FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
SECETION OF RULE 13
1. AN INPROVED PROCESS FOR THE PREPARATION OF
"H-TYPE"CRYSTALS OF
N-(TRANS-4-ISOPROPYLCYCLOHEXLYARBONYL)-D-PHENYLALANINE.
Alembic Limited Alembic Road; Vadodara-390003 GUJARAT. INDIA

manner in which it is to be performed.
The following specification particularly describes and aseertains the nature of the invention, and the

Technical Field:
The present invention relates to a crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and method for the direct isolation of "H-type" crystals.
BACKGROUND OF THE INVENTION
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (I ) is a known substance having therapeutic utility in depressed blood glucose levels.
N-(trans-4-isopropylcyclo hexylcarbonyl)-D-phenylalanine is disclosed in Japanese Patent Application No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484) and in J. Med. Chem. 32, 1436 (1989 ). The Japanese application describes how the compound may be crystallized out from aqueous methanol to yield crystals having a melting point of 129°C. to 130°C. These crystals or a crystalline form are referred herein as "B-type".
The U.S. pat no. 5463116 also describes how the compound "B-Type" crystals may be recrystallized from aqueous acetone, ethanol and isopropanol to yield different type of crystals having a melting point of 136°C to 142°C . These crystals or a crystalline form are referred herein as "H-type".


(I)
The known B-type crystals suffer from problems of instability, especially when subjected to mechanical grinding. The instability results, for example, in conversion of the B-type crystals into other forms. The B-type of crystals are therefore not ideal for use in medicine pharmaceutical formulations. It is in general desirable that a medicinal product containing a crystalline active ingredient have a composition which is well defined and stable in terms of the crystalline form of the active ingredient. Conversion of one crystalline form into unknown amounts of different, forms during processing or storage is undesirable and in many cases would be regarded as analogous to the appearance of unquantified amounts of impurities in the product.
Therefore, it would be desirable to have available a practicable process for preparing stable "H - Type " crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine without isolating the "B- Type" of crystals.
The present inventions discloses a new process for producing "H - Type " crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine without isolating the "B- Type" crystals from'^ aprotic organic solvents^ 0
what are the type of B-type crystali should br
clealy defnee

Summary of the invention
The present invention provides a method for preparing "H - Type" crystals of N-(trans-4-sopropylcyclohexylcarbonyl)-D-phenylalanine which comprises Chorination of trans-[4-sorpopyl cyclohexyl carboxylic acid] with a chlorinating agent forms crude trans-4-isopropyl :yclohexyl carboxylic acid chloride which reacts with phenylalanine,-methyl ester hydrochloride n presence of a base in a solvent comprising at least one solvent component selected from the ;roup of inert solvents like dichloromethane, chloroform, ethylene dichloride and toluene; emove solvent by evaporation leaves a residue of unevaporated crude ester; hydrolysis of the :rude ester in presence of an alkali metal hydroxide in a protic solvent constisting of water, nethanol, ethanol and subsequently extracting in organic solvents after adjusting the pH.
Detailed description of the invention
The present invention provides a practical economical and simple process for preparing "H -Type" crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine on large scale from he reaction mixture directly and without isolating its "B-Type" crystals, after the hydrolysis lubsequently converting B-form to H-form.
The chlorinating agent is preferably selected from the group consisting of thionyl chloride, )xalyl chloride, PCI5 and PCI3, more preferably thionyl chloride.
n the hydrolysis step of inventive process, the solvent is recovered under reduced press«reafter :ompletion of the reaction and further azeotropically distilled with water to remove the trace imount of solvent. Finally the "H - Type" crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-)-phenylalanine is isolated/extracted from water immiscible organic solvents, preferably iromatic and aliphatic hydrocarbons, most preferably in toluene after adjusting the pH between .5 to 5.5 more preferably 2.0 to 2.5 with dilute hydrochloric acid. The acidification of the iqueous layer is conducted at a temperature between 20 - 65° C more preferably about 30 - 40 2. The solvent for extraction is also preferably used in excess from about 6-12 volumes more ireferably 8-9 volumes.
The completion of hydrolysis may be monitored by any of the method known to the chemical irts such as thin layer chromatography, gas chromatography or HPLC.
To isolate "H-Type" crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine the oliiene layer should be allowed to cool preferably to a temperature between 15/t 4 50 C, most ireferably about 25° C or ambient temperature of the laboratory. These crystals may be separated »ut by filtration and optionally washed and / or dried. Using the present inventive process, the "H - Type" crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine can be obtained

