Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-23
2002-06-18
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06407262
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a process for the production of inhibitors of ACE (Angiotensin Converting Enzyme) and, in particular, to a process for separation of diastereomeric mixtures of compounds of formula 1 and 2.
wherein R
1
=H or R
1
denotes a carboxyl-esterifying group, such as C
1
-C
6
alkyl, or C
7
-C
8
aralkyl.
BACKGROUND OF THE INVENTION
The previously reported syntheses of Ramipril (1, wherein R
1
=H) use two approaches. The first approach utilizes the reaction of racemic amino esters 4a and 4b (R
2
denotes a carboxyl-esterifying group, such as C
1
-C
6
alkyl, C
7
-C
8
aralkyl, preferably benzyl or tert-butyl)
with a compound of formula 3, wherein the atoms indicated with an asterisk have the S configuration,
using amide formation methods known in peptide chemistry (such as those described in CA 1,338,162, EP 79022, U.S. Pat. No. 5,977,380, ES 549789 and ES 2004804, for example) to prepare the mixture of compounds 5 and 6,
wherein R
2
denotes a carboxyl-esterifying group, such as C
1
-C
6
alkyl, or C
7
-C
8
aralkyl. This route gives a 1:1 mixture of diastereomers 5 and 6 from which the desired diastereomer 5 is separated using silica gel chromatography. Subsequent removal of the protecting group by hydrogenolysis or treatment with an acid or base yields Ramipril (compound of formula 1, R
1
=H). This approach is disclosed in EP 79022, for example. This procedure suffers from the disadvantage of requiring two additional synthetic steps to install the carboxyl protecting group of 4a and 4b and to remove the ester group on 5, and the disadvantage of requiring costly and hard-to-implement silica gel chromatographic purification to separate 5 and 6.
The compound of the formula 3 is well known (for example in European patent 037, 231) and is accessible in various ways. Several routes for the synthesis of the racemic mixture 4a and 4b have been disclosed in the patent literature (Patent EP 79022, Patent EP 50800, Patent ES 549251, Patent CN 1106386 for example) and in the literature (V. Teetz et al
Tetrahedron Letters
, 1984, 25(40), 4479-4482, for example).
The second approach utilizes enantiopure amino ester 4a (R
2
denotes a carboxyl-esterifying group, such as C
1
-C
6
alkyl, C
7
-C
8
aralkyl, preferably benzyl or tert-butyl) as one partner in a coupling reaction with compound 3, using the methods commonly known in peptide chemistry (such as those described in CA 1,338,162, EP 79022, U.S. Pat. No. 5,977,380, ES 549789 and ES 2004804, for example) to prepare 5 wherein R
2
denotes a carboxyl-esterifying group, such as C
1
-C
6
alkyl or C
7
-C
8
aralkyl.
When the compound of formula 5 (wherein R
2
denotes a carboxyl-esterifying group, such as C
1
-C
6
alkyl or C
7
-C
8
aralkyl) is prepared using a coupling of 4a with 3, the ester protecting group (R
2
) is removed by hydrogenolysis or treatment with an acid or base, then the resulting product (1, Ramipril where R
1
=H) is crystallized from a substantially pure solution. However, this general route also has its difficulties. Firstly, the efficient large-scale enantioselective synthesis of chirally pure 4a has not been reported. However, there are two reported enantioselective syntheses of compound 4a or derivatives. An enantioselective synthesis of 7a was reported by L. M. Harwood and L. C. Kitchen (
Tetrahedron Letters
, 1993, 34(41), 6603-6606) but the chemistry does not appear suitable to scale-up and the overall yield is low (13%)
An enantioselective (but not diastereoselective) route, reported by H. Urbach and R. Henning, (Heterocycles, 1989, 28(2), 957-965) gave 4a (R
2
=Benzyl) in an overall yield of 5.5%, which appears to be too low for commercial implementation.
