NZ237908A - Preparation of two fosinopril salt polymorphs - Google Patents

Description

237 908 I""'"" ' 22.^-c 2 6 AUG J993 I3~U NEW ZEALAND PATENTS ACT, 1953 No. : Hat o: OFFtce 22 tipII 1S91 COMPLETE SPECIFICATION "SELECTIVE PROCESSES FOR FOSINOPRIL POLYMORPHS" Ho, E.R. SQUIBB & SONS, INC., a corporation of Delaware, United States of Ahum ira, of Lawrencevi1le-Princeton Road, Princeton, New Jersey, United States "f Ainnrica h<'t <>bv 'l(jr I arc lite invention for which we pray that a patent may be granted to ms, and the method by which it is to be performed, to be particularly described m fiti'l by I tie following statement (followed by page la) 237908 HA 503 - w - iELECTIVE PROCESSES FCR rOCINOPRIL POLTMCR This invention relates to processes for the preparation and interconversion of polymorphs of fosinoprii, an inhibitor of angiotensin converting enzyme (ACE) useful as an antihypertensive agent.

U.S. Patent No. 4,337,201 (issued June 29, 1982) describes inter alia the compound hrV which has the generic name fosinoprii and forms the alkali metal salt [1 [S* (R*) ], 2cr, 4p ] -4-cyclo-hexyl-1-[[[2-methyl-l-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline, monosodium salt. Fosinoprii and related compounds are ACE inhibitors having antihypertensive activity and other utilities as described in U.S. Patent No. 4,337,201.

Calorimetric, spectroscopic, and other 5 analyses have established that fosinoprii sodium exists as two polymorphs, A and B (see Figures 1 to 4). Figure 1 shows a differential scanning calorimetry thermogram of the two polymorphs.

Figure 2 shows powder X-ray diffraction spectra of 10 the two polymorphs. Figures 3A and 3B show infrared diffuse reflectance spectra of the polymorphs. Figure 4 shows carbon-13 NMR spectra of the two polymorphs. Polymorph B has been found to be much more exothermic than polymorph A upon 15 dissolving, so that polymorph A is believed to be more thermodynamically stable (see Table 1, below).

TABLE 1 Heats of Solution of Two Different Polymorphs of Fosinoprii Sodium Form A: AHg = -0.90 Kcal/mole Form B: AHg = -2.46 Kcal/mole When fosinoprii salt or fosinoprii and an alkali metal 2-, 3- or 4- ethylhexanoate are placed in a keto or hydroxylic solvent or mixture 30 thereof, the amount of water present determines which polymorph is formed. When the water comprises greater than about 0.2% by weight of the total amount of water and solvents added together, formation of polymorph A lji:; *• f ~ I 29 JUN 1993 - 3 23 7 f predominates. No water need be present for formation of polymorph B. When the water comprises about 0.2% by weight or less of the total amount of water and solvents added together, formation of polymorph B predominates. In either case, the polymorph formed crystallizes and is conventionally isolated from the solution.

In accordance with the present invention, a process is provided for preparing fosinopril-alkali metal salt polymorph A from either fosinoprii (structure I) or polymorph B. In this process, either polymorph B or fosinoprii and an alkali metal 2-, 3- or 4- ethylhexanoate are mixed with water and a keto or hydroxylic solvent or mixture thereof, after which polymorph A is isolated from the mixture. Water should be present in an amount greater than about 0.2% by weight of the total amount of water and solvents added together. It is preferred that the amount of water present be limited, however, to minimize the amount of product lost to the mother liquor. Thus, it is preferred that the water comprise about 1 to 3% by weight of the amount of water and solvents together.

Also in accordance with the present invention, a process is provided for preparing fosinopril-alkali metal salt polymorph B from fosinoprii or polymorph A. In this process, polymorph A or fosinoprii and an alkali metal ethylhexanoate are mixed with a keto or hydroxylic solvent or mixture thereof having about 0.2 to 0% by weight water (i.e., no water present), after which polymorph B is isolated from the mixture. 29 JUN jgg3 ! ntci?, r* \ ' O Further in accordance with the present invention, a process is provided for preparing polymorph 3 m which water is removed from a solution cf (1) polymorph A or (2) fosinoprii and 5 an alkali metal 2-, 3- or 4- ethylhexanoate in a keto or hydroxylic solvent or mixture thereof and polymorph B is isolated from the solution. Removal of the water should be effected so that the amount of water is less than about 0.2% by weight of the amount of the 10 water and solvents together. Removal by vacuum concentration is preferred.

Throughout this specification, the term "alkali metal" refers to sodium (which is preferred), lithium, and potassium. Exemplary alkali metal 2-, 3- or 4-15 ethylhexanoates are sodium 2-, 3- or 4- ethylhexanoate (which is preferred), potassium 2-, 3- or 4- ethylhexanoate, lithium 2-, 3- or 4- ethylhexanoate, and the like.

