WO2005066134A1 - Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts - Google Patents
Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts Download PDFInfo
- Publication number
- WO2005066134A1 WO2005066134A1 PCT/EP2004/014552 EP2004014552W WO2005066134A1 WO 2005066134 A1 WO2005066134 A1 WO 2005066134A1 EP 2004014552 W EP2004014552 W EP 2004014552W WO 2005066134 A1 WO2005066134 A1 WO 2005066134A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- dicarboxylic acid
- benazepril
- formula
- compound
- Prior art date
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- 0 CCOC(C(CCc1ccccc1)NC(CCc(cccc1)c1N1CC(O*)=O)C1=O)=O Chemical compound CCOC(C(CCc1ccccc1)NC(CCc(cccc1)c1N1CC(O*)=O)C1=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- DICARBOXYLIC ACID SALTS The present invention is directed to novel salts of esters of benazepril, which are convertible to benazepril hydrochloride.
- Benazepril hydrochloride is marketed as an angiotensin-converting enzyme inhibitor which is useful for the treatment of hypertension in man.
- Benazepril is 3-[[1-(ethoxy-carbonyl)-3-phenyl-(7S)-propyl]amino]-2,3,4,5-tetrahydro- 2-oxo- 7W-1-(3S)-benzazepine-1 -acetic acid; its structural formula (I) is
- Benazepril hydrochloride is the active ingredient of Lotensin ® tablets and Lotensin HCT ® tablets, and is one of the active ingredients of Lotrel ® capsules, all marketed by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, for the treatment of hypertension.
- benazepril hydrochloride is the (S,S)-diastereomer which is one of four possible diastereomers, namely the ⁇ S,S), ⁇ R,R), (R,S) and ⁇ S,R) diastereomers.
- R represents a selectively removable protecting group, e.g., optionally substituted benzyl or benzhydryl (substituted, e.g., by nitro), -butyl, allyl, tetrahydrofuranyl or tetrahydropyranyl.
- carboxylic acid ester protecting groups are well-known in the art, e.g., as described in Greene, Protective Groups in Organic Synthesis, John Wiley and Sons and, e.g., as used in penicillin and cephalosporin synthesis. Allyl esters (the protecting group R being allyl) are described, e.g., in Peptide Protein Res, Vol. 26, pp. 493-497 (1985).
- the allyl ester can be prepared, e.g., by treatment of the carboxylic acid with allyl bromide in the presence of, e.g., cesium carbonate.
- Diesters of formula (II) are prepared as illustrated, e.g., in U.S. Patent No. 4,785,089, which is incorporated here by reference. The reaction sequence is as follows:
- (S)-enantiomer (R)-enantiomer R represents a selectively removable protecting group.
- the enantiomeric purity of (A), (B) and (II) starting materials is about 95-99%. It has now been discovered that the basic diesters of formula (II) unexpectedly form crystalline bis-dicarboxylic acid addition salts with dicarboxylic acids, that is salts in which the molecular ratio of a compound of formula (II) and the dicarboxylic acid is 1 :2.
- a particular embodiment relates to the salts of formula (III)
- X represents a direct bond, lower alkylene, arylene or mono- or b/s-hydroxy-lower alkyiene; and R has the meaning as defined above.
- Lower alkylene represents straight-chain or branched alkylene of 1-7 carbon atoms.
- Arylene represents, e.g., phenylene, advantageously para-phenylene.
- Representative dicarboxylic acids of the formula (IV) HOOC— X— COOH (IV) are oxalic acid, D- or L-tartaric acid, optionally substituted (malonic acid, glutaric acid or succinic acid), D- or L-maiic acid, D- or L-citramalic acid, terephthalic acid, aspartic acid and the like.
- Optionally substituted refers to such being unsubstituted or substituted by, e.g., lower alkyl, and lower alkyl represents straight chain or branched alkyl of 1-7 carbon atoms.
- Particular embodiments of salts of formula (III) are, e.g., salts of formula (III) wherein R is f-butyl; and the dicarboxlyic acid of the formula (IV) HOOC— X— COOH (IV) is oxalic acid, tartaric acid or isopropylmalonic acid.
- the salts are typically prepared by treating one mole of a compound of formula (II) with 1-2 mole equivalents, preferably 2 mole equivalents, of the dicarboxylic acid in an organic solvent, at a temperature ranging from about room temperature to the reflux temperature of the solvent and, if required, purified by recrystallization using an appropriate solvent or mixture of solvents.
- the new highly enantiomerically pure diester salts of formula (III) are useful as intermediates for the preparation of benazepril and salts thereof of high enantiomeric purity.
- the enantiomeric purity of the final product (benazepril) and salts thereof is about 99-100%, preferably about 99.6-100%, advantageously 99.8-100%.
- the diester dicarboxylic acid salts of formula (III) are selectively converted to benazepril or a salt thereof by selective removal of the protecting group R using methodology well-known in the art.
- the f-butyl ester or the benzhydryl ester group is cleaved by treatment with an anhydrous acid, e.g., by solvolysis with HCI gas in an organic solvent, such as ethyl acetate to obtain benazepril hydrochloride.
- Benzyl esters are selectively converted to the acid by, e.g., catalytic hydrogenolysis, e.g., in the presence of Pd on charcoal.