There are three reported methods for the resolution of bicyclic amino acids of this type. An enantioenriched sample of amino acid 7a was obtained by resolution of 7a and 7b is reported in patent ES 549251. Amino acid 7a can be converted to amino ester 4a by methods known to those skilled in the art.
This resolution removes 7b from a mixture of 7a and 7b, giving, after removal of the chiral base by acidification of the residue, a 52% yield of material (7a) in unspecified optical purity. However, this resolution uses an expensive chiral amine (S)-1-(1-naphthyl)ethylamine.
The other reported resolution methods resolve the racemic mixture of 4a and 4b. A resolution separating 4a (R
2
=carboxyl esterifying group) from a racemic mixture of 4a and 4b using N-acyl derivatives of optically active R or S amino acids containing a phenyl nucleus has been disclosed in patent EP 115345. This procedure gives 4a (wherein R
1
=Benzyl) in a yield corresponding to 102.1% of theoretical, with an optical purity of 87%. This resolution, as disclosed, uses the toxic solvent dichloromethane and an expensive anti-solvent cyclohexane.
A resolution protocol for the obtention of 4a from a racemic mixture of 4a and 4b has been reported using S-mandelic acid (J. Martens and S. Lubben,
Journal fur Prakt. Chemie
1990, 332(6), 1111-1117). This protocol returns 4a in high purity (>98%) but in lower yield (43% for the mandelic acid salt). Unfortunately, these two approaches require a sequence of steps when used in the production of Ramipril, as it is reported: protection of the amino acid as a carboxylic ester, free-basing the HCl salt, formation of the salt with the resolving agent, isolation of the diastereomeric salt, free-basing the diastereomeric salt, and formation of the HCl salt. Using this many steps to produce the material consumes expensive plant time and reduces efficiency.
SUMMARY OF THE INVENTION
According to a first aspect of the present invention there is provided a process for separating diastereomeric mixtures of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydro-cyclopenta[b]pyrrole-2-carboxylic acid derivative of compound formula 1 and (2R,3aR,6aR)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid derivative of compound of formula 2, the process comprising:
(a) treating the mixture of 1 and 2 with a solvent or a mixture of solvents selected from a group consisting of C
2
-C
4
nitrile solvents, C
1
-C
6
alcohol solvents, C
6
-C
8
aromatic hydrocarbon solvents, C
3
-C
10
ether solvents, C
3
-C
6
ketone solvents, C
2
-C
7
ester solvents, C
1
to C
3
chlorinated solvents, and C
5
-C
10
hydrocarbon solvents,
(b) adding an organic or inorganic acid, if desired, selected from a group consisting of benzoic acid, mandelic acid, maleic acid, fumaric acid, methane sulfonic acid, toluene sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid,
(c) allowing the compound of formula 1 to precipitate and filtering the slurry to obtain a solid compound of formula 1, where R
1
=H or R
1
denotes a carboxyl-esterifying group, such as C
1
-C
6
alkyl, preferably tert-butyl, and C
7
-C
8
aralkyl, preferably benzyl.
The process involves the treatment of an equal or unequal amount of diastereomeric compounds 1 and 2 with a solvent or a mixture of solvents, treating the mixture of 1 and 2 in a solvent with an inorganic or organic acid, if necessary, stirring the mixture of 1 and 2 in a solvent or a mixture of solvents, allowing the desired isomer to precipitate with or without seeding, adding a solvent (or a mixture of solvents) if desired, and isolating the desired substantially pure compound 1 at a temperature of −50 to 50° C. as a solid. The isolated product 1 may be treated with an acid or base if necessary, or subjected to hydrogenolysis if necessary to give Ramipril.
When R
1
is benzyl, for example, the preferred acid salt is maleic acid and the salt produced is (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-amino]propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid benzyl ester maleic acid salt.
McPhail Cameron
Wang Zhi-Xian
Anderson Rebecca
Brantford Chemicals Inc.
Hughes Ivor M.
Hughes Neil H.
Sarkis Marcelo K.
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