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    • 专利摘要:
    a) chlorinating racemic 6,8-halooctanoic acid with S (-) α-methylbenzylamine; b) separating the crystallized diastereomeric salt of R (+) 6,8-dihalo-octanoic acid-S (-) α-methylbenzylamine by filtration; c) purifying diastereomeric salts of R (+) 6,8-dihalo-octanoic acid-S (-) α-methylbenzylamine by recrystallization; d) separating said diastereomeric salts by reacting with a strong inorganic acid in an aqueous solution diluted to 2-10% by weight to obtain R (+) 6,8-di-halooctanoic acid; e) esterifying R (+) 6,8-di-halo-octanoic acid to yield the corresponding alkyl ester; f) reacting an aqueous solution of an alkali disulfide with an alkyl ester of R (+) 6,8-di-halo-octanoic acid in an organic solvent in the presence of a compound for phase transfer catalysis: g) R (+) α- A method of synthesizing R (+) α-lipoic acid is disclosed that includes hydrolyzing an ester of lipoic acid.
    公开号:KR20030070001A
    申请号:KR10-2003-7004734
    申请日:2001-10-08
    公开日:2003-08-27
    发明作者:빌라니플라비오；나르디안토니오；살비안니바레；파라벨라지오반나
    申请人:라보라토리오 치미코 인터나지오날레 에스.피.에이.；
    IPC主号:
    专利说明:

    SYNTHESIS OF R (+) α-LIPOIC ACID}
    [2] Methods of separating racemic mixtures or racemates, ie, separating racemates into the constituent enantiomers, are well known in the art. The racemate is first converted into a mixture of diastereomers by reaction with an optically active material. The diastereoisomers obtained as above characterized by different physical properties, in particular solubility, are generally separated by fractional crystals. Enantiomers of the starting racemic mixture are obtained from the separated diastereomers by a simple chemical separation reaction of the diastereomers.
    [3] U.S. Patent 5,281,722 discloses diastereomeric salts obtained from pure enantiomers of α-lipoic acid by reaction of the α-methylbenzylamine with optical isomers. Known procedures are in the process for preparing the diastereomeric salts and in the separation of the racemic mixture of thioctic acid into both optically active enantiomeric forms R (+) and S (-) of α-lipoic acid. The use of these salts as intermediate products is disclosed. The method for separating racemic thioctic acid has a low yield, particularly for the separation of R (+) α-lipoic acid enantiomers (see Examples 7 and 8 of US Pat. No. 5,281,722).
    [4] Indeed, the purification methods disclosed at the state of the art for diastereomeric salts have low enantiomer richness of the R (+) α-lipoic acid isomeric salts. This is further confirmed by several recrystallizations performed on the diastereomeric salts prior to the separation reaction by acid.
    [5] The tests performed by the Applicant separated two purified optically active enantiomers by separating the diastereomeric salts purified by the addition of an inorganic acid, such as, for example, 1N hydrochloric acid, as disclosed in US Pat. No. 5,281,722. Obtaining the thiomeric forms R (+) and S (−) demonstrates the production of enantiomers of low quality α-lipoic acid (polymer present).
    [6] Levels of skill in the art are diastereomeric salts obtained from enantiomers of α-lipoic acid by reaction with optically active bases to separate isomers R (+) and S (-) of α-lipoic acid. Discloses their use. However, as demonstrated by the Applicant, the methods disclosed at the state of the art not only result in low separation yields of racemates but also are not satisfactory in the quality of the optical isomers obtained as described above. It is characterized by a complex and long purification method.
    [7] Thus, there is a need for a method of synthesizing the R (+) optical isomers of α-lipoic acid which may represent an alternative to the state of the art methods including racemic thioctic acid as the intermediate product of the reaction. In particular, there is a need for synthetic methods that can provide optical isomers of α-lipoic acid of high quality and high purity with higher yields.
