CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. § 119(c) of provisional applications Serial Numbers 60/393,495 filed July 3,2002; 60/396,904 filed My 18, 2002; 60/413,622, filed September 25,2002; 60/414,199, filed September 26,2002; 60/423,750, Sled 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. 16*62/61106), the contents of all of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to processes for preparing nateglinide and intermediates thereof.
BACKGROUND OF THE INVENTION
Nateglinide, known as (-)-N-{trans-4-isoporpylcyclohexanecarbonyl)-D-Pheaylalanine, has the following structure and characteristics
(Formula Removed)
Formula Cj^H^NO}
Molecular Weight 317.42
Exact Mass 317.199093
Condition C 71.89% H 8.57% N 4.41% O 15.12%
Nateglinide is marketed as STARLK, which is prescribed as oral tablets having a dosage of 60mg and 120mg for the treatment of type n diabetes. STARLDC may be used as cnonotherapy or in combination with metaformin to stimulate the pancreas to secrete
insulin. According to the maker of STARLK, nateglinide is a white powder that is freely soluble in raethanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Metabolites of nateglinide are disclosed in Hiroko Takesada, etaL, Bioorg. Med Chemical, 4(10) 1771r«l (1996). U.S. Pat No. 4,816,484 and its subsequent reissue (US Re 34878) disclose
nateglinide and a method for its preparation. The process of the '484 patent xeacts a D-
phenylalanine ester derivative with a DCC derivative of 4-
isopropylcyclohexanecarboxylic acid, followed by de-esterification to obtain nateglinide,
as illustrated below:

(Formula Removed)

The yield obtained is 65%.
The ester acts as a protecting group, limiting the amount of undesirable cross reactions. The process of U.S. Pat No. 4,816,484 howevermay 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 -from aqueous methanol might result in esterifieatibn. of the product
A general problem with preparing nateglidine is the presence of die corresponding undesirable cis isomer during the process, which leads to a final product that is contaminated with the corresponding cis isomer. la order to increase the ratio of the therapeutically effective trans isomer over its corresponding cis isomer, the process of the '484 patent heats a cis-trans mixture of the 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 m Hisashi Sainted, et al, J. Med, Cfaem. 32(7) 1436 - 1441 (1989).
A Chinese article discloses another reaction scheme for preparing nategtinlde, in which the cis to trans ratio of isopropylcyclohexylcarboxylic acid is decreased by treatment with BCOH in methanol at elevated temperatures. Xue-yan Zhu, et aL, Hecheng Huaxuc 9(6) 537- 540 (2001) (hereinafter "Xue-yan Zhu"). The reaction uses phosphorus pentachloride ("PCls") to chlorinate isqpropylcyclohexane carboxylic acid, to obtain an acid chloride, which is then reacted with D-phenylalanine to obtain nateglmide. The reaction has the following scheme, which may result in contamination of the final product with natcglinjdc's corresponding cis impurity:

(Formula Removed)

Another article discloses aprocess for preparingthe trans isomer of 4-isopropylcyclohexane carbonyl chloride (syn, of 4-isopropylcyclohexane acid chloride ("IPCHAC") by chlorination of 4-isopropylcyctohexanecarboxylic acid with PCls [Jpn. KokaiTokkyoKohop (1995) (hereinafter "Kokai")]. Kokai and a Japanese patent, JP 070107899A, disclose that use of thionyl chloride leads to formation of the corresponding cis isomer.
In addition to fee above references, nateglinide is also disclosed in U.S. Pat Nos. 5,463,116 and 5,488,150, and three Japanese publications: WO 02/34254, WO 02/34285 and WO 02/34713. All of these references are incorporated herein by reference.
There is a need in the ait for additional processes for preparing nateglinide.
SUMMARY OF THE INVENTION
In. one aspect the present invention provides a process for preparing trans-4-isopropylcyclohexane acid chloride comprising the steps of:
a) combining trans-4-isopropylcycloiiexane carboxylic acid with thionyl chloride
In the presence of a C1to a C6 organic amide to obtain trans-4-
isopropylcyclohcxanc acid chloride substantially free of its corresponding cis
isomeri and
b) recovering the trans-4-isopiopylcyclohexane acid chloride.
