This application claims the benefit under 35 U.S.C. §119(e) of provisional applications Serial Numbers 60/393,495 filed July 3,2002; 60/396,904 filed July 18, 2002; 60/413,622, filed September 25,2002; 60/414,199, filed September 26,2002; 60/423,750, filed November 5,2002; 60/432,093, filed December 10,2002; 60/432,962, filed December 12,2002; 60/442,109, filed January 23,2003;
60/449,791, filed February 24,2003 and 60/ , filed June 16,2003 (attorney
docket No. 1662/61106), the contents of all of which are incorporated herein by reference.
FIELD OF THE INVENTION
15 The present invention relates to processes for preparing nateglinide and
iutemzediates thereof.
BACKGROUND OF THE INVENTION
Natcglinide, known as (-}-N-{trans-4-isoporpyicycIohexanecarbonyl)-D-20 Phenylalanrae, has the following structure and characteristics:
(Formula Romoved)
Formula

Molecular With Exact Mass Composition
Nateglinide is marketed as STARLBC, which is prescribed as oral tablets having a dosage of 60mg aad 120mg for the treatment of type E diabetes. STARLDC may be used as monotherapy or in combination with mefaforoun to stimulate the pancreas to secrete
insulin. According to the maker of STARLIX,nateglinide is a white powder thet is freely soluble in mefhanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetomtrile and octanol, and practically insoluble in water. Metabolites of nateglinide are disclosed in Ifiroko Takesada, etaL, Bicorg. Med Chemical, 4(10) 1771-81 (1996). U.S. Pat No. 4,516,484 and its subsequent reissue (US Re 34878) disclose
nateglinide and a method for its preparation. The process of the '484 patent reacts a D-
phenylalanine ester derivative wifli aDCC derivative of 4-
isopropylcyclohexanecarixaylic acid, followed by de-esterification to obtain nateglinide,
as illustrated below:

(Formula Romoved)

Description (Complete)The yield obtained is 65%.
The ester acts as a protecting group, limiting die amount of undesirable cross reactions. The process of U.S. Pat No. 4,816,484 however may contaminate the final product with the methyl ester since removal of the ester as a protecting group would probably not be
complete, leaving at least some minor amounts of the ester as an impurity in the final product In addition, crystallization fiom aqueous metbanol might result in esterLfieatjon of the product
A general problem with preparing nateglidine is the presence of the corresponding undesirable cis isomcr during the process, which leads to a final product that Is contaminated With, the corresponding ciisomer. la order to increase fee ratio of the therapeutically effective trans isomer over its corresponding cis isomer, the process of the '484 patent heats a cis-trans mixture of fee methyl ester of 4-isopropylcyclohcxane carboxylic acid in the presence of sodium hydride. A discussion of U.S. Pat No. 4,816,484 may be found fh Hisasni Sninkai, et al, J. Med. Chem. 32(7) 1436 - 1441
A Chinese article discloses another reaction scheme for preparing nateglimde, in which the cis to trans ratio of isorwpyicyclohexylcarboxylic acid is decreased by treatment with KOH in rnetfaanol at elevated temperatures, Xue-yan Zhu, et aL, Hecheng Huaxuc 5(6) $37- 540 (2001) (hereinafter "Xue-yan Zhu"). tne reaction uses phosphorus pentachloride ("PCls") to chlorinate isopropylcyclohexane carboxylie acid, to obtain an acid chloride, which is then reacted with D-phenylalaniae to obtain nateglinide. The reaction has the following scheme, which may result in contamination of the final product with naicglinidc's corresponding cis impurity:
(Formula Romoved)

Anofcer article discloses a process for preparing the tans isomerof4-isopropylcyclohcxane carbonyi chloride (syn. of 4-isopropyicyclohexaiie acid chloride

jcboxylic acid with PCls [Jpn.
("1POJAC*1) by chlorination of 4-isopropylcycl
Kokai Tokkj-o Kohop (1995) (hereinafter "Kckai)]- Kokai and a Japanese patent. IP 070I07S99A, disclose that use of thionyl chloride leads to ibnnation of the corresponding eisisomer.
In addition to fee above references, nateglirude is also disclosed in U.S. Pat Nos. 5,463,116" and 5,488,150, and ftree Japanese publications: WO 02/34254, WO 02/34285 and WQ 02/34713. AH of ffiteserejGsences are mwiporated herein by reference.
Hiere is a need in the ait for additional processes for preparing natcglinide.
SUMMARY OF TEE INVENTION
tn one aspect; the present invention provides a pzocess for preparing frans-4-isopropylcyclohexane acid cMoride comprising the steps of:
a) combining feans-4-isopropyfcyclohexane carboxyKc add with thiooyi chloride in the presence of a C1 to a C6 organic amide to obtain rrans-4-isopropylcyclohcxanc acid chloride substantially free of its coircspooding cis isomer; and
b) recovering the transp44sopropylcyclhxeane acid chloride.
In another aspect, fee present invention provides a process for preparing nateglinide comprising the steps of:
a) combining trans-4-isopropyIcydohcxanc carboxyKc acid with thioayl chloride in the presence of a C1 to a C6 organic amide to obtain trans-4-isopropylcyelohexane acid chloride substantsally free of its correspODding cis isomei;and
b) converting the acid chloride to nateglinidc; and ' c) recovering the nateglinide.
