Process for the preparation of enantiomerically enriched 3-aminopiperidine

Abstract

The present invention relates to a process for the preparation of enantiomerically enriched 3-aminopiperidine, as in particular of its R-enantiomer (R)-3-aminopiperidine. The invention also relates to an enantiomerically enriched intermediate of said process and to specific acid-addition salts of 3-aminopiperidine (hereinafter also APIP) that are useful for obtaining a single enantiomer of APIP, and to crystalline (R)-3-aminopiperidine-dihydrochloride-monohydrateand crystalline (S)-3-aminopiperidine-dihydrochloride-monohydrate.

Claims

1. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its R-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is a compound of the formula A, ##STR00003## wherein k is 0, 1, 2, 3, 4 or 5, R is C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-alkoxy or halogen, and X is S(O).sub.2, C(O) or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.

2. The process according to claim 1, wherein the carboxylic acid A is selected from (S)-2-phenylsulfonylamino-propionic acid, (S)-2-(4-methylphenyl)sulfonylamino-propionic acid, (S)-2-(4-chlorophenyl)sulfonylamino-propionic acid, (R)-2-(3-phenylureido)-propionic acid and (R)-2-(3-(4-chlorophenyl)ureido)-propionic acid.

3. The process of claim 1, wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.

4. The process of claim 1, wherein k is 0, 1, 2 or 3.

5. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its S-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is the compound of the formula A, ##STR00004## wherein k is 0, 1, 2, 3, 4 or 5, R is C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-alkoxy or halogen, and X is S(O).sub.2, C(O) or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.

6. The process according to claim 5, wherein the carboxylic acid A is selected from (R)-2-phenyl sulfonylamino-propionic acid, (R)-2-(4-methylphenyl)sulfonylamino-propionic acid, (R)-2-(4-chlorophenyl)sulfonylamino-propionic acid, (S)-2-(3-phenylureido)-propionic acid and (S)-2-(3-(4-chlorophenyl)ureido)-propionic acid.

7. The process of claim 5, wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.

8. The process of claim 5, wherein k is 0, 1, 2 or 3.

9. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its R-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is the compound of the formula A, ##STR00005## wherein k is 0, 1, 2, 3, 4 or 5, R is CN, NO.sub.2, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-alkoxy or halogen, or two adjacent variables R may together represent an optionally substituted butadien-1,4-diyl, and X is S(O).sub.2 or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.

10. The process of claim 9, wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.

11. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its S-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is the compound of the formula A, ##STR00006## wherein k is 0, 1, 2, 3, 4 or 5, R is CN, NO.sub.2, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-alkoxy or halogen, or two adjacent variables R may together represent an optionally substituted butadien-1,4-diyl, and X is S(O).sub.2 or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.

12. The process of claim 11, wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.

13. The acid-addition salt of 3-aminopiperidine with the chiral carboxylic acid A, ##STR00007## and the hydrates thereof, wherein k is 0, 1, 2, 3, 4 or 5, R is C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-alkoxy or halogen, and X is S(O).sub.2, C(O) or NHC(O).

14. The acid-addition salt of claim 13, which has an enantiomeric excess with regard to one of the enantiomers of 3-aminopiperidine of at least 70%.

15. The acid-addition salt of claim 13, wherein k is 0, 1, 2 or 3.

16. The acid-addition salt of 3-aminopiperidine with the chiral carboxylic acid A, ##STR00008## and the hydrates thereof, wherein k is 0, 1, 2, 3, 4 or 5, R is CN, NO.sub.2, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-alkoxy or halogen, or two adjacent variables R may together represent an optionally substituted butadien-1,4-diyl, and X is S(O).sub.2 or NHC(O).

17. The acid-addition salt of claim 16, which has an enantiomeric excess with regard to one of the enantiomers of 3-aminopiperidine of at least 70%.

Description

(1) The following examples shall serve the further illustration of the invention and are not intended to limit the scope of the present invention.

(2) FIG. 1 shows the powder X-ray diffraction pattern of (R)-aminopiperidine dihydrochloride monohydrate obtained from example 5.

(3) FIG. 2 shows the NIR spectrum of of (R)-aminopiperidine dihydrochloride monohydrate obtained from example 5.

(4) FIG. 3 shows the IR spectrum of of (R)-aminopiperidine dihydrochloride monohydrate obtained from example 5.