In another aspect, the present invention provides a, process for preparing nateglinide comprising the steps of:
a) combining trans-4-isopropylcyclohexanc carboxylic acid with thionyl chloride
in fixe presence of a C1to a C6 organic amide to obtain trans-4-
isopropylcyclohexane acid chloride substantially firee of its corresponding cis
isomer;and
b) converting the acid chloride to nateglinidc; and
c) recovering the nateglmide.
In another aspect* the present invention provides a process for preparing nateglinide in a two phase system comprising the steps of:
a) preparing an aqueous solution of an alkaline earth or alkali metal salt of D-
phenylalanine;
b) combining the aqueous solution with a water immiscible organic solvent
containing trans-4-isopropylcyclohexane acid chloride, to form an aqueous and
an organic phase, wherein uateglirdde forms through reaction between the D-
phcnylalanine and the trans-4-isopropylcyclohexane acid chloride; and
c) recovering the nateglinide.
In another aspect, the present invention provides a process for preparing nateglinide comprising the steps of:
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-isopropylcyclohexane acid chloride as a neat reagent to the
aqueous solution to form nateglinide; and
c) recovering the nateglinide.
In another aspect the present invention provides a process for preparing nateglinide comprising the steps of
a) combining a solution of a tri-alkyl aniine salt of D-pnenylalanine with, trans-4-
isopropylcyclohexanc acid chloride in a C1 to a C7 amide to form nategliuide;
and
b) recovering the nateglinide.
BRIEF DESCRIPTION OFTHE FIGURES
Figure 1 is an XRPD pattern of nategtinide Form Z. Figure 2 is an FTTR spectrum of nateglinide Fonn Z. Figure 3 is a DSC thcrmogram of nateglinide Fonn Z.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides facile processes for the preparation of nateglinide and its intermediates. In one embodiment, the present invention provides a process for preparing trans-4-isopropylcyclohexane acid chloride, an intermediate in the synthesis of nateglinide, substantially free of the corresponding cis-isomer. As used herein, "substantially free" refers to being undctectable by gas chromatography ("GC"), as carried out under the conditions disclosed in the present invention. Preferably, the amount of cis-4-isopropylcyclohexane acid chloride is less than about 0.1% (wl/wt) compared to the corresponding trans isomer, more preferably less man about 0.05% (wt/wt) and most preferably less than about 0.03% (wt/wt).
The present invention prepares trans-4-isopropylcyclohexane carbonyl chloride (syvr. Isopropylcyclohcxane acid chloride-(IIPCHAC")) by reacting trans-4-isopropylcyclohexanecarboxylic acid with thionyl chloride in me presence of an organic amide. Examples of such organic amides include cyclic and acyclic C1to C6 amides such as N^-dimethylaeetamide, N-methylpynofidone and N,N- dinrethylfoimaraide. The amide acts as a catalyst The reaction between thionyl chloride and trans-isopropylcyclohexane carboxylic acid 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-isomer is not formed nor detected in amounts of less than about 0-05% even at elevated temperature (60-80*C).
In a preferred embodiment, a mixture of N,N-dimethylfbrmamide, thionyl chloride and trans-4-isopropylcyclohexanecarboxylic acid is prepared. The mixture may be prepared in a suitable aprotic organic solvent, or preferably with a neat reagent Examples
of such solvents include C5 to C12aliphatic and aromatic hydrocarbons (including ftaorinated and chlorinated), ethers, esters, among others.
The trans intermediate used, trans-4-isopropylcyclohexane carboxylic acid, is preferably substantially free of the corresponding cis isomer, i,e.y less than about 0.2% of the corresponding cis isomer. The trans-4-isopropylcyclohexanecarboxylic acid may be prepared according to the methods known in the art, such as example 31 of US Pat 4,816,484 (Re 34,878), where aprocess for the preparation of t-4-isopropylcyclohexanecarboxylic acid by the hydrogenation of cumic acid is disclosed. A preferred re-crystallization solvent system for the traos-4-isopropyIcyclohexane carboxylic acid is a mixture of methanol and water.