    [8] Summary of the Invention
    [9] The present invention is the corresponding esterified enantiomer by separation and phase transfer catalysis of racemic 6,8-di-halo-octanoic acid by optically active base (S) -α-methylbenzylamine A novel method for synthesizing R (+) α-lipoic acid via the reaction of alkali R (+) 6,8-di-halooctanoate with alkali disulfide was found, which is characteristic of the state of the art methods. The disadvantages were the complexity, low yield and low quality of the optical isomers obtained.
    [10] Surprisingly surprisingly, Applicants have chlorided 6,8-di-halo-octanoic acid with an optically active base S (-) α-methylbenzylamine to give (+)-6,8-di-halo-octanoic acid. An diastereomeric salt of -S (-) α-methylbenzylamine is obtained, which is then purified by fractional crystallization and the salt is separated by acid to enantiomer (+)-6,8-di-haloocta In order to obtain carbonic acid and to obtain esterified R (+) α-lipoic acid, a novel synthesis of R (+) α-lipoic acid by esterification is followed by reaction with an aqueous solution of alkaline disulfide by phase transfer catalysis. A method of synthesis was found.
    [1] The present invention relates to the formation of diastereoisomeric salts of racemic 6,8-di-halooctanoic acid with an isomer of α-methylbenzylamine, the separation of R (+)-dihalooctanoic acid and the corresponding by phase transfer catalysis. To a method for synthesizing R (+) α-lipoic acid through its conversion to α-lipoic acid.
    [11] It is therefore an object of the present invention to a method for the synthesis of R (+) α-lipoic acid comprising the following steps:
    [12] a) chlorinating racemic 6,8-halooctanoic acid with S (-) α-methylbenzylamine, wherein S (-) α-methylbenzylamine / racemic 6,8-di-halooctanoic acid Molar ratio is 0.45 to 0.65);
    [13] b) filtration separating the crystallized diastereomeric salt of R (+) 6,8-dihalo-octanoic acid-S (-) α-methylbenzylamine by filtration;
    [14] c) purifying diastereomeric salts of R (+) 6,8-dihalo-octanoic acid-S (-) α-methylbenzylamine by recrystallization;
    [15] d) separating said diastereomeric salts by reacting with a strong inorganic acid in an aqueous solution diluted to 2-10% by weight to obtain R (+) 6,8-di-halooctanoic acid;
    [16] e) esterifying R (+) 6,8-di-halo-octanoic acid to yield the corresponding alkyl ester;
    [17] f) Alkyl esters and alkalis of R (+) 6,8-di-halo-octanoic acid in an organic solvent in the presence of a compound for phase transfer catalysis selected from the group consisting of quaternary ammonium or phosphonium salts having the formula: Reacting an aqueous solution of disulfide:
    [18]
    [19] [Wherein,
    [20] A is nitrogen or
    [21] X is selected from the group consisting of Cl, Br, I, HSO 4 and H 2 PO 4 ,
    [22] Substituents R 1 , R 2 , R 3 and R 4 are selected from the group consisting of linear and branched alkyl radicals of 1 to 20 carbon atoms (C 1 -C 20 ), wherein the substituents are the same or different from each other, or Only one of said substituents is selected from the group consisting of arylalkyl radicals of the formula — (CH 2 ) n C 6 H 5 , wherein n is 1 to 16;
    [23] g) hydrolyzing the ester of R (+) α-lipoic acid.
    [24] Halogen substituents of racemic 6,8-di-halo-octanoic acid which are the same or different from each other are selected from the group consisting of Cl, Br and I. The racemic 6,8-di-halo-octanoic acid is preferably described in J.A.C.S. Volume 79, 1957, p. 6483-6487, a commercially available product, 6,8-dichlorooctanoic acid, prepared according to the description contained therein.
    [25] The molar ratio of S (-) α-methylbenzylamine / racemic 6,8-di-halooctanoic acid in the chloride step a) according to the synthesis process disclosed herein is preferably 0.48 to 0.60, even more preferably 0.50. To 0.58. The chloride of step a) is carried out at atmospheric pressure in an organic solvent, preferably ethyl acetate, at a temperature of 20 to 40 ° C., preferably 25 to 30 ° C. The concentration of racemic 6,8-di-halooctanoic acid in chloride step a) is 10-40% w / v, preferably 15-35% w / v, even more preferably 20-30% w of the solvent. / v
    [26] Step b), ie the separation by filtration of the diastereomeric salts, takes place at a temperature of 0 to 10 ° C, preferably 2 ° C.
