FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. "A novel and improved process for the preparation of Nateglinide and its polymorph form-H".
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD -382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.


£( Oi APR 2005 /+1

TITLE: A novel and improved process for the preparation of Nateglinide and its polymorph form-H

FIELD OF INVENTION :
The present invention relates to commercially viable process for the preparation of Nateglinide and its polymorph form-H.

BACKGROUND AND PRIOR ART
Nateglinide is a derivative of unnatural amino acid D-Phenyl alanine .It is taken
immediately before meal and acts directly on pancreatic p-cells to restore the
physiological early phase insulin secretion pattern, immediately after meals onset,
which is lost in people with type-2 diabetes. It also enhances insulin secretion after
meals during periods of elevated glucose levels (Hyperglycemia).
Nateglinide is chemically known as N-[[trans-4-(\-
Methylethyl) cyclohexyl] carbonyl]-D-phenylalanine Or
(-)-N-(f rarts-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine Nateglinide has CAS Registry Number [ 105816-04-4] and is represented by a compound of formula-1

Formula-1
[1]
European patent 0196222 (1986) & J. Med. Chem (1989) vol. 32 page 1436 discloses synthesis of Nateglinide from trans 4-isopropyl cyclohexane carboxylic acid as shown in Scheme-1

Scheme-1




H9C.
1-{[(trans-4-isopropylcyclohexyl)-carbonyl]oxy}pyrrolidine-2,5-dione
tC]
O
[C]
NH COOMe
CH3 [F]
Nateglinide methyl ester
,xCOOH
H,C
DCC / CHCI,
N—OH
CH,
"■3 0
trans-4-isopropylcyclohexane
carboxylic acid 1-hydroxypyrrolidine-
[A] 2,5-dione
[B]
COOMe
NEtj / CHCI3 H3C
[i^yX^COOHMeOH> r^Y^V'
KJ K SOCI2 % \[^J iH2
D-phenylalanine
methyl ester [E]

NaOH
COOH
D-phenylalanine [D]

fcH, [G]
Nateglinide
The coupling of the acid of formula [A] with N-hydroxy succinimide [B] involves use of DCC, which is a skin-irritant and moisture sensitive reagent, as stated in WO2004/018408A1
US 4816484 and its subsequent reissue US RE 34878 discloses preparation of Nateglinide as per Scheme-2 as follows:

Scheme-2

HSC

CH,

.COOH HO—N O
DCC

H,C.

H2N-^ ^COOMe

CH,


NH ^-COOMe
NH ^XOOH
[1] NaOH / MeOH
»-
[2] H+ H,C.
HaC.
m.p. 137-138° C

NATEGLINIDE M.P. 129-30° C

The process involves use of Me ester in D-phenyl alanine methyl ester which acts as a protecting group during coupling, as stated in WO2004/005240A1 deprotection of ester group is probably not complete thus leaving an impurity in the finished product. Moreover crystallization of Nateglinide from aqueous methanol may result in esterification of the product.
JP 7017899 [Equivalent to JP4008794 ] discloses preparation of Nateglinide from trans isopropyl cyclohexyl carboxylic acid in a single step using PCI5 as per Scheme-3
Scheme-3


.**'
NH,

H3C
H,C

xCOOH
^V^
+ PCIc D-Phenylalanine
DCE

H,C
COOH

COOH
rT^

trans-4-isopropyl cyclohexane
carboxylic acid

Nateglinide

As stated in WO2004018408A1 this process has following drawbacks:

[1] Use of 1,2 dichloroethane as a solvent in the final step is undesirable and is a class -II solvent so its use is to be avoided in manufacture of pharmaceutical ingredients. [2] The process uses PCI5, which is extremely corrosive and hygroscopic whose handling on large scale is difficult and inconvenient.
US 4816484, US RE 34878 and EP 196222 also describe other process for the preparation of Nateglinide in which trans-4-isopropycyclohexyl carboxylic acid is converted to its acid chloride and reacted with D-Phenylalanine in acetone using 10% sodium hydroxide to provide Nateglinide as described in scheme-4 : Scheme-4
COOH

CIOC,,,
HOOC,„
CH.
PCL
NaOH / Acetone
CH,
CH3
Trans acid chloride
Dichloroethane
...**v

