CN103626668B - Chemical resolution preparation method of S-configuration pregabalin - Google Patents
Chemical resolution preparation method of S-configuration pregabalin Download PDFInfo
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Abstract
The invention provides a method for preparing S-configuration pregabalin by resolving a pregabalin racemate. The method comprises the following steps: by taking toluenesulfonamide-D-phenylglycine or benzenesulfonamido-D-phenylglycine as a resolving agent, resolving in a water-borne alcoholic solution; and fully washing by using a resolving solvent, thus obtaining a compound of S-pregabalin and toluenesulfonamide-D-phenylglycine or benzenesulfonamido-D-phenylglycine; performing depolymerization in an aqueous solution or an alcoholic solution, thus obtaining the S-configuration pregabalin. The technical method provided by the invention is simple to operate and high in resolution efficiency, hardly causes environmental pollution and is suitable for industrial production, and the resolving agent and the resolving solvent are easy to recycle.
Description
Technical field
The present invention relates to technical field of compound preparation, particularly relate to S-configuration lyrica resolution process technical field, specifically about the chemical resolution preparation method of S-configuration lyrica.
background of invention
Lyrica (Pregbalin) chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, is the novel γ-aminobutyric acid of one (GABA) receptor stimulant of Pfizer company research and development.Within 2004, go on the market with trade(brand)name Lyrica through European Union's approval first, be used for the treatment of the partial seizure of adult patients.Within 2006, go on the market in the U.S., add new indication, be used for the treatment of generalized anxiety disorder and sociability anxiety disorder, within 2009, get permission again to be used for the treatment of Spinal injury, wound, multiple sclerosis, diabetic neuropathy pain and zoster neuralgia, be used widely clinically at present, become one of global best-selling drugs.
Containing a chiral carbon atom in lyrica molecule, there is enantiomer, wherein, S-configuration biological activity is better than R-configuration, clinical application be S-configuration lyrica.
Bibliographical information S-configuration lyrica multiple preparation method.Chen Yongsheng etc. are in organic chemistry the 31st volume the 10th phase in 2011: in " progress of synthesis of lyrica ", review the preparation method of pregabalin.
From chirality source compound or adopt the method for asymmetric induction to prepare the method for pregabalin, all there is the expensive and high deficiency of production cost of synthetic route length, severe reaction conditions, desired raw material, can not suitability for industrialized production be used for.
All adopt in actual production and first synthesize enantiomer, then obtain pregabalin through splitting.Representational synthetic route is as follows: (1) Huckabee etc. reports with nitrile ethyl acetate and isovaleric aldehyde by Knovenagel condensation in WO 9638405, then with diethyl malonate, Michael addition occurs, and hydrolysis decarboxylation obtains 3-isobutylglutaric acid.Through cyclization, ammonia solution, obtain 3-carbamyl-5-methylhexanoic acid raceme.After splitting with α-phenylethylamine, reset through Hoffmann, obtain the lyrica of S-configuration.Chen Ao etc. at Chinese Journal of Pharmaceuticals, 2004,35, report in 195 by 3-carbamyl-5-methylhexanoic acid raceme Hoffmann reset obtain racemic pregabalin, adopt S-(+)-amygdalic acid split, obtain pregabalin.(2) Grote etc. report isovaleric aldehyde and diethyl malonate condensation in WO 9640617, with potassium cyanide addition, and hydrolysis decarboxylation, obtain 3-itrile group-5-methylhexanoic acid ethyl ester, hydro-reduction, obtains lyrica raceme, adopt S-(+) fractionation of-amygdalic acid, obtain pregabalin.(3) Wang etc. are at CN 101362696, isovaleric aldehyde and Nitromethane 99Min. condensation is reported in 2009, again with diethyl malonate addition, 4-isobutyl--2-oxo-pyrrolidine-3-ethyl formate is prepared through catalytic hydrogenation, acidic hydrolysis obtains lyrica raceme, with S-(+) fractionation of-amygdalic acid, obtain pregabalin.