    [27] In step c), ie purification by recrystallization of the diastereomeric salt of R (+) 6,8-di-halooctanoic acid-S (-) α-methylbenzylamine, the solvent used is aliphatic or aromatic carboxyl Alkyl esters of acids, wherein alkyl is C 1 -C 3 , preferably alkyl esters of aliphatic carboxylic acids having 2 to 4 carbon atoms, 40 to 65 ° C., preferably 45 to 60 ° C., even more preferably Is heated at a temperature of from 50 to 55 ° C.
    [28] In step d), ie separation of the diastereomeric salt, the aqueous inorganic acid is preferably sulfuric acid diluted to 4 to 8% by weight, even more preferably the sulfuric acid is diluted to 5% by weight.
    [29] Step e), ie esterification of R (+) 6,8-di-halo-octanoic acid, comprises an esterification reaction according to methods well known in the art of esterification of aliphatic carboxylic acids with aliphatic or aromatic alcohols. .
    [30] According to the invention the alkyl ester of R (+) 6,8-di-halo-octanoic acid is linear or branched C 1 -C 6 ester, preferably linear or branched C 1 -C 3 ester, even more Preferably methyl ester and ethyl ester.
    [31] According to the invention, the amount of alkyl ester of R (+) 6,8-di-halo-octanoic acid in the reaction carried out in step f) is 5 to 60% by weight, preferably 10 to 40% by weight, based on the organic solvent. %, Even more preferably 15 to 30% by weight.
    [32] The organic solvent used in the reaction carried out in step f) is a solvent that cannot be mixed with water and is a linear or branched aliphatic C 5 -C 10 hydrocarbon or aromatic C 5 -C 10 hydrocarbon (also halogen, nitro or nitrile group). Has a substitution group selected from the group consisting of; Esters of aliphatic or aromatic carboxylic acids; Linear or cyclic ethers; Linear or cyclic C 4 -C 10 ketones; Carbon disulfide; Selected from the group consisting of carbon tetrachloride. The solvent is preferably benzene or toluene.
    [33] The process for synthesizing R (+) α-lipoic acid according to the invention can be mixed with water, containing an alkyl ester of R (+) 6,8-di-halo-octanoic acid from an aqueous solution containing the corresponding alkali disulfide. Phase transition of disulfide ions into an organic phase that is absent. An aqueous solution of alkali disulfide may be prepared by reacting sulfur (S) with the corresponding alkali sulfide in water.
    [34] Preferred alkali disulfides are sodium disulfide (Na 2 S 2 ) and potassium disulfide (K 2 S 2 ), or mixtures thereof, with sodium disulfide even more preferred.
    [35] In the reaction carried out in step f) of the R (+) α-lipoic acid synthesis method according to the invention, the molar ratio of the alkyl ester of alkali disulfide / R (+) 6,8-di-halo-octanoic acid is from 0.8 to 1.2. , 0.9 to 1.1, still more preferably 0.95 to 1.0.
    [36] Compounds for phase transfer catalysis used in the synthesis of R (+) α-lipoic acid, which is the object of the present invention, are tetrabutylammonium bromide, tetrabutylphosphonium bromide, methyltrioctylammonium chloride (ALIQUAT® 336), methyl -(C 8 -C 10 ) -trialkylammonium chloride (ADOGEN® 464) and tetrabutylammonium hydrogensulfate; Tetrabutylammonium bromide and tetrabutylammonium hydrogensulfate are even more preferred.
    [37] According to the synthesis process disclosed in the present invention, the quaternary salt, which is a compound for phase transfer catalysis in the reaction carried out in step f), is 0.5 to 10 mol%, based on the alkyl ester of 6,8-di-halo-octanoic acid, It is preferably present in an amount of 1 to 5 mol%, even more preferably 2 to 4 mol%.
