CN103626668A - 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 compound preparing technical field, particularly relate to S-configuration lyrica resolution process technical field, specifically the chemistry about S-configuration lyrica splits preparation method.
background of invention
Lyrica (Pregbalin) chemical name is a kind of novel γ-aminobutyric acid (GABA) receptor stimulant of (S)-3-aminomethyl-5-methylhexanoic acid ，Shi Pfizer company research and development.Within 2004, through European Union's approval, with trade(brand)name Lyrica, go on the market first, be used for the treatment of the part epileptic seizures of adult patients.The listing of the 2006 Nian U.S., increased new indication, be used for the treatment of generalized anxiety disorder and sociability anxiety disorder, within 2009, get permission to be again 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.
In lyrica molecule, contain a chiral carbon atom, have enantiomer, wherein, S-configuration biological activity is better than R-configuration, clinical application be S-configuration lyrica.
Bibliographical information the multiple preparation method of S-configuration lyrica.Chen Yongsheng etc. are in organic chemistry the 31st the 10th phase of volume in 2011: in " progress of synthesis of lyrica ", summarized 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 synthetic route length, severe reaction conditions, desired raw material costliness and the high deficiency of production cost, can not be for suitability for industrialized production.
In actual production, all adopt first synthetic enantiomer, then obtain pregabalin through splitting.Representational synthetic route is as follows: (1) Huckabee etc. reported 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, through Hoffmann, reset, obtain the lyrica of S-configuration.Chen Ao etc. are at Chinese Journal of Pharmaceuticals, and report is reset 3-carbamyl-5-methylhexanoic acid raceme Hoffmann to obtain racemization lyrica in 2004,35,195, adopts S-(+)-amygdalic acid splits, and obtains pregabalin.(2) Grote etc. has reported 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. is at CN 101362696, isovaleric aldehyde and Nitromethane 99Min. condensation in 2009, have been reported, again with diethyl malonate addition, through catalytic hydrogenation, prepare 4-isobutyl--2-oxo-pyrrolidine-3-ethyl formate, acidic hydrolysis obtains lyrica raceme, with S-(+) fractionation of-amygdalic acid, obtain pregabalin.
Directly lyrica raceme being carried out to chemistry and splits that to prepare pregabalin method as follows of bibliographical information: WO 2009/082861 A1 report splits by aroyl or the arylsulfonyl compound of Pidolidone; WO 2009/122215 A1 report splits lyrica raceme with L-configuration tartrate as resolving agent; WO 2009/044409 report is used two pairs of methyl benzoyl-L-TARTARIC ACIDs to split for resolving agent carries out chemistry to lyrica raceme.
In the chemical method for splitting of known lyrica, while using S-(+)-amygdalic acid and L-TARTARIC ACID to split, crystallization difficulty, resolving agent is water-soluble large, is difficult to reclaim, and cyclic utilization rate is low, causes production process loaded down with trivial details, and cost is high.While using two pairs of methyl benzoyls-L-TARTARIC ACID to split, ester is good for poor stability, preparation difficulty in addition.While 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 recycling, split the high lyrica mesotomy agent of efficiency, simplifying lyrica split process is the key factor of producing pregabalin, and pregabalin quality and production cost are had to material impact.
Summary of the invention
Main purpose of the present invention is to split and obtain the problem and shortage that pregabalin method exists for existing R/S-lyrica raceme, and a kind of new chemical method for splitting is provided.
In exploring the split process of lyrica, we surprisingly find that the sweet acid of benzenesulfonyl-D-benzene and the sweet acid of p-toluenesulfonyl-D-benzene can effectively split lyrica raceme.Fractionation efficiency is high, optical purity is high, and resolving agent is easy to recovery.While especially using the sweet acid of tosyl group-D-benzene to split lyrica raceme, do not need secondary to split, simple to operate.The sweet acid of benzenesulfonyl-D-benzene and the sweet acid of p-toluenesulfonyl-D-benzene can be prepared by the sweet acid of D-benzene and benzene sulfonyl chloride or Tosyl chloride generation sulfonylation easily.That the method possesses is simple to operate, split the feature that efficiency is high, resolving agent is easy to recycling; Production cost is low, can obtain high purity pregabalin, is suitable for scale operation.
The technical solution used in the present invention realizes above-mentioned purpose by following steps.
