Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/22—Separation; Purification; Stabilisation; Use of additives
  • C07C231/24—Separation; Purification
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/58—Preparation of carboxylic acid halides
  • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to processes for preparing nateglinide and intermediates thereof.
• Nateglinide known as (-)-N-(trans-4-isoporpylcyclohexanecarbonyl)-D- Phenylalanine, has the following structure and characteristics:
• nateglinide is marketed as STARLIX, which is prescribed as oral tablets having a dosage of 60mg and 120mg for the treatment of type II diabetes.
• STARLIX maybe used as monotherapy or in combination with metaformin to stimulate the pancreas to secrete insulin.
• nateglinide is a white powder that is freely soluble in methanol, 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, et al., Bioorg. Med. Chemical, 4(10) 1771-81 (1996).
• U.S. Pat. No. 4,816,484 and its subsequent reissue disclose nateglinide and a method for its preparation.
• the process of the '484 patent reacts a D- phenylalanine ester derivative with a DCC derivative of 4- isopropylcyclohexanecarboxylic acid, followed by de-esterification to obtain nateglinide, as illustrated below:
• 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 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.
• crystallization from aqueous methanol might result in esterification of the product.
• a Chinese article discloses another reaction scheme for preparing nateglinide, in which the cis to trans ratio of isopropyl cyclohexylcarboxylic acid is decreased by treatment with KOH in methanol at elevated temperatures.
• Xue-yan Zhu et. al., Hecheng Huaxue 9(6) 537- 540 (2001) (hereinafter "Xue-yan Zhu”).
• the reaction uses phosphorus pentachloride ("PC1 5 ”) to chlorinate isopropylcyclohexane carboxylic acid, to obtain an acid chloride, which is then reacted with D-phenylalanine to obtain nateglinide.
• PC1 5 phosphorus pentachloride
• the reaction has the following scheme, which may result in contamination of the final product with nateglinide' s corresponding cis impurity:
• Another article discloses a process for preparing the trans isomer of 4- isopropylcyclohexane carbonyl chloride (syn. of 4-isopropylcyclohexane acid chloride ("IPCHAC”) by chlorination of 4-isopropylcyclohexanecarboxylic acid with PCI5 [Jpn. Kokai Tokkyo Kohop (1995) (hereinafter "Kokai”)].
• IPCHAC 4-isopropylcyclohexane acid chloride
• PCI5 Jpn. Kokai Tokkyo Kohop (1995) (hereinafter "Kokai”
• Kokai and a Japanese patent, JP 070107899A disclose that use of thionyl chloride leads to formation of the corresponding cis isomer.
• 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.
• the present invention provides a process for preparing trans-4- isopropylcyclohexane acid chloride comprising the steps of: a) combining trans-4-iso ⁇ ropylcyclohexane carboxylic acid with thionyl chloride in the presence of a Ci to a C 6 organic amide to obtain trans-4- isopropylcyclohexane acid chloride substantially free of its corresponding cis isomer; and b) recovering the trans-4-isopropylcyclohexane acid chloride.
• the present invention provides a process for preparing nateglinide comprising the steps of: a) combining trans-4-isopropylcyclohexane carboxylic acid with thionyl chloride in the presence of a C ⁇ to a C 6 organic amide to obtain trans-4- isopropylcyclohexane acid chloride substantially free of its corresponding cis isomer; and b) converting the acid chloride to nateglinide; and c) recovering the nateglinide.
• 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 nateglinide forms through reaction between the D- phenylalanine and the trans-4-isopropylcyclohexane acid chloride; and c) recovering the nateglinide.
• 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.
• 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- isopropylcyclohexane acid chloride in a Ci to a C 7 amide to form nateglinide; and b) recovering the nateglinide.
• Figure 1 is an XRPD pattern of nateglinide Form Z.
• Figure 2 is an FTIR spectrum of nateglinide Form Z.
• Figure 3 is a DSC thermogram of nateglinide Form Z.
• the present invention provides facile processes for the preparation of nateglinide and its intermediates.
• 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.
• substantially free refers to being undetectable by gas chromatography ("GC"), as carried out under the conditions disclosed in the present invention.