(5) FIG. 4 shows the powder X-ray diffraction pattern of (R)-aminopiperidine dihydrochloride anhydrate obtained from example 5.

ABBREVIATIONS

(6) Ts-L-Ala: (S)-2-(4-methylphenyl)sulfonylamino-propionic acid pCl-Ps-L-Ala (S)-2-(4-chlorophenyl)sulfonylamino-propionic acid Ps-L-Ala: (S)-2-phenyl sulfonylamino-propionic acid PC-L-Ala: (S)-2-(3-phenylureido)-propionic acid Cl-PC-L-Ala: (S)-2-(3-(4-chlorophenyl)ureido)-propionic acid rac-APIP: racemic 3-aminopiperidine (R)-APIP: (R)-3-aminopiperidine (S)-APIP: (S)-3-aminopiperidine S/R: enantiomeric ratio of (S)-APIP/(R)-APIP TBME: tert.-butylmethyl ether MeOH: methanol MEK: methyl ethyl ketone (2-butanone) r.t.: room temperature (22° C.) conc.: concentrated

(7) Analytics:

(8) The enantiomeric ratio S/R was measured via chiral HPLC after derivatisation with mosher's acid chloride on a Chiralpak AD 250/4.6/10 column with hexane/isopropanol 90:10 as eluent. The detection wavelength was 220 nm. The retention times were: Rt(R-APIP)=8 min and Rt (S-APIP)=14 min, respectively.

(9) Measurements of powder X-ray diffraction patterns were performed at room temperature (22° C.) on a powder diffractometer STOE STADI P using Cu-Kα.sub.1 radiation (1.540598 Å) in Debeye Scherrer geometry. Samples were contained in capillaries having an internal diameter of about 0.3 mm.

I Preparation of APIP

Example 1: Preparation of Piperidine-3-Carboxylic Acid Hydrazide (Nipecotic Acid Hydrazide)

(10) 157 g racemic ethyl nipecotate and 53 g hydrazine hydrate were stirred overnight at 80° C. The solution was cooled to r.t, and gradually diluted with 280 g TBME. The resulting suspension was stirred for one hour. Racemic nipecotic acid hydrazide (123 g) was isolated via filtration under suction and drying at 50° C. as white crystalline solid. Melting point: 111° C.

Example 2: Preparation of Piperidine-3-Carboxylic Acid Hydrazide (Nipecotic Acid Hydrazide) Monohydrochloride

(11) 157 g racemic ethyl nipecotate (technical grade, 1.0 mol) and 55.1 g hydrazine hydrate (1.1 mmol) were stirred overnight at 80° C. The solution was diluted with 100 g distilled water and cooled to r.t. Then 99 g of conc. hydrochloric acid (1.0 mol) were slowly added, and the suspension was stirred overnight. The precipitated crystals were filtered and washed with cold water (2×10 ml), isopropanol (2×10 ml) and pentane (50 ml) to afford 119 g of racemic nipecotic acid hydrazide monohydrochloride. Additional 25.4 g could be obtained from the mother liquor via evaporation and recrystallization from water. Thus, a total of 144 g pure racemic nipecotic acid hydrazide monohydrochloride (80%) was isolated.

(12) Melting point: 127° C.

Example 3: Preparation of (R)-APIP Dihydrochloride from R-Ethyl Nipecotate Tartric Acid Salt

(13) To a well stirred suspension of 153.6 g R-ethyl nipecotate L-tartaric acid salt in 157 g xylene (technical mixture) was added dropwise under cooling a solution of 69.3 g technical potassium hydroxide in 78 g water. The organic phase was separated; the water phase was extracted again respectively with 50 and 40 g xylene. The combined organic phase was dried over 10 g sodium sulfate. The drying agent was filtered off and 39 g hydrazine hydrate was added. The biphasic mixture was heated to 80° C. for 2 days under vigorous stirring. The mixture was concentrated under vacuum and the residue was taken up in water and was concentrated again to yield 168 g of a 40.6% solution of R-nipecotic acid hydrazide in water.