(1), salify: take benzene sulfonamido-D-PG or be resolving agent to benzene sulfonamido-D-PG, lyrica raceme is split; Resolution solvent is the alcoholic solution that contains 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 with benzene sulfonamido-D-PG salt composite is suspended in to water, add inorganic acid for adjusting pH value, fully stir.Filter, reclaim resolving agent, recycle.Filtrate neutralizes with alkali, and crystallization is dry, obtains pregabalin.Also can and be dissolved in alcoholic solution benzene sulfonamido-D-PG salt composite pregabalin and benzene sulfonamido-D-PG salt composite or pregabalin, with alkali, regulate pH value, 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 benzene sulfonamido-D-PG is prepared with D-PG generation sulfonamide reaction in water by benzene sulfonyl chloride or to benzene sulfonyl chloride.Resolution solvent is moisture alcoholic solution, and the alcohol using is methyl alcohol, ethanol, propyl alcohol, Virahol, preferably Virahol; Water and alcohol volume ratio are 2-10:98～90, preferably 3:97～5:95.Lyrica raceme quality and resolution solvent volume ratio are 1g:10～20mL, preferably 1g:14～16mL.Salification process solvent temperature be room temperature to reflux temperature, preferably 40～50 ℃, salify recrystallization temperature is room temperature to 40 ℃, preferably room temperature to 30～35 ℃.Filter out salt composite, with resolution solvent, wash.
In step (2) is separated collecting process, the pregabalin obtaining and benzene sulfonamido-D-PG or the salt composite of benzene sulfonamido-D-PG is suspended in water, liquid volume used is 5-15 times of salt composite quality, preferably 6～8 times; With acid for adjusting pH, be 0.5～1, acid used can be hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.Fully stir, suction filtration, washing, reclaims resolving agent benzene sulfonamido-D-PG or to benzene sulfonamido-D-PG.The temperature that stirs solution collecting process is room temperature to 60 ℃, preferably room temperature to 50 ℃.It is 6-7 that filtrate regulates pH with alkali lye, concentrating under reduced pressure part water, and cooling 0-5 ℃, insulation crystallization, filters, and with cold water washing, obtains pregabalin.Also can or be dissolved in 10-50% alcohol solution the salt composite of benzene sulfonamido-D-PG pregabalin and benzene sulfonamido-D-PG, alcohol used is methyl alcohol, ethanol, propyl alcohol or Virahol, particular methanol or ethanol.With alkali, regulating pH is 6-7, directly separates out pregabalin.Concentrated filtrate, acid out, reclaim resolving agent.
In step (1), become 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, reclaims resolving agent benzene sulfonamido-D-PG or benzene sulfonamido-D-PG is recycled.Salt composite washings is directly applied mechanically next salification process.
Different from the known method for splitting of bibliographical information, by method of the present invention, split lyrica raceme and obtain pregabalin process: 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 better technology contents of the present invention and essence, by specific embodiment, further illustrate operating process of the present invention.Should be noted that specific embodiment is not to limit the scope of the invention, the change that those skilled in the art make the present invention or modification 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 to Methyl benzenesulfonyl amido-D-PG and volume ratio 3%, heating for dissolving; Add 2.40g lyrica raceme, insulation low rate mixing 0.5h, cooling is 30～35 ℃ naturally, crystallization 4h.Suction filtration, will obtain solid transfer to the aqueous isopropanol 15mL of volume ratio 3%, and 50 ℃ of insulated and stirred 1h, are cooled to 30 ℃, crystallization 1h, suction filtration, dry, obtain 3.0g pregabalin with to Methyl benzenesulfonyl amido-D-PG salt composite.
(2), separate collecting 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 3h, filters, use 4mL water washing, dry, reclaim resolving agent to Methyl benzenesulfonyl amido-D-PG 2.0g.With 20% sodium hydroxide, regulate pH=6～6.5.Concentrating under reduced pressure goes out 8mL water, lowers the temperature 0～5 ℃, and insulation crystallization 4h, filters, and uses 2mL cold water washing, and drying under reduced pressure, obtains white pregabalin 0.8g.Fusing point: 183-186 ℃, 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, cooling is 30～35 ℃ naturally, crystallization 6h.Suction filtration, will obtain solid transfer to the aqueous isopropanol 30mL of volume ratio 3%, and 50 ℃ of insulated and stirred 2h, are cooled to 30 ℃, crystallization 3h, and suction filtration, dry, obtain 2.80g pregabalin and benzene sulfonamido-D-PG salt composite.