• the amount of cis- 4-isopropylcyclohexane 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 trans-4-isopropylcyclohexane carbonyl chloride (syn. Isopropylcyclohexane acid chloride-("IPCHAC”)) by reacting trans-4- isopropylcyclohexanecarboxylic acid with thionyl chloride in the presence of an organic amide.
• organic amides include cyclic and acyclic Ci to C 6 amides such as N,N-dimethylacetamide, N-methylpyrrolidone and N,N- dimethylformamide.
• the amide acts as a catalyst.
• a mixture of N,N-dimethylformamide, 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.
• suitable aprotic organic solvent include C 5 to C 12 aliphatic and aromatic hydrocarbons (including fluorinated and chlorinated), ethers, esters, among others.
• trans-4-isopropylcyclohexane carboxylic acid is preferably substantially free of the corresponding cis isomer, i.e., 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 a process for the preparation of t-4- isopropylcyclohexanecarboxylic acid by the hydrogenation of cumic acid is disclosed.
• a preferred re-crystallization solvent system for the trans-4-isopropylcyclohexane 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 from 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.
• 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.
• the pressure is reduced, and the temperature is raised slightly, to about 40 °C, to evaporate the solvent or other volatiles.
• the product, trans-4-isopropylcyclohexane acid chloride (liquid at room temperature), is obtained, substantially free of the corresponding cis isomer.
• the purity of the product from this process is preferably at least about 95% as measured by HPLC, and the cis-isomer 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-isopropylcyclohexane 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.
• 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 Ci to C 7 tri-alkyl amines, such as tri- ethyl amine.
• a suitable base such as sodium/potassium carbonate or hydroxide may be added to phenylalanine to obtain the desired salt.
• 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.
• a two phase system i.e., an aqueous phase and an organic water immiscible phase.
• water immiscible solvents in the organic phase include aromatic hydrocarbons and saturated hydrocarbons, more preferably a C 5 to a C 12 hydrocarbon.
• Preferred solvents include toluene and heptane.
• Water immiscible esters and ketones, such as ethyl acetate, may also be used.
• a solution of trans-4- isopropylcyclohexane acid chloride in a water immiscible organic solvent and an aqueous solution of sodium/potassium salt of D-phenylalanine 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 60°C, more preferably about 40°C to about 50°C.
• 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.
• nateglinide Under basic conditions, after synthesis of nateglinide, a salt or anion 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.
• 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 nateglidine 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 1 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.
• 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 under reduced pressure.
• the nateglinide 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.
• the organic phase is concentrated, preferably by evaporation under reduced pressure, to obtain nateglinide.
• the present invention provides a process for preparing nateglinide by using only an aqueous solvent and adding isopropylcyclohexane acid chloride as a neat reagent, i.e., acylation 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 formamide ("DMF"), from about 0.05% to about 8%, preferably less than 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.
• a water immiscible organic solvent is not at least initially added to the aqueous solution containing salt of D- phenylalanine. Rather, 4-isopropylcyclohexane 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.
• nateglinide is recovered from the reaction mixture. Nateglinide may also be recovered by precipitation or from an organic solvent/phase as discussed above.
• dimer A possible reaction scheme for the dimer is illustrated in the following diagram:
• the product 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 dimer, i.e., the dimer is not detectable by GC.
• the 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 dimer to nateglinide.
• a strong base refers to a base that reacts essentially completely to give hydroxide ions when put in water.
• 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.
• 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.
• a tri-alkyl amine salt of D-phenylalanine is reacted with trans-4-isopropylcyclohexane acid chloride in a cyclic or a non-cyclic Ci to a C 6 amide as a solvent.
• amides include dimethyl formamide, dimethyl acetamide (“DMA”) and N-methyl pyrolidone.
• tri-alkyl salts of D- phenylalanine are reacted with trans-4-isopropylcyclohexane acid chloride in DMF.
• the resulting product may then be recovered as described above.
• Preferred tri-alkyl amines are to C amines, with tri-ethyl amine being the most preferred.
• nateglinide prepared by the processes of the present invention may be crystallized/recrystallized as various polymorphic forms of nateglinide.