In another aspect,, the present irryention provides a process for preparing nateglirade in a two phase system comprising the steps of,
a) preparing an aqueoie solution of an alkaline earth or alkali metal salt of D-
phenylalaame;
b) cnmhfning $1$ aquep^L*; $o|iifk>n wiffr a water i'mmiscible prganic solvent
containing trans-4-isopropylcycIohexane acid chloride, to form an aqueous and an organic phase, wherein nateglinide forms through xeactioa between the D-phenylalanine and the trans-4-iscpropyIcyclohcxane acid chloride; and c) recovering the nateglinide.
En another aspect, the present invention provides a process ibrpreparrag nateglinidc
comprising fee steps o£
a) preparing an aqueous solution of an alkaline earth or alkali metal salt of D-
phenylalanine in water free of a co-solvent;
b) adding trans-4-isopropyicyclohexane acid chloride as a neat reagent to the
aqueous solution to formnateglinide; and
c) recovering the nateglinide.
la another aspect the present invention provides a process for preparing nateglinide comprising the steps of:
a) combining a solution of a tri-alkyl amine salt of D-phenylalanine with trans-4-
isoprop ylcydakexaiie acid chloride in a C1 to a C6 amide to form nateg&ude;
and
b) recovering the nareglinide.
BRIEF DESCRIPTION OF THE FIGURES
Figure I is an XRPD pattern of oategSnide Form Z, Figure 2 is an FJIR spectrum of aategunidePonn 2. Figure 3 is a DSC themogram of nafeghnideBonn 2.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides facile processes for the preparation of nateglinidc and its intermediates. ID one embodiment, the present invention provides a process for preparing trons-4-isopropyleyclohexane acid chloride, an intermediate m the synthesis of ttateglinidc, substantially free of the corresponding eis-isomer. As used herein, "substantially free" refers to being undctectablc by gas chromatography ("GC"), as carried out under the conditions disclosed in tie present invention. Preferably, the amount of cis-4-isopropyIcyclohexane acid chloride is less than about 0.1% (wt/wt) compared to the corresponding trans isomer, more preferably less than about 0.05% (wt/wt) and most preferably less than about 0.03% (wt/wt).
The present invention prepares traos-4-isopropylcyclohc3cane carbonyl chloride (sy». Isopropylcyclohexane acid cMoridc-ClPCHAC")) by reacting trans-4-isopropylcyclohexmecaiboxylic acid with thionyi chloride in the presence of an organic amide. Examples of such organic amides include cyclic and acyclic Q to Q amides such as N^-dimethylacetamide, N-raetnylpyiroKdone and N,N- dime&Ylformairade. The amide acts as a catalyst The reaction between thionyi chloride and trans-isopropylcycJoriesane carboxyiic acad without catalyst at 70-80°C affords up to 20% of the cis-isomer. However, in the presence of an organic amide catalyst, the cis-£som«r is not formed nor detected in amounts of less than about 0.05% even at elevated temperature
In a preferred embodiment, a mixture ofN,N-Kfimethylfbrmamide, thionyi chloride and trans^isopropylcyciohexanecarboyyiic acid is prepared. The mixture may be
prepared in a snfisble aprotic organic solvent, orpreferably witii a neat reagent Examples
of such solvents include C5 to C12 aliphatic and aromatic hydrocarbons (including fluonnated and chlorinated), ethers, esters, among others.
The trans intermediate used, trans-4-isopiopylcyclohexane carboxylic acid, is preferably substantially fee of me conesponding cis isomer,i,e, less than about 0,2% of the corresponding cis isomer. The tians--4-isopiopylc^lohexanecartioxyh'c acid may be prepared according to the methods known in the art, such as example 31 of US Pat 4,816,484 (Re34,87S), where a process for fte preparation of t-4-ise^ropylcyoclohexanecariKJxyfic add by the hydrogeaation of cumic acid is disclosed. A preferred re-crystallization solvent system for the trans-4-isopropyIcycIohexane carboxylic add is a mixture of methanol and water.
The reaction is preferably earned out with from about 1 to about 5 acid equivalents of thionyl chloride and an effective amount of amide preferably from about 0.05% to about 10%wt/wt (amide/acid). The reaction may be earned out at a temperature of from about minus 10°C to about 60°CT wSh about room temperature being preferred.
After preparing the mixture of 4-isopropylcyclohexanecarboxylic acid, tfuonyl chloride and the amide, the mixture is preferably stirred and allowed to sit for a few hours (about 1 to about 5 hours) for the carboxylic acid to be chlorinated. The chlorinated product (IPCHAC) is then recovered, such as by separation from the solvent or other volatiles, including the neat reagent In a preferred embodiment, the pressure is reduced, and the temperature is raised slightly, to about 4O°C, to evaporate the solvent or other volatiles. After evaporation, the produc^ trans-4-isopropylcyclohexane acid chloride (liquid at room tconpcrature), is obtained, substantially free of the corresponding cis isomer. The purity of the product from flris process is preferably at least about 95% as measured by HFLC, arxl me c^isomcr is preferably undetectable by GC.