Bibliographical information direct carries out chemical resolution to lyrica raceme, and to prepare pregabalin method as follows: aroyl or the arylsulfonyl compound of WO 2009/082861 A1 report Pidolidone split; WO 2009/122215 A1 reports with L-configuration tartrate as resolving agent fractionation lyrica raceme; WO 2009/044409 reports that use two pairs of methyl benzoyl-L-TARTARIC ACIDs carry out chemical resolution to lyrica raceme for resolving agent.
In the chemical resolution method of known lyrica, when using S-(+)-amygdalic acid and L-TARTARIC ACID to split, crystallization difficulty, resolving agent is greatly water-soluble, is difficult to reclaim, and cyclic utilization rate is low, and cause production process loaded down with trivial details, cost is high.When using two pairs of methyl benzoyls-L-TARTARIC ACID to split, ester is good for poor stability, prepares difficulty in addition.When using aroyl-L-glutaminic acid or arylsulfonyl Pidolidone to split lyrica, split efficiency low, need secondary to split, operating process is complicated.
Find Stability Analysis of Structures, be easy to recycle, split the high lyrica mesotomy agent of efficiency, simplifying lyrica split process is the key factor of producing pregabalin, has material impact to pregabalin quality and production cost.
summary of the invention:
Main purpose of the present invention carries out fractionation for existing R/S-lyrica raceme to obtain pregabalin method Problems existing and deficiency, provides a kind of new chemical resolution method.
In the split process exploring lyrica, we surprisingly find that the sweet acid of benzenesulfonyl-D-benzene and the sweet acid of p-toluenesulfonyl-D-benzene effectively can split lyrica raceme.Fractionation efficiency is high, optical purity is high, and resolving agent is easy to recovery.When especially using the sweet acid of tosyl group-D-benzene to split lyrica raceme, secondary is not needed to split, simple to operate.The sweet acid of benzenesulfonyl-D-benzene and the sweet acid of p-toluenesulfonyl-D-benzene can be prepared conveniently by the sweet acid of D-benzene and benzene sulfonyl chloride or Tosyl chloride generation sulfonylation.The method possesses simple to operate, that fractionation efficiency is high, resolving agent is easy to recycling feature; Production cost is low, can obtain high purity pregabalin, be suitable for scale operation.
The technical solution used in the present invention realizes above-mentioned purpose by following steps.
(1), salify: with benzene sulfonamido-D-PG or to benzene sulfonamido-D-PG for resolving agent, lyrica raceme is split; Resolution solvent is the alcoholic solution containing suitable quantity of water.Pregabalin becomes to salt out with benzene sulfonamido-D-PG or to benzene sulfonamido-D-PG; With resolution solvent, it is fully washed, obtain pregabalin and benzene sulfonamido-D-PG salt composite or pregabalin and to benzene sulfonamido-D-PG salt composite.
(2), depolymerization: by pregabalin and benzene sulfonamido-D-PG salt composite or pregabalin be suspended in water to benzene sulfonamido-D-PG salt composite, add mineral acid adjust ph, fully stir.Filter, reclaim resolving agent, recycle.Filtrate neutralizes with alkali, crystallization, dry, obtains pregabalin.Also and can be dissolved in alcoholic solution to benzene sulfonamido-D-PG salt composite by pregabalin and benzene sulfonamido-D-PG salt composite or pregabalin, use alkali adjust ph, directly separate out pregabalin.Filtrate acid out, reclaims resolving agent.Reaction equation is shown in following formula.
