Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

• the invention relates to a process for preparing substantially optically pure repaglinide and pharmaceutically acceptable salts, solvates and esters thereof.
• the invention further relates to a process for preparing precursors of repaglinide and in particular for preparing (S) ( + ) -1- (2-piperidino-phenyl) -3- methyl-1-butylamine .
• Repaglinide is the generic name for (S) -2-ethoxy-4- [N- [1- (2- piperidinophenyl) -3-methyl- 1-butyl] aminocarbonylmethyl] -benzoic acid of the following formula V
• Repaglinide is a known non-sulfonylurea hypoglycemic agent, which has an insulinotropic effect by blocking the K ATP ⁇ channels of pancreatic B-cells. It is particularly used for lowering blood glucose levels in patients suffering from type II diabetes mellitus (NIDDM) .
• NIDDM type II diabetes mellitus
• the drug is currently being marketed in oral dosage forms containing 0.5mg, lmg and 2mg repaglinide .
• Repaglinide and related compounds, as well as the preparation thereof, are disclosed in EP 0 147 850, EP 0 207 331, EP 0 589 874, EP 0 965 591, WO 2004/101540 and Grell et al . in J. Med. Chem. Vol. 41(26), p. 5219-5246, 1998. Crystal forms of repaglinide are known from EP 589 874, WO 2004/018442, WO 2005/021524 and WO 2004/101540. In the following description, any reference to the term "repaglinide” is intended to include its (S) -enantiomer, solvates, esters and salts thereof in any amorphous or crystalline form.
• the processes for the preparation of repaglinide as are known from the prior art comprise the coupling of (S) ( + ) -1- (2-piperidino-phenyl) -3-methyl-l-butylamine with a substituted carboxylic acid to obtain repaglinide ester.
• Optically pure repaglinide is finally obtained by converting the ester- protected carboxyl group to the free carboxyl group, followed by column chromatography to improve yield and purity of the product .
• the coupling step of these processes is usually performed by using a solvent selected from a large group of organic solvents together with acid-activating or dehydrating agents, or agents which activate the amino group.
• EP 0 589 874 discloses a process for the preparation of repaglinide ethyl ester, wherein the coupling step is preferably performed using N, N' -dicyclohexyl carbodiimide as an acid-activating compound in toluene, or using triphenylphosphine and triethylamine as dehydrating agents in
• EP 0 147 850 refers to a coupling reaction of (S) ( + ) -1- (2- piperidino-phenyl) -1-butylamine with 2- (3-ethoxy-4- (ethoxy- carbonyl) phenyl) acetic acid wherein N, N' -Carbonyldiimidazole is used as an acid-activating compound in THF. After purification by column chromatography the yield of the ester product was 51.2%.
• WO 2004/101540 discloses a process for the preparation of repaglinide comprising coupling of an amine compound with 2- (3- ethoxy-4- (ethoxycarbonyl) phenyl) acetic acid or its derivative.
• the acid-activating compound preferably used therein is 1,1'- carbonyldiimidazol (CDI) in a mixture of toluene and acetonitrile .
• Grell et al . in J. Med. Chem. Vol. 41(26), p. 5219-5246, 1998 refer to a synthesis of benzoic acid derivatives, wherein the above mentioned coupling reaction is performed using CDI in THF, triphenylphosphine/CCl 4 /triethylamine in acetonitrile, or N, N' -dicyclohexyl carbodiimide in toluene.
• the crude product was purified by column chromatography. A general problem of these conventional processes is to obtain the repaglinide ester in a satisfactory yield and purity.
• the above prior art documents also disclose a process for the preparation of the optically pure (S) ( + ) -1- (2-piperidino- phenyl) -3-methyl-l-butylamine educt.
• the racemic 1- (2-piperidino-phenyl) -3-methyl-l-butylamine is contacted with an optically active acid in order to obtain a mixture of diastereomeric addition salts, which can be separated and converted into the desired enantiomers.
• the optically active acid is selected from mandelic acid, substituted mandelic acid, camphor-sulfonic acid, tartaric acid, substituted tartaric acid, or optically active phosphoric acid.