COOH
H,C
CH3 Nateglinide
Trans acid
As stated in WO2004/018408 Al Phosphorous pentachloride used for the preparation of acid chloride is extremely corrosive and hygroscopic which is very difficult to handle during scale up operation.
WO 2004/018408 discloses a synthesis of Nateglinide in which trans4-isopropyl cyclohexane carboxylic acid is converted to a mixed anhydride using alkyl chloroformate in ketonic solvent and reacting further with D-Phenylalanine in presence of alkali/base to give Nateglinide, these steps are depicted in Scheme-5:

Scheme-5

>vVCOOH
H3C.
Ketonic solvent
H,C
CICOOR
Base
Alkyl chloroformate
4-trans-cyclohexane carboxylic acid

rf^
NH ^COOH

alkali / base

COOH
K,C.

NATEGLINIDE

The drawbacks of this process are low overall yield [44 % ] , too many purifications, and use of mixtures of solvents making the process less attractive for commercial production.
WO03/093222 describes the preparation of novel crystalline form "C" of N-(trans-4-isopropyl cyclohexylcarbonyl)- D- phenylalanine by reacting D-Phenylalanine methyl ester HC1 with trans-4-isopropyl cyclohexane carboxylic acid in presence of propane phosphonic acid anhydride or LiOH-Al2O3 in halogenated hydrocarbon solvents such as dichloromethane, dichloroethane at a temperature between -10°C to 90°C followed by base hydrolysis.
Alternatively, the product can be obtained by reacting trans-A isopropyl cyclohexane carbonyl chloride with D-phenylalanine methyl ester HC1 in halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, in presence of base such as triethyl amine, pyridine at a temperature between -10°C to 90 C followed by base hydrolysis.
The use of reagent like propane phosphonic acid anhydride in ethyl acetate makes the process uneconomical.
WO 02/32854A1 [equivalent to US 20040030182, EP1334963, CN1481356] describes a process wherein trans-4-isopropyl cyclohexyl carbonyl chloride is reacted with D-Phenylalanine in a mixed solvent of ketone solvent and water in the presence of an alkali and then adjusting the temperature of the mixture to 58°C to 72°C and the concentration ketone solvent to more than 8 wt % and less than 22 wt % to conduct precipitation of Nateglinide crystals.
WO 02/32853A1 [equivalent to US20040024219,EP 1334962, CN 1481355, CA 2425533] also describes a process for the preparation of Nateglinide, which comprises

the step of reacting trans-4-isopropyl cyclohexyl carbonyl chloride with D-Phenylalanine in a mixed solvent consisting of an organic solvent and water by keeping the different ratio of organic solvent and water, under conditions kept alkaline with potassium hydroxide.
WO2004/005240A1 provides a process for the preparation of an intermediate in the synthesis of Nateglinide wherein trans-4- isopropylcyclohexane acid chloride is formed by reacting 4- isopropylcyclohexane carboxylic acid with thionyl chloride in the presence of an effective amount of an organic amide. It also provides processes for preparation of Nateglinide by acylation of a suitable salt of D-phenylalanine with trans- 4- isopropylcyclohexane acid chloride in both a single and a two-phase system, and in water free of a cosolvent.
US 2004/0077725A1 describes a process where in trans-4-isopropyl cyclohexyl carbonyl chloride is reacted with D-Phenylalanine methyl ester hydrochloride in presence of triethylamine in chloroform at room temperature for 10 hours to get a methyl ester of Nateglinide which on base hydrolysis in isopropyl alcohol yields Nateglinide.
In addition to the above references, nateglinide is also discussed in US patents 5463116 and 5488150 which describe the preparation of form H type crystals of Nateglinide by treating B-type nateglinide crystals ( obtained by following Ex-3 of Japanese patent application laid open No. 63-54321) with a solvent at a temperature of atleast 10°C and forming crystals in the solvent at a temperature of atleast 10°C. In general processes described in the prior art
Use hygroscopic, expensive reagents; involve multi-step extractive workup and involve the use of hazardous reagents like PC15 , DCC, propane phosphonic acid anhydride in ethyl acetate which are not preferred for large scale commercial operations.