The frans-4-isopropylcyclohexane acid chloride prepared may men be used to prepare nategfinide substantially free of the corresponding cis isomer. The processes of the present invention prepare nateglinidc by acylation of a salt of D-phenylalanine with trans-4-isop£Dpylcyclohexane acid chloride.
Preferred salts ofphenylalaaine for acyiation are the sodium and potassium salts. Other salts of alkali metals such as that of lithium may also be used In addition to alkali metals, salts of alkaline earth metals such as magnesium and calcium may also be used. Another group of salts that tnay be used are those of C1 to C7 tri-aBcyl amines, such as tri-
ethyi amine. One of skill in the art would appreciate feat a. suitable base such as
sodinm/poJassium carbonate or hydroxide may be added to phenylalanine to obtain the desired salt
ln. one embodiment the present invention provides for preparation of nateglinide by use of a two phase system, i. e., an. aqueous phase and an organic water immiscible phase. Examples of water immiscible solvents in the organic phase include aromatic hydrocarbons and saturated hydrocarbons, more preferably a C5 to a C12 hydrocarbon. Preferred solvents include toluene and heptane. Water immiscible esters and ketones, such as ethyl acetate, may also be used.
In one embodiment of the two phase system, a solution of trans-4-isopropylcyclohexane acid chloride in a water immiscible organic solvent and an aqueous solution of sodium/potassium salt ofD-phenyialanine is added to the reaction medium, resulting in a two phase system. Inetenperature of the reaction is maintained fbom about 0*C to about 60°Cr mort preferably about 40"C to about 50.0 As a result, natsglinide forms between the two phases.
Hie pH of the reaction is preferably above about & A sufficient amount of a base such as sodium hydroxide is used to keep the pH above about 8, preferably from about 12 to about 14. Under basic conditions, after synthesis of joateglinide, a salt oramonof nateglidine, preferably the sodium salt; fonns and accaanulates in the aqueous phase. It is believed fee yield increases as thepH increases above about 8 probably due to its inhibition of side reactions,
Nateglinide is then recovered from the aqueous phase, preferably by acidification, hi the acid form, nateglinide readily dissolves hi toluene or ethyl acetate. Acidification of an aqueous solution of nateglinide results in precipitation of nateglinide. While the sodium salt ofnateglidine is soluble hi water, nateglidine itself is insoluble in water. Hence acidification will neutralize the salt, resulting hi precipitation. The pH of the aqueous phase is preferably adjusted to fh?m about I to about 5, more preferably from about 2 to about 3. Acids such as hydrochloric acid, sulfuric acid, formic acid, acetic acid and phosphoric acid may be used to adjust the pH.
After acidification, the product precipitates. Precipitation is preferably carried out at rcHOTitemperature, thougher temperures may also be used The precipitate may be
separated by techniques well known in the art, such as filtration, preferably at room temperature. The product may be washed with water or an organic solvent, and preferablydried The product nay be dried, preferably from about 4C°C to about 120°CVmasi preferably about l00.C under reducedpressure.
fooae embedment, the naicglinide is moved to the watar irmmiscible organoc
solvent; such as ethyl acetate and toluene. The organic solvent extracts tae nategiimde, preferably at apH where me naie.glimde is neutral (preferably less than about 4, more preferably from about 1 to about 2), resultmg in natcglinide moving substantially to the organic phase. Nateglinide may then be recovered from the organic phase by conventional techniques. la one embodiment the organic phase is concentrated, preferably by evaporation, under reduced pressure, to obtain nateglinide.
la another embodiment the present invention provides a process for preparing nateglinide by wing only an aqueous solvent and adding isopropylcyclohexane add chloride as a neat reagent, ie, acylationtriay be earned man aqueous solvent system in the absence of a water immiscible organic solvent The seat reagent may contain negligible amounts of N^-dimethylfbrmamide ("DMF"), from about 0.05% to about 8%? preferably less than about 5%, more picfcrafaly about 1%, weight of DMF compared to the weight of me neat reagent. ThepH of the reaction is preferably above about 8, more preferably at least about 12.
This embodimenl is similar to those described above, except a water immiscible organic solvent is not at lea$t initially added to the aqueous solution containing salt of D-phenylalanin6- ftather, 4-isopropyIcyclohexaae acid chloride is added as a neat reagojt in shgjit excess. Preferred solvents for the solution are dipolar aprotic sol vents such as acetonitrile and lower kctones such as acetone in a mixture with water. Use of water without a co-solvent is also preferred. The temperature of me reaction is preferably kept from about -5°C to about <50°C, more preferably fiom aboot 40*C to about 50*C, After addition of the 4-isopropylcyclohcxane acid chloride;, nateglinide is recovered fix>rn the reaction mixture. I^eglmide may also be recovered by precipitation or from an organic solvent/phase as discussed above.
The preparation of nateglinide ofien results in. an undesirable product, referred, to herein as 3 dimer. A possible reaction scheme for the dimer is illustrated in the following
Formula Romoved)

When water is used, without a co-solvent, preferably in. conjunction with a strong base such as sodium or potassium, hydroxide, the product is substantially free of the undesirable diner, i.e., the dimcr is not detectable by GC. The amount of the dimer in the final product is this embodiment is preferably from about 0.04% to about 04% wt/wt of the dimer to pateglinide. As used herein, a slrong base refers to a base diat reacts
essentially completely to give hydroxide ions when put in water.
