FIELD OF THE INVENTION
The present invention provides an improved and industrially advantageous process for the preparation of pure nateglinide form H in consistence manner directly from nateglinide alkyl ester. In particular, the present invention provides an improved and industrially advantageous process for the preparation of pure nateglinide form H in consistence manner.
BACKGROUND OF THE INVENTION
Nateglinide of formula-I, is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas, and is chemically known as N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl alanine.

Formula I

It is an useful therapeutic agent for the treatment of type II diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes] and is being marketed under the trade name STARLIX®.
U.S. patent 4,816,484 (referred herein as '484) and its subsequent reissue (U.S. patent RE 34,878) discloses hypoglycemic agents including nateglinide. Several methods have been disclosed for the preparation of hypoglycemic agents including nateglinide. In one of the methods, carboxylic acid is treated with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide (DCC) to prepare the corresponding N-hydroxysuccinimide ester, which is further reacted with D-phenylalanine methyl ester hydrochloride to yield the corresponding D-phenylalanine methyl ester derivative which on subsequent base assisted hydrolysis followed by acidification with a dilute acid results in the formation of desired product as depicted below:

This patent is silent about the polymorphic nature of nateglinide.
Nateglinide exists in various crystalline forms. The innovator has disclosed two crystal forms of nateglinide, designated as B-type and H-type, and processes for their preparation in U.S. patent 5,463,116. The patent discloses that nateglinide formed according the process of ‘484 as B-type crystals. This patent also discloses that B-type crystals are unstable and susceptible to change during grinding as demonstrated by differential scanning calorimetry (DSC). The DSC thermogram of B-type shows a sharp endotherm at 131.4°C before grinding while that of H-type shows a sharp endotherm at 140.3°C. After grinding, the DSC thermogram of B-type shows a second endotherm at 138.2°C, suggesting a solid-solid transformation during grinding.
According to U.S. patent 5,463,116, the temperature during crystallization and filtration determines whether the crystal form is B-type or H-type. Temperatures above 10°C, more preferably above 15°C, lead to formation of H-type, while those below 10°C lead to formation of B-type.
Nateglinide crystalline form H has been prepared using several processes by crystallizing nateglinide in a suitable solvent or solvent mixture such as acetone, ethanol and isopropanol with water. It is known that form H crystals of nateglinide prepared in accordance with the method described above, the synthesized crystals were small and it took a long time to complete the separation by filtration when the filtering device available on the industrial scale was used (US 7,208,622). Therefore, the above-described method is not practical for industrial purpose.
Numerous other processes for the preparation of stable form H are known in the art either directly from nateglinide methyl ester by hydrolysis or from nateglinide itself and are incorporated herein as reference.
US patent 7,208,622 describes a process in which trans 4-isopropylcyclohexane carbonyl chloride upon reaction with D-phenyl alanine in the presence of caustic solution followed by acidification in a mixture of water and acetone and crystallization at 58°C to 72oC affords crystalline form H of nateglinide.
US patent 7,767,847 discloses a process for the preparation of nateglinide form H, which comprises the hydrolysis of nateglinide methyl ester with aqueous sodium hydroxide in presence of methanol. After hydrolysis and work-up, the isolated material is further dissolved in methanol at 50°C to 60°C and treated with concentrated hydrochloric acid in 5 ml of water to adjust pH between 2 and 3. Thereafter water is added at the above temperature and the precipitate obtained was stirred for 20 minutes at the above temperature to prepare Form H. Alternatively nateglinide form H has been prepared by boiling wet substance [Form G, prepared from methanol water treatment as above] in n-hepatane for about 1.5 hours, followed by cooling, filtering and drying.
An Indian patent application IN 483/MUM/2002 discloses a process for the preparation of nateglinide form H, which comprises the hydrolysis of nateglinide methyl ester using aqueous sodium hydroxide, methanol and after work –up, nateglinide form H has been prepared using aliphatic or aromatic hydrocarbon such as toluene or petroleum ether.
In one of our earlier Indian patent application IN 2403/DEL/2007 a process for the preparation of nateglinide form H has been disclosed wherein the hydrolysis of nateglinide methyl ester has been carried out using aqueous sodium hydroxide in presence of tetrahydrofuran and after work up, form H has been prepared using another solvent with tetrahydrofuran such as acetone, methanol, water, acetonitrile. We have observed that in small scale, nateglinide form H has been prepared, but on higher scale preparation of nateglinide form H is not consistent.
In one another of our earlier Indian patent application IN 215/DEL/2008 a process for the preparation of nateglinide form H has been carried out, wherein the hydrolysis of nateglinide methyl ester has been carried out using aqueous sodium hydroxide in presence of acetone and after work up, form H has been isolated from same solvent system. We have observed that in small scale, nateglinide form H has been prepared using acetone /water, but on higher scale the preparation of nateglinide form H is not consistent.
All of the above disclosures require an organic solvent during the step of hydrolysis of nateglinide methyl ester to nateglinide.
US patent 5,488,150 discloses a process for the preparation of nateglinide form H, which comprises the dispersion of nateglinide form B in water followed by stirring at 30°C for 1 day. The resulting crystals are filtered and dried at 90°C under reduced pressure overnight to obtain nateglinide form H.
A PCT publication WO 2007/113650 discloses a process for the preparation of nateglinide form H, which comprises heating nateglinide in cyclohexane at reflux temperature followed by drop wise addition of ethyl acetate at same temperature. The temperature is then dropped to 45°C to 48°C and maintained for 16 - 18 hours. The resulting solid is then filtered at 35°C to 40°C, washed with cyclohexane, and dried at 80°C to 85°C to obtain nateglinide form H.