• EP 0 589 874 discloses a process for the preparation of (S) (+) - 1- (2-piperidino-phenyl) -3-methyl-l-butylamine by salt formation of the corresponding racemic amine with N-acetyl glutamic acid in a solvent mixture comprising methanol and acetone. After precipitation the addition salt has to be recrystallized to obtain the (S) -enantiomer in a satisfactory yield and purity.
• WO 2004/101540 discloses the use of L-mandelic acid as optically active acid together with ethyl acetate or acetonitrile as a solvent. After filtration the product has to be recrystallized at least once to yield the desired (S) -amine in an optical purity of >95% (e.e. ) .
• the problem of the prior art processes for the preparation of substantially optically (S) ( + ) -1- (2-piperidino- phenyl) -3-methyl-l-butylamine is the necessity to perform repeated crystallization steps in order to achieve a satisfactory optical purity.
• an object of the present invention to provide a process for preparing substantially optically pure repaglinide which is economical and provides the product in a high yield and high optical purity. Therefore, a particular object is to provide a highly efficient process for preparing substantially optically pure (S) ( + ) -1- (2-piperidino-phenyl) -3- methyl-1-butylamine, which is a precursor used to prepare repaglinide. In particular, it is an object to improve the yield and optical purity of this precursor and at the same time to avoid time-consuming recrystallization and purification steps .
• the invention relates to a process for the preparation of substantially optically pure (S) ( + ) -1- (2- piperidino-phenyl) -3-methyl-l-butylamine of the formula I
• optically active acid in a solvent or solvent mixture to give a mixture of diastereomeric acid addition salts, wherein the optically active acid is 0,0'- dibenzoyl- (+) -tartaric acid,
• step b) converting the (S) (+) -1- (2-piperidino-phenyl) -3-methyl-l- butylamine 0, 0' -dibenzoyl- (+) -tartrate obtained in step b) to substantially optically pure (S) ( + ) -1- (2- piperidino-phenyl) -3-methyl-l-butylamine of formula I.
• (S) ( + ) -1- (2- piperidino-phenyl) -3-methyl-l-butylamine of formula I is also referred to as " (S) -amine”
• (R) (-) -1- (2-piperidino-phenyl) - 3-methyl-l-butylamine of formula VIII is also referred to as " (R) -amine”.
• the substantially optically pure (S) -amine obtained by the process according to the invention preferably has an optical purity of at least 70% (e.e.), more preferably at least 90%
• the contacting in step a) is performed at an elevated temperature, i.e. at about 50 0 C to the reflux temperature of the solvent. It is even more preferred to perform the contacting at about 60 0 C to about 90°C, such as about 85°C.
• the optically active acid used in the present invention is O, O' -dibenzoyl- ( + ) -tartaric acid, also referred to as ( + ) - dibenzoyl tartaric acid. It is preferably used in an amount of from 0.25 to 0.75 molar equivalents and in particular in an amount of 0.5 molar equivalents, with respect to the racemic amine of formula II.
• Suitable solvents for contacting the racemic amine of formula II and (+) -dibenzoyl tartaric acid to obtain the corresponding mixture of diastereomeric addition salts are selected from isobutylmethyl ketone, 1-butanole, methylethyl ketone, butyl acetate, 2-methylpropyl acetate, 2-butanone, 2-pentanone, toluene, 2-methylethyl acetate (isopropyl acetate) or mixtures thereof or mixtures of one or two or more of these solvents or solvent mixtures with methanol.
• the solvent is isobutylmethyl ketone, 2-methylethyl acetate or butyl acetate or a mixture of any one of these solvents with methanol.
• the solvent or solvent mixture for contacting the racemic amine of formula II and (+) -dibenzoyl tartaric acid comprises small amounts, e.g. 0 to 5 vol.-%, preferably 0.5 to 2 vol.-%, more preferably about 1 vol.-%, of methanol. It has surprisingly been found that the presence of a small amount of methanol improves filterability of the (S)- amine acid addition salt separated in step b) .
