FIELD OF THE INVENTION
The present invention relates to an improved process for synti^zing 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 JV-(trans-4-isopropylcyclohexylcarbonyl)-£)-phenylalanine.
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 D-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.
PCX 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. Xhe 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 and 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 W-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine alkyl ester of formula II
(Formula Removed)
Formula II
-wherein Alk is straight or branched chain C/-CV alkyl,
in the presence of base in a solution of suitable ketonic 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, prepared according to example 1.
Figure 2 illustrates the differential scanning calorimetry for nateglinide form H, prepared according to example 1.
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'^ert Fro 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, Af-(trans-4-isopropylcyclohexyl carbonyl)-D-phenylalanine alkyl ester (herein referred as nateglinide methyl ester) of formula II
(Formula Removed)
Formula II
wherein Alk is straight or branched chain C/-Q alkyl,
can directly be converted to pharmaceutically pure nateglinide form H. The alkyl ester is selected from straight or branched chain Cj-C4 alkyl and preferably ethyl and methyl esters are used. Typically, Ar-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine alkyl ester of formula II (wherein Alk is preferably methyl) is suspended in a solution of demineralized water, a suitable ketonic solvent and treated with base at 2-I5°C, over a period of few minutes with constant stirring. Suitable ketonic solvent can preferably be selected from Ca-Cio ketones, more preferably aliphatic ketones like acetone, diethyl ketone, ethyl methyl ketone, diisopropyl ketone, methyl propyl ketone, methyl isobutyl ketone, the like and mixtures thereof can be employed. In the preferred embodiment, the solvent used is acetone. The base can be selected from alkali metal hydroxides, alkaline metal carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, the like or a mixture thereof. Preferably potassium hydroxide and sodium hydroxide are used, most preferably sodium hydroxide is used.
The base can be added in pellet form, powdered form or as solution in water. 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. The amount of base used varies between 1.05 to 5.0 molar equivalents, but preferably 1.15-3.5 molar equivalents are used.
In the present invention, the reaction is conducted preferably in the presence of large volumes of water. Moreover, whenever needed additional amount of water may added any time during the course of reaction. The ratio of solvent and water used varies from 0.05:0.95 to 0.95:0.05, but is preferably 1.0:1.0 to 2.0:1,0. The total quantity of solvents may vary depending upon the solvent and reaction condition employed and the combined quantity 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 conditions are ideal for non racemization of the resulting nateglinide.
The temperature of the reaction mass is slowly raised to 15-20°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. optionally, after completion of the reaction, the solution is filtered. Depending upon the requirement, additional amount of water may be added to the reaction mixture after the completion of the reaction. Temperature of the reaction mixture could be brought down to 5-10°C. The pH of the mixture is then adjusted to 1.0-3.0 with the addition of suitable mineral acid preferably dilute 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
5-60°C, preferably at 10-20°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 L-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
Nateglinide methyl ester (80.0 g) was added to a solution of sodium hydroxide (14.50 g) in demineralized water (800 ml) and acetone (800 ml) at 5to
10°C. The temperature was slowly raised to 15-20°C and reaction mass was stirred at 15-20°C for 4 hours when the HPLC indicated the reaction to be complete. The reaction mixture was filtered, pH was adjusted to 1.5 - 2.5 with slow addition of IN hydrochloric acid and the reaction mass was stirred for 10 hours at 15-20°C. The precipitated solid was filtered under vacuum, successively slurry washed with demineralized water (5 x 400 ml), suck dried for 1 hour and then dried at 45-50°C under vacuum till the moisture content was below 0.5% to afford 70.63 g of nateglinide as a white crystalline solid having purity 99.73 % by HPLC (Yield = 92.93 %) having XRD and DSC as displayed in figure 1 and 2 respectively.