Another PCT publication WO 2010/106550 discloses a process for the preparation of nateglinide form H, which comprises heating the mixture of nateglinide, cyclohexane and ethyl acetate at 65°C to 70°C for 15 minutes followed by addition of charcoal. The resulting contents are filtered and filtrate is stirred for 15 minutes at 75°C to 80°C. The contents are cooled slowly to 48°C to 50°C over 6 hours and maintained for 18 hours to 20 hours. The contents are then cooled to 35°C to 40°C and filtered followed by cyclohexane washing. The resulting compound is dried under vacuum at 80°C to 85°C for 10 hours to 12 hours to obtain nateglinide form H.
Both the PCT publications use cyclohexane and ethyl acetate for preparation of nateglinide form H, one using ethyl acetate as anti- solvent and other as co-solvent. But in both the disclosures, the final product has been filtered at higher temperature of 35°C to 40°C, which may be harmful, if inhaled.
A Chinese patent CN 100383114 discloses a process for the preparation of nateglinide form H from nateglinide form B using methanol, amino methane and water.
A Korean patent application KR 20130125149A discloses new polymorphs of nateglinide form-1 and form-2 and their methods of preparation. Nateglinide form-1 has been prepared from a mixed solvent of methylene chloride and hexane. Nateglinide form-2 has been prepared using cyclohexane. In the exemplified process 1 g of nateglinide form B has been taken in 350 ml of cyclohexane and refluxed for 3 hours, followed by cooling to 20°C, stirred and further cooled to 0°C. The resulting mixture is then stirred for 2 hours at same temperature and filtered. The resulting crystals are dried under reduced pressure at 40°C for 6 hours to obtain nateglinide crystal form-2. It is also mentioned that for preparation of form-2 the step of refluxing is carried out in the presence of at least one of the dehydrating agent and the adsorbant.
The X-Ray powder diffraction pattern [XRPD] and differential scanning calorimetry [DSC] of said nateglinide form-2 matches with that of nateglinide form H. However, melting point i.e. 129.5°C to 131.7°C of nateglinide form-2 is different than that of nateglinide form H i.e. 136°C to 142°C. Nateglinide form-2 obtained as per the above patent application has been isolated at 0°C. However, as per the innovator’s observations disclosed in US Patent 5,463,116, it reports that temperatures above 10°C, more preferably above 15°C, lead to formation of nateglinide form H, while those below 10°C lead to formation of nateglinide form B, which are contradictory with disclosure in said Korean publication. Further the solvent used for the preparation of nateglinide form-2 is in huge volumes i.e. 350 volumes, which is not suitable at industrial scale and makes the process unattractive for large scale.
In view of the above, number of processes are available for the preparation of nateglinide form H, which have their own advantages and disadvantages. Most of the processes perform filtration step using organic solvent at higher temperature i.e. above 35°C or using alcoholic solvents for crystallization. Organic solvents are harmful and some are volatile so not advisable to filter at higher temperature. Using alcoholic solvent during crystallizations leads to the esterification back to nateglinide alkyl ester which needs extensive purification to obtain the pure nateglinide and thus, reducing the yield and purity of product. Therefore, there is an urgent need to develop an industrially friendly process for the manufacture of pure nateglinide form H in consistent manner, without allowing other forms to coexist, and unique with respect to simplicity, cost effectiveness. The present invention aims to develop a process avoiding use of alcoholic solvent in final recrystallization step and to use mild reaction conditions to result in the preparation of pure nateglinide form H consistently in large scale.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved and industrially advantageous process for the preparation of pure nateglinide form H consistently directly from nateglinide alkyl ester.
Another object of the present invention is to provide an improved process and industrially advantageous for the preparation of pure nateglinide form H consistently using any other form of nateglinide.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of pure nateglinide form H comprising the steps of:
a) hydrolyzing nateglinide alkyl ester of the formula II,