The reaction is preferably carried out with from about 1 to about 5 acid equivalents of thionyl chloride and an effective amount of amide preferably fiom about 0.05% to about 10% wt/wt (amide/acid). The reaction may be carried out at a temperature of from about minus 10°C to about 60°C, with about room temperature being preferred.
After preparing the mixture of 4-isopropylcyclohexanecarboxylic acid, thionyl 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 Ma preferred embodiment, the pressure is reduced, and the temperature is raised slightly, to about 40°C, to evaporate the solvent or other volatiles. After evaporation, the product, ttans-4-isopropylcyclohexane acid chloride (liquid at room temperature), is obtained, substantially free of the corresponding cis isomer. The purity of the product from fins process is preferably at least about 95% as measured by HPLC, and the cis-isomcr is preferably undetectable by GC.
The trans-4~isopropylcyclohexane acid chloride prepared may then be used to prepare nateglinide substantially free of the corresponding cis isomer. The processes of the present invention prepare nateglinide by acylation of a salt of D-phenylalanine with trans-4-isopropylcyclohexajie acid chloride.
Preferred salts of phenylalanine for acylation 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 may be used are those of C1 to C7T tri-alky, such as tri-ethyl amine. One of skill in the art would appreciate that a suitable base such as
sodium/potassium carbonate or hydroxide may be added to phenylalanine to obtain file desired salt
In one embodiment, the present invention provides for preparation of categlinide 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 ketoncs, such as ethyl acetate, may also be used.
hi one embodiment of me two phase system, a solution of trans-4-isopropylcyclohcxane acid chloride in a water immiscible organic solvent and an aqueous solution of sodium/potassium salt of D-phenylalaninc is added to the reaction medium, resulting in a two phase system. The temperature of the reaction is maintained from about 0°C to about 6*0°C, more preferably about 40°C to about 50°C. As a result, nateglinide forms between the two phases.
The pH of the reaction is preferably above about 8. 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 nateglinide, a salt or am'on of nateglidine, preferably the sodium salt, forms and accumulates in the aqueous phase. It is believed the yield increases as the pH increases above about 8 probably due to its inhibition of side reactions.
Nateglinide is then recovered from the aqueous phase, preferably by acidification. In the acid form, nateglinide readily dissolves in toluene or ethyl acetate. Acidification of an aqueous solution of nateglinide results in precipitation of nateglinide. While the sodium salt of nategiidine is soluble in water, nateglidine itself is insoluble in water. Hence acidification will neutralize the salt, resulting in precipitation. The pH of the aqueous phase is preferably adjusted to from about I to about 5, more preferably from about 2 to about 3. Acids such as hydrochloric acid, sulfuric acid, formic acid, acetic aoid and phosphoric acid may be used to adjust the pH.
After acidification, the product precipitates. Precipitation is preferably carried out at room temperature, though other temperatures 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 preferably
dried The product may be dried, preferably from about 40°C to about 120°C, most preferably about 100°C nader reduced pressure.
In one embodiment, the nateglimde is moved to the water immiscible organic solvent, such as ethyl acetate and toluene. The organic solvent extracts the nateglinide, preferably at a pH where the nateglinide is neutral (preferably less than about 4, more preferably from about 1 to about 2), resulting in nateglinide moving substantially to the organic phase. Nateglinide may then be recovered from the organic phase by conventional techniques. In one embodiment, the organic phase is concentrated, preferably by evaporation under reduced pressure, to obtain nateglinide.
In another embodiment, the present invention provides a process for preparing nateglinide by using only an aqueous solvent and adding isopropylcyclohexane acid chloride as a neat reagent, ie, acytation may be carried in an aqueous solvent system in the absence of a water immiscible organic solvent The neat reagent may contain negligible amounts of N,N-dimethyl fonnamide ("DMF"), from about 0.05% to about 8%, preferably less man about 5%, more preferably about 1%, weight of DMF compared to the weight of the neat reagent. The pH of the reaction is preferably above about 8, more preferably at least about 12.