• the separation of the mixture of the diastereomeric acid addition salts in step b) is typically performed by crystallization of the reaction mixture and isolation of the crystallized (S) -amine acid addition salt.
• the crystallization is performed by cooling the mixture to a temperature of about -20 0 C to about 20 0 C. More preferably, the mixture is cooled to a temperature of about -20 0 C to 10 0 C and most preferably to a temperature of about -20 0 C to -10 0 C.
• crystals are separated by filtration, optionally washed with a solvent, such as ethyl acetate or diethyl ether, and dried.
• a solvent such as ethyl acetate or diethyl ether
• step b) seeding crystals of (S) ( + ) - 1- (2-piperidino-phenyl) -3-methyl-l-butylamine O, O' -dibenzoyl- (+) -tartrate can be added to the crystallization mixture.
• This seeding is preferably performed at a temperature of 0 0 C to the boiling point of the solvent, more preferably at a temperature of about 30 0 C to about 60 0 C, and most preferably at a temperature of about 40°C to about 50°C.
• step c) the (S) -amine acid addition salt obtained in step b) is converted to the free (S) -amine by e.g. adjusting the pH of a solution of the (S) -amine acid addition salt to about 7.5 to 10.
• the process according to the present invention which comprises the use of a specific optically active acid, i.e. (+) -dibenzoyl tartaric acid, has a number of advantages.
• the process in particular allows to efficiently provide the (S)- amine in an optical purity of >99 % (e.e.) by a single precipitation step of the corresponding (S) -amine acid addition salt and further conversion to the free amine, without the need for further crystallization or purification steps .
• step a) of the process according to the first aspect of the invention instead of racemic amine of formula II a mixture comprising the (S) -amine and the (R)- amine in any molar ratio is contacted with 0, 0' -dibenzoyl- (+)- tartaric acid in a solvent or solvent mixture to give a mixture of diastereomeric acid addition salts.
• a mixture comprising the (S) -amine and the (R) -amine can be a mixture in which the amount of (S) -amine is higher than that of (R)- amine.
• such a mixture is obtained by contacting racemic amine of formula II with 0, 0' -dibenzoyl- (-) -tartaric acid to give a mixture of diastereomeric acid addition salts, crystallizing and separating the (R) -amine acid addition salt to give an (S) -amine enriched mother liquor and neutralizing the obtained mother liquor to obtain a free (S) -amine enriched solution which can be used as starting material in a process according to the first aspect of the invention.
• the polymorphic purity of the (S) -amine acid addition salt obtained in step b) can be further enhanced by slurrying it in acetone/methanol or butyl acetate/methanol, such as butyl acetate/methanol (98:2) .
• the invention relates to a process for the preparation of a mixture comprising the (S) -amine of formula I
• a solution containing the (R) -amine comprising treating a solution containing the (R) -amine with a racemization agent selected from the group consisting of ion exchange resins, potassium tert . -butoxide (t-BuOK) , 1,4- diazabicyclo [2.2.2 ] octane, Raney nickel and mixtures thereof, wherein the amount of the (S) -amine in the obtained mixture is higher than in the solution containing the (R) -amine.
• a racemization agent selected from the group consisting of ion exchange resins, potassium tert . -butoxide (t-BuOK) , 1,4- diazabicyclo [2.2.2 ] octane, Raney nickel and mixtures thereof, wherein the amount of the (S) -amine in the obtained mixture is higher than in the solution containing the (R) -amine.
• the obtained mixture comprises the (S) -amine and the (R) -amine in a molar ratio of 40:60 to 60:40, more preferably of about 50:50.
• the solution containing the (R) -amine i.e. the solution used as starting material, comprises a mixture of the (R) -amine and (S) -amine in a molar ratio of about 80:20 to 60:40, such as 65:35.
• ion exchange resins which are useful as racemization agent include weakly acidic cation exchange resins, preferably macroporous methacrylic acid divinylbenzene copolymers such as Lewatit like Lewatit CNP 105.
• the racemization reaction is performed at a temperature ranging from room temperature to the reflux temperature of the solvent used such as 25 to 30 0 C, 60 to 65°C or 80 to 90 0 C.