    [38] The temperature of the reaction carried out in step f) is 20 to 130 ° C., preferably 60 to 100 ° C., even more preferably 80 to 90 ° C.
    [39] Step g), ie hydrolysis of the ester of R (+) α-lipoic acid, is carried out with organic solvents, for example alcohols, which can be mixed with water in a volume ratio of 50:50 to 95: 5 at a temperature of from 0 to 100 ° C. Hydrolysis by alkali / alkaline earth hydroxides in the presence of polyols, ethers and hydroxy ethers, ketones and hydroxy ketones. The concentration of ester relative to the organic solvent is 5-50% w / v, and the molar ratio of ester / hydroxide is 0.5-1.
    [40] The free R (+) α-lipoic acid can be recovered by treatment with an aqueous inorganic or water soluble organic acid diluted to 1-20% by weight.
    [41] Reaction products and intermediate products are characterized by 1 H-NMR, mass and HPLC analysis.
    [42] The following are some embodiments that disclose the invention without limitation.
    [43] Example 1
    [44] a) 40 g (0.187 mol) of racemic 6,8-dichlorooctanoic acid are dissolved in 150 ml of ethyl acetate at 25 to 30 ° C. To the solution is added 12.3 g (0.101 mol) of S (-) α-methylbenzylamine. The solution is first cooled at 18-20 ° C until precipitation begins and then at 0-5 ° C. The solid obtained was filtered and washed with ethyl acetate (10 mL) to give 15.3 g of a wet salt of (+)-6,8-dichlorooctanoic acid-S (−) α-methylbenzylamine.
    [45] b) The mother liquor resulting from the crystallization taking place in step a) is extracted with 100 ml of 5% by weight sulfuric acid and the pH value of the aqueous phase is checked to be 1. The organic phase is washed twice with 20 ml of water and then concentrated by solvent evaporation at atmospheric pressure until the volume reaches 130-140 ml. 0.75 g (0.08 mol) of R (+) α-methylbenzylamine is added to the solution, first cooled at 18-20 ° C. until precipitation begins, and then cooled at 0-5 ° C. The solid is filtered and washed with 10 ml of ethyl acetate to give 8.2 g of a wet salt of (-)-6,8-dichlorooctanoic acid-R (+) α-methylbenzylamine.
    [46] c) The mother liquor resulting from the crystallization carried out in step b) is extracted with 50 ml of 5% by weight sulfuric acid and the pH value of the aqueous phase is checked to be <1. The organic phase is washed twice with 20 ml of water and then concentrated by solvent distillation at atmospheric pressure until the volume reaches 40 to 45 ml. 50 ml of ethyl acetate is added to the solution and 9.8 g (0.081 mol) of S (-) α-methylbenzylamine is first cooled at 18-20 ° C until precipitation starts and then at 0-5 ° C. The solid is filtered and washed with 10 ml of ethyl acetate to give 12 g of a wet salt of (+)-6,8-dichlorooctanoic acid-S (−) α-methylbenzylamine.
    [47] d) The wet salts of (+)-6,8-dichlorooctanoic acid-S (-) α-methylbenzylamine obtained in steps a) and c) are combined and crystallized twice with 55 ml of ethyl acetate each time. 16 g of wet product are obtained and dried in vacuo to give 13.5 g of salt of (+)-6,8-dichlorooctanoic acid-S (−) α-methylbenzylamine. The salt is suspended in a mixture of water (60 mL) and toluene (60 mL) and acidified with 5% by weight sulfuric acid until the pH is 1. The organic phase is separated and concentrated in vacuo to yield 9 g (+ = 45%) of (+)-6,8-dichlorooctanoic acid.
    [48] [α] 24 D = 26.7 (c = 2, ethanol)
    [49] Example 2
    [50] 9 g (0.042 mol) of (+)-6,8-dichlorooctanoic acid are dissolved in 120 ml of methanol containing 0.45 ml of 37% by weight aqueous hydrochloric acid. The solution is refluxed for 2 hours, the solvent is evaporated under reduced pressure, 17 ml of toluene is added and the resulting solution is washed twice with 10 ml of water. The toluene phase is concentrated under vacuum to afford 9.4 g (yield = 98.6%) of methyl (+)-6,8-dichlorooctanoate.