SUMMARY OF THE INVENTION :
The main object of the invention is to provide a process for the preparation of
Nateglinide without use of hazardous material.
It is another object of the invention is to avoid use of hygroscopic and expensive raw
materials.
It is yet another object of the present invention to provide a process which avoids
multistep extractive workup.
The present invention relates to the disclosure of an efficient and cost effective and novel method for the preparation of Nateglinide involving reaction of N,0-bis trimethyl silyl protected D-phenyl alanine with trans-4-isopropylcyclohexyl-l-carbonyl chloride using a base in suitable solvent(s). The isolated nateglinide is processed to its polymorphic form H using ethyl acetate-cyclohexane. The use of oxalyl chloride for converting trans-4-isopropyl cyclohexane carboxylic acid into trans-4-isopropyl cyclohexane carboxylic acid chloride is also an object of the present invention.
The use of N,0-bis trimethyl silyl protected D-phenyl alanine for preparing Nateglinide is an object of the present invention and is not restricted to be formed from HMDS only but is meant to be preparable from other silylating agents also.

DETAILED DESCRIPTION :
The present invention discloses a novel method of synthesis for the preparation of Nateglinide from trans-4-isopropyl cyclohexane carboxylic acid, its conversion to an acid chloride by oxalyl chloride, and subsequent reaction with N,0-bis trimethylsilyl D-Phenylalanine in dichloromethane using triethylamine as a base to give Nateglinide, which is purified and further processed to give form-H. The present invention is described as per Scheme-6 as follows : Scheme-6

CH,
^
-CHa
CYCLOHEXANE / EtOAc 45-50° C
coci

COOH
(COCI)2 / CH2CI2
H3C ~CH3
trans-4-isopropyl cyclohexanecarboxylic acid
NH
reflux for 2 hrs
H3C -CH3
trans-4- isopropyl cyclohexane carboxylic acid chloride
2 HMDS /ACN reflux 3hrs
NHTMS
COOH
err
D-Phenyl alanine
Not isolated
\^ COOTMS
COCI
COOH ° NATEGLINIDE
NHTMS COOTMS
CH
H,C
NATEGLINIDE FORM-H
trans-4- isopropyl cyclohexane carboxylic acid chloride

Step-1
For converting trans-4-isopropyl cyclohexane carboxylic acid into trans-4-isopropyl
cyclohexane carboxylic acid chloride different chlorinating agents have been tried but
all are either difficult to handle or generate noxious byproducts such as POCI3 or
SO2.We have modified this reaction by replacing the chlorinating agent which is not
only equally efficient but generates gaseous products which are ecofriendly.
The preferred chlorinating agent used in this invention is oxalyl chloride, which
generates CO and CO2 and HC1 as byproducts.
The preferred solvent for this reaction is selected from:
Aromatic hydrocarbons like Benzene, toluene, xylene , optionally mixtures thereof.
Paraffins like hexane, heptane, octane, optionally mixtures thereof.

Cycloalkanes like cyclohexane, cyclopentane methyl cyclopentane, methyl
cyclohexane etc. optionally mixtures thereof.
Halogenated solvents like dichloromethane, chloroform, 1,2-dichloroethane, carbon
tetrachloride optionally mixtures thereof. The most preferred solvent is
Dichloromethane.
The temperature of the reaction varies from 25°-150°C preferably at the reflux temperature of the solvent.
After the reaction is over, the solvent (methylene chloride) is distilled under vacuum and traces are removed by maintaining 60-65°C under vacuum The product thus formed has a purity of around 98% which is sufficient to carry forward for the next step.
Step-2
D-Phenyl alanine can be converted into N,0-bis trimethylsilyl D-Phenylalanine by using any of the available reagents like HMDS, BSU, BSA, or other silylating agents, the preferred reagent is HMDS, and solvents for carrying out silylation is selected from solvents like :
Aromatic hydrocarbons like Benzene, toluene, xylene , optionally mixtures thereof. Halogenated solvents like dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride , optionally mixtures thereof.
Ethers like THF, dioxane, 2-Methyl THF, dialkyl ether like diethyl ether,di propyl ether, dibutyl ether, optionally mixtures thereof. Paraffins like hexane , heptane, octane or optionally mixtures thereof. Cycloalkanes like cyclohexane, cyclopentane , methyl cyclopentane, methyl cyclohexane etc optionally mixtures thereof. Nitrile group of solvents like acetonitrile, propionitrile , optionally mixtures thereof.
Out of all the most preferred is by using HMDS in acetonitrile as solvent.
Nitrogen is purged throughout silylation procedure to provide an inert atmosphere, which prevents the ingress of moisture.
The silylation reaction is quantitative and N,0-bis trimethylsilyl D-Phenylalanine is found to be an excellent reaction intermediate for coupling reaction. Moreover the deprotection of silylated compounds is also very facile and generates products, which are easily removed during workup procedure. The yield of the coupling reaction is high.
The temperature for the conversion of D-Phenylalanine into N,0-bis trimethylsilyl
D-Phenylalanine is dependent on the boiling point of the solvent used, and is from 25
to 150°C, preferably the reflux temperature of the solvent selected.
In the coupling reaction, first D-Phenylalanine is taken in solvent (Acetonitrile) and to
it is added HMDS. Reaction mass is then stirred and refluxed under nitrogen for 3 hrs
to complete silylation. The reaction mass is then cooled to -5°C to 0°C and to it is
added triethyl amine.
After that, a solution of trans-4-isopropyl cyclohexane carboxylic acid chloride in
same solvent (Acetonitrile) is added over a period of 35 to 40 minutes maintaining
temperature -4° to 0°C. The reaction is further stirred at -4° to 0°C for 3 hours and
quenched with ice water containing cone. HC1 , stirred for one hour, filtered ,