• the solvent can be selected from the group consisting of toluene, dimethylacetamide, dimethylformamide, dimethyl- sulfoxide, N-methylpyrrolidin-2-one, pyrrolidin-2-one, 1,4- dioxane, aliphatic alkanols such as methanol and ethanol, cyclic alkanols, ethylene glycol, diethylene glycol, diglyme and mixtures thereof.
• the starting (R) -amine containing solution which is treated according to the above process can be recovered from a fractional crystallization of diastereomeric salts.
• an (R) -amine enriched mother liquor obtained from fractional crystallization using an optically active acid such as a process described in the first aspect of the present invention, is evaporated to dryness to give crude (R) -enriched 1- (2-piperidino-phenyl) -3-methyl-l- butylamine acid addition salt.
• crude (R) -enriched 1- (2- piperidino-phenyl) -3-methyl-l-butylamine is regenerated, e.g. by preparing the free amine base, extracting this base with an organic solvent and evaporating the solvent.
• the organic solvent used in this extraction step is CH2CI2 or toluene.
• the free amine base can be obtained by acidifying the (R) -enriched 1- (2-piperidino- phenyl) -3-methyl-l-butylamine acid addition salt, e.g. by addition of HCl, extracting the free optically active acid, e.g. with toluene, and freeing the (R) -enriched amine with e.g. ammonia.
• the free amine base can be obtained by ion exchange chromatography.
• Raney nickel Preferably Raney nickel, more preferably Raney nickel W-4 and most preferably freshly prepared Raney nickel W-4 (Zaklady org. syntezy, Bratislava, 1975, Alfa) is used as racemization agent. Moreover, it is particularly preferred that before racemization the Raney nickel is washed one or several times with ethanol, such as degassed ethanol, then absolute ethanol and finally toluene, such as degassed dry toluene. If Raney nickel is used as racemization agent, the solvent used is preferably toluene. In addition, this racemization reaction is preferably carried out at a temperature of 60 0 C to the reflux temperature of toluene, more preferably at 80 to 90 0 C such as 85°C.
• the reaction is performed under hydrogen atmosphere.
• the racemization reaction using Raney nickel is carried out in toluene at a temperature of about 80 to 90 0 C for about 6 to 24 hours and then at about reflux temperature for about 4 to 20 hours under hydrogen atmosphere.
• the organic solvent used in the racemization step is methanol or ethanol and macroporous methacrylic acid divinylbenzene copolymer (Lewatit CNP 105) is used as racemization agent. This reaction is preferably performed at a temperature of about 25-30 0 C.
• reaction is preferably carried out in DMSO at elevated temperatures.
• the regenerated (R) -enriched 1- (2-piperidino-phenyl) -3-methyl-l-butylamine is dried azeo- tropically before racemization, preferably in toluene.
• the invention relates to a process for the preparation of substantially optically pure (S) -amine of the formula I
• step b) contacting the mixture obtained in step a) with 0,0'- dibenzoyl- (+) -tartaric acid in a solvent or solvent mixture to give a mixture of diastereomeric acid addition salts;
• step c) converting the (S) (+) -1- (2-piperidino-phenyl) -3-methyl-l- butylamine 0, 0' -dibenzoyl- (+) -tartrate obtained in step c) to substantially optically pure (S) ( + ) -1- (2- piperidino-phenyl) -3-methyl-l-butylamine of formula I.
• the starting solution containing the (R) -amine comprises the (R) -amine in a higher amount than the (S) -amine.
• the starting solution containing the (R) -amine can generally be obtained by any suitable enantiomer separation procedures such as chiral column chromatography, stereoselective synthesis or fractional crystallization.
• the solution containing the (R) -amine can be obtained by contacting a mixture comprising the (S) -amine and the (R)- amine, e.g.
• racemic amine with an optically active acid in a solvent or solvent mixture to give a mixture of diastereomeric acid addition salts and separating the resulting mixture to obtain the (S) -amine acid addition salt, e.g. by filtration of the crystallized amine acid addition salt, and an (R) -amine acid addition salt enriched mother liquor which is converted to a solution containing the free (R) -amine.