This embodiment is similar to those described above, except a water immiscible organic solvent is not at least initially added to the aqueous solution containing salt of D-phenylalamnft- Rather, 4-isopropylcycloliexane acid chloride is added as a neat reagent in slight excess. Preferred solvents for the solution are dipolar aprotic solvents such, as acetonitrile and lower ketones such as acetone in a mixture with water. Use of water without a co-solvent is also preferred. The temperature of the reaction is preferably kept from about -5°C to about 60°C, more preferably from about 40*C to about 50°C. After addition of the 4-isopropylcyclohexane acid chloride, nateglinide is recovered from the reaction mixture. Nateglinide may also be recovered by precipitation or from an organic solvent/phase as discussed above.
The preparation of nateglinide often results in an undesirable product, referred to herein as a dimer. A possible reaction scheme for the dimer is illustrated in the following diagram:
(Formula Removed)

When water is used, without a co-solvent, preferably in conjunction wife a strong base such as sodium or potassium hydroxide, the product is substantially free of the undesirable dimer, i.e., the dimcr is not detectable by GC. Hie amount of the dimer in the final product in this embodiment is preferably from about 0.04% to about 0.1% wt/wt of the dinner to nateglinide. As used herein, a strong base refers to a base that 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-alkyl amine salt of D-phenylalaoinc is reacted with. trans-4-isopropylcyclohcxane acid chloride in a cyclic or a non-cyclic C1 to a C6 amide as a solvent Examples of such amides include dimethyl formamide, dimethyl acetamide ("DMA") and N-raethyl pyrolidone. In one embodiment, tri-alkyl salts of D-phenylalanine are reacted with trans-4-isopropylcycIohexane acid chloride in DMF. The resulting product may then be recovered as described above. Preferred tri-alkyl amines are C1 to C7 amines, with tri-ethyl amine being the most preferred.
One of skill in the art would appreciate that the nateglinide prepared by the
processes of the present invention may be crystallized/recrystailized as various
polymorphic forms of nateglinide. For example, U-S. Pat Nos. 5,463,116 and 5,488,150, both incorporated herein by reference, disclose two crystal forms of nateglinide, designated B-type and H-type, and processes for their preparation. Another crystalline fonn of nateglinide designated Type-S is disclosed in two Chinese articles: ACTA Phann. Sinica 2001,36(7), 532-34 and Yaowu Fenxi Zazhi, 2001,21(5), 342*44. The nateglinide prepared by the present invention may be re-crystallized from a mixture of lower alcohol such as methanol or ethanol with water. Additional polymorphic forms and processes for their preparation are disclosed in 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 nateglinide Form Z disclosed in the above applications.
A hydrate of nateglimde, 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 either by the Karl Fischer method or LOD. Nateglinide Fonn Z has an XRPD pattern with peaks at 4.7,5.3,13.5,13.9,15.1,15-7,16.1,1$.7,19.5,21.5 ±0.2 degrees 29 (Fig. 1). The more characteristic peaks are observed at 4.7,5.3,15.1,15.7 and 16.1 ±0.2 degrees 20. Form Z is also characterized by a FTIR spectrum (Figure 2) with peaks at about 699,1542,1645,1697,2848,2864,2929,3279 and 3504 cm"1. The more characteristic peaks are observed at about 1645,1697,3279 and 3504 cm"1.
Nateglinide Form Z is generally prepared by acidification of a solution of an alkali metal or alkalme earth metal salt of nateglinide in an aqueous solvent. Preferred solvent is water free of a co-solvent Preferred salts are sodiurn'and potassium salts, with the sodium salt being most preferred. Before acidification, the solution preferably has apH 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 nateglinide, which may be recovered by techniques well known in the art, such as filtration.
Even thought Example 2 of the present invention results in nateglinide Form Z, the processes of the present invention may be manipulated to obtain other polymorphic forms of nateglinide. The other polymorphic forms may be obtained either directly (such as from a solution) or through another polymorphic form (such as by recrystallization).
Nateglinide 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 nateglidine. The principal operations of conventional size redaction are milling of a feedstock material and sorting of the milled material by size. A fluid energy mill, or micromzcr, is an especially preferred type of mill for its ability to produce particles of small size in a narrow size distribution. 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 rccirculating particle stream. Smaller particles arc earned, aloft inside the mill and swept into a vent connected to a particle size classifier such as a cyclone. The feedstock is preferably first milled to about 150 to about 850 μm, which may be done using a conventional ball, roller, or hammer mill.
Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transderrnally, bucally, or nasally. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, 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
»
administration suitable forms for administration include suppositories -with hydrophilic or hydrophobic vehicle. For topical administration the invention provides suitable transdermal delivery systems known in the art, and for nasal delivery there are provided suitable aerosol delivery systems known in the art
Pharmaceutical compositions of the present invention contain nateglidine substantially free of the corresponding cis-isomer. In addition to the active ingredients), the pharmaceutical compositions of the present invention may contain one or more excipients. Selection of excipients and the amounts to use may be readily determined by the formulation 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 administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most 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 well-known in the pharmaceutical arts.
The active ingredient and excipients maybe formulated into compositions and dosage forms according to methods known in the art The dosage and formulation of STARLIX may be used as a guidance. The dosage used is preferably from about 30 to about 240 mg of nateglmide, more preferably from about 60 to about 120 mg of nateglidine.
The pharmaceutical compositions of me present invention, 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 IS minutes before each meaL The dose is not taken if the meal is skipped. The pharmaceutical compositions may also be used in combination with metalbnnin.
Instrumentation used
Instrument GC - HP® model 5890
Oven: Initial temp 80°C, hold for 2 min, raise to 100°C at 10°C/min, then
raise to 300°C at 20°C/min
Injector: 250°C (split mode, 1:50)
Detector: 300°C
Column: Rrx-1,15m, 0.25 mm ID, 0.25 mm film thickness
Injection amount: 1 ml
Instrument: HPLC - HP* model 1050 equipped with a Jasco UVIDEC-100V detector
Column: Ace 5 C18 A6667 column (250 x 4.6 mm)
Temperature: room temperature
Loop: 20ml
Injection volume: 40 ml
Flow rate: 1.5 ml/rain
Wave length: 214 nm
Solvent A: acetonitrile
Solvent B: water containing TFA till pH 2,5
The gradient pro file: solvent B 50% 17 min, 0% 21 min, 0% 31 trrin, 50% 35 min.
The purity determinations are expressed as area percentages of HPLC.
X-Ray diffraction -was performed on X-Ray powder diffiactometer, Sctotag8, variable goniometer, Cu-tube, solid state detector. Sample holder. A round standard aluminum sample holder with round zero background quartz plate. The sample was put on the sample holder and immediately analyzed as is. Scaiming parameters: Range: 2-40 deg26, Continues Scan, Rate: 3deg./ram.
DSC821* Mettler Toledo* Sample weight 3-Smg, Heating rate: 10 ecymin, Number of holes in the crucible: 3
Perkin -Elmer®, Spectrum One FTIR spectrometer, Range: 4000-400cm-l, No. of scans: 16, resolution: 4.0cm-1, DRIFT technique.
EXAMPLES
Some of the following examples use neat IPCHAC or trans-4-Isopropylcyclohcxane carboxylic acid, which contain from about 0.05 to about 8% DMF (weight/weigbt) of DMF to IPCHAC or the carboxylic acid. The carboxylic acid in Example 1 contains about 1% DMF weight to weight of DMF to the carboxylic acid. The DMF is not considered a co-solvent
Example 1
Preparation of IPCHAC bv chlorination in the presence of an amide N,N-dimethylformamide (0,1 ml), followed by neat trans-4-
isopropylcyclohexanecaiboxylic acid (9.92 g) [containing a level of cis isomer of less than 0.1 %] were added to thionyl chloride (S.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~C bath to afford 1039 g of fee desired product, trans-4-isopiopylcyclohexanc acid chloride, with a purity of 97%, as a colorless liquid. No cds-isomer was detected by GC.
Yield: 96%.
Example 2
Preparation of IPCHAC by chlorination in the presence of an amide in cthvl acetate
N,N-dunethylformamide (0.1 g) was added to a mixture of trans-4-
isopropylcyclohcxanecarboxvlic acid (20.0 g) in ethyl acetate (8 ml). The mixture was
heated to 40°C and thionyi chloride (16.1 g) was gradually added for 1 hour. The mixture
•was stiried for 1h at 40°C and volatiles were removed under reduced pressure in a 40°C bath to afford 22.43 g of the desired product, trans-4-isopiopylcyclohexane acid chloride, with a purity of 98%, as a colorless liquid. No cis-isomer was detected by GC Yield 99%.