    [51] [α] 20 D = 26.5 (c = 1, toluene)
    [52] Example 3
    [53] A mixture of 60% by weight of 5.65 g (0.043 mol) of sodium sulfide, 1.18 g (0.037 mol) of sulfur and 20 ml of water is heated at 85 ° C. for 30 minutes. After filtration to remove the insoluble portion, the solution was 9.4 g (0.041 mol) of methyl (+)-6,8-dichlorooctanoate maintained at 82 ° C. over 3 hours, 0.37 g (0.0011 mol) tetrabutylammonium bromide ) And 18.5 ml of toluene. The mixture is refluxed (90 ° C.) for 1 hour and cooled at 30 ° C., the organic phase is separated and washed with 5 ml of water. The whole was concentrated in vacuo to yield 8.6 g (yield = 94.4%) of methyl ester of R (+) α-lipoic acid.
    [54] The final product is characterized by 1 H-NMR and mass spectrometry:
    [55] 1 H-NMR-δ (300 MHz, CDCl 3 ): 1.4 (2H, m); 1.67 (4 H, m); 1.83 (1 H, t d); 2.24 (2H, t); 2.4 (1H, t d); 3.1 (2H, m); 3.5 (1 H, m); 3.66 (3 H, s).
    [56] Mass (EI): 220 (M + ); 189 (-CH 3 O).
    [57] [a] 20 D = 88 (c = 1.8, toluene)
    [58] Example 4
    [59] 8.6 g (0.039 mol) of methyl ester of R (+) α-lipoic acid are added to a solution consisting of 90% by weight of 2.36 g (0.042 mol) of potassium hydroxide, 19 ml of methanol and 3.8 ml of water. The resulting mixture is heated at 50 ° C. for 2 hours, cooled at 30 ° C. and 40 ml of toluene are added. The whole is acidified with 10% by weight phosphoric acid while maintaining the temperature below 30 ° C. The organic phase is separated and washed three times with 10 ml of 10% by weight aqueous sodium chloride solution each time. The solution is dehydrated over sodium sulfate and concentrated to dryness by evaporation of the solvent under vacuum. 3.3 ml of ethyl acetate and 41 ml of cyclohexane are added, the solution is heated at 40 ° C. and treated with decolorized carbon and the resulting clear solution is slowly cooled at 0 ° C. The solid was filtered and washed with 5 ml of cyclohexane to give 3.6 g (yield = 45%) of R (+) α-lipoic acid.
    [60] [a] 20 D = 119.1 (c = 1, ethanol)
    [61] e.e. > 99% (HPLC).
    权利要求:
    Claims (31)
    [1" claim-type="Currently amended] a) chlorinating racemic 6,8-halooctanoic acid with S (-) α-methylbenzylamine, wherein S (-) α-methylbenzylamine / racemic 6,8-di-halooctanoic acid Molar ratio is 0.45 to 0.65);
    b) separating the crystallized diastereomeric salt of R (+) 6,8-dihalo-octanoic acid-S (-) α-methylbenzylamine by filtration;
    c) purifying diastereomeric salts of R (+) 6,8-dihalo-octanoic acid-S (-) α-methylbenzylamine by recrystallization;
    d) separating said diastereomeric salts by reacting with a strong inorganic acid in an aqueous solution diluted to 2-10% by weight to obtain R (+) 6,8-di-halooctanoic acid;
    e) esterifying R (+) 6,8-di-halo-octanoic acid to yield the corresponding alkyl ester;
    f) Alkyl esters and alkalis of R (+) 6,8-di-halo-octanoic acid in an organic solvent in the presence of a compound for phase transfer catalysis selected from the group consisting of quaternary ammonium or phosphonium salts having the formula: Reacting an aqueous solution of disulfide:

    [Wherein,
    A is nitrogen or
    X is selected from the group consisting of Cl, Br, I, HSO 4 and H 2 PO 4 ,
    Substituents R 1 , R 2 , R 3 and R 4 are selected from the group consisting of linear and branched alkyl radicals of 1 to 20 carbon atoms (C 1 -C 20 ), wherein the substituents are the same or different from each other, or Only one of said substituents is selected from the group consisting of arylalkyl radicals of the formula — (CH 2 ) n C 6 H 5 , wherein n is 1 to 16;
    g) hydrolyzing the ester of R (+) α-lipoic acid
    Method of synthesizing R (+) α-lipoic acid comprising a.