(14) To this solution was added 50 g of cracked ice. The pH was adjusted with 77 g conc. hydrochloride acid to a value of 2.0. Approx. one fifth of this solution was set aside, and to the main part of the solution was added 1 ml conc. hydrochloride acid. Diazotation was carried out at <0° C. first with 18 g isopentyl nitrite, then the remaining nipecotic acid dihydrochloride solution, which had been put aside, was carefully added under cooling, and finally 53 g isopentyl nitrite were added dropwise at a temperature between −5 to −2° C. (about 200 g of cracked ice were added in portions to keep the mixture cold). Afterwards, the solution was stirred at 0° C. for one hour. The water phase was separated and poured during 20 min onto 100 g of boiling water. Boiling was continued for 10 min, 5 g of conc. hydrochloride acid was added and the solution was concentrated to a final volume of 330 g with an APIP content of 66.2 g (as dihydrochloride, yield is 76% over three steps) and a content of the side product nipecotic acid of 4.6 g. The solution was concentrated to a thick mass, which was taken up in 74 g of boiling methanol. On cooling, R-APIP×2 HCl crystallized as thick mass. APIP×2 HCl was isolated after dilution with 150 g acetone via filtration. After drying in vacuo, 56.9 g dry R-APIP×2 HCl was obtained.

Example 4: Preparation of (R)-APIP Dihydrochloride with Hexyl Nitrite

(15) To 68.3 g of a solution of R-nipecotic acid hydrazide in water (assay 41.9%. 200 mmol) was added 70 g ice and 46.8 g conc. hydrochloric acid (475 mmol, 1.95 eq referring to the total amount of hydrazide). The clear solution was cooled to −10° C., and 33 g n-hexyl nitrite was added during 30 min under cooling (ice/salt bath). 17.1 g of a solution of R-nipecotic acid hydrazide in water (assay 41.9%. 50 mmol) was added during 10 min under cooling.

(16) Afterwards, additionally 16 g n-hexyl nitrite was added during 20 min under cooling. The solution was stirred for one hour at −5° C., the water phase was separated and poured in portions onto 100 g of boiling water (>95° C.). The pH-value is now 1.9 (measured via pH-paper). 5 g of conc. hydrochloric acid was added and the solution was concentrated to a thick mass, which was taken up in 50 g of boiling methanol. Isopropanol (100 g) was added, and the solution was concentrated to a mass of approx. 70 g. The solution was seeded, and diluted with acetone (100 g). R-APIP×2 HCl (36 g, 83%) was isolated via filtration and drying in vacuo.

Example 5: Preparation of (R)-APIP Dihydrochloride

(17) To a solution of 136 kg (R)-nipecotic acid hydrazide in 194 kg deionized water was added 274 kg ice and 219 kg conc. hydrochloric acid. The solution was cooled to 0° C. and 50 kg isopentylnitrite was slowly added at a temperature of □2 to +2° C. A solution of 14.6 kg (R)-nipecotic acid hydrazide in 18.4 kg water was added. The solution was cooled again to 0° C., and 117 kg isopentylnitrite was slowly added at a temperature of −2 to +2° C. Finally the solution was stirred for 30 min at 0° C. This clear solution was pumped in small portions (about 301) to 400 kg water at 90° C. After complete addition, the solution was heated at 90° C. for 30 min. The solution was cooled to r.t. and the phases were separated.

(18) To three combined water phases obtained this way from a total of 544 kg (R)-nipecotic acid hydrazide was added 200 kg conc. hydrochloric acid. The solution was concentrated to a thick syrup and dissolved in hot methanol (1300 kg). The solution was cooled to r.t., seeded with (R)-aminopiperidine dihydrochloride hydrate and diluted gradually with 900 kg acetone. The resulting crystals of (R)-aminopiperidine dihydrochloride monohydrate were isolated via centrifugation (601 kg wet; water content: 9% (Karl-Fischer-Titration)).

(19) The powder X-ray diffraction pattern of the sample is shown in FIG. 1. The characteristic reflections are quoted in the following table as 2θ values or as interplanar spacings D together with relative intensities:

(20) TABLE-US-00001 2θ D [Å] I rel [%] 11.0 8.1 20 16.4 5.4 34 17.0 5.2 73 20.9 4.2 100 24.5 3.6 92 25.3 3.5 32 25.9 3.4 44 26.7 3.3 48 27.3 3.3 26 28.4 3.1 42 29.3 3.0 27 30.0 3.0 31 30.7 2.9 36 31.0 2.9 53 31.8 2.8 29

(21) The NIR-spectrum of (R)-aminopiperidine dihydrochloride monohydrate is shown in FIG. 2. The IR spectrum of (R)-aminopiperidine dihydrochloride monohydrate is shown in FIG. 3.

