FIELD OF THE INVENTION
The present invention relates to an improved process for synthesizing highly pure nateglinide form H. More particularly, the present invention relates to the process for synthesizing highly enantiomerically pure nateglinide form H directly from nateglinide alkyl ester.
BACKGROUND OF THE INVENTION
Nateglinide, of formula-I is marketed as starlix and is a useful therapeutic agent for the treatment of type II diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes].
(Formula Removed)
Formula I
Nateglinide 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.
Nateglinide has been first disclosed in US patent 4,816,484 and its subsequent reissue U.S. patent Re 34,878 wherein methanol-water is used to recrystallize nateglinide.
Nateglinide is known to exist in a number of polymorphic forms, however in view of the regulatory and stability related issues, form B and form H of nateglinide are most sought after.
US patent . 5,463,116 discloses form H of nateglinide and further discusses that form H of nateglinide have enhanced stability to grinding. Several processes are disclosed for the generation of nateglinide form H 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 and are incorporated herein as reference.
US patent 7,208,622 describes a process in which trans 4-isopropylcyclohexane carbonyl chloride upon reaction with Z)-phenyl alanine in the presence of caustic solution followed by acidification in a mixture of water and acetone and crystallization at 58-72°C affords crystalline form H of nateglinide.
PCT Application No. WO 05/005373 discloses a process for the preparation of form H by treating nateglinide methyl ester in methanol with aqueous sodium hydroxide to yield the alkali salt and product is liberated with concentrated hydrochloric acid used in two lots.
Most of the prior art methods for the preparation of form H of nateglinide involve the use of alcoholic solvents. The major drawback of using alcoholic solvent during crystallization of nateglinide is that in the presence of alcohol, some of the nateglinide esterifies back to nateglinide alkyl ester, thus reducing the yield and purity of the product. Extensive purifications are required to obtain the purified product.
In view of the above, there is an urgent demand for an improved and reliable process of preparing pure nateglinide form H, which is free from other forms as well as from nateglinide ester impurity and will be suitable for large-scale preparation.
Accordingly, the object of the present invention, thus, is to provide an industrially advantageous process for the preparation of pure nateglinide form H, without allowing other forms to coexist, with low levels of nateglinide alkyl ester, L-enantiomer and other impurities and unique with respect to its simplicity, cost effectiveness, scalability.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to an improved process for the preparation of pharmaceutically pure nateglinide form H, directly from N-(trans-4-isopropylcyclohexyl) carbonyl]-D-phenylalanine alkyl ester of formula II
(Formula Removed)
Formula II
wherein Alk is straight or branched chain C1-C4 alkyl,
in the presence of base in a solution of suitable ethereal solvent and water and at relatively dilute conditions, followed by acidification with mineral acid such as hydrochloric acid in the presence of demineralized water and isolating nateglinide form H in high yield and purity.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the powder X-ray diffraction pattern for nateglinide form H. Figure 2 illustrates the differential scanning calorimetry for nateglinide form H. DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention describes an improved process for the preparation of nateglinide form H in high yield and purity.
Nateglinide form H, encompassed by the present invention may be characterized by at least one of X-Ray power diffraction (XRD), FT-infrared spectroscopy (FTIR) or differential scanning calorimetry (DSC) techniques.
The XRD patterns of nateglinide form H is measured on PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacing and relative intensities.
DSC is conducted using standard conditions under nitrogen gas flow at a temperature of 10°C/minute.
In one embodiment of the present invention, W-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II

(Formula Removed)Formula II

wherein Alk is straight or branched chain Ct-C4 alky I,
can directly be converted to pharmaceutically pure nateglinide form H. The alkyl ester is selected from straight or branched chain Ci-C4 alkyl and preferably ethyl and methyl esters are used. Typically, jV-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II (wherein Alk is preferably methyl) is suspended in a solution of demineralized water, a suitable ethereal solvent and treated with base at 2-15°C, over a period of few minutes with constant stirring. Suitable ethereal solvent can preferably be selected from, but not limited to solvents like tetrahydrofuran, 1,4-diethoxy tetrahydrofuran, 1,4-dimethoxy tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, the like and mixtures thereof. In the preferred embodiment, the solvent used is tetrahydrofuran. The base can be selected from alkali metal hydroxide, alkaline metal carbonate such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, the like or a mixture thereof. Preferably sodium hydroxide is used.