• 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 form of nateglinide designated Type-S is disclosed in two Chinese articles: ACTA Pharm. Sinica 2001, 36(7), 532-34 and Yaowu Fenxi Zazhi, 2001, 21(5), 342-44.
• 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 nateglinide, 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 Form Z has an XRPD pattern with peaks at 4.7, 5.3, 13.5, 13.9, 15.1, 15.7, 16.1, 18.7, 19.5, 21.5 ⁇ 0.2 degrees 20 (Fig. 1). The more characteristic peaks are observed at 4.7, 5.3, 15.1, 15.7 and 16.1 ⁇ 0.2 degrees 2 ⁇ .
• 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 .
• Nateglinide Form Z is generally prepared by acidification of a solution of an alkali metal or alkaline earth metal salt of nateglinide 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.
• the 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 nateglinide, which may be recovered by techniques well known in the art, such as filtration.
• 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 reduction are milling of a feedstock material and sorting of the milled material by size.
• a fluid energy mill, or micronizer is an especially preferred type of mill for its ability to produce particles of small size in a narrow size distribution.
• 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.
• the feedstock is preferably first milled to about 150 to about 850 ⁇ m, which may be done using a conventional ball, roller, or hammer mill.
• compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, 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.
• 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.
• compositions of the present invention contain nateglidine substantially free of the corresponding cis-isomer.
• 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 admimstration. 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 may be 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 nateglinide, more preferably from about 60 to about 120 mg of nateglidine.
• compositions of the present invention are administered from about 10 minutes to about 1 hours prior to a meal, more preferably about 15 minutes before each meal. The dose is not taken if the meal is skipped.
• the pharmaceutical compositions may also be used in combination with metaformin.
• 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
• Solvent A acetonitrile
• Solvent B water containing TFA till pH 2.5
• the gradient profile solvent B 50% 17 min, 0% 21 min, 0% 31 min, 50% 35 min.
• the purity determinations are expressed as area percentages of HPLC.
• X-Ray diffraction was performed on X-Ray powder diffractometer, Scintag , 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. Scanning parameters: Range: 2-40 deg 2 ⁇ , Continuos Scan, Rate: 3deg./min.
• IPCHAC or trans-4- Isopropylcyclohexane carboxylic acid which contain from about 0.05 to about 8% DMF (weight/weight) 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.
• N,N-dimethylformamide (0.1 g) was added to a mixture of trans-4- isopropylcyclohexanecarboxylic acid (20.0 g) in ethyl acetate (8 ml). The mixture was heated to 40°C and thionyl chloride (16.1 g) was gradually added for 1 hour. The mixture was stirred for 1 h 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-isopropylcyclohexane acid chloride, with a purity of 98%, as a colorless liquid. No cis-isomer was detected by GC. Yield 99%.
• IPCHAC IPCHAC by chlorination in the presence of an amide and heptane N,N-dimethylformamide (0.2 g) was added to a mixture of trans-4- isopropylcyclohexanecarboxylic 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.
• Example 5 Preparation of IPCHAC by chlorination in the presence of an amide N-Methylpyrolidone (0.11 g), followed by a neat trans-4-isopropylcyclohexanecarboxylic acid (9.92 g) were added to thionyl chloride (8.33 g), at room temperature. The mixture was stirred for 2.5 h at room temperature and volatiles were removed under reduced pressure in a 4- ⁇ C bath to afford 10.97 g of the desired product, trans-4- isopropylcyclohexane acid chloride. No cis-isomer was detected by GC. Yield 99%.
• Example 6 Example 6
• 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-isopropylcyclohexane 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 (30 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (25 ml).
• 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 trans-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 minutes.
• the mixture was stirred for lh and was treated with 10% HC1 (53 ml) to adjust pH to 1, under stirring, resulting in complete precipitation.
• the mixture was allowed to warm to room temperature and stirred 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/2.2 mbar. Assay 88%, purity >99%.
• the yield was 76%.
• the aqueous phase was treated with 10% HC1 (75 ml) to adjust pH to 1, under stirring.
• 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 100°C to afford the desired product, nateglinide, as a white solid with purity >99.7%. Yield 63%.

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