washed with water and dried. The dried material is purified in ethyl acetate - hexane and dried to give Nateglinide in 82 to 85% yield with a melting point of 124-128°C and an HPLC purity of 98.5-99.5%
Step-3
Nateglinide prepared in step-2 is further processed using cyclohexane-Ethyl acetate to
give Nateglinide form - H crystals, which is stable and preferred form suitable for use
as pharmaceutical compound.
The general process for preparing form H of Nateglinide is described as follows.
Nateglinide is stirred at reflux in cyclohexane and to it is added ethyl acetate till
reaction mixture becomes clear. Then the solution is cooled to 60 -65°C and seeded
with Nateglinide form H material. Further the reaction mass is cooled to 45-48 C and
maintained for 16 to 18 hours under stirring. After that the reaction mass is cooled to
35 to 40°C and filtered. The solid material is washed with cyclohexane and dried. The
compound thus produced is identified as Nateglinide form -H with an yield of 76 to
80 % and has a melting point of 134-139°C and has an HPLC purity of >99.7 %
In yet another embodiment product of step-2 is converted to form H of Nateglinide as
follows.
Nateglinide is dissolved in methanol To it is added aqueous solution of NaOH
dropwise till pH 6 to 7 is reached The reaction mass is slowly cooled to 10-15°C,To it
is added aqueous solution of HCl and maintained at 10-15°C foe 30-40 minutes.The
reaction mass is filtered and washed with Methanol-Water (1:2), followed by water
wash. Add this material to methanol to get clear solution. Stir for 10-20 minutes. Add
HCl to this mass at 10-15°C till pH 2-3 is obtained. The reaction mass is stirred for
another 20-30 minutes and water is added to it and stirred further for 30-50 minutes.
pH observed is 3-4.The reaction mass is filtered and washed with water. The wet cake
is charged to cyclohexane and heated at 75-80°C for 1 to 2 hours . Slowly cooled to
25 - 30 C for 4 hours. Filtered the mass and washed with cyclohexane and dried this
material for about 6 hours at 85 to 90°C. Crystallise this material in EtOAc-
Cyclohexane [1:10 V/V].This purification procedure gives purity of Nateglinide >
99.7 and yield of 60 % by wt..
The present invention is illustrated by following examples which do not not limit
the scope of invention.
Example-1
Preparation of Trans-4-isopropyl cyclohexane carbonyl chloride
In 250 ml multinecked round bottom flask equipped with stirrer, thermometer and
reflux condenser is charged 100 ml of methylene chloride and 45 gms of trans —4-
isopropyl cyclohexane carboxylic acid and stir at room temperature. To it is charged
37 gms of oxalyl chloride dropwise over a period of 15-20 minutes. The reaction mass
is then heated to reflux and maintained at reflux temperature for 1.5 to 2 hours. After
the reaction is complete distil off methylene chloride to give product
Product weight is 48 gms with a purity 98-99% by GC .
Example-2
Preparation of Nateglinide [ Crude Nateglinide]
In one litre capacity four necked flask equipped with oil bath for heating, stirrer,
thermometer, condenser, and nitrogen gas passing arrangement, is charged 80 ml of
acetonitrile followed by 35 gms of D-phenyl alanine, under nitrogen. To it is added
with stirring 54 ml HMDS under stirring at room temperature. The reaction mass is
then heated to reflux temperature and maintained for 3 hours. The reaction mass is
then cooled under nitrogen flow to room temperature and then to -5 to 0 C. To it 61
ml of triethyl amine is added. Then 42 gms of trans-4-isopropyl cyclohexane carbonyl