(22) To this solid was added methanol (400 kg) and isopropanol (1000 kg). The solvent was distilled under reduced pressure until a water content <1.0% was measured. The suspension was first diluted with methanol (400 kg) and then gradually with acetone (800 kg). The resulting solid was isolated via centrifugation (563 kg wet) and dried at elevated temperatures under reduced pressure to afford 522 kg chemically pure (R)-aminopiperidine dihydrochloride in the form of its anhydrate with an optical purity of >99 ee.

(23) The powder X-ray diffraction pattern of the sample is shown in FIG. 4. The characteristic reflections are quoted in the following table as 2θ values or as interplanar spacings D together with relative intensities:

(24) TABLE-US-00002 2θ D [Å] I rel [%] 9.0 9.8 30 15.8 5.6 27 17.9 4.9 70 19.7 4.5 75 21.7 4.1 39 23.1 3.8 64 24.4 3.6 100 25.3 3.5 78 28.9 3.1 95 30.7 2.9 49

Example 6: Preparation of Rac-APIP Dihydrochloride with Isopentyl Nitrite

(25) To 36 g (250 mmol) of racemic nipecotic acid hydrazide in 125 ml water were added 45 ml (500 mmol) of conc. hydrochloric acid under cooling (ice/salt). 25.1 g isopentyl nitrite (300 mmol) was added during 30 min at 0° C. and stirred at the same temperature for additional 30 min. HPLC shows complete conversion to the desired azide with no starting material left. The mixture was poured drop wise during 10 min onto 500 ml of hot (80° C.) water. Boiling was continued for additional 60 min. The solution was cooled to room temperature, conc. hydrochloric acid (40 ml) was added and the solution was concentrated to a viscous mass. Water (100 ml) was added, and the solution was concentrated again. Isopropyl alcohol (100 ml) was added, and the solution was concentrated again. The residue was dissolved in hot methanol (50 ml). To the cooled methanol solution was added acetone (100 g) dropwise under vigorous stirring.

(26) The precipitated 3-aminopiperidine dihydrochloride was isolated (40 g of wet product) and dried via azeotropic distillation under reduced pressure with two portions (50 ml each) of isopropanol. Hot methanol was added and the suspension was stirred over night at r.t. The suspension was diluted with 70 g acetone and the solid material was isolated via filtration. 33.2 g (192 mmol, corresponds to 77% yield) of 3-aminopiperidine dihydrochloride was obtained as a white powder. Chemical purity (HPLC) is 98.7% with a water content (determined by Karl Fischer titration) of 0.046%.

Example 7: Preparation of Rac-APIP Dihydrochloride with Acetic Acid as Cosolvens

(27) To 5.40 g of racemic nipecotic acid hydrazide dihydrochloride (25 mmol) in 10 g water and 2.5 g acetic acid were added dropwise 3.5 g isopentyl nitrite (30 mmol) at □15° C. The clear solution was warmed to 0° C. during a period of 2 h and poured at once into 50 ml of boiling water. Boiling was continued for additional 10 min. The solution was cooled to r.t., conc. hydrochloride acid (2 ml) was added and the solution was concentrated to a viscous mass, which was dissolved in 10 ml of hot methanol. On cooling the clear solution to r.t. a thick crystalline mass developed. Acetone (20 ml) was added and the crystals were isolated via filtration. After drying for 12 h at 50° C., 3.71 g of racemic 3-aminopiperidine dihydrochloride (21 mmol, corresponds to 84% yield) with a water content of 0.68% were obtained.

Example 8: Preparation of Rac-APIP Dihydrochloride with Isopropanol as Cosolvens

(28) To 5.40 g of racemic nipecotic acid hydrazide dihydrochloride (25 mmol) in 5 g water and 5 g isopropanol were added dropwise 3.5 g isopentyl nitrite (30 mmol) at □15° C. The clear viscous solution was warmed to 0° C. during a period of 1 h and poured at once into 50 ml of boiling water. Boiling was continued for additional 10 min. The solution was cooled to r.t., conc. hydrochloride acid (2 ml) was added and the solution was concentrated to a viscous mass, which was dissolved in 10 ml hot methanol. On cooling the clear solution to r.t. a thick crystalline mass developed. Acetone (20 ml) was added and the crystals were isolated via filtration. After drying for 12 h at 50° C., 3.42 g of racemic 3-aminopiperidine dihydrochloride (20 mmol, corresponds to 80% yield) with a water content of 0.64% were obtained.