The reaction works with equal efficiency if base is added to a suspension of nateglinide alkyl ester in a mixture of water and organic solvent mentioned above. In the present invention, the reaction is conducted preferably in the presence of large volumes of water. Moreover, whenever needed additive amount of water may added any time during the course of reaction.
The amount of base used varies between 1.05 to 5.0 molar equivalents, but preferably 1.15-3.5 molar equivalents are used. The ratio of solvent and water used varies from 0.05:0.9 to 0.9:0.1, but is preferably from 0.2:0.8. Total quantity of solvents may vary depending upon the solvent and reaction condition employed and can be between 5 times to 200 times, preferably between 10 times to 100 times. Both the solvent composition and the temperature of reaction mass during crystallization plays an
important role in obtaining the desired polymorphic form and it has been found that use of dilute solution is ideal for non racemization of the resulting nateglinide.
The temperature of the reaction mass is slowly raised to 25±5°C over a period of about a few minutes to a few hours, preferably for a period of about 1-12 hours. Progress of the reaction can be monitored by high performance liquid chromatography or thin layer chromatography. The reaction solution is filtered if suspended particles are present. Depending upon the requirement, additional amount of water may be added to the reaction mixture after the completion of the reaction. Optionally small amount of organic solvent selected form acetonitrile, acetone, diethyl ketone, ethyl methyl ketone and the like can also be added. The pH of the mixture is then adjusted to 1.0-3.0 with addition of suitable mineral acid preferably hydrochloric acid with constant stirring at ambient temperature to precipitate nateglinide form H. The strength of the hydrochloric acid used may vary between 0.1 N to 12 N, preferably between 0.5 N to 3.5 N. The order and manner of combining hydrochloric acid and water at this stage are not crucial and may be varied. The hydrochloric acid and water may be added individually to the reaction mixture in any order or can be combined together as dilute solution. After complete addition of the acid, the reaction mass is stirred at 15-60°C, preferably at 20-40°C over a period of 1-24 hours, preferably for 4-15 hours.
The precipitated nateglinide form H is isolated using conventional methods like filtration and washed with excess of demineralized water. It is first suck dried for a period of about 1-10 hours and then dried in oven at 40-80°C for about 12-60 hours till the moisture content is below 0.5% to provide nateglinide in high yield and purity greater than 99.5%. Nateglinide thus isolated is of pharmaceutical grade in which no unidentified impurity is above 0.1% and displays physicochemical characteristics which corresponds to that of form H of nateglinide.
Nateglinide alkyl ester of formula II, used as starting material can be prepared by the methods reported in prior art or as reported in our co-pending application no. 232/DEL/2007.
Major advantages realized in the present invention are the high yield and high purity of nateglinide form H directly from nateglinide alkyl ester without using alcoholic solvents, thus preventing the formation of nateglinide ester impurity. Moreover the formation of Z,-enantiomer is minimized using dilute solutions and hence no further purification or crystallization is required
The present invention will now be illustrated by the following examples, which are not intended to limit the effective scope of the claims. Consequently, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as claimed. The present invention has been described in terms of its specific embodiments and various modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention.