    [2" claim-type="Currently amended] The method of claim 1,
    Wherein the halogen substituents of racemic 6,8-di-halo-octanoic acid which are the same or different from each other are selected from the group consisting of Cl, Br and I.
    [3" claim-type="Currently amended] The method of claim 2,
    Wherein the racemic 6,8-di-halo-octanoic acid is 6,8-dichlorooctanoic acid.
    [4" claim-type="Currently amended] The method of claim 1,
    The molar ratio of S (-) α-methylbenzylamine / racemic 6,8-di-halooctanoic acid in chloride step a) is 0.48 to 0.60.
    [5" claim-type="Currently amended] The method of claim 4, wherein
    The molar ratio of S (-) α-methylbenzylamine / racemic 6,8-di-halooctanoic acid is from 0.50 to 0.58.
    [6" claim-type="Currently amended] The method of claim 1,
    Wherein the concentration of racemic 6,8-di-halooctanoic acid in chloride step a) is 10-40% w / v of the solvent.
    [7" claim-type="Currently amended] The method of claim 6,
    Wherein the concentration of racemic 6,8-di-halooctanoic acid is from 15 to 35% w / v of the solvent.
    [8" claim-type="Currently amended] The method of claim 7, wherein
    Wherein the concentration of racemic 6,8-di-halooctanoic acid is 20-30% w / v of the solvent.
    [9" claim-type="Currently amended] The method of claim 1,
    In step d), ie separation of the diastereomeric salt, the aqueous inorganic acid is sulfuric acid diluted to 4 to 8% by weight.
    [10" claim-type="Currently amended] The method of claim 9,
    The sulfuric acid is diluted to 5% by weight.
    [11" claim-type="Currently amended] The method of claim 1,
    Wherein the alkyl ester of R (+) 6,8-di-halo-octanoic acid is linear or branched C 1 -C 6 ester.
    [12" claim-type="Currently amended] The method of claim 11,
    Wherein the alkyl ester of R (+) 6,8-di-halooctanoic acid is a linear or branched C 1 -C 3 ester.
    [13" claim-type="Currently amended] The method of claim 12,
    Wherein the alkyl ester of R (+) 6,8-di-halooctanoic acid is methyl ester or ethyl ester.
    [14" claim-type="Currently amended] The method of claim 1,
    The amount of alkyl ester of R (+) 6,8-di-halo-octanoic acid in the reaction carried out in step f) is from 5 to 60% by weight relative to the organic solvent.
    [15" claim-type="Currently amended] The method of claim 14,
    The amount of alkyl ester of R (+) 6,8-di-halo-octanoic acid is 10 to 40% by weight relative to the organic solvent.
    [16" claim-type="Currently amended] The method of claim 15,
    The amount of alkyl ester of R (+) 6,8-di-halo-octanoic acid is from 15 to 30% by weight relative to the organic solvent.
    [17" claim-type="Currently amended] The method of claim 1,
    Solvents in which the organic solvent used in the reaction carried out in step f) cannot be mixed with water, linear or branched aliphatic C 5 -C 10 hydrocarbons or aromatic C 5 -C 10 hydrocarbons (also with halogen, nitro and nitrile groups) Has a substitution group selected from the group consisting of; Esters of aliphatic or aromatic carboxylic acids; Linear or cyclic ethers; Linear or cyclic C 4 -C 10 ketones; Carbon disulfide; And from the group consisting of carbon tetrachloride.