Example 9: Preparation of Racemic APIP Dihydrochloride with Sodium Nitrite

(29) 18 g of racemic nipecotic acid hydrazide monohydrochloride (100 mmol) were dissolved in 36 g water and 21 g of 37% hydrochloric acid (210 mmol) and cooled to □10° C. To the solution were added 7.6 g of NaNO.sub.2 (110 mmol) in small portions in such a way that the temperature is kept ≤□5° C. Stirring was continued for 30 min at a temperature of □5 to 0° C. The cold solution was then poured in small portions into 20 g of boiling water. The reaction mixture was stirred under reflux for additional 30 min and then cooled—to r.t. to give a solution of racemic APIP dihydrochloride in water.

II Enantiomeric Resolution of Racemic APIP by Fractional Crystallization of Diastereomeric Acid Addition Salts

Example 10: Resolution of Rac-APIP with Ts-L-Ala

(30) The solution of rac-APIP dihydrochloride obtained in Example 9 was diluted with 50 g distilled water, and then 100 ml of a 2N aqueous solution of sodium hydroxide (200 mmol) were added dropwise on an ice-water bath so that the pH-value is adjusted to 12. Afterwards 44 g of N-(para-toluenesulfonyl)-L-alanine (180 mmol) were added and the suspension was heated to 90° C. for 30 min to afford a clear solution. This solution was then cooled to 60° C. The precipitated crystals were aged at this temperature for 1 h and then stirred at r.t. overnight. The obtained salt was collected by filtration, washed with 10 ml isopropanol, 2×10 ml pentane and dried to give 31.35 g of (R)-APIP.Math.2 Ts-L-Ala.Math.H.sub.2O as white solid. Yield: 52% (based on the amount of rac-APIP used).

(31) Enantiomeric ratio S/R=9.57:90.43.

(32) The obtained acid addition salt was purified by recrystallization from 210 g of water, Yield: 18.62 g, 31% (based on the amount of rac-APIP used).

(33) Enantiomeric ratio S/R=0.2:99.8.

Example 11: Resolution of Rac-APIP with Ts-L-Ala

(34) A solution of 400 mg (10 mmol) sodium hydroxide in 5.0 g water were added dropwise to a solution of 865 mg (5 mmol) rac-APIP dihydrochloride in 5.0 g water and the mixture was stirred for 10 min. 2428 mg (10 mmol) Ts-L-Ala were added and the mixture was heated at 80° C. until a clear solutions was obtained. The solution was cooled slowly to r.t. and the suspension was stirred for 3 h. The formed solid was collected by filtration, washed with mother liquor, water, isobutanol, TBME and pentane (1 ml each) and dried to afford (R)-APIP.Math.2 Ts-L-Ala.Math.H.sub.2O.

(35) Yield: 1435 mg, 95% (based on the amount of enantiomer used).

(36) Enantiomeric ratio S/R=2.06:97.94; S-factor (efficiency of optical resolution)=0.91.

(37) The obtained acid addition salt was purified by recrystallization from 13.0 g water.

(38) Yield: 1087 mg, 72% (based on the amount of enantiomer used).

(39) Enantiomeric ratio S/R=0.0:100.0.

(40) Melting point: 152° C.

(41) Specific rotation [α].sub.D.sup.20=−3.8 (c=0.5, MeOH).

Example 12: Resolution of Rac-APIP with Ts-L-Ala

(42) 400 mg (10 mmol) sodium hydroxide in 5.0 g water and 300 mg (5 mmol) acetic acid were added subsequently to a suspension of 865 mg (5 mmol) rac-APIP dihydrochloride in 5.0 g water and stirred for 10 min. 1460 mg (6 mmol) Ts-L-Ala were added and the mixture was heated at 80° C. until a clear solution was obtained. The solution was cooled slowly to r.t. and the suspension was stirred for 3 h. The solid was collected by filtration, washed with mother liquor, water, isobutanol, TBME and pentane (1 ml each) and dried to afford (R)-APIP.Math.2 Ts-L-Ala.Math.H.sub.2O.

(43) Yield: 1265 mg, 84% (based on the amount of enantiomer used).

(44) Enantiomeric ratio S/R=2.0:98.0.

(45) The obtained acid addition salt was purified by recrystallization from 12.0 g of water.

(46) Yield: 858 mg, 57% (based on the amount of enantiomer used).