- Benzhydryl (diphenylmethyl) esters are cleaved under anhydrous acidic conditions similarly to f-butyl esters. Allyl esters can be converted to the acid using a rhodium(l) or palladium(O) catalyst, e.g., r ⁇ s(triphenylphosphine) rhodium(l) chloride or tetrakis(triphenylphosphine) palladium(O). If the compound of formula (I) (the free base) is obtained, such can be converted to a pharmaceutically acceptable salt thereof, e.g., to benazepril hydrochloride using methodology known in the art. A further aspect of the invention relates to a process for the preparation of benazepril, the structural formula (I) of which is
- R represents a selectively removable protecting group
- S denotes the (S)-configuration of the asymmetric carbon atoms; by treatment with a dicarboxylic acid to obtain a crystalline b/s-dicarboxylic acid salt of formula (III)
- said salt being of high enantiomeric purity; (b) converting said salt to the corresponding free base; and (c) converting said diester free base to benazepril or a pharmaceutically acceptable salt thereof by selective removal of the R protecting group; and (d) if required, converting the resulting benazepril free base to a pharmaceutically acceptable salt thereof.
- one mole of the compound of formula (II) is typically treated with 1 to 2 mole equivalents of the dicarboxylic acid, preferably 2 mole equivalents.
- the salt formation is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent.
- Preferred solvents are alcohols, such as ethanol or isopropanol; esters, such as ethyl acetate; or mixtures of solvents to crystallize the product, e.g., isopropyl alcohol and heptane.
- Temperatures are given in degrees Centigrade (°C).
- the structure and composition of the products is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic methods, such as IR and NMR. The abbreviations used are conventional in the art.
- Benazepril hydrochloride 15.6 g (20 mmol) of the b/ ' s-D-tartrate salt of Example 1 is suspended in 200 mL of EtOAc.
- a 10% aqueous solution of potassium carbonate (ca. 120 mL) at room temperature under vigorous stirring.
- the phases are separated and the organic phase is washed twice with water, dried and evaporated to dryness.
- the residue is dissolved in dry EtOAc and the solution is again evaporated to dryness.
- the resulting diester free base which is obtained as an oil is again dissolved in 100 mL of dry ethyl acetate.
- To this solution is added a stream of dry HCI gas (ca.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Resins (AREA)
- Polyesters Or Polycarbonates (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK04804148T DK1699764T3 (en) | 2003-12-22 | 2004-12-21 | Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts |
SI200430414T SI1699764T1 (en) | 2003-12-22 | 2004-12-21 | Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts |
PL04804148T PL1699764T3 (en) | 2003-12-22 | 2004-12-21 | Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts |
DE602004006896T DE602004006896T2 (en) | 2003-12-22 | 2004-12-21 | BIS-DICARBOXYLIC ACIDS OF BENAZEPRIL AND PREPARATION OF BENAZEPRIL OVER THESE SALTS |
EP04804148A EP1699764B1 (en) | 2003-12-22 | 2004-12-21 | Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US53174603P | 2003-12-22 | 2003-12-22 | |
US60/531,746 | 2003-12-22 |
Publications (1)
Publication Number | Publication Date |
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WO2005066134A1 true WO2005066134A1 (en) | 2005-07-21 |
Family
ID=34748775
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/014552 WO2005066134A1 (en) | 2003-12-22 | 2004-12-21 | Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1699764B1 (en) |
AT (1) | ATE364039T1 (en) |
CY (1) | CY1107067T1 (en) |
DE (1) | DE602004006896T2 (en) |
DK (1) | DK1699764T3 (en) |
ES (1) | ES2286706T3 (en) |
PL (1) | PL1699764T3 (en) |
PT (1) | PT1699764E (en) |
WO (1) | WO2005066134A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104788376A (en) * | 2014-01-17 | 2015-07-22 | 海门慧聚药业有限公司 | New crystal form of benazepril hydrochloride and preparation method thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4575503A (en) * | 1983-02-10 | 1986-03-11 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
-
2004
- 2004-12-21 EP EP04804148A patent/EP1699764B1/en active Active
- 2004-12-21 AT AT04804148T patent/ATE364039T1/en active
- 2004-12-21 PT PT04804148T patent/PT1699764E/en unknown
- 2004-12-21 ES ES04804148T patent/ES2286706T3/en active Active
- 2004-12-21 PL PL04804148T patent/PL1699764T3/en unknown
- 2004-12-21 DE DE602004006896T patent/DE602004006896T2/en active Active
- 2004-12-21 WO PCT/EP2004/014552 patent/WO2005066134A1/en active IP Right Grant
- 2004-12-21 DK DK04804148T patent/DK1699764T3/en active
-
2007
- 2007-08-30 CY CY20071101120T patent/CY1107067T1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4575503A (en) * | 1983-02-10 | 1986-03-11 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104788376A (en) * | 2014-01-17 | 2015-07-22 | 海门慧聚药业有限公司 | New crystal form of benazepril hydrochloride and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
DK1699764T3 (en) | 2007-10-08 |
PT1699764E (en) | 2007-08-08 |
PL1699764T3 (en) | 2007-10-31 |
ES2286706T3 (en) | 2007-12-01 |
DE602004006896D1 (en) | 2007-07-19 |
ATE364039T1 (en) | 2007-06-15 |
EP1699764A1 (en) | 2006-09-13 |
EP1699764B1 (en) | 2007-06-06 |
CY1107067T1 (en) | 2012-10-24 |
DE602004006896T2 (en) | 2007-11-22 |
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