    [18" claim-type="Currently amended] The method of claim 17,
    The solvent is benzene or toluene.
    [19" claim-type="Currently amended] The method of claim 1,
    The alkali disulfide is sodium disulfide (Na 2 S 2 ) or potassium disulfide (K 2 S 2 ), or a mixture thereof.
    [20" claim-type="Currently amended] The method of claim 19,
    Wherein the alkali disulfide is sodium disulfide.
    [21" claim-type="Currently amended] The method of claim 1,
    In the reaction carried out in step f), the molar ratio of alkali disulfide / alkyl ester of R (+) 6,8-di-halo-octanoic acid is between 0.8 and 1.2.
    [22" claim-type="Currently amended] The method of claim 21,
    The molar ratio is from 0.9 to 1.1.
    [23" claim-type="Currently amended] The method of claim 22,
    The molar ratio is from 0.95 to 1.0.
    [24" claim-type="Currently amended] The method of claim 1,
    Quaternary ammonium or phosphonium salts include tetrabutylammonium bromide, tetrabutylphosphonium bromide, methyltrioctylammonium chloride (ALIQUAT® 336), methyl- (C 8 -C 10 ) -trialkylammonium chloride (ADOGEN ( 464) and tetrabutylammonium hydrogensulfate.
    [25" claim-type="Currently amended] The method of claim 24,
    The quaternary salt is tetrabutylammonium bromide or tetrabutylammonium hydrogensulfate.
    [26" claim-type="Currently amended] The method of claim 1,
    The quaternary ammonium or phosphonium salt is present in an amount of from 0.5 to 10 mole percent relative to the alkyl ester of 6,8-di-halo-octanoic acid.
    [27" claim-type="Currently amended] The method of claim 26,
    The quaternary salt is present in an amount of from 1 to 5 mole percent relative to the alkyl ester of 6,8-di-halo-octanoic acid.
    [28" claim-type="Currently amended] The method of claim 27,
    The quaternary salt is present in an amount of from 2 to 4 mole percent relative to the alkyl ester of 6,8-di-halo-octanoic acid.
    [29" claim-type="Currently amended] The method of claim 1,
    The temperature of the reaction carried out in step f) is from 20 to 130 ° C.
    [30" claim-type="Currently amended] The method of claim 29,
    The temperature is from 60 to 100 ° C.
    [31" claim-type="Currently amended] The method of claim 30,
    The temperature is from 80 to 90 ° C.
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    US3739019A|1973-06-12|Preparation of optically active trans chrysanthemic acid
    同族专利:
    公开号 | 公开日
    IT1319196B1|2003-09-26|
    DE60103179T2|2005-05-04|
    AT266020T|2004-05-15|
    DE60103179D1|2004-06-09|
    ITMI20002188D0|2000-10-10|
    AU2059602A|2002-04-22|
    JP2004511477A|2004-04-15|
    US20040002610A1|2004-01-01|
    US6864374B2|2005-03-08|
    CZ301710B6|2010-06-02|
    ITMI20002188A1|2002-04-10|
    EP1335911A1|2003-08-20|
    WO2002030919A1|2002-04-18|
    ES2219577T3|2004-12-01|
    JP4257574B2|2009-04-22|
    KR100822532B1|2008-04-16|
    EP1335911B1|2004-05-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-10-10|Priority to ITMI20002188
    2000-10-10|Priority to ITMI2000A002188
    2001-10-08|Application filed by 라보라토리오 치미코 인터나지오날레 에스.피.에이.
    2001-10-08|Priority to PCT/EP2001/011576
    2003-08-27|Publication of KR20030070001A
    2008-04-16|Application granted
    2008-04-16|Publication of KR100822532B1
    优先权:
    申请号 | 申请日 | 专利标题
    ITMI20002188|IT1319196B1|2000-10-10|2000-10-10|Synthesis of ralpha-lipoic acid.|
    ITMI2000A002188|2000-10-10|
    PCT/EP2001/011576|WO2002030919A1|2000-10-10|2001-10-08|SYNTHESIS OF Rα-LIPOIC ACID|
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