(47) Enantiomeric ratio S/R=0.0:100.0.

Example 13: Resolution of Rac-APIP with pCl-Ps-L-Ala

(48) 80 mg (2 mmol) sodium hydroxide in 1.0 g water were added dropwise to a solution of 173 mg (1 mmol) rac-APIP dihydrochloride in 1.0 g water and the mixture was stirred for 10 min. 527 mg (2 mmol) pCl-Ps-L-Ala was added and the mixture was heated at 40° C. for 30 min. The solution was cooled slowly to r.t. and the suspension was stirred for 2 h. The formed solid was collected by filtration, washed with mother liquor, water (2×0.5 ml), acetone (1 ml), and pentane (2 ml) and dried to afford (R)-APIP.Math.2 pCl-Ps-L-Ala.Math.H.sub.2O.

(49) Yield: 273 mg, 85% (based on the amount of enantiomer used).

(50) Enantiomeric ratio S/R=4.41:95.59; S-factor (efficiency of optical resolution)=0.77.

(51) A pure acid addition salt was independently prepared from 5 mmol (R)-APIP.Math.2HCl, 10 mmol NaOH and 10 mmol pCl-Ps-L-Ala in 10 g water which had an optical purity of 100% and shows the following physical data:

(52) Enantiomeric ratio S/R=0.0:100.0.

(53) Melting point: 139° C.

(54) Specific rotation [α].sub.D.sup.20=−0.3 (c=1.0, MeOH).

Example 14: Resolution of Rac-APIP with Ps-L-Ala

(55) 400 mg (10 mmol) sodium hydroxide in 5.0 g water were added dropwise to a solution of 865 mg (5 mmol) rac-APIP dihydrochloride in 5.0 g water and the mixture was stirred for 10 min. 2293 mg (10 mmol) of Ps-L-Ala were added and the mixture was heated at 80° C. until a clear solutions was obtained. The solution was cooled slowly to r.t. and the suspension was stirred for 3 h. The formed solid was collected by filtration, washed with mother liquor, water, isobutanol, TBME and pentane (1 ml each) and dried to afford (R)-APIP.Math.2 Ps-L-Ala.Math.H.sub.2O as white solid. Yield: 765 mg, 53% (based on the amount of enantiomer used).

(56) Enantiomeric ratio S/R=2.99:97.01.

Example 15: Resolution of Rac-APIP with Ps-L-Ala

(57) 400 mg (10 mmol) sodium hydroxide in 5.0 g water and 300 mg (5 mmol) acetic acid were added dropwise to a solution of 865 mg (5 mmol) rac-APIP dihydrochloride in 5.0 g water and the mixture was stirred for 10 min. 1146 mg (5 mmol) of Ps-L-Ala were added and the mixture was heated at 80° C. until a clear solutions was obtained. The solution was cooled slowly to r.t. and the suspension was stirred for 3 h. The formed solid was collected by filtration, washed with mother liquor, water, isobutanol, TBME and pentane (1 ml each) and dried to afford (R)-APIP.Math.2 Ps-L-Ala.Math.H.sub.2O as white solid.

(58) Yield: 1069 mg, 74% (based on the amount of enantiomer used).

(59) Enantiomeric ratio S/R=3.71:96.29.

(60) The obtained acid addition salt was purified by recrystallization from 6.0 g of water. Yield: 605 mg, 42% (based on the amount of enantiomer used).

(61) Enantiomeric ratio S/R=0.03:99.97.

(62) Melting point: 180.6° C.

(63) Specific rotation [α].sub.D.sup.20=−4.4 (c=0.5, MeOH).

Example 16: Resolution of Rac-APIP with PC-L-Ala

(64) 400 mg (10 mmol) sodium hydroxide in 5.0 g water were added dropwise to a solution of 865 mg (5 mmol) rac-APIP dihydrochloride in 5.0 g water and the mixture was stirred for 10 min. 2082 mg (10 mmol) of PC-L-Ala were added and the mixture was heated at 80° C. until a clear solution—was obtained. The solution was cooled slowly to r.t. and the suspension was stirred for 3 h. The formed solid was collected by filtration, washed with mother liquor, water, isobutanol, TBME and pentane (1 ml each) and dried to afford (S)-APIP.Math.2 PC-L-Ala.Math.2H.sub.2O as white solid.

(65) Yield: 1220 mg, 88% (based on the amount of enantiomer used).