Exemplary keto solvents are acetone (which is preferred), methylethylketone, methylisobutyl-20 ketone, and the like. Exemplary hydroxylic solvents are methanol (which is preferred), ethanol, isopropyl alcohol, and the like. Other solvents may be present but are not required.

The mixing step of the processes of the 25 present invention may be accomplished by, for example, slurrying or stirring. Isolation may be accomplished by, for example, filtration of the reaction mixture.

The invention will now be further described 30 by the following working examples, which are preferred embodiments and are illustrative rather than limiting. All temperatures are in degrees Celsius. ?."?7 r\\ i ■ Example 1 Preparation of Fosir.opril Sodium Polymorph A A solution of 20.0 g of the cinchcnidine salt, [R-(R*,Sx)]-[[2-methyl-l-(1-oxopropoxy)-prcpoxy ] - (4-phenylbutyl )phosphinyl] acetic acid, cinchcnidme salt (1:1) in 200 ml of methylene chloride was washed with three 200-ml portions of 10 distilled water, each time adjusting the pH of the biphasic mixture to 2.0 with 6 N hydrochloric acid. Following the addition of 0.06 g of pyridine and 2.98 g of triethylamine, the solution was cooled to -10°C. To the cold solution was added 15 3.62 g pivaloyl chloride. The reaction mixture was stirred for 1 hour, followed by the addition of 6.88 g of (trans)-4-cyclohexyl-L-proline, mono-hvdrochloride and 2.98 g of triethylamine. The mixture was then warmed to 25°C and stirred for 20 90 minutes at that temperature. The product-rich solution was washed with three 200-ml portions of water, each time adjusting the pH of the biphasic mixture to 2.0 with 6 N hydrochloric acid. The organic layer was concentrated under vacuum to 21 g 25 of an amber oil.

The oil was dissolved in 200 ml of acetone and 30.0 ml of 1N sodium 2-ethylhexanoate in acetone containing 13.56 percent water by volume. After stirring the crystal slurry for 6 hours at room 3 0 temperature, the product was collected by 29 JUN 1993 237 HAS 03 filtration and washed on the filter with 70 ml of acetone. The wet cake was dried under vacuum, yielding 15.2 g (37.8 M%) of fosinoprii sodium polymorph A.

Example 2 Conversion of Polymorph B to Polymorph A To a mixture of 490 ml of acetone and 10 ml of water was added 50.1 g of fosinoprii sodium polymorph B. The slurry was stirred for 2 hours at room temperature and the product was isolated by filtration. Vacuum-drying afforded 49.5 g 15 (99 M%) of fosinoprii sodium polymorph A.

Example 3 Conversion of Polymorph A to Polymorph B To 15 ml of methanol was added 1.0 g of fosinoprii sodium polymorph A. The resultant solution was vacuum-concentrated at 35°C to dryness, yielding 1.0 g of fosinoprii sodium 25 polymorph b.

Claims (9)

WHAT WE CLAIM IS:

1 . A process for selectively preparing a fosinoprii salt polymorph, which comprises: (a) mixing together (i) either (1) a fosinoprii salt or (2) fosinoprii and an alkali metal 2-, 3- or 4-ethylhexanoate, (ii) a keto solvent or a hydroxylic solvent or a mixture thereof, and (iii) water; (b) regulating the amount of water present so that the water comprises more than 0.2% by weight of the total water and solvent to form polymorph A, or 0.2% or less by weight of the total water and solvent to form polymorph B; and (c) isolating the polymorph formed from the mixture.

2. The process of Claim 1, wherein the alkali metal 2-, 3- or 4- ethylhexanoate is sodium 2-, 3- or 4- ethylhexanoate.

3. The process of Claim 1, wherein a keto solvent is used to prepare polymorph A.

4. The process of Claim 3, wherein the keto solvent is acetone.

5. The process of Claim 1, wherein a hydroxylic solvent is used to prepare polymorph B. N-Z. PAT: 29 JUN 1993 23"SO 8 - 8-

6. The process of Claim 5, wherein the hydroxylic solvent is methanol.

7. The process of Claim 1, wherein the amount of water is substantially 1 to 3r7 by weight of the total water and solvent so that polymorph A is formed.

8. The process of Claim 1, wherein the amount of water is regulated by removing water so that the water comprises substantially 0.2% by weight or less of the total water and solvent in the mixture and polymorph B is formed.

9. The process of Claim 8, wherein the water is removed by vacuum concentration. DATED THIS ^ DAY OFUfcO'U^v ^gc <2 A. J. PARK & SON PER ^ agents for the applicants