~ in step (1) salification process, lyrica raceme can obtain with multiple currently known methods; Benzene sulfonamido-D-PG or to benzene sulfonamido-D-PG by benzene sulfonyl chloride or prepare with D-PG generation sulfonamide reaction in water benzene sulfonyl chloride.Resolution solvent is moisture alcoholic solution, and the alcohol used is methyl alcohol, ethanol, propyl alcohol, Virahol, preferred Virahol; Water and alcohol volume ratio are 2-10:98 ~ 90, preferred 3:97 ~ 5:95.Lyrica raceme quality and resolution solvent volume ratio are 1g:10 ~ 20mL, preferred 1g:14 ~ 16mL.Salification process solvent temperature be room temperature to reflux temperature, preferably 40 ~ 50 DEG C, salify recrystallization temperature is room temperature to 40 DEG C, preferred room temperature to 30 ~ 35 DEG C.Filter out salt composite, wash with resolution solvent.
In step (2) depolymehzation process, the pregabalin obtained and benzene sulfonamido-D-PG or the salt composite of benzene sulfonamido-D-PG is suspended in water, liquid volume used be the 5-15 of salt composite quality doubly, preferably 6 ~ 8 times; Be 0.5 ~ 1 with acid for adjusting pH, acid used can be hydrochloric acid, sulfuric acid or phosphoric acid, preferred hydrochloric acid.Abundant stirring, suction filtration, washing, reclaims resolving agent benzene sulfonamido-D-PG or to benzene sulfonamido-D-PG.The temperature stirring depolymehzation process is room temperature to 60 DEG C, preferred room temperature to 50 DEG C.Filtrate alkali lye regulates pH to be 6-7, concentrating under reduced pressure part water, cooling 0-5 DEG C, and insulation crystallization, filters, with cold water washing, obtain pregabalin.Also or can be dissolved in 10-50% alcohol solution to the salt composite of benzene sulfonamido-D-PG by pregabalin and benzene sulfonamido-D-PG, alcohol used is methyl alcohol, ethanol, propyl alcohol or Virahol, particular methanol or ethanol.Regulate pH to be 6-7 with alkali, directly separate out pregabalin.Concentrated filtrate, acid out, reclaim resolving agent.
Become in step (1) in the process of salt formation mixture, filter out the filtrate of salt composite, after concentration and recovery alcohol, adding water-dispersion, is 1-2 with acid for adjusting pH, crystallization, filter, washing, reclaim resolving agent benzene sulfonamido-D-PG or benzene sulfonamido-D-PG is recycled.Next salification process directly applied mechanically by salt composite washings.
Different from the known method for splitting of bibliographical information, split lyrica raceme by method of the present invention and obtain pregabalin process: be simple to operate, split efficiency high, resolving agent and fractionation solution are easy to recovery.Whole split process yield is high, cost is low, environmental pollution is little, has good prospects for commercial application.
In order to understand technology contents of the present invention and essence better, further illustrate operating process of the present invention by specific embodiment.It should be noted that specific embodiment is not limit the scope of the invention, the change that those skilled in the art make the present invention or amendment and without prejudice to essence of the present invention, still within the scope of the present invention.
Embodiment 1:
(1), salification process
In the clean there-necked flask of 50mL, add the aqueous isopropanol 40mL of 5.50g p-methylphenyl sulphonylamine base-D-PG and volume ratio 3%, heating for dissolving; Add 2.40g lyrica raceme, insulation low rate mixing 0.5h, Temperature fall 30 ~ 35 DEG C, crystallization 4h.Suction filtration, will obtain solid transfer in the aqueous isopropanol 15mL of volume ratio 3%, 50 DEG C of insulated and stirred 1h, are cooled to 30 DEG C, crystallization 1h, suction filtration, dry, obtain 3.0g pregabalin and p-methylphenyl sulphonylamine base-D-PG salt composite.
(2), depolymehzation process
Above-mentioned salt composite 3.0g is suspended in 15mL deionized water, with 10% salt acid for adjusting pH=0.5-1, stirring at room temperature 3h, filters, use 4mL water washing, dry, reclaim resolving agent p-methylphenyl sulphonylamine base-D-PG 2.0g.PH=6 ~ 6.5 are regulated with 20% sodium hydroxide.Concentrating under reduced pressure goes out 8mL water, lowers the temperature 0 ~ 5 DEG C, and insulation crystallization 4h, filters, use 2mL cold water washing, drying under reduced pressure, obtain white pregabalin 0.8g.Fusing point: 183-186 DEG C, yield 33.3%, ee=98.90%.