Formula II

“wherein R is straight or branched chain C1 to C4 alkyl”
using base and water in the absence of an organic solvent;
b) acidifying the mixture obtained in step a) using a suitable mineral acid;
c) filtering the reaction mixture;
d) subjecting the wet nateglinide obtained in step c) with cyclohexane;
e) heating the reaction mixture obtained in step d) to 35°C to 70°C;
f) cooling the mixture obtained in step e) to 25°C to 30°C; and
g) isolating pure nateglinide form H.

According to one another aspect, the present invention provides a process for the preparation of pure nateglinide form H comprising the steps of:
a) subjecting nateglinide with cyclohexane and water,
b) heating the reaction mixture obtained in step a) to 35°C to 70°C;
c) cooling the mixture obtained in step b) to 25°C to 30°C; and
d) isolating pure nateglinide form H.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the X-Ray powder diffraction pattern for nateglinide form H obtained according to example 1.
Figure 2 illustrates the X-Ray powder diffraction pattern for nateglinide form H obtained according to example 3.
Figure 3 illustrates the X-Ray powder diffraction pattern for nateglinide form H obtained according to example 4.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, "pure nateglinide form H" refers to nateglinide form H having 2% or less of other polymorphic forms of nateglinide, preferably no detectable quantity of other polymorphic forms of nateglinide.
The present invention provides an improved process for the preparation of pure nateglinide form H directly from nateglinide alkyl ester of the formula II.
Nateglinide form H, encompassed by the present invention may be characterized by at least one of X-Ray powder diffraction (XRPD), differential scanning calorimetry (DSC) or fourier transform infrared (FTIR) spectroscopy.
The XRPD pattern of nateglinide form H is measured on PANalytical X'Pert Pro diffractometer with copper radiation and expressed in terms of two-theta, d-spacing and relative intensities.
DSC analysis is performed using a TA instruments differential scanning calorimeter Mettler Toledo DSC823e. The sample is placed in an aluminum DSC pan and the accurate weight is recorded. The pan is covered with a lid and then crimped. The sample cell is equilibrated at 50°C and heated under a nitrogen purge at a rate of 10°C/min up to 300°C. Indium metal and zinc metal are used as the calibration standard. The temperature reported is at the transition maxima.