The term co-solvent refers to a second solvent used in combination with a first solvent in such amounts to substantially change a property of the solvent, such as solubility. Impurities and traces of a solvent are not co-solvents. Hence, water free, of or without co-solvent may include a small amount of other solvents, but preferably less than about 5% v/v, and most preferably less than about 1% v/v of other solvents.
In another embodiment, a tri-alkylamine salt of D-phenylalanine is reacted with trans-4-isopropylcycIohexane acid chloride in a cyclic or a non-cyclic C1 to a C6 amide as a solvent Examples of such amides include dimethyl fonaamide, dimethyl acetamide ("DMA") and N-metnyl pyrolidoae, In one embodiment, tri-alkyl salts of D-phenylalanine are reacted with trans-4-i$optopyicycIohexane acid chloride in DMF. The rcsultmg prodnct may then be recovered as described above. Preferred hi-alkyl amines are C1 toC7 amines, wiui tri-ethy] amine being the most preferred.
One of skill in the art would appreciate that the nateglinidt prepared by the
processes of the present invention, may be crystallized/recrystailized as various
polymorphic fimns of nategfimde. For example, U-S. Pat Nos. 5,463,116 and 5,488,150, both incorporated herein by reference, disclose two crystal forms of naieglinide, designated B-rypeaBdH-type, and processes for thir preparation Another crystalline
form of nategjinide designated Type-S is disclosed in two Chinese articles: ACTA Phann. Sinica 2001,36(7), 532-34 and Yacwu Fcnxi Zazhi, 2001,21(5), 342-44, The nateglmlde preparedby the present invention may be re-crystallized from a mixture of lower alcohol such as mefhanol or efhanol with water. Additional polymorphic forms and processes for their preparation are disclosed m U.S. provisional application Nos. 60/396,904,
60/413,622,60/432,962,60/442,109,60/449,791 and 60/ ,filed June 16,2003
(attorney docket No, 1662/61106). Example 2 and 9 of the present invention results in nategiinide Form Z disclosed in the above applications,
A hydrate of nategEtoide, Form Z, has a water content of about 10 to about 50%, more preferably about 10% to about 40%, and most preferably from about 15% to about 25%, measured cither by the Karl Fischer method or LOD. Nategiinide Form Z has an XRPD pattern \virn peaks at 4.7,5.3,13.5, 13.9,15.1,15-7,16.1,18.7,1*5,21.5 ±0.2 degrees 20 (Fig. 1), The more characteristic peaks are observed at 4.7,53,15.1,15.7 and 16.1 ±0.2 degrees 20. Form Z is also characterized by a FFIR spectrum (Figure 2) with peaks at about 699,1542,1645,1697,2848,2864,2929,3279 and 3504 cm-r The more characteristic peaks arc observed at about 1645,1697,3279 and 3504 cm"1.
Nategiinide Form Z is generally prepared by acidification of a solution of an alkali metal or alkaline earth metal salt of nategiinide in an aqueous solvent Preferred solvent is water free of a co-solvent Preferred salts are sodium'and potassium salts, with the sodium salt being most preferred. Before acidification, me solution preferably has a pH of above about 8, while after acidification, the pH is preferable from about 1 to about 5, most preferably from about 2 to about 5. Acidification results in precipitation of nategiinide, which may be recovered by techniques well known in fire art, such as filtration.
Even thought Example 2 of the present invention results in nategiinide Form Z, the processes of the present invention may be manipulated to obtain other polymorphic forms of nategliaide. The other polymorphic forms may be obtained ciflisr directly (such as from a solution) or through another polymorphic form (such as by rccrystalliation).
Nategiinide of defined particle size may be produced by known methods of particle size reduction starting with crystals, powder aggregates and course powder of either
crystalline or amorphous nareglfdfnr. The principal operations of conventional size redaction, are milling
A fluid energy mill, or imciomzcr, is aa especially preferred type of mifl for its abiHtyto produce partides of small in a narrow size distributiou.As those skilled in
the art are aware, micronizers use the kinetic energy of collision between particles suspended in a rapidly moving fluid (typically air) stream to cleave the particles. An air jet mill is a preferred fluid energy milL The suspended particles are injected under pressure into a recirculating particle stream. Smaller particles are carried aloft inside the mill and swept into a vent connected to a particle size classifier such as a cyclone. The feedstock is preferably first mifled to about 1 50 to about 850 urn, which may be done using a conventional ball, roller,, or hammer mifl.
