the desired stereoisomer, is very easily effected. Also separation at an early stage avoids wasting reactant in preparing undesired isomers of the final product.
~L
'' H-284a CAN
~55~3 Accordingly this invention also provides a process for preparing a compound of formula (I) as defined above which comprises (i) reacting a compound of formula 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 (III) Y-SH (III) 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 basej e.g.
a tertiary amine, such as triethylamine, and (ii) cyclising the product of step (i) by heating, e.g.
at 40 to 60C, preferably about 45C.
Conveniently the reaction step (ii) 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 "one-pot" process can be used to go from II to I.
It is understood that the above mentioned reaction process forms as an intermediate in situ a compound of ormula (IV) 1 R ~___~R5 D-BrCH2CHCO-_-N ~ (IV) COS ~3 B ~3 wherein R1 is lower alkyl, B ~3 is a cation (derived from the base when Y is hydrogen), e.g. an alkali metal or an ammonium ion such as an alkylammonium cation. The compounds of formula IV substantially free of L,L
stereoisomers are also within the scope of this invention.
H-284a CAN
55~43 Preferably R1 is methyl. Preferably B ~ is the triethylammonium ion.
This lnvention also provides a process ~or preparing a compound of formula I as hereinbe~ore defined which comprises cyclising a compound of formula IV by heating, preferably in the presence of a polar solvent such as acetonitrile. Preferably the cyclisation is effected at a temperature of from 40 to 60C, e.g.
about 45C. The starting materials of formula II may be prepared according to processes described in our copending Canadian Patent ~pplication No. 370,546. The desired D,L-stereoisomer may be separated from the corresponding L,L-stereoisomer ~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 D,L-form of the acid of formula II is obtained as the DCHA salt. It may be converted to the acid by known means, e.g. treating with KHSO4.
The following Examples further illustrate this invention in which Examples 1 and 2 illustrate the praparation of intermediates:
1-(3-bromo-2-D-methylpropanoyl)-L-proline tert-butyl ester Racemic 3-bromo-2-methylpropionic acid (50g) in methylene dichloride (50 ml) was added over a ~ hour period to a solution of dicyclohexylcarbodiimide (60 g) in methylene chloride (400 ml) kept at -5 to 0C by external cooling. L-proline tert-butyl ester (50 g) in methylene dichloride (50 ml) was then added over a ~ hour period. The mixture was allowed to slowly warm to room temperature and left overnight. The precipitate formed in the reaction, was filtered and the filtrate evaporated. The residue was dissolved in diethyl ether H-28~a CAN
(300 ml) and washed successively with 1N HCl, water, 1N NaOH and water. The ether layer was dried (MgSO4) 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, 4.35.
C13H22BrNO3 requires C, 48.8; H,6.9; N, 4.4%
The relative isomer proportions were estimated to be 80:20 from the nmr spectrum of the tertiary butyl groups in the product, in CDC13.
1-(3-Bromo-2-D-methylpropanoyl-L-proline (a) To trifluoroacetic acid (300 g) cooled to 0C was added 1-(3-bromo-2-methylpropanoyl)-L-proline, t-butyl ester (90 g of an 80:20 mixture of D,L and L,L forms).
The mixture was warmed to 25C and kept there for ~
hour. The trifluoroacetic ac-id 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, MeOH-d4, NaOD
solution. Signals appeared at ~ 1.50 and 1.55 for D,L
and L,L isomers respectively and were in the ratio 80:20.
(b) The residue was dissolved in diethyl ether (500 ml) and treated with excess di-cyclohexylamine (90 g). A
solid formed and was filtered and recrystallised from propan-2-ol to give 1-(3-bromo-2-D-methylpropanoyl)-L-proline di-cyclohexylamine salt (83 g, 95~ D,L form).
(c) The di-cyclohexylamine salt was converted back into the free acid by treatment with KHSO4 solution (1N 5 volumes) and it was extracted with methylene dichloride solvent. The solvent was removed by evaporation and the residue dissolved ln Na2CO3 solution and this was washed with ether (3 x), acidified with HCl (2N) and the H-2~4a CAN
1 ~554~3 acid was extracted with ether. After the ether solution had been dried (MgS04) and evaporated the residue was recrystallised from di-isopropyl ether to give 1-(3~bromo-2-D-methylpropanoyl)-L-proline as the monohydrate (m.p. 74-5).