(66) Enantiomeric ratio S/R=98.88:1.12. S-factor (efficiency of optical resolution)=0.86.

(67) 1000 mg of the obtained acid addition salt was purified by recrystallization from 6.0 g of water.

(68) Yield: 504 mg.

(69) Enantiomeric ratio S/R=99.93:0.07.

(70) Melting point: 135.2° C.

(71) Specific rotation [α].sub.D.sup.20=+3.4 (c=0.5, MeOH).

Example 17: Resolution of Rac-APIP with Cl-PC-L-Ala

(72) A mixture of 100 mg (1 mmol) rac-APIP and 246 mg (1 mmol) (S)-2-(3-(4-chlorophenyl)ureido)-propionic acid in 1000 mg ethanol was homogenized at 70° C., cooled down to r.t., diluted with 1 ml isopropanol and stirred for 1 h. The solids were filtered off, washed with mother liquor, isopropanol, TBME and pentane (1 ml each) and dried to afford (S)-APIP.Math.2 Cl-PC-L-Ala.Math.2H.sub.2O.

(73) Yield: 209 mg, 67% (based on the amount of enantiomer used).

(74) Enantiomeric ratio S/R=96.74:3.26.

Example 18: Resolution of Rac-APIP with Cl-PC-L-Ala

(75) A mixture of 350 mg (3.5 mmol) rac-APIP and 1723 mg (7 mmol (S)-2-(3-(4-chlorophenyl)ureido)-propionic acid in 7000 mg of aqueous ethanol (50% (v/v)) was homogenized at 70° C. and cooled down to 40° C. thereby obtaining a precipitation. The suspension was stirred at this temperature for 1 h and then at r.t. for another 1 h. The solid was collected by filtration, washed with mother liquor, isopropanol, TBME and pentane, (1 ml each) and dried to afford (S)-APIP.Math.2 L-p-Chlor-PC-Ala.Math.2H.sub.2O.

(76) Yield: 1025 mg, 93% (based on the amount of enantiomer used).

(77) Enantiomeric ratio S/R=90.04:9.96.

(78) The obtained acid addition salt was purified by stirring in 5.0 g of aqueous ethanol (50% (v/v)) at 70° C., then at r.t.

(79) Yield: 858 mg, 78% (based on the amount of enantiomer used).

(80) Enantiomeric ratio S/R=99.7:0.3.

(81) Melting point: 138°.

(82) Specific rotation [α].sub.D.sup.20=+3.2 (c=0.5, MeOH)

III Conversion of Diastereomeric Acid Addition Salt of (R)-APIP with a Chiral Acid into (R)-APIP Dihydrochloride Monohydrate ((R)-APIP.Math.2 HCl.Math.H.SUB.2.O)

Example 19: Conversion of (R)-APIP.Math.2 Ts-L-Ala.Math.H.SUB.2.O into (R)-APIP.Math.2 HCl.Math.H.SUB.2.O

(83) 18.6 g (31 mmol) of (R)-APIP.Math.2 Ts-L-Ala.Math.H.sub.2O (from Example 10) were suspended in 80 g water, cooled with an ice-water bath and treated with 15.3 g (155 mmol) conc. hydrochloric acid. The precipitated Ts-L-Ala was collected by filtration, washed with 3×10 ml water and dried to obtain 13.93 g (57 mmol; 92% yield) of recovered Ts-L-Ala. The mother liqueur was washed with 2×50 ml MEK to remove last traces of Ts-L-Ala, filtered over celite and evaporated. The resulting yellow oil was dissolved in 20 g methanol, diluted with 20 g isopropanol and evaporated to dryness. This procedure was repeated once again to afford 6.42 g (R)-APIP.Math.2HCl.Math.H.sub.2O with an APIP (free base) content of 53.6% by weight and a water content of 4.2%. (Thus a mixture of the hydrate and the anhydrous APIP was obtained in this case).

(84) Yield: 31% (based on the amount of racemate used).

(85) Combined mother liqueurs from salt formation and purification were evaporated to dryness and dissolved in 160 g of water. 27.6 g (280 mmol) conc. hydrochloric acid was added dropwise under ice cooling so that the pH-value is adjusted to 1. The solid was filtered off and dried to obtain 24.45 g (101 mmol) of recovered Ts-L-Ala.

(86) Total yield of recovered Ts-L-Ala: 38.38 g (158 mmol), 88% (based on the total amount used).