Pharmaceutical compositions maybe prepared as medicaments to be administered orally, parenterally; rectally, fcaosdezmally, bucally, or nasally. Suitable forms for oral administration include tablets, compressed or coated pills, drsgees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions. Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal
fiqrng for flritmftiqfrftrifm includa s»ippogitnri«*g with hyHmp^h
hydrophobic vehicle. For topical administration the invention provides suitable traasdermal delivery systems known in the art, and jfor nasal delivery there are provided suitable aerosol delivery systems known in the art
Pharmaceutical compositions of the present invention contain nateglidine substantially free of tbjc corresponding cis-isomer. la addition to the active ingredients), the pharmaceutical compositions of the present invention may contain one or more excipients. Selection of exdpients and the amounts to use roay be readily determined fay the foimulation scientist based upon experience and consideration of standard procedures and reference works in the field,
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic adrninistration. Although the most suitable route in any given case will depend on the nature and severity of fee condition being treated, the most
i
preferred route of the present invention is oraL The dosages may be conveniently
presented in unit dosage form and prepared by any 'of the methods weflrfcnown in the pharmaceutical arts.
The active ingredient and excipieats maybe formulated mto compositions and dosage forms according to methods known in tfie art The dosage and formulation of STARLDC may be used as a guidance. The dosage used is preferably fiom about 30 to about 240 mg of nateglinide, morcprefiaably fiom about 60 to about 120 mg of oategEdine,
The pharmaceutical conqxsitioiis of fee present myentioa, preferably in the form of a coated tablet, are administered from about 10 minutes to about 1 hours prior to a meal, more preferably about 1 5 minutes before each meaL The dose is not taken if the meal is skipped. The phamuiccutKaJ congestions may also teusedm combination with metafbnnin.
Instrumentation
Instrument GC - HP® model 5890
Oven: Initial temp 80°C, hold for2 min, raise to 100CC at HPGfain, tfaeo
raise to 300°C at 20*C/min
fajector: 250°C (split mode, 1 30)
Detector: 300°C
Column: Rtx-1, 15m, 0.25 mm ID, 0.25 mm film tbicfcaess
fiycction amount; Z ml
Instrument HPLC -HP* model 1050 equipped wflh a Jasco UVIDEO-iOOV detector
Column: Ace 5 CIS A6667 column (250 x 4.6 mm)
Temperature : room temperature
Loop: 20 ml
Injection volume: 40 ml
Flow rate: 1.5ml/mia
Wave length: 214 nm
Solvent A: acetonitriJe
Solvent B: water containing TFA till pH 2 .5
The gradient proi^e: solvent B 50% 1 7 min, 0% 21 am, 0% 31 imn, 50% 35 min.
The purity determinations are expressed as area percentages of HPLC.
X&ay diffraction was performed on X-Kay powder diffiactometer, Scmtag®, variable goniometer,. Oil-tube,, solid state detector. Sample holder: A round standard aluminum sample holder with round zero background quartz plate. Tic sample was put on the sample holder and immediately analyzed as is. Scanning parameters: Range: 2-40 deg 2G, Contmuos Scan, Rate: 3deg/mm.
DSC821' Mettler Toledo* Sample weight 3-5mg, Heating rate: IO*C/min, Number of holes ia the crucible: 3
Perkia -Efener® Spectrum One FTIR spectrometer, Range: 4000-400era-l, No. of scans: 16, resolution: 4.0em-l» DRIFT technique.
EXAMPLES
Some of the following examples use neat IPCHAC or trans-*-Isopropylcyclohexane carboxyfic acid, which contain from about 0,05 to about 8% DMF (weight/weight) of DMF to IPCHAC or the carfboxylic acid. The carboxyiic acid in Example 1 contains about 1% DMF weight to weight of DMF to the carboxyiic acid. The DMF is not considered a co-solvent
Example 1
Preparation of IPCHAC by cblonnarion in the presence of an amide N,N-cIimethyIformamide (0.1 ml), followed by neat tKJns-4-
isopropylcyclohcxanecaiboxylic acid (9.92 g) {containing a level of cis isomer of less than 0.1 %] were added to thionyl chloride (8.32 g) at room temperature. The mixture was stirred for 2 h at room temperature and volatiles were removed under reduced pressure in a
40-Cbathto afford 1039 g of the desired product, trans-4-isoprepylcyclohexaneacid
chloride, with a purity of 97%, as a colorless liquid. No cds-isomer was detected by GC.
Yield: 96%.
Example 2
Ptooaration of IPCHAC by chlorinatioa in the presence of an amide in ethv! acetate
N,N-diracthylfoimanjide (0.1 g) was added to a mixture of fcrans-4-
isopropylcycIohexanecarboxyKc acid (20.0 g) ia ethyl acetate (8 ml). The mixture was
heated to 40°C and tbionyi ddoride (15.1 g) was gradually added for I hour. The mixture
•was stiixed for 1 h at 40°C and volatile; -were removed under reduced pressure in a'4Q*C bath to afford 22.43 g of the desired product, frans-4-isopiopykyclohexane acid chloride, with a purity of 98%, as a colorless liquid. No cis-isomer was detected by GC. Yield 99%.
Preparation of IPCHAC by chlorinahon in fee presence of an amide N,N-dimediyIfonnamide (0.63 g) -was added to a neat traus-4-
isopropyJteyclohexanecaiboxylic acid (250 g) placed into a two liter reactor. The mixture was cooled to 1S°C and thionyl chloride (1S9.8 g) was gradually added for 15 minutes. The mixture was stiired for 1 h, keeping the texnpcratuxe around 15*C to afford a clear solution. Next part of traras-4-isopropyicyclohexanecarboxylic acid (250 g), followed by N,-N-dimethylfbnnamide (0.63 g) were introduced into the reactor. Additional amount of thionyl chloride 089.8 g) was added dtopwise lor 15 min. The mixture was stirred for I h, keeping me temperature around !5°C to afford a clear solution of the crude desired product, which was directly used for me preparation of nateghmde. No cis-isomer was detected by GC.