Embodiment 2:
(1), salification process
In the clean there-necked flask of 100mL, add the aqueous isopropanol 40mL of 5.0g benzene sulfonamido-D-PG and volume ratio 3%, heating for dissolving; Add 2.40g lyrica raceme, insulation low rate mixing 0.5h, Temperature fall 30 ~ 35 DEG C, crystallization 6h.Suction filtration, will obtain solid transfer in the aqueous isopropanol 30mL of volume ratio 3%, 50 DEG C of insulated and stirred 2h, are cooled to 30 DEG C, crystallization 3h, suction filtration, dry, obtain 2.80g pregabalin and benzene sulfonamido-D-PG salt composite.
(2), depolymehzation process
Above-mentioned salt composite 2.80g is suspended in 15mL deionized water, with 10% salt acid for adjusting pH=0.5-1, stirring at room temperature 3h, filters, use 5mL water washing, dry, reclaim resolving agent benzene sulfonamido-D-PG 1.8g.PH=6 ~ 6.5 are regulated with 10% sodium hydroxide.Concentrating under reduced pressure goes out 8mL water, lowers the temperature 0 ~ 5 DEG C, and insulation crystallization 4h, filters, use 2mL cold water washing, drying under reduced pressure, obtain white pregabalin 0.86g.Fusing point: 183-185 DEG C, yield 35.8%, ee=94.60%.
Embodiment 3:
(1), salification process
In the clean there-necked flask of 50mL, add the aqueous isopropanol 45mL of 5.50g p-methylphenyl sulphonylamine base-D-PG and volume ratio 3%, heating for dissolving; Add 2.40g lyrica raceme, insulation low rate mixing 0.5h, Temperature fall 30 ~ 35 DEG C, crystallization 6h.Suction filtration, will obtain solid transfer in the aqueous isopropanol 15mL of volume ratio 3%, 50 DEG C of insulated and stirred 2h, are cooled to 30 DEG C, crystallization 2h, suction filtration, dry, obtain 3.10g pregabalin and p-methylphenyl sulphonylamine base-D-PG salt composite.
(2), depolymehzation process
Above-mentioned salt composite 3.10g is dissolved in volume ratio 50% methanol solution 20mL, regulates pH=6.5-7 with ammoniacal liquor, stirring at room temperature 3h, be cooled to 0 DEG C, incubated overnight, filter, use 2mL cold water washing, dry, obtain white pregabalin 0.7g.Fusing point: 183-186 DEG C, yield 29.2%, ee=98.60%.
Filtrate concentrates out methyl alcohol, with 10% salt acid for adjusting pH=1 ~ 2.Lower the temperature 0 ~ 5 DEG C, insulation 1h, filtered and recycled resolving agent p-methylphenyl sulphonylamine base-D-PG 2.15g.
Embodiment 4:
(1), salification process
In the clean there-necked flask of 250mL, add the aqueous isopropanol 160mL of 23.0g p-methylphenyl sulphonylamine base-D-PG and volume ratio 3%, heating for dissolving; Add 10.0g lyrica raceme, insulation low rate mixing 0.5h, Temperature fall 30 ~ 35 DEG C, crystallization 6h, suction filtration.To solid transfer be obtained in the aqueous isopropanol 100mL of volume ratio 3%, 50 DEG C of insulated and stirred 1h, are cooled to 30 DEG C, crystallization 1h, suction filtration (filtrate is preserved for splitting next time), drying, obtain 12.4g pregabalin and p-methylphenyl sulphonylamine base-D-PG salt composite.