Example 2; Preparation of nateglinide form H
Nateglinide methyl ester (8.0 g) was added to a solution of sodium hydroxide (1.450 g) in demineralized water ( 40 ml) and acetone (80 ml) at 5 to 10°C. The temperature was slowly raised to 15-20°C and the reaction mass was stirred at 15-20°C for 4 hours when the HPLC indicated the reaction to be complete. The mixture was filtered and pH was adjusted to 1.5 - 2.5 with slow addition of IN hydrochloric acid. Additional water (40 ml) was added to the reaction mixture and the reaction mass was stirred for 10 hours at 15-20°C. The precipitated solid was filtered under vacuum, successively slurry washed with demineralized water (5 x 400 ml), suck dried for 1 hour and then dried at 45-50°C under vacuum till the moisture content was below 0.5% to afford 7.23 g of nateglinide as a white crystalline solid having purity 99.89% by HPLC (Yield: 95.13 %).
Example 3: Preparation of nateglinide form H
Nateglinide methyl ester (8.0 g, 0.024 moles) was added slowly to a solution of sodium hydroxide (14.50 g, 0.036 moles) in demineralized water ( 40.0 ml) and acetone (80 ml) at 5 to 10°C. The temperature was slowly raised to 15-20°C and the reaction mass was stirred at 15-20°C for 4 hours when the HPLC indicated the reaction to be complete. The mixture was filtered and the pH was adjusted to 1.5-2.5 with slow addition of IN hydrochloric acid. The reaction mass was
stirred for 10 hours at 15-20°C. The precipitated solid was filtered under vacuum, successively slurry washed with demineralized water (5 x 40 ml), suck dried for 1 hour and then dried at 45-50°C under vacuum till the moisture content was below 0.5% to afford 7.08 g of nateglinide as a white crystalline solid having purity 99.83% by HPLC (Yield = 93.15 %).
Example 4; Preparation of nateglinide form H
Nateglinide methyl ester (10.0 g, 0.03 moles) was added to a solution of sodium hydroxide (1.81 g, 0.045 moles) in demineralized water ( 50 ml) and acetone (100 ml) at 5 to 10°C. The temperature was slowly raised to 15-20°C and the reaction mass was stirred at 15-20°C for 4 hours when the HPLC indicated the reaction to be complete. The mixture was filtered, pH was adjusted to 1.5 - 2.5 with the slow addition of 0.1 N hydrochloric acid and the reaction mass was stirred for 10 hours at 15-20°C. The precipitated solid was filtered under vacuum, successively slurry washed with demineralized water (5 x 50 ml), suck dried for 1 hour and then dried at 45-50°C under vacuum till the moisture content was below 0.5% to afford 8.92 g of nateglinide form H as a white crystalline solid having purity 99.78% by HPLC (Yield = 93.89 %).
Example 5; Preparation of nateglinide form H
Nateglinide methyl ester (10.0 g, 0.03 moles) was added to a solution of sodium hydroxide (1.81 g, 0.045 moles) in demineralized water (90 ml) and acetone (100 ml) at 5 to 10°C. The temperature was slowly raised to 15-20°C and reaction mass was stirred at 15-20°C for 4 hours when the HPLC indicated the reaction to be complete. The mixture was filtered to remove suspended particles, pH was adjusted to 1.5 - 2.5 with slow addition of IN hydrochloric acid. The reaction mass was stirred for 10 hours at 15-20°C and the precipitated solid was filtered under vacuum, successively slurry washed with demineralized water (5 x 50 ml), (till the filtrate indicated the absence of chloride ion), suck dried for 1 hour and then dried at 45-50°C under vacuum till the moisture content was below 0.5% to afford 8.7 g of nateglinide as a white crystalline solid having purity 99.74% by HPLC (Yield = 92.31%).

WE CLAIM
1. A process for the preparation of highly pure nateglinide form H comprising:
hydrolyzingjV-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine alkyl ester (nateglinide 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 ketonic 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 ketonic solvent is
selected from aliphatic ketones like acetone, diethyl ketone, ethyl methyl
ketone, diisopropyl ketone, methyl propyl ketone, methyl isobutyl ketone, the
like and mixtures thereof.
4. The process according to claim 1, wherein the suitable ketonic solvent is
acetone.
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 or
potassium hydroxide.
7. The process according to claim 1, wherein the acid 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.