• the optically active acid can be selected from the group consisting of (-) -camphorsulfonic acid, (-) -dibenzoyl tartaric acid, (+) -dibenzoyl tartaric acid, N-formyl-L-aspartic acid, N-formyl-D-aspartic acid, N-acetyl-L-aspartic acid, N-formyl- L-glutamic acid and N-acetyl-L-glutamic acid.
• N- acetyl-L-glutamic and most preferably (+) -dibenzoyl tartaric acid is used.
• the starting solution containing the (R) -amine is recovered from the mother liquor obtained in the separation step of step b) of the process according to the first aspect of the invention.
• step a) any suitable racemization agent can be used.
• step a) of the process of the third aspect of the invention is performed as described above for to the process of the second aspect of the invention.
• steps b) , c) and d) of the process according to the third aspect of the invention are carried out as described above for steps a) to c) of the process of the first aspect of the invention.
• steps a) to d) are repeated once or several times.
• the invention relates to a process for the preparation of the racemic amine of formula II
• the molar ratio of the imine compound to the reducing agent is less than 1:2.
• the molar ratio of the imine compound to the reducing agent is from about 1:1 to about 1:1.8 and particularly is from 1:1.2 to 1:1.5 such as about 1:1.3.
• Suitable examples for reducing agents include sodium or potassium borohydrides, LiAlH 4 , sodium cyanoborohydrides, sodium and the like.
• catalytical hydrogenation using any catalyst known in the art can be also applied.
• NaBH 4 and more preferably NaBH 4 in methanolic solution is used as reducing agent.
• the reaction time is more than 3 hours such as about 4 hours. In particular, the reaction is performed at about 1 hour at about 0 0 C to 5°C, then about 1 hour at about 15°C and then about 2 hours at room temperature.
• the chemical reduction process is performed by slowly adding methanol to a cooled mixture comprising the imine compound and stirring this mixture for another hour at about 0 0 C to 5°C. Then, as a preferred reducing agent, NaBH 4 is added in small portions over Ih. This mixture is preferably stirred for Ih at 15°C and further for 2h at room temperature, before THF is added and stirred over night for precipitation of the product. Purification of the precipitated product is preferably performed by filtration and washing with THF first, followed by rinsing with water twice.
• the racemic amine can be converted into a salt by reacting with an inorganic acid such as HCl or an organic acid such as glutaric acid.
• the imine compound of formula VI can be prepared by reacting 2-piperidino-benzonitrile of formula VII
• the 2-piperidino-benzonitrile of formula VII can be prepared according to any process known in the art.
• the molar ratio of 2-piperidino-benzonitrile to iBuMgBr is preferably less than 1:2.5 and more preferably is from 1:1 to 1:2.3 such as from 1:1.3 to 1:1.8 like about 1:1.5.
• the reaction is preferably performed in toluene and the reaction temperature is preferably ranging from 100 0 C to 108 0 C and more preferably is from 103 0 C to 105 0 C.
• 2-piperidino-benzonitrile is slowly added to a preheated mixture of toluene and iBuMgBr over Ih. It is even more preferred to perform this reaction step at a temperature of about 87 0 C under nitrogen atmosphere. Further, the mixture is preferably heated to the reflux temperature of the solvent, and even more preferably to a temperature of about 103°C to 105°C for 3h.
• the racemic amine of formula II is preferably prepared without isolating the imine compound of formula VI, i.e. in a one pot synthesis. Moreover, it is preferred that neither the imine compound of formula VI is purified by a basic extraction nor the racemic amine of formula II is purified by an acidic extraction .
• racemic amine of formula II prepared by a process according to the fourth aspect of the invention is suitably used as starting material for the process according to the first aspect of the invention.
• the invention relates to a process for the preparation of substantially optically pure repaglinide derivative of the formula III
• R is selected from H or Ci-C 5 alkyl or R together with the benzoic acid moiety to which it is bound forms a salt;
• the acid activating compound is 4- (4, 6-dimethoxy-l, 3, 5- triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM);
• the acid activating compound and the solvent is selected from combinations of N, N' -carbonyldiimidazole in CH2CI2; thionylchloride in toluene and/or triethylamine; or triphenylphosphine in CCI4, triethylamine and/or acetonitrile .