According to one aspect, the present invention provides an improved process for the preparation of pure nateglinide form H directly from nateglinide alkyl ester of the formula II. The alkyl ester can be selected from straight or branch chain C1 to C4 alkyl ester and preferably methyl ester is used. Generally hydrolysis of nateglinide alkyl ester of the formula II can be carried out using a suitable base in the presence of water without using any organic solvent. Particularly hydrolysis of nateglinide alkyl ester of the formula II can be accomplished at a temperature of about 35°C to about 50°C and it takes about 8 hours to about 10 hours for completion of reaction. The suitable base can be selected from hydroxides of alkali metal such as sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metal such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. Preferably sodium hydroxide can be used to hydrolyze nateglinide ester of formula II. The base can be added in pellet form, powdered form or as solution in water. The amount of base can be varied from 1.05 to 5.0 molar equivalents. Preferably 1.15 to 3.5 molar equivalents can be used; more preferably 1.5 molar equivalents can be used. Particularly, the amount of water can be varied between 10.0 volumes to 50.0 volumes. Preferably 20.0 volumes can be used. Moreover, if required an additional amount of water can be added any time during the course of reaction.
The progress of the reaction can be monitored by suitable chromatographic techniques such as high pressure liquid chromatography (HPLC), gas chromatography (GC), ultra pressure liquid chromatography (UPLC), thin layer chromatography (TLC) and the like.
After completion of the reaction, the reaction mixture can be filtered through celite and can be washed with water. The pH of the filtrate can be adjusted to around 6.5 to 7.5 at about 35°C to about 70°C using a suitable mineral acid preferably concentrated hydrochloride is used and can be further stirred for about 30 minutes to 60 minutes. The pH of the mixture can be further adjusted to about 1.5 to 2.5 using mineral acid preferably concentrated hydrochloride is used and can be further stirred for about 1 hour to 2 hours. The resulting mixture can be cooled to 25°C to 30°C and can be stirred for about 1 hour to 2 hours. The resulting mixture can be filtered and slurry washed using water till the pH around 6.5 to about 7.0. The resulting wet solid can be dried or used as such in the next step. The resulting wet solid can be taken in cyclohexane. The volume of cyclohexane used can varies between 8.0 volumes to 16.0 volumes and preferably between 10.0 volumes to 12.0 volumes. The resulting reaction mixture can be heated to about 35°C to 70°C and can be stirred for few minutes to few hours, preferably about 1 hour to 8 hours and more preferably about 2 hours to 5 hours. Thereafter the reaction mixture can be cooled to below 35°C and stirred at 25°C to 30°C for about few minutes to few hours, preferably about 1 hour to 5 hours. The resulting product can be isolated by conventional method such as filtration, decantation, centrifugation, or a combination thereof. Preferably the reaction mixture can be filtered at 25°C to 30°C and can be dried at 40°C to 45°C under vacuum for 6 hours to 12 hours till loss on drying is not greater than 0.5% w/w.
According to another aspect, the present invention provides a process for the preparation of pure nateglinide form H from any form of nateglinide using cyclohexane and water. Generally the nateglinide can be in any polymorphic form or mixture of polymorphs and can be in dry form or wet form. The nateglinide can be prepared by using the process in our earlier Indian patent applications IN 215/DEL/2008. The nateglinide can be taken in a mixture of cyclohexane and water. The volume of cyclohexane can varies between 8.0 volumes to 16.0 volumes and preferably between 10.0 volumes to 12.0 volumes. The volume of water can vary between 0.2 volumes to 5.0 volumes; preferably between 0.3 volumes to 4.0 volumes; more preferably 3.0 volumes of water can be used. The resulting mixture can be heated to about 35°C to 70°C and can be stirred for about 2 hours to 5 hours. The resulting mixture can be gradually cooled to 25°C to 30°C over a period of few minutes to few hours, preferably for a period of about 1 hour to 5 hours and can be further stirred at 25°C to 30°C for about 1 hour to 5 hours. The resulting product can be isolated by conventional method such as filtration, decantation, centrifugation or a combination thereof.
Nateglinide alkyl ester of formula II, used as starting material can be prepared by methods reported in prior art or reported in our Indian patent IN 275884.
We have not found any reference wherein nateglinide form H is prepared directly from nateglinide alkyl ester of formula II by hydrolysis using base and water in the absence of organic solvent to obtain wet nateglinide, followed by treatment with cyclohexane. Therefore preparation of nateglinide form H directly from nateglinide alkyl ester of formula II by hydrolysis using base in absence of organic solvent followed by treatment with cyclohexane forms the novel and inventive part of the invention. Also the preparation of nateglinide form H using nateglinide in any polymorphic form or mixture of polymorphic form, cyclohexane and water is not known specifically.
The major advantage of present invention is to provide an improved and industrially advantageous process for preparation of pure nateglinide form H consistently using mild reaction conditions.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples:
Example 1: Preparation of nateglinide form H
To a solution of sodium hydroxide (3.62 g) in demineralized water (400 mL), nateglinide methyl ester (20 g) was added at 25°C to 30°C and stirred for 30 minutes. The resulting reaction mixture was then heated to 40°C to 45°C and stirred for 8 hours. After completion of reaction, the reaction mixture was filtered through celite. The filtrate was then heated to 40°C to 45°C and pH was adjusted to neutral using concentrated hydrochloride and further stirred for about 45 minutes. Thereafter the pH was further adjusted to 1.8 using concentrated hydrochloride at 40°C to 45 °C and stirred for 1 hour at same temperature. The resulting mixture was then gradually cooled to 25°C to 30°C and stirred for another 1 hour. The solid, thus obtained, was filtered and slurry washed with demineralized water till the neutral pH and followed by suck drying. To the resulting wet solid, cyclohexane (200 mL) was added and then heated to 40°C to 45°C and stirred for 2 hours. The mixture was then cooled gradually to 25°C to 30°C and stirred for another 1 hour. The resulting mixture was then filtered and dried under vacuum at 40°C to 45°C for 8 hours to obtain 17.8 g title compound having purity of 99.90% w/w by HPLC and DSC -140.71°C.
Example 2: Preparation of nateglinide form H
To a solution of sodium hydroxide (21.72 g) in demineralized water (2400 mL), nateglinide methyl ester (120 g) was added at 25°C to 30°C and stirred for 30 minutes. The resulting reaction mixture was then heated to 40°C to 45°C and stirred for 8 hours. After completion of reaction, the reaction mixture was filtered through celite and pH was adjusted to neutral using concentrated hydrochloride and further stirred for about 30 minutes. Thereafter the pH was further adjusted to 2.0 using concentrated hydrochloride and stirred for 1 hour at same temperature. The resulting mixture was then gradually cool to 25°C to 30°C and stirred for another 1 hour. The solid thus obtained was filtered and slurry washed with demineralized water till the neutral pH, followed by suck drying. To the resulting wet solid, cyclohexane (1200 mL) was added and then heated to 40°C to 45°C and stirred for 2 hours. The mixture was then cooled gradually to 25°C to 30°C and stirred for another 1 hour. The resulting mixture was then filtered and dried under vacuum at 40°C to 45°C for 8 hours to obtain 108.6 g title compound having purity of 99.98% w/w by HPLC.
Example 3: Preparation of nateglinide form H
To a solution of cyclohexane (13.2 L) and demineralized water (3.3 L), nateglinide (1.1 Kg) was added at 25°C to 30°C and stirred for 30 minutes. The reaction mixture was then heated to 65°C to 70°C and stirred for further 5 hours. The resulting reaction mixture was then gradually cooled to 25°C to 30°C and stirred for 2 hours. The solid, thus obtained was filtered and dried under vacuum at 40°C to 45°C for 8 hours to obtain 1.08 Kg title compound having purity of 99.09% w/w by HPLC. XRD pattern and DSC confirm that product is Form H.
Example 4: Preparation of nateglinide form H
Step -1: Preparation of nateglinide
To a solution of sodium hydroxide (0.365 Kg) in demineralized water (20 L), nateglinide methyl ester (2 Kg) and acetone (20 L) were added at 25°C to 30°C and stirred for 30 minutes. The resulting reaction mixture was then cooled to 15°C to 20 °C and stirred for 4 hours. After completion of reaction, the reaction mixture was filtered through celite. The filtrate was then cooled to 15°C to 20°C and pH was adjusted to neutral using concentrated hydrochloride and further stirred for about 45 minutes. Thereafter the pH was further adjusted to 2.0 using concentrated hydrochloride at 15°C to 20°C and stirred for 8 hours at same temperature. The solid, thus obtained, was filtered and slurry washed with demineralized water till the neutral pH and followed by suck drying.
Step -2: Preparation of nateglinide form H
To the resulting wet solid, cyclohexane (24 L) and demineralized water (6 L) was added and then heated to 60°C to 70°C and stirred for 5 hours. The mixture was then cooled gradually to 25°C to 30°C. The resulting mixture was then filtered and dried under vacuum at 40°C to 45°C for 8 hours to obtain 1.76 Kg of title compound having purity of 99.28% w/w by HPLC.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples are provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents

WE CLAIM:
1. A process for the preparation of pure nateglinide form H comprising the steps of:
a) hydrolyzing nateglinide alkyl ester of the formula II,

Formula II

“wherein R is straight or branched chain C1 to C4 alkyl”
using base and water in the absence of an organic solvent;
b) acidifying the mixture obtained in step a) using a suitable mineral acid;
c) filtering the reaction mixture;
d) subjecting the wet nateglinide obtained in step c) with cyclohexane;
e) heating the reaction mixture obtained in step d) to 35°C to 70°C;
f) cooling the mixture obtained in step e) to 25°C to 30°C; and
g) isolating pure nateglinide form H.
2. The process as claimed in claim 1, wherein in step a) the suitable base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
3. The process as claimed in claim 1, wherein in step a) the suitable base is preferably sodium hydroxide.
4. The process as claimed in claim 1, wherein in step b) the suitable mineral acid is hydrochloric acid.
5. A process for the preparation of pure nateglinide form H comprising the steps of:
a) subjecting nateglinide with cyclohexane and water,
b) heating the reaction mixture obtained in step a) to 35°C to 70°C;
c) cooling the mixture obtained in step b) to 25°C to 30°C; and
d) isolating pure nateglinide form H.
6. The process as claimed in claim 5, wherein step a) nateglinide used is any form of nateglinide.