Example 4
Preparation of IPCHAC fay chlorination in the presence of an amide and heptane N,N-dimetnylfonnanMde (0.2 g) wa$ added to a mixture of trans-4-isopropylcyclohexanccarboxyKc acid (39.5 g) in heptane (25 ml). The mixture was heated to 40°C and thionyl chloride (32.6 g) was gradually added for 1 h. The mixture was stirred for. 1 h at40-45<>C and volatiles were removed under reduced pressure in a 40°C bath to afford 5S.S2 g of a heptane solution of the desired product, trana-*-isopropylcyclohexanc acid chloride, as a colorless liquid containing approximately 0.28% of the starting trans-4-isopiopylcyclohexanecarboxylio acid. No cis-isomer was detected by GC, Yield 95%. The solution was directly used for the preparation of nateglinide. Example 5
Preparation of IPCHAC by: chlorination in the presence of an amide N-MethylpyroIidone (O.I I g), followed by a neat ttans-4-isopropyIcycIohexanecarboxylic acid (9.92 g) were added to fiaonyl chloride (8,33 g), at room temperature. The mixture was stirred for 23 h at room temperature and volatiles were removed under reduced
pressure ma 4~C bath, to afford 10.97 g of the desired product, trans-4-
isopcopylcyclohexane add chloride. No cis-isomer was detected by GCL Yield 99%,
Example 6
Preparation of ngtegfinide with a two phase system witfatojuene/water
D-phenyialanine (7.74 g) was dissolved in & solution of sodium hydroxide (2.1 g) in water
(100 ml). The clear aqueous solution was covered -with toluene (25 ml) and cooled to 10"
C. A solution of trans-4-isopropyIcyclohexane acid chloride 10,39 g in toluene (50 ml)
and 10% sodium hydroxide solution were simultaneously added to the two phase mixture,
maintaining the temperature around 10* C and pH > 8. The reaction mixture was allowed
to wann to room temperature and stirred for 2 hours. The phases were separated. The
aqueous phase was extracted with toluene (30 ml). The organic phases were combined,
washed with water (30 ml) and discarded. The aqueous phases were combined and the pH
was adjusted to 2-3 with 10% hydrochloric acid. The precipitated solid was filtered ofi£
washed with water (20 ml) and dried at 6"0*C under reduced pressure to afford 10.15 g of
the desired product Yield 61%.
Example?
Preparation of natcdmide with a neat reagent in a wjatg/acetoae, mixture
D-Phenylalanine (7.71 g, 0.0462 mol) was dissolved in a 10 % NaOH (65 ml) solution and acetone (70 ml) was added, and the reaction mixture was cooled to 15 °C. Neat isopiopylcyclohexryl acid chloride (11.13 g, 1.25 equivalent) was added to fee solution over 6 minutes while stirring and maintaining the temperature of 17-21 "C. Tie rest of fee fsopropylcyclohexyl acid chloride in the dropping funnel was washed with acetone (—10 ml) and added to the reaction solution. The reaction mixture was allowed to warm to room temperature (25-28"C). Precipitation occurred and stirring became difficult After pH was adjusted to >11, the reaction mixture was gradually transformed into a clear solution. The mixture was stibtfed for 1 hour and was made acidic wife 10% HCl (22 ml, pH 1-2). The organic phase was separated and volafiles were removed under reduced pressure at HJO'C to afford 16.32 g of a crude product as a white solid. The yield was 87%, Examples
Preparation of nategjfaade. with a neat reagent ia a water/acetone mixture
D-Phmylalarane (7.73 g, 0.0462 astol) was dissolved ia a 30% NaOH solution (70 ml), acetone (70 ml) was added, and the reaction mixture was cooled to 15°C. Neat isopropylcyclohexane add chloride (11.19 g, 125 equivalent) was added to tbe solution over 6 minutes while stirring and maintaining the temperature 15-23 °C. Tho rest in the dropping was funnel washed with acetone (~IO ml) and added to me reaction solution. The reaction mixture was allowed to warm to room temperature (25-28°C). Precipitation occiirred and stirring became difficult After pH was >11, the mixture was stirred for ih aad was made acidic with. 10% HO (35 ml, pH 1-2). The mixture was partitioned between water (50 ml) and EA (90 ml). The organic phase was separated. The aqueous phase was additionally extracted with EA (90 ml). The organic phases were combined, dried wife sodium sulfate, filtered and evaporated to afford 19.61 g of a crude product as a white solid. The solid was dried in a vacuum oven at 65-70°C to afford 15.26 g of a white solid.. The yield was 80%. Example 9 Preparation of nategiinide with a neat reagent in a water free of a co-solvent