Examples
Preparation of IPCHAC bv chlorination in the presence of ant amide
N,N-dimethylformamide (0,63 g) was added to a neat traus-4-
isopropyteyclohexanccarboxylic acid (250 g) placed into a two liter reactor. The mixture
was cooled to 18°C andthionyl chloride (189.8 g) was gradually added for 15 minutes. The mixture was stirred for 1 h, keeping the temperature around 15°C to afford a clear solution. Next part of treras-4-isopropylcyclohcxanecarboxy acid (250 g), followed by N,N-dimefrylformamide (0.63 g) were introduced into the reactor. Additional amount of tirionyl chloride (189.8 g) was added dropwise for 15 mm. The mixture was stirred for I h, keeping the temperature around 15°C to afford a clear solution of the crude desired product, which was directly used for the preparation of nateglinide. No cis-isomer was detected by GC.
Example 4
Preparation of IPCHAC by chlorination fa the presence of an amide and heptane N,N-dimethylfonnamide (0.2 g) was added to a mixture of trans-4-isopropylcyclohexanccarboxylic 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 at 40-459C and volatiles were removed under reduced pressure in a 40°C bath to afford 58.52 g of a heptane solution of the desired product, trans-4-isopropylcyclohexanc acid chloride; as a colorless liquid containing approximately 0.28% of the starting trans-4-isopropylcycloliexanecarboxylic 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 chlorihation in the presence of an amide N-Memylpyrolidone (0.11 g), followed by a neat trans-4-isopropyIcycIohexanecarboxylic acid (9.92 g) were added to thionyl chloride (833 g), at room temperature. The mixture was stirred for 2.5 h at room temperature and volatiles were removed under reduced

pressure in a4C bath to afford 10.97 g of the desired product, trans-4-
isopropylcyclohexane acid chloride. No cis-isomer was detected by GC. Yield 99%,
Exaorole6
Preparation of nateglinide with a two prase system with toluene/water
D-phenyialanine (7.74 g) was dissolved in a 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-isopropylcyclohexane 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 warm 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 off
washed with water (20ml) and dried at 6"0*C under reduced pressure to afford 10.15 g of
the desired product Yield 51%.
Example,7
Preparation of nateplitude with aneat reagent in a watef/acjrtone.auxture
D-Phenylalanine (7.71 g, 0.0462 mol) was dissolved in a 10 % NaOH ($5 ml) solution and acetone (70 ml) was added, and the reaction mixture was cooled to 15 °C. Neat isopropylcyclohexyi acid chloride (11.13 g, 1.25 equivalent) was added to the solution over 6 minutes while stirring and maintaining the temperature of 17-21 °C. The rest of the isopropylcyclohexyi 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 stirred for 1 hour and was made acidic with 10% HCl (22 ml, pH 1-2). The organic phase was separated and volatiles were removed under reduced pressure at ~6"0°C to aflford 16.32 g of a crude product as a white solid. The yield was 87%, Example 8
Preparation of nateglinide with a neat reagent in a water/acetone mixture
D-Phcnyialanine (7.73 g, 0.0462 mol) was dissolved in a 10% NaOH solution (70 ml), acetone (70 ml) was added, and the reaction mixture was cooled to 15°C. Neat isopropylcyclohexane acid chloride (11.19 g, 1,25 equivalent) was added to the solution over 6 minutes while stirring and maintaining the temperature 15-23 °C. The rest in the dropping was funnel washed with acetone (-10 ml) and added to me reaction solution. The reaction mixture was allowed to warm to room temperature (25-28 °C). Precipitation occurred and stirring became difficult After pH was >I1, the mixture was stirred for Ih and was made acidic with 10% HCI (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 with 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%.