• the substantially optically pure (S)- amine is preferably reacted with an ethyl ester derivative of the formula IV, wherein R is ethyl, to obtain substantially optically pure (S) (+) -2-ethoxy-4- [N- [ 1- (2-piperidinophenyl) -3- methyl-1 -butyl ] aminocarbonyl-methyl ] -benzoic acid ethyl ester, which is also referred to as repaglinide ethyl ester.
• the acid activating compound and the solvent are selected from combinations of N, N' -carbonyl- diimidazole in CH2CI2; thionylchloride in toluene and/or triethylamine; triphenylphosphine in CCI4, triethylamine and/or acetonitrile; and 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) -4- methylmorpholinium chloride (DMT-MM) in THF.
• N, N' -carbonyl- diimidazole in CH2CI2 thionylchloride in toluene and/or triethylamine
• triphenylphosphine in CCI4, triethylamine and/or acetonitrile
• 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) -4- methylmorpholinium chloride (DMT-MM) in THF 4- (4, 6-dimethoxy-l
• the solvent preferably is CH2CI2. If the acid activating compound is thionylchloride, then the solvent preferably is toluene and/or triethylamine, most preferably a mixture having a volume ratio of toluene to triethylamine from 5:1 to 25:1 such as about 13:1. If the acid activating compound is triphenylphosphine, then the solvent preferably is CCl 4 , triethylamine and/or acetonitrile, most preferably a mixture having a volume ratio of CCI4 to triethylamine to acetonitrile of about 1:4.5:27. If the acid activating compound is DMT-MM, then the solvent preferably is THF.
• the substantially optically pure (S) -amine used for the preparation of substantially optically pure repaglinide derivative of the formula III according to the fifth aspect of the invention has been prepared as described above in a process according to the first or third aspect of the invention, preferably by a process according to the first aspect of the invention.
• optically pure (S) -amine prepared according to the present invention can be used for coupling with the substituted acetic acid of formula IV to give substantially optically pure repaglinide derivative of the formula III.
• the substituted acetic acid of formula IV can be prepared by any process known in the art (e.g. J. Med. Chem. 1998, 41, 5219-5246 or WO 01/35900) .
• the invention is also directed to the use of substantially optically pure (S) -amine for the preparation of substantially optically pure repaglinide or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the substantially optically pure (S) -amine has been prepared by a process according to the first aspect of the invention or according to a process according to the third aspect of the invention.
• the substantially optically pure (S) -amine prepared by a process according to the first aspect of the invention or according to a process according to the third aspect of the invention can be used as a resolving agent for resolution of racemic repaglinide to give substantially optically pure (S)- repaglinide or a pharmaceutically acceptable salt, solvate or ester thereof.
• the invention is also directed to the use of racemic amine of formula II for the preparation of substantially optically pure repaglinide or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the racemic amine has been prepared by a process according to the fourth aspect of the invention.
• the invention is also directed to the use of substantially optically pure repaglinide derivative of the formula III for the preparation of substantially optically pure repaglinide or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the substantially optically pure repaglinide derivative of the formula III has been prepared by a process according to the fifth aspect of the invention .
• the invention relates to a process for the preparation of substantially optically pure repaglinide of the formula V
• the obtained substantially optically pure (S) -amine of the formula I, the obtained racemic amine of the formula II or the obtained substantially optically pure repaglinide derivative of the formula III are then converted into substantially optically pure repaglinide of the formula V.
• This conversion can be performed by processes known in the art such as the processes described in the documents discussed in the present background section or by processes described in the present application such as the processes according to the first and/or fifth aspect of the invention.
• the process for the preparation of substantially optically pure repaglinide comprises the steps (i) or (iii) or a combination of steps (i) and (iii) .
• the combination of these preparation steps is highly efficient with respect to the yield and purity of the repaglinide product.