D-PhenyJalanine (Phe-OH, 7.73 g) was treated with 3,5% NaOH (185 ml, 3.5 equivalents), at room temperature to afford a clear solution of the corresponding Na-salL Neat ttans-4-isopropylcyclohexane acid chloride (EPCHAC, 9.02 g, 1.01 equivalent) was added to the solution of phenylalanine obtained above, over 3 minutes, whfle stirring at room temperature. The resulting mixture was stirred for 1 hour, and was treated with 10% HC1 (32 ml) to adjust the pH to 3, while stirring. The mixture was stirred for 1 hour, and filtered The solid was washed with water (200 ml) and sucked well to afford 33.3 g of the moist product, which lost weight after drying at 78"C/2.2 mbar. Assay 98.4%, purity >99%, yield 86%. Form "L was obtained as polymorphic form. (The mioiraal values of purity and yield are over 99% and 80% respectively.] Example 10 Preparation of nategfanide with a two phase systgn of ethvl acetate/wafer
D-phenylalanine (7.74 g) was dissolved in a solution of sodium hydroxide (2.1 g)
in water (25 ml). The clear aqueous solution was covered with ethyl acetate (50 ml) and
cooled to 10°C. A solution of trans-4-isopropylcyclohexanc acid chloride (10.39 g) in ethyl acetate (15ml) and 10% sodium hydroxide solution were simultaneously added to the two phase mixture, maintaining the temperature around IO°C andpH >8. The reaction mixture was allowed to warm to loom temperature and stirred for 2 n. Water (30 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (25 ml). The organic phases were combined, washed with water (25 ml) and discarded. The aqueous phases were combined and the pH was adjusted to 2-3 with 10%
hydrochloric acid. The precipitated solid was filtered off, washed with water (20 ml) and
dried at 60*C under reduced pressure to afford 9.54 g of the desired product Yield 60%.
Example 11
Preparation ofnafcegHnidc with ajwo phase system of ethyl acetate/water
A mixture of NaHCO3 (1937 g), D-phenylaknme (7.72 g) and water (30 ml) was stincd at 50°C nil the cessation of the gas evaluation. The clear aqueous solution was covered with ethyl acetate (25 ml). A solution of trans-4-isopropylcyclohex3ne acid chloride (II.33 g) in EA (25 ml) was added to the hot mixture for 1 h. The reaction mixture was stirred for 2 h at 50°C (pH was >7 whole time of the reaction). The two phase reaction mixture was diluted with water (150 ml) and covered with EA (125 ml). The pH was adjusted to 1 with 10% hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with EA (100 ml). The organic extracts were combined, dried with anhydrous sodium sulfate, filtered, and evaporated to afford 17.45 g of a erode product as a white solid. The yield was 90%. Example12 Preparation of nateghnide with a neat reagent in water
D-Pnenylalanme (30.92 g) was treated with 10% KOH (360 ml, 3.5 equivalents), at room temperature to afford a clear solution of the corresponding K-salt The solution was cooled to JO°C. Neat teafls-4-isopropylcyclohexaae acid chloride (IPCHAC, 35.92 g, 1.01 equivalents) was added to the solution, over 3 mtn, while stirring at 10-12*0, A partial precipitation occurred in 2-3 minutes. The mixture was stirred for Ih and was treated with 10% HCI (53 ml) to adjust pH to 1, under stirring, resulting in complete precipitation. The mixture'was allowed to warm to room temperature and stiffed for 1 h and filtered. The
solid was washed with water (200 ml) and sucked well to afford 145 g of the moist
product, which .lost in weight after drying at T8TCJ23, mbar. Assay 88%, purity >99%.
The yield was 76%.
Example 13
Preparation Lof tTafffpTfrridc in a mixture of water and acctonitrite with a weak base
A anwctunt of NaHCO3 (18.63 g),D-pheaylalanine (7.51 g), aeetoninile (75 ml), and water
(30 ml) was stored at 20°C until the cessation of gas evolution. Ethyl acetate (25 ml) was
added to the clear solution. A solution of trans^isopiopylcyclonexaneacM chloride (10.9
g) in acetoratrile (3OmI) was added to the mixture for lh,st room temperature, The
reaction mixture was sfeed for an additional hour (pH was>9)and evaporated. The
residue was partitioned between waiter (200 ml) and ethyl acetate (100 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml), The aqueous phase was treated with 10% SO (75 ml) to adjust pH to 1, under stirring. The mixture was extracted with ethyl acetate (2x50 mi). The organic extracts were combined, dried with anhydrous sodium sulfate, filtered, and evaporated to afford 12.61 g of a crude product as a white solid The yield was 50%. Example 14 Preparation of nate^Gnide in an amide with a weak base
D-pncnylalanine (7.71 g) and ttiethyfamine (19 ml) were simultaneously added to a soJwtiozj of trans-4-isopropylcyc!0hexancacid chloride (7.93 g) in
(21 ml), maintaining the tempeiature around 40°C and pH >1 0. The reaction mixture was
stincd for 1 hour, dihited with water (100 ml) and covered with efhyl acetate (100 ml),
The pH was adjusted to Iwifii 10% hydrochloric acid. The organic phase was separated
and the aqueous phase was extracted ivith ethyl acetate (2 x 100 ml). The organic extracts
were combined and evaporated to afford 15.0 g of a crude product as a white solid. The
yield was 41%.