that contains toluene less than 300PPM more preferably less than 150 PPM. Similarly the "H - Type " crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine also may be isolated from other solvents like benzene, hexane, xylene by these extraction techniques.
BRIEF DESCRIPTION OF THE DRAWINGS
Anex 1 shows a powder X-ray diffraction pattern of # NAE/F/88/042 of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine;
Anex. 2 shows an infra red absorption spectrum of # NAE/F/88/042 of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine;
Anex. 3 shows differential scanning calorimeter (DSC) traces of # NAE/F/88/042 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine;
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine in "H-type" crystalline form. Examples of the physical properties of the H-type crystals are as follows.
The inventors have measured, the melting points of H-type crystals and found it to be in the range of 136°C to 142°C By contrast, when the melting point of B-type crystals was measured by the same technique a melting range of 128°C to 131°Cj$was

obtained.
As mentioned above the invention provides a method for the production of crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine "H-type " crystals.the method comprising obtaining N-trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine "H-type" crystals directly from the penultimate stage in non aqueous media.
Crystals which have come out of solution are preferably separated from the solvent e.g., by filtration or centrifuging and are desirably then dried for example at a temperature in the range of from 20°C. to 120°C.
The H-type crystals as obtained in the manner mentioned above can be separated from suspension by filtration or centrifugation. In isolating them, cooling may be effected, if desired. In that case, the cooling temperature is preferably no lower than 10°C. The isolated crystals are dried, for example at a temperature in the range of from 20°C. to 120°C.
Embodiments of the present invention will be more concretely illustrated by the following examples but the invention is not limited thereto.
EXAMPLES
Example 1:
To 50 gm trans-[4-lsorpopyl cyclohexyl carboxylic acid] was added dichloromethane;(150 ml) and thionyl chloride (23 ml ) at 25 -30 °C. The reaction mixture was agitated at 25 - 30°C for 90 minutes and dichloromethane was distilled under reduced

pressure. The residue was added to the mixture of phenylalanine methyl ester hydrochloride (70 gm) and triethylamine (128 ml) in dichloromethane at 0-5°C. The contents were agitated for 45 minutes and reaction progress was monitored by t.l.c. To this 600 ml DM Water was added and layers were separated, organic layer was washed with 3% HCI, 5% sodium bicarbonate and finally with saturated brine solution. The organic layer was dried over anhydrous sodium sulfate and dichloromethane was recovered under reduced pressure to obtain 100-110 g of the crude N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Example 2 :
Above N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester dissolved in methanol (1500 ml) was cooled to 35 °C and sodium hydroxide solution (600ml, 4 % aqueous solution) was added in three portions. The contents were agitated for 45 minutes at 25 -30OC and reaction progress was monitored by t.l.c. Subsequently methanol (1200 ml) was distilled under reduced pressure. To this 600 ml DM Water was added and azeotropically distilled were the traces of methanol. The aqueous reaction mixture was extracted in toluene (700 ml) at 55 °C after acidification ( pH 2) using diluted hydrochloric acid (1:1) . The layers were separated and aqueous layer was further extracted with Toluene (150* ml). The combined organic layers were washed with brine solution (300 ml), charcoalized and filtered, subsequently toluene (300 ml) was distilled under reduced pressure and remaining solution was dried and cooled to 40 °C and seeded with pure H-form crystals at 40°C. The contents were cooled to 25 -30°C slowly and then to 15 °C and agitated for 15 minutes. The contents were filtered and washed with cold toluene and dried under reduced pressure at 60-65oC to yield 72 gm of