chloride dissolved in 80 ml of acetonitrile is added dropwise to this stirred reaction
mass over a period of 35 to 40 minutes by maintaining the reaction mixture
temperature at -4 to 0°C under nitrogen. The reaction mixture is stirred at -5 to 0°C
for 3 hours. The reaction mixture is then quenched nito -1.2 L of icewater containing
60 ml Cone. HC1. The reaction mass is stirred for one hour and the solid is filtered
and washed with 4x200 ml water. The material is unloaded and transferred in tray and
dried in air and then in an oven at 75-80°C for 6-8 hours. The material (~66 gms) is
then transferred in 250 ml flask and dissolved in 130 ml ethyl acetate under hot
condition. This solution is then added to 1.2 L n-hexane in 2L round bottom flask
with stirring. Solid material is precipitated .The reaction mass is stirred at room
temperature for 3 hours. The solid is filtered and washed with 2x150 ml n-hexane.
The material is dried in oven at 95-100°C for 6-8 hours.
Product Weight : 55-57 gms [Crude Nateglinide]
Yield : 82-85%
Purity by HPLC : 98.5-99.5 %
M.P. : 124-128°C
Example- 3
Preparation of Nateglinide form-H from crude Nateglinide
In 1 L capacity multi necked round bottom flask equipped with stirrer, oil bath for
heating, condenser, thermometer and dropping funnel is charged 550 ml of
cyclohexane followed by 55 gms of crude Nateglinide [ product of Example-2]. The
reaction mass is heated to reflux temperature. Added to it at reflux temperature, 110
ml of ethyl acetate dropwise. Reaction mass is then a clear solution. The reaction mass
is cooled to 60°C and is seeded with Nateglinide form-H material. The reaction mass is
then cooled to 45-48°C and maintained at this temperature under stirring for 16-18
hours. Filter the solid at 35-40°C. The wet cake is washed with 2x110 ml of
cyclohexane. The material in unloaded in tray and dried in oven at 90-95 C. This
product is characterized as Nateglinide form -H material.
Product Weight : 40-45 gms
Purity by HPLC : >99.7%
Melting Point : 134-139°C
Example-4
Purification of Crude Nateglinide to give Nateglinide form-H
In 2 L capacity multi necked round bottom flask is added 100 gms of Crude Nateglinide and to it added 800 ml of Methanol and stirred for 10 minutes to give a clear solution to it is added NaOH solution [ 12.5 gms of NaOH in 350 ml water] dropwise and stirred for 10 minutes. (pH= 6-7).The reaction mass is cooled to 10-15°C . Aqueous HC1 [13.1 ml cone. HC1 in 16 ml water] is added at 10-15°C , thick mass is observed (pH=5-6) , and maintained at 10-15°C for another 30-40 minutes The reaction mass is filtered and washed with aq. methanol [400 ml Methanol + 800 ml Water] at 10-15°C , followed by 800 ml of water. The wet cake is unloaded and added to 2050 ml methanol, clear solution is observed. The reaction mass is stirred for 10-20 minutes. Aqueous HC1 [13.1 ml cone. HC1+16 ml water] is added at 10-15°C to this mass (pH=2-3) and stirred for 20-30 minutes. To it is added 2400 ml water and stirred for 30-50 minutes (pH=3-4)The reaction mass is filtered and washed with 200 ml of water. The material is unloaded and wet cake is taken in 1500 ml cyclohexane and heated to 75-80°C and maintained at this temperature for 1-2 hour. The reaction mass is slowly cooled to 25-30°C for 4 hours. The reaction mass is filtered and washed with 100 ml of cyclohexane. The material is dried for 6 hours at 85 to 90°C This dried material is taken in 1000 ml cyclohexane and 100 ml ethyl acetate, and heated to reflux for 2-3 hours , and slowly cooled to 35-40°C. The reaction mass is stirred for 4

hours and cooled to 30-35°C, filtered and washed with 100 ml of cyclohexane.The material is dried at 85-90°C for 12-18 hours. The product is characterized as Nateglinide form H.
Product Weight : 50-60 gms
Purity by HPLC > 99.7%