• Substantially optically pure repaglinide prepared according to the present invention can also be used in pharmaceutical compositions that exhibit hypoglycemic effect and are used in long-term antidiabetic treatment which have been previously described in e.g. EP 0 147 850, EP 0 207 331, EP 0 208 200, EP 0 589 874, US 6830759 and IPCOM000142425D.
• solvent A 0.02 M diammonium hydrogen phosphate pH 6.0: Accurately weight about 2.64 g of diammonium hydrogen phosphate and dissolve in about 950 ml of water. Adjust with phosphoric acid solution to a pH 6.0, transfer into a 1000 ml volumetric flask and dilute with water to volume. Filter through a 0.22 ⁇ m membrane filter and degas.
• Sample solution (SaS) about 1.5 mg of the sample per ml.
• Example 3 was repeated with the exception that instead of isobutyl methyl ketone a solvent or solvent mixture as indicated in the table below was used.
• the mother liquors of the first optical resolution of racemic 1- (2-piperidino-phenyl) -3-methyl-l-butylamine obtained in Examples 1 to 9 were evaporated to dryness to recover the (R) - enriched 1- (2-piperidino-phenyl) -3-methyl-l-butylamine dibenzoyl tartaric acid salt.
• the amine base was freed with ammonia and extracted with CH 2 Cl 2 . After complete evaporation of the solvent, the crude extract showed to contain 79.8% of the (R) -enantiomer (as determined by chiral HPLC) , with a water content of 0.15%.
• racemic 1- (2-piperidino-phenyl) -3-methyl-l-butylamine glutaric acid salt were suspended in dichloromethane (500 mL) and water (250 mL) . 4M NaOH was added for neutralization and the pH was adjusted to 8 to 9. After separation of phases the organic phase was washed with water (10OmL), dried with anhydrous Na 2 SO 4 , filtrated and evaporated under reduced pressure to give 31,2 g (96%) of racemic 1- (2-piperidino- phenyl) -3-methyl-l-butylamine as yellow oil.
• Example 15 was repeated to give racemic 1- (2-piperidino- phenyl) -3-methyl-l-butylamine which was then converted to substantially optically pure (S) ( + ) -1- (2-piperidino-phenyl) -3- methyl-1-butylamine as described in Example 1.
• Example 20 Optical resolution of racemic 1- (2-piperidino- phenyl) -3-methyl-l-butylamine, regeneration of (R) -enriched 1- (2-piperidino-phenyl) -3-methyl-l-butylamine and subsequent racemization
• racemic 1- (2-piperidino-phenyl) -3-methyl-l- butylamine (2.8g) in butyl acetate (9.7 ml) at a temperature of 80 to 90 0 C (+) -dibenzolytaratric acid (2.02 g) was added in one portion.
• the reaction mixture was stirred under nitrogen atmosphere at gently reflux for 1 to 2 minutes, whereupon a clear solution was obtained.
• the reaction mixture was allowed to cool to a temperature of 45°C and seeding crystals were added. After 2 hours at room temperature the reaction mixture precipitated.
• the reaction mixture was allowed to cool at -10 to -5°C.
• the precipitated material was filtered and successively washed on the filter with freezing butyl acetate (2 x 2 ml) and small amounts of diethyl ether (0.5 ml) .
• the precipitated solid (1.45g, 58%) was analyzed by HPLC, m.p., and optical rotation.
• the optical purity (chiral HPLC) was 98% of (S) -1- (2-piperidino-phenyl) -3-methyl-l-butylamine .
• RaNi W4 catalyst A water suspension of RaNi W4 catalyst was rapidly washed three times with degassed ethanol (the ethanol was undenatured) , three times with absolute ethanol and then two times with degassed dry toluene.
• Toluene was decanted and RaNi (30 mg) was transferred to a solution of (R) -enriched 1- (2- piperidino-phenyl) -3-methyl-l-butylamine (250 mg) in degassed toluene (10 ml) .
• the resulting mixture was stirred in an oil bath at a temperature of 85°C for 18 hours and at reflux for 12 hours under hydrogen atmosphere (balloon) . Thereafter, the reaction mixture was filtered through a sintered glass filter with a pad of silica gel.

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