Example 15
Preparation of nategfinfde with a neat reagent in water
D-Phenylalanine (83.5 g) was added to a solution of sodium hydroxide (5635 g) in water
(1550 ml), heated to 45°C and stirred for 5 min to afford a clear solution. A neat trans-4-
isopropylcyclohexaneacid chloride (96.68 gX containing <0,1 % cis-isomer was added for
10 min and the reaction nrixnw wasstirrcd for 30 min at 45-50°C. Ethyl acetate (360 ml)
was introduced andpH 1 was adjusted by a 66% sulfuric acid (84.07 g). The moftzrtwas stirred for 15 min at 48°C and the aqueous phase was separated and discarded. The hot (4045*C) organicphase was washed twice with water (150 ml) at 48*CV under staring. The aqueous phases weie separatedand discarded. The first portion of hot heptane {48°C, 400ird)wasaddedtoihel»t solttliottandtte
mixture: was cooled to 31*C arid seeded to promote the crystallization. The residue of warn heptane (31°C; 740 ml, total 1050 ml) was added for 10 rain. The mixture was slowly cooled to 10°C and stirred for 1 h. The solid was filtered off and washed with a cold (-5°C) mixture of ethyl acetate and heptane (1 ;3,240 ml) to afford 228.04 g of a wet (45%}prodocL Yield 7?%.
The wet product was re-crystallized from a mixture of ethyl acetate and heptane (1.3:1, total 1110 ml) and dried for 2 h at IOO°C to afford the desired product, Dategliaide, as a white solid wfih parity >99;7%. VieM 63%.
Having thus described the invention with reference to particular preferred embodiments
and illustrafaVe examples, those in the art may appreciate modifications to the inventioa as
described and illustrated thai do not deport from the spirit and scope of the invention as
disclosed m the specification. The Examples are set forth to aid in understanding the
invention but are not intended tor and should not be construed to, limit its scope in any
way. The eocarnples do not indMe detailed descriptions fo conventional methods, Such
methods are well known to those of ordinary skill in the art and axe described in numerous publications. All references mentioned herein ate incorporated in their entirety.

WE CLAIM:
1. A process for preparing nateglinide comprising the steps of:
(a) combining trans-4-isopropylcyclohexane carboxylic acid with
thionyl chloride in the presence of a C1 to a C6 organic amide, with
about 1 to about 5 acid equivalents of thionyl chloride, from about
0.05% to about 10% weight of the amide to the acid, at a temperature
from about minus 10°C to about 80°C, to obtain trans-4-
isopropylcyclohexane acid chloride substantially free of its
corresponding cis isomer,
(b) converting the said trans-4-isopropylcyclohexane acid chloride to
nateglinide; and
(c) recovering the nateglinide.

2. The process as claimed in claim 1, wherein the combining is
carried out at a temperature of from about 10°C to about 60°C.
3. The process as claimed in claim 1 or 2, wherein the ratio of the
cis isomer is less than about 0.03% weight to weight to the trans
isomer.
4. The process as claimed in claim 1, 2 or 3, wherein the said
combining results in a reaction mixture that is maintained for about 1
hour to about 5 hours.
5. The process as claimed in claim 1, 2, 3 or 4, wherein the said
combining is carried out in a solvent selected from the group consisting
of aromatic and saturated hydrocarbons, esters and ethers.
6. The process as claimed in claim 1, 2, 3, 4 or 5, wherein the
organic amide is selected from the group consisting of N,N-

dimethylacetamide, N-methylpyrrolidone and N,N- dimethylformamide.
7. The process as claimed in claim 6, wherein the amide is N,N-
dimethylformamide.
8. The process as claimed in claim 1, wherein the said conversion
step comprises:

a) adding the trans-4-isopropylcyclohexane acid chloride to
toluene, heptane, ethyl acetate or mixtures thereof; and
b) combining the toluene, heptane or ethyl acetate containing
the trans-4-isopropylcyclohexane acid chloride with an aqueous
solution containing sodium salt of D-phenylalanine to form an
aqueous and an organic phase, wherein nateglinide forms
between the two phases.

9. The process as claimed in claim 8, wherein said recovering
involves precipitating nateglinide, and separating the precipitate.
10. The process as claimed in claim 9, wherein the nateglinide
separated is nateglinide Form Z.
11. The process as claimed in claim 8, wherein said recovering
involves moving the nateglinide to an organic phase, and concentrating
the organic phase.
12. The process as claimed in claim 9, 10 or 11, wherein the moving
or precipitation is carried out through acidification of the aqueous
solution.
13. The process as claimed in claim 12, wherein the acidification
results in a pH of from about 1 to about 5.
14. The process as claimed in claim 13, wherein the pH is from about
2 to about 3.

15. The process as claimed in claim 1, 8, 9, 10, 11, 12, 13 or 14,
optionally comprises the step of crystallizing/recrystallizing the
recovered nateglinide.
16. The nateglinide prepared by the process as claimed in claim 3, 8,
9, 10, 11, 12, 13, 14 or 15.
17. A process for preparing nateglinide substantially as herein
described with reference to the forgoing description.
18. A nateglinide substantially as herein described with reference to
the forgoing description.