EXAMPLES
Example 1: Preparation of Nateglinide form H from nateglinide methyl ester
To a solution of sodium hydroxide (18.12 g, 1.5 moles) in demineralized water (1500 ml) and tetrahydrofuran (400 ml) at 5 to 10°C, W-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (100 g, 0.30 moles) was added. The temperature was slowly raised to 20-22°C and reaction mass was stirred at 20-22°C for 8-10 hours and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the mixture was filtered to remove suspended particles. To the filtrate, demineralized water (1000 ml) was added and pH was adjusted to 1.5 - 2.5 with IN hydrochloric acid. The reaction mass was stirred
for 8 hours at 25-30°C, the solid, thus precipitated, was filtered and slurry washed with demineralized water (5 x 500 ml). The filtered material was suck dried for 2 hours and then dried at 45-60°C under vacuum (till the moisture content was below 0.5%) to afford 92.55 g of nateglinide form H having purity of 99.88 % by high performance liquid chromatography. Yield = 96.70 %
Example 2; Preparation of Nateglinide form H from nateglinide methyl ester
To a solution of sodium hydroxide (18.12 g, 1.5 moles) in demineralized water (1500 ml) and tetrahydrofuran (400 ml) at 5 to 10°C, AXtrans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (100 g, 0.30 moles) was added. The temperature was slowly raised to 20-22°C and reaction mass was stirred at 20-22°C for 8-10 hours and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the mixture was filtered to remove suspended particles and pH was adjusted to pH to 1.5 - 2.5 with IN hydrochloric acid at 25-30°C. Demineralized water (1000 ml) was added to the reaction mixture and reaction mass was further stirred for 8 hours at 25-30°C. The precipitated solid was filtered and slurry washed with demineralized water (5 x 500 ml). The filtered material was suck dried for 2 hours and then dried at 45-60°C under vacuum (till the moisture content was below 0.5%) to afford 91.10 g of nateglinide form H having purity of 99.85 % by high performance liquid chromatography.Yield = 95.19 %
Example 3: Preparation of Nateglinide form H from nateglinide methyl ester
To a solution of sodium hydroxide (18.12 g, 1.5 moles) in demineralized water (1500 ml) and tetrahydrofuran (400 ml) at 5 to 10°C, 7V-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (100 g, 0.30 moles) was added. The temperature was slowly raised to 20-22°C and reaction mass was stirred at 20-22°C for 8-10 hours and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the mixture was filtered to remove
suspended particles and pH was adjusted to pH to 1.5 - 2.5 with 0.25 N hydrochloric acid and reaction mass was stirred for 8 hours at 25-30°C . The precipitated solid was filtered and slurry washed with demineralized water (5 x 500 ml). The filtered material was suck dried for 2 hours and then dried at 45-60°C under vacuum (till the moisture content was below 0.5%) to afford 86.10 g of nateglinide form H having purity of 99.91 % by high performance liquid chromatography. Yield = 89.80 %
Example 4: Preparation of Nateglinide form H from nateglinide methyl ester
To a solution of sodium hydroxide (0.54 g) in demineralized water ( 45 ml) and tetrahydrofuran (12 ml) at 5-10°C, Af-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (3.0 g) was added. After stirring the reaction mass for 15-20 minutes at 5-10°C, the temperature was slowly raised to 20-22°C and reaction mixture was further stirred at 20-22°C for 8-10 hours. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, acetonitrile (7.5 ml) was added to the reaction mixture and the solution was filtered to remove suspended particles. pH of the reaction mass was adjusted to 1.5 to 2.5 with IN hydrochloric acid. Demineralized water (30 ml) was added to the reaction mixture and the mixture was stirred for 8 hours at 25-30°C minutes. The precipitated solid was filtered and slurry washed with demineralized water (5 x 50 ml). The filtered material was suck dried for 2 hours and dried at 45 -60°C under vacuum (till the moisture content was below 0.5%) to afford 2.0 g of nateglinide form H.
Example 5; Preparation of Nateglinide form H from nateglinide methyl ester
To a solution of sodium hydroxide (0.54 g) IN demineralized water ( 45 ml) and tetrahydrofuran (12 ml) at 5-10°C, N-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (3.0 g) was added. After stirring for 15-20 minutes at 5-10°C, the temperature was slowly raised to 20-22°C and reaction mixture was further stirred at 20-22°C for 8-10 hours. Progress of the reaction was monitored by thin
layer chromatography. After completion of the reaction, acetone (7.5 ml) was added to the reaction mixture and the solution was filtered to remove the suspended particles. pH of the reaction mass was adjusted to 1.5 to 2.5 with of IN hydrochloric acid. Demineralized water (30 ml) was added to the reaction mixture and the mixture was stirred for 8 hours at 25-30°C minutes. The precipitated solid was filtered and slurry washed with demineralized water (5 x 50 ml). The filtered material was suck dried for 2 hours and dried at 45 -60°C under vacuum (till the moisture content was below 0.5%) to afford 1.2 g of nateglinide form H.