Analysis:
Found: C, 38.1; H, 5~7; N, 4.5 CgH14BrNO3,H2O re~uires C, 38.3; H, 5.7; N, 5.0~.
~4S, 9aS)-Hexahydro-4-methyl-1H,5H-pyrrolo[2,1-c]-[1,4]thiazepine-1,5-dione. (I :R1 = Me, R = R5 = H) ~ A solution of 1-(3-bromo-2-D-methylpropanoyl)-L-proline (1.3 g) in CH2Cl2 (50 ml) was cooled to 0C and treated in turn with triethylamine (1 ml) then ethyl chloroformate (0.5 ml). After ~ hour triethylamine (0.5 ml) was added and H2S gas was bubbled in at 20 ml/min for 20 minutes to give a mixture containing the triethyl-amine salt of 1-(3-bromo-2-D-methylpropanoyl)-L-Pro-SH.
The solvent was removed by evaporation, then the residue dissolved in acetonitrile (50 ml) and heated at 45C for 4 hours. The solvent was removed by evaporation and the residue was dissolved in methylene dichloride. 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 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).
Anal~sis:
Found: C, 54.7; H, 6.8; N, 6.B5.
CgH13NO2S requires C, 54.3; H, 6.6; N, 7.0
Claims (6)
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of formula ( I ) ( I ) wherein R1 is lower alkyl, R4 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 (II) substantially free from the L,L isomer, wherein R1, R4 and R5 are as defined above with a haloformate ester and a sulphide of formula XII
Y-SH (III) wherein Y represents hydrogen or an alkali metal, with the proviso that when Y is hydrogen the reaction is carried out in the presence of base, and cyclising the product by heating, or b) cyclising by heating a compound of formula (XIII) (IV) H-284a CAN
substantially free of L,L stereoisomer wherein R1, R4 and R5 are as defined above, B ? is a cation.
a) reacting a compound of formula (II) substantially free from the L,L isomer, wherein R1, R4 and R5 are as defined above with a haloformate ester and a sulphide of formula XII
Y-SH (III) wherein Y represents hydrogen or an alkali metal, with the proviso that when Y is hydrogen the reaction is carried out in the presence of base, and cyclising the product by heating, or b) cyclising by heating a compound of formula (XIII) (IV) H-284a CAN
substantially free of L,L stereoisomer wherein R1, R4 and R5 are as defined above, B ? is a cation.
2. A process as claimed in Claim 1 wherein Y is hydrogen which is carried out in tertiary amine solvent.
3. A process as claimed in Claim 1 wherein B ? is an alkylammonium cation.
4. A compound of formula I as defined in Claim 1 whenever prepared by a process as claimed in Claim 1 or by an obvious chemical equivalent.
5. A compound of formula I as defined in Claim 1 whenever prepared by a process as claimed in Claim 2 or by an obvious chemical equivalent.
6. A compound of formula I as defined in Claim 1 whenever prepared by a process as claimed in Claim 3 or by an obvious chemical equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000424590A CA1155443A (en) | 1980-02-26 | 1983-03-25 | Processes for preparing proline derivatives and analogous compounds |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8006414 | 1980-02-26 | ||
| GB8006414 | 1980-02-26 | ||
| CA000370546A CA1154782A (en) | 1980-02-26 | 1981-02-10 | Processes for preparing proline derivatives and analogous compounds |
| CA000424590A CA1155443A (en) | 1980-02-26 | 1983-03-25 | Processes for preparing proline derivatives and analogous compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1155443A true CA1155443A (en) | 1983-10-18 |
Family
ID=27166966
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000424590A Expired CA1155443A (en) | 1980-02-26 | 1983-03-25 | Processes for preparing proline derivatives and analogous compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1155443A (en) |
-
1983
- 1983-03-25 CA CA000424590A patent/CA1155443A/en not_active Expired
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