(2), depolymehzation process
Above-mentioned salt composite 12.4g is suspended in 80mL deionized water, with 10% salt acid for adjusting pH=0.5-1, stirring at room temperature 3h, filters, use 10mL water washing, dry, reclaim resolving agent p-methylphenyl sulphonylamine base-D-PG 8.0g.PH=6 ~ 6.5 are regulated with 20% sodium hydroxide.Concentrating under reduced pressure goes out 40mL water, lowers the temperature 0 ~ 5 DEG C, and insulation crystallization 4h, filters, and with 5mL cold water washing 2 times, drying under reduced pressure, obtains white pregabalin 3.95g.Fusing point: 184-186 DEG C, yield 39.5%, ee=97.30%.
Embodiment 5:
(1), salification process
In the clean there-necked flask of 500mL, add the aqueous isopropanol 100mL of 23.0g p-methylphenyl sulphonylamine base-D-PG and volume ratio 3%, add washings 90mL in embodiment 2.Heating for dissolving; Add 10.0g lyrica raceme, insulation low rate mixing 0.5h, Temperature fall 30 ~ 35 DEG C, crystallization 6h.Suction filtration, will obtain solid transfer in the aqueous isopropanol 100mL of volume ratio 3%, 50 DEG C of insulated and stirred 1h, are cooled to 30 DEG C, crystallization 1h, suction filtration, dry, obtain 13.6g pregabalin and p-methylphenyl sulphonylamine base-D-PG salt composite.
(2), depolymehzation process
Above-mentioned salt composite 13.6g is suspended in 90mL deionized water, with 10% salt acid for adjusting pH=0.5-1, stirring at room temperature 3h, filters, use 10mL water washing, dry, reclaim resolving agent p-methylphenyl sulphonylamine base-D-PG 9.0g.PH=6 ~ 6.5 are regulated with 20% sodium hydroxide.Concentrating under reduced pressure goes out 40mL water, lowers the temperature 0 ~ 5 DEG C, and insulation crystallization 4h, filters, and with 5mL cold water washing 2 times, drying under reduced pressure, obtains white pregabalin 4.51g.Fusing point: 184-186 DEG C, yield 45.1%, ee=98.20%.
Reference example 1:
By the salify mother liquor reclaim under reduced pressure Virahol of the pregabalin of enforcement 4 and p-methylphenyl sulphonylamine base-D-PG, add the abundant dispersed with stirring of 80mL water in residuum, reconcile pH=1 ~ 2 with hydrochloric acid.Lower the temperature 0 ~ 5 DEG C, insulation 1h, filters, uses 30mL water washing, reclaims resolving agent p-methylphenyl sulphonylamine base-D-PG 11.6g.
Reference example 2:
By the salify mother liquor recycle of alkali liquor Virahol of the pregabalin of enforcement 5 and p-methylphenyl sulphonylamine base-D-PG, add the abundant dispersed with stirring of 80mL water in residuum, reconcile pH=1 ~ 2 with hydrochloric acid.Lower the temperature 0 ~ 5 DEG C, insulation 1h, filters, uses 30mL water washing, reclaims resolving agent p-methylphenyl sulphonylamine base-D-PG 12.5g.
Claims (9)
1. the chemical resolution preparation method of a S-configuration lyrica, it is characterized in that: step (1) salify, p-methylphenyl sulphonylamine base-D-PG or benzene sulfonamido-D-PG are resolving agent, with lyrica raceme salify in containing the alcoholic solution of water, separate out p-methylphenyl sulphonylamine base-D-PG or benzene sulfonamido-D-PG and S-configuration lyrica salt composite; Step (2) depolymerization, suspends in water the p-methylphenyl sulphonylamine obtained base-D-PG or benzene sulfonamido-D-PG and S-configuration lyrica salt composite, regulates pH depolymerization, obtains optically pure S-configuration lyrica.
2. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, is characterized in that: in step (1) salification process, and the resolving agent of use is p-methylphenyl sulphonylamine base-D-PG or benzene sulfonamido-D-PG; Alcoholic solution containing water is solvent, and described alcohol is methyl alcohol, ethanol, propyl alcohol or Virahol; The volume ratio of water and alcohol is 2-10:98-90.
3. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, is characterized in that: in step (1) salification process, and lyrica raceme and resolving agent amount are than being 1:1-1.5; Lyrica raceme quality is 1g:10-20mL with the alcoholic solution ratio containing water.
4. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, is characterized in that, in step (1) salification process, resolving agent being added heating for dissolving in the alcoholic solution containing water, adding lyrica raceme; Salification process solvent temperature be room temperature to reflux temperature, salify recrystallization temperature is room temperature to 40 DEG C; The crystallization time is 4-20h.
5. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, is characterized in that: in step (1) salification process, filter out salt composite, uses the abundant stirring to pulp washing of resolution solvent; Salt composite quality and resolution solvent ratio are 1g:3-15mL; Temperature be room temperature to reflux temperature, be down to 0 DEG C to 40 DEG C filtration.
6. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, it is characterized in that: in step (2) depolymehzation process, become salt composite to suspend in water with benzene sulfonamido-D-PG salt composite or S-configuration lyrica with tolysulfonyl amido-D-PG S-configuration lyrica, volume of water is 4 ~ 12 times of salt composite quality; Adding inorganic acid for adjusting pH is 0.5-1, and described mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid; Abundant stirring, filters, and reclaims resolving agent, recycles; After concentrated filtrate 1/2nd, being neutralized to pH with alkali is 6.0-7.0, and alkali used is sodium hydroxide, potassium hydroxide, sodium carbonate, solution of potassium carbonate or ammoniacal liquor; Crystallization, dry, obtain S-configuration lyrica.
7. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, it is characterized in that: in step (2) depolymehzation process, becoming salt composite to be dissolved in volume fraction with benzene sulfonamido-D-PG salt composite or S-configuration lyrica with tolysulfonyl amido-D-PG S-configuration lyrica is in 10-50% alcoholic solution, and alcohol used is methyl alcohol, ethanol, propyl alcohol or Virahol; Alcoholic solution volume and salt composite mass ratio are 4-12mL:1g; Regulate pH to be 6.0-7.0 with alkali, alkali used is sodium hydroxide, potassium hydroxide, sodium carbonate, solution of potassium carbonate or ammoniacal liquor; Cooling crystallization, dry, obtain S-configuration lyrica; Filtrate concentration and recovery alcohol, with inorganic acid for adjusting pH to 1-2, acid used is hydrochloric acid, sulfuric acid or phosphoric acid; Abundant stirring, filters, and reclaims resolving agent, recycles.
8. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, is characterized in that: in step (1) salification process, filter out the mother liquor of salt composite, after reclaiming alcohol, add water, with inorganic acid for adjusting pH to 1-2, acid used is hydrochloric acid, sulfuric acid or phosphoric acid; Abundant stirring, filtration, reclaim resolving agent, recycle.
9. the chemical resolution preparation method of a kind of S-configuration lyrica according to claim 1, is characterized in that, in step (1) salification process, wash filtrate is directly used in the salification process of step (1) in next split process.
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| CN104193630B (en) * | 2014-08-07 | 2015-09-30 | 陈红 | A kind of chemical resolution preparation method of S-configuration lyrica |
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| WO2009082861A1 (en) * | 2008-01-02 | 2009-07-09 | Zhejiang Jiuzhou Pharmaceutical Co., Ltd. | New resolution process of (s)-3-aminomethyl-5-methylhexanoic acid |
| CN101500985A (en) * | 2006-07-04 | 2009-08-05 | 化学实验室国际股份公司 | Process for the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates |
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| CN101500985A (en) * | 2006-07-04 | 2009-08-05 | 化学实验室国际股份公司 | Process for the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates |
| WO2009082861A1 (en) * | 2008-01-02 | 2009-07-09 | Zhejiang Jiuzhou Pharmaceutical Co., Ltd. | New resolution process of (s)-3-aminomethyl-5-methylhexanoic acid |
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