N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine in "H-
type" crystalline form.
IR (cm-1): 3309,1714,1649,1214,700; 1H NMR (6 ppm): 10.8
(s,1H,-COOH),7.1-7.4 (m,5H,aromatic), 6.3(d,1H,-NH), 3.2(m, 1H,
-CH);13C NMR(ppm): 177.2 (-CONH), 174.7(-COOH), 77.3(-
CH2Ph)
Example 3:
The product isolated in example 1, dissolved in methanol (1500 ml) was cooled up to 35 °C and sodium hydroxide solution (600ml, 4 % aqueous solution) was added in thiree portions. The contents were agitated for 45 minutes at 25 (300C,and reaction progress was monitored by t.l.c. Subsequently methanol (1200 ml) was distilled under reduced pressure. To this 600 ml DM Water was added and azeotropically distilled were the traces of methanol. The aqueous reaction mixture was extracted in petroleum ether (880 ml) 55 °C after acidification ( pH 2 )using diluted hydrochloric acid (1:1). The layers were separated and aqueous layer was extracted with petroleum ether (200 ml). The combined organic layers were washed with brine solution (300 ml), charcoalized and filtered, subsequently petroleum ether (480 ml) was distilled under reduced pressure and remaining solution was dried and cooled to 40 °C and seeded with pure H-form crystals at 40°C. The contents were cooled to 25 -30°C slowly and then to 15 °C and agitated for 15 minutes. The contents were filtered and washed with cold petroleum ether and dried under reduced pressure at 60-65oC to yield 64 gm of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine in "H-type" crystalline form .
IR (cm-1): 3307,1713,1648,1214,708; 1H NMR (5 ppm): 10.8 (s,1H,-COOH),7.2-7.5 (m,5H,aromatic), 6.2(d,1H,-NH), 3.2(m, 1H, -CH); 13C NMR(ppm): 177.3 (-CONH) ,174.7(-COOH), 77.4(-CH2Ph)

Claim's
We Claim ::
k/
1. A method for preparing "H-type" crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine which comprises Chlorination of trans-[4-lsorpopyl cyclohexylcarboxylic acid] with a chlorinating agent form crude trans-4-lsorpopyl cyclohexyl carboxylic acid chloride which reacts with phenylalanine methyl ester hydrochloride in presence of a(|)ase)in ajsolvent comprisin at least one solvent component selecflafrom the group of inert" solvents like dichloromethane , chloroform , ethylene dichloride and toluene; remove solvent by evaporation leaves a residue of unevaporated crude ester;hydrolysis of the crude ester in presence of an alkali metal hydroxide in a protic solvent constisting of water, methanol, ethanol and subsequently-extracting in organic solvents afte radjusting the pH
2. The process according to claim 1 wherin "H-type" crystals of N-(trans 4-isopropylcyclohexyl carbonyl)-D-phenylalanine are isolated directly withjaut isolating "B-Tyjsfe" crystals .
3. The process according to claim 1 wherein the chlorinating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, PCI5 and PCI3.
4. The process according to claim 3 wherein the chlorinating agent is thionyl chloride.

5. The process according to claim 1 wherein "H-type" crystals of N-(trans-4-isopropylcyclohexyl carbonyl)-D-phenylalanine are isolated from water immiscible organic solvents.
6. The process according to claim 5 wherein the solvents are aromatic and aliphatic hydrocarbons.
7. The process according to claim 6 wherein the solvent is preferably toluene.
&r The isolated "H-type" crystals of N (trans 4-isopropylcyclohexyl -carbonyl)-D-phenylalanine according claims 5 and 6 which is substantially free of solvent.
The process according to claim 5 further comprising separating said crystals from the solvent wherein the temperature of the suspension is at a temperature between15 - 40 °C.
Dated: 31/5/2002
Signature:
Name: KESHAV DEO
Designation: DGM Research &Development ALEMBIC LIMITED ALEMBIC ROAD VADODARD: 390 003