Example 6: Preparation of Nateglinide form H from nateglinide methyl ester
To a solution of sodium hydroxide (4.53 g, 0.11 moles) in demineralized water (625 ml) and tetrahydrofuran (125 ml) at 5 - 10°C, N-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (25 g, 0.075 mol) was added. The temperature was slowly raised to 20-22°C and reaction mass was stirred at 20-22°C for 8 hours and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the mixture was filtered to remove suspended particles and pH was adjusted to pH to 1.5 - 2.5 with IN hydrochloric acid. The reaction mass was stirred for 8 hours at 25-30°C. The precipitated solid was filtered under vacuum, slurry washed with demineralized water (5 x 100 ml), suck dried for 2 hours and then dried at 45-60°C under vacuum (till the moisture content was below 0.5%) to afford 22.88 g of nateglinide form H having purity of 99.78 % by high performance liquid chromatography. Yield = 95.57 %
Example 7: Preparation of Nateglinide form H from nateglinide methyl ester
To a solution of sodium hydroxide (4.53 g, 0.11 moles ) in demineralized water ( 875 ml) and tetrahydrofuran (125 ml) at 5-10°C, N-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (25 g, 0.075 mol) was added.. The
temperature was slowly raised to 20-22°C and reaction mass was stirred at 20-22°C for 8-10 hours and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the mixture was filtered to remove suspended particles and pH was adjusted to pH to 1.5- 2.5 with slow addition of IN hydrochloric acid. The reaction mass was stirred for 8 hours at 25-30°C, the precipitated solid was filtered under vacuum, slurry washed with demineralized water (5 x 100 ml). The filtered mass was suck dried for 2 hours and then dried at 45-60°C under vacuum (till the moisture content was below 0.5%) to afford 23.21 g of nateglinide form H having purity of 99.85 % by high performance liquid chromatography. Yield = 96.82 %.
Example 8: Preparation of Nateglinide form H
Nateglinide (10.0 g, polymorphic form B) was dissolved in tetrahydrofuran (25 ml) and the mixture was cooled to 20-22°C. Demineralized water (400 ml) was slowly added to the solution and the mixture was stirred for 8 hours at 25-30°C. The precipitated solid was filtered, washed with demineralized water (3 x 100 ml) and dried at 45 -60°C to afford 9.5 g of nateglinide form H having purity of 99.58 % by high performance liquid chromatography.
Example 9: Preparation of Nateglinide form H
Nateglinide (10.0 g,) was dissolved in tetrahydrofuran (25 ml), acetonitrile (12.5 ml) was the added and the mixture was stirred at 25-30°C for 5 minutes. Demineralized water (300 ml) was slowly added to the solution and the mixture was stirred for 6 hours at 25-30°C. The precipitated solid was filtered, washed with water (3 xlOO ml) and dried at 45-60°C to afford 8.0 g of nateglinide form H having purity of 99.67% by high performance liquid chromatography.
Example 10: Preparation of Nateglinide form H
Nateglinide (10.0 g, polymorphic form B) was dissolved in a mixture of tetrahydrofuran (25 ml) and methanol (25 ml) and the mixture was stirred at 25-30°C for 5 minutes. Demineralized water (300 ml) was slowly added to the solution and the mixture was stirred for 6 hours at 25-30°C. The precipitated solid was filtered, washed with demineralized water (3 xlOO ml) and dried at 45-60°C to afford 8.44 g of nateglinide form H.

WE CLAIM
1. A process for the preparation of highly pure nateglinide form H comprises:
hydrolyzing AL(trans-4-isopropylcyclohexyl) carbonyl] £)-phenylalanine alkyl ester of formula II,
(Formula Removed)
Formula II
wherein Alk is straight or branched chain C/-Q alkyl,
with base in a solution of suitable ethereal solvent and water at a temperature of
5-35°C;
optionally adding demineralized water to the reaction mixture;
treating the reaction mass with mineral acid to adjust pH of 1.0- 3.0, at a temperature of 15-60°C and;
isolating highly pure nateglinide Form H.
2. The process according to claim 1, wherein the alkyl ester is preferably methyl
ester or ethyl ester.
3. .The process according to claim 1, wherein the suitable ethereal solvent is
selected from tetrahydrofuran, 1,4-diethoxy tetrahydrofuran, 1,4-dimethoxy
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, the like and mixtures thereof.
4. The process according to claim 1, wherein the suitable ethereal solvent is
tetrahydrofuran.
5. The process according to claim 1, wherein the base is selected from alkali metal
hydroxide, alkaline metal carbonate such as potassium carbonate, sodium
carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, the like or
a mixture thereof.
6. The process according to claim 1, wherein the base is sodium hydroxide.
7. The process according to claim 1, wherein the acid used is preferably
hydrochloric acid.
8. The process according to claim 1, wherein additional demineralized water is
added before the addition of hydrochloric acid.
9. The process according to claim 1, wherein additional demineralized water is
added after the addition of hydrochloric acid.
10. The process according to claim 1, wherein additional demineralized water is
added in mixture with hydrochloric acid.