Preparation of nateglinide with a neat reagent in a water free of a co-solvent
D-Phenylalanme (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-salt. Neat trans-4-isopropylcyclohexane acid chloride (IPCHAC, 9.02 g, 1.01 equivalent) was added to the solution of phenylalanine obtained above, over 3 minutes, while 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, white stirring. The mixture was stirred for 1 hour, and filtered. The soKd 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 Z was obtained as polymorphic form. (The minimal values of purity and yield are over 99% and 80% respectively.] Example.10 Preparation of nategdinide wim a two phase system of ethyl acetate/water
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 10°C and pH >8. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (30ml) 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 precqritated 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 of nateglmidc with a two phase system of ethyl acetate/water
A mixture of NaHCO3 (1937 g), D-phenylalanine (7.72 g) and water (30 ml) was stirred at 50°C till the cessation of the gas evaluation. The clear aqueous solution was covered with ethyl acetate (25 ml). A solution of trans-4-isopropylcyclohexane acid chloride (11.33 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 I with 10% hydrochloric add. 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 crude product as a white solid. The yield was 90%. Examplc 12 Preparation of nateglmidc with a neat reagent in water
D-Phenylalanine (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 10°C. Neat tems-4-isopropylcyclohexane acid chloride (IPCHAC, 35.92 g, 1.01 equivalents) was added to the solution, over 3 min, while stirring at 10-12°C. A partial precipitation occurred in 2-3 nunutes. The mixture was stirred for 1h 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 stilted 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 78?C/22, mbar. Assay 88%, purity >99%.
The yield was 76%,
Example 13
Preparation of nateglinide in a mixture of water and acctonitrile with a weak base
A mixture of NaHCO3 (18.63 g), D-phenylalanine (7.61 g), acetotdtrile (75 ml), and water (30 ml) was stirred at 20*C until the cessation of gas evolution, Ethyl acetate (25 ml) was added to the clear solution. A solution of trans-4-isopropylcyclohexancacid chloride (10.9 g) in acctouitrile (30ml)was added to the mixture for In, at room temperature. The reaction mixture was stirred for an additional hour (pH was >9) and evaporated. The residue was partitioned between water (200 ml) and ethyl acetate (100 mi). 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% HC1 (75 ml) to adjust pH to 1, under stirring. The mixture was extracted with ethyl acetate (2x50 ml). 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 nateglinide in an amide with a weak base
D-phcaylalanine (7.71 g) and triethylamine (19 ml) were simultaneously added to a solution of trans-4-isopropylcyclohexaneacid chloride (7.93 g) in N,N-dimethylfonnaraide (21 ml), maintaining the temperature around 40°C and pH >10. The reaction mixture was stirred for 1 hour, diluted with water (100 ml) and covered with ethyl acetate (100 ml). The pH was adjusted to 1 with 10% hydrochloric acid. The organic phase was separated and the aqueous phase was extracted -with 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 nateglinide with a neat reagent in water
D-Phenylalanine (83.5 g) was added to a solution of sodium hydroxide (56.35 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 g), containing <0.1% cmsomer was added for
10 min and the reaction mixture was stirred 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 mixture was stored for 15 min at48°C and the aqueous phase was separated and discarded. The hot (4O45°C) organic phase -was washed twice with water (150 ml) at48*Cr under stirring, Tbe aqueous phases were separated and discarded. The first portioji of hot heptane(480C, 400 ml) was added to the hot solution and the mixture was stirred for 40 min 48°C.The mixture was cooled to 31ttC and seeded to promote the crystallization. The residue of warm heptane (31°C, 740 ml, total 1050 ml) was added for 10 mtn 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%) product Yield 79%. The wet product was re-crystallized from a mixture of ethyl acetate and heptane (1.3:1,
white solid with purity>997%. Yield 63%.
Having thus described tbe invention with reference to particular preferred embodiments and illustrative examples, those in the art may appreciate modifications to tbe invention as described and illustrated mat do not depart from the spirit and scope of the invention as disclosed in the specification. Tbe Examples are set forth to aid m understanding the invention but are not intended to and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skin in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

WE CLAIM:
1. A process for preparing nateglinide comprising the steps of:
a) acylating a salt of D-phenylalanine with trans-4-isopropylcyclohexane acid
chloride to form nateglinide; and
b) recovering the nateglinide.

2. The process of claim 1, wherein step (a) comprises combining a solution of a tri-alkyl
amine salt of D-phenylalanine with trans-4-isopropylcyclohexane acid chloride in a Ci to a Cj
amide to form nateglinide.
3. The process of claim 2, wherein the tri-alkyl amine is tri-ethyl amine,
4. The process of claim 2 or 3, wherein the organic amide is selected from the group
consisting of N,N-dimethylacetamide, N-methylpyrrolidone and N,N- dimethylformamide.
5. The process of claim 4, wherein the amide is N,N-dimethylformamide.
6. The process of claim 1, wherein step (a) comprises:

a) preparing an aqueous solution of an alkaline earth or alkali metal salt of D-
phenylalanine; and
b) combining the aqueous solution with a water immiscible organic solvent
containing trans-4-isopropylcyclohexane acid chloride, to form an aqueous and an organic phase,
wherein nateglinide forms through reaction between the D-phenylalanine and the trans-4-
isopropylcyclohexane acid chloride.

7. The process of claim 6, wherein the water immiscible organic solvent is a C5to a C12
hydrocarbon.
8. The process of claim 7, wherein the hydrocarbon is aromatic.
9. The process of claim 8, wherein the hydrocarbon is toluene.
10. The process of claim 7, wherein the hydrocarbon is saturated.
11. The process of claim 10, wherein the hydrocarbon is heptane.
12. The process of claim 6, wherein the water immiscible organic solvent is an ester.
13. The process of claim 12, wherein the ester is ethyl acetate.
14. The process of claim 6, 7, 8, 9, 10, 11, 12 or 13, wherein the aqueous solution contains

water free of a co-solvent.
15. The process of claim 1, wherein step (a) comprises:
a) preparing an aqueous solution of an alkaline earth or alkali metal salt of D-
phenylalanine in water free of a co-solvent; and
b) adding trans-4-isopropylcyclohexane acid chloride as a neat reagent to the
aqueous solution to form nateglinide.

16. The process of claim 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein a strong base is used to
prepare the solution of the salt.
17. The process of claim 16, wherein the base is sodium or potassium hydroxide.
18. The process of claim 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein the aqueous
solution has a pH of at least about 8.
19. The process of claim 18, wherein the pH is at least about 12.
20. The process of claim 15, wherein a strong base is used and the nateglinide recovered is
substantially free of a dimer having the following structure:
(Formula Removed)

21. The process of claim 20, wherein the dimer is present at a level of from about 0.04% to about 0.1% weight of the dimer to weight of nateglinide.
22. The process of claim 1 5, wherein the nateglinide has a purity of at least about 99%.
23. The process of claim 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein the water contains less
than about 1% v/v of any other solvent.
24. The process of claim 6, 7, 8, 9, 10, 1 1, 12, 13, 15, 20, 21, 22 or 23, wherein the trans-4-
isopropylcyclohexane acid chloride is prepared by chlorinating trans-4-isopropylcyclohexane
carboxylic acid with thionyl chloride in the presence of a C1 to a C6 organic amide.
25. The process of claim 24, wherein the trans-4-isopropylcyclohexane acid chloride is
substantially free of its corresponding cis isomer.
26. The process of claim 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or
25, wherein recovering involves precipitating nateglinide, and separating the precipitate.
27. The process of claim 26, wherein the nateglinide separated is nateglinide Form Z.
28. The process of claim 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or
25, wherein recovering involves moving the nateglinide to an organic phase, and concentrating
the organic phase.
29. The process of claim 26, 27 or 28, wherein the moving or precipitation is carried out
through acidification of the aqueous solution.
30. The process of claim 29, wherein the acidification results in a pH of from about 1 to
about 5.
3 1 . The process of claim 30, wherein the pH is from about 2 to about 3 .
32. The process of claim 2, 3, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22,23,
24, 25, 26, 27, 28, 29, 30 or 31, further comprising the step of crystallizing/recrystallizing the
recovered nateglinide.
33. The nateglinide prepared by the process of claim 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32.

34. A process for preparing nateglinide substantially as herein described with reference
to the forgoing description.
35. A nateglinide substantially as herein described with reference to the forgoing
description.