(2), separate collecting 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 3h, filters, use 5mL water washing, dry, reclaim resolving agent benzene sulfonamido-D-PG 1.8g.With 10% sodium hydroxide, regulate pH=6～6.5.Concentrating under reduced pressure goes out 8mL water, lowers the temperature 0～5 ℃, and insulation crystallization 4h, filters, and uses 2mL cold water washing, and drying under reduced pressure, obtains white pregabalin 0.86g.Fusing point: 183-185 ℃, 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 to Methyl benzenesulfonyl amido-D-PG and volume ratio 3%, heating for dissolving; Add 2.40g lyrica raceme, insulation low rate mixing 0.5h, cooling is 30～35 ℃ naturally, crystallization 6h.Suction filtration, will obtain solid transfer to the aqueous isopropanol 15mL of volume ratio 3%, and 50 ℃ of insulated and stirred 2h, are cooled to 30 ℃, crystallization 2h, suction filtration, dry, obtain 3.10g pregabalin with to Methyl benzenesulfonyl amido-D-PG salt composite.
(2), separate collecting process
Above-mentioned salt composite 3.10g is dissolved in volume ratio 50% methanol solution 20mL, with ammoniacal liquor, regulates pH=6.5-7, stirring at room 3h, is cooled to 0 ℃, and incubated overnight is filtered, and uses 2mL cold water washing, dries, and obtains white pregabalin 0.7g.Fusing point: 183-186 ℃, 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 ℃, insulation 1h, filtered and recycled resolving agent is to Methyl benzenesulfonyl amido-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 to Methyl benzenesulfonyl amido-D-PG and volume ratio 3%, heating for dissolving; Add 10.0g lyrica raceme, insulation low rate mixing 0.5h, cooling is 30～35 ℃ naturally, crystallization 6h, suction filtration.To obtain solid transfer to the aqueous isopropanol 100mL of volume ratio 3%, 50 ℃ of insulated and stirred 1h, are cooled to 30 ℃, crystallization 1h, suction filtration (filtrate be preserved for next time split), dry, obtain 12.4g pregabalin with to Methyl benzenesulfonyl amido-D-PG salt composite.
(2), separate collecting 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 3h, filters, use 10mL water washing, dry, reclaim resolving agent to Methyl benzenesulfonyl amido-D-PG 8.0g.With 20% sodium hydroxide, regulate pH=6～6.5.Concentrating under reduced pressure goes out 40mL water, lowers the temperature 0～5 ℃, and insulation crystallization 4h, filters, and uses 5mL cold water washing 2 times, and drying under reduced pressure, obtains white pregabalin 3.95g.Fusing point: 184-186 ℃, 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 to Methyl benzenesulfonyl amido-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, cooling is 30～35 ℃ naturally, crystallization 6h.Suction filtration, will obtain solid transfer to the aqueous isopropanol 100mL of volume ratio 3%, and 50 ℃ of insulated and stirred 1h, are cooled to 30 ℃, crystallization 1h, suction filtration, dry, obtain 13.6g pregabalin with to Methyl benzenesulfonyl amido-D-PG salt composite.
(2), separate collecting 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 3h, filters, use 10mL water washing, dry, reclaim resolving agent to Methyl benzenesulfonyl amido-D-PG 9.0g.With 20% sodium hydroxide, regulate pH=6～6.5.Concentrating under reduced pressure goes out 40mL water, lowers the temperature 0～5 ℃, and insulation crystallization 4h, filters, and uses 5mL cold water washing 2 times, and drying under reduced pressure, obtains white pregabalin 4.51g.Fusing point: 184-186 ℃, yield 45.1%, ee=98.20%.
Reference example 1:
By the pregabalin of enforcement 4 and the salify mother liquor reclaim under reduced pressure Virahol to Methyl benzenesulfonyl amido-D-PG, in residuum, add the abundant dispersed with stirring of 80mL water, with hydrochloric acid, reconcile pH=1～2.Lower the temperature 0～5 ℃, insulation 1h, filters, and uses 30mL water washing, reclaims resolving agent to Methyl benzenesulfonyl amido-D-PG 11.6g.
Reference example 2:
By the pregabalin of enforcement 5 and the salify mother liquor recycle of alkali liquor Virahol to Methyl benzenesulfonyl amido-D-PG, in residuum, add the abundant dispersed with stirring of 80mL water, with hydrochloric acid, reconcile pH=1～2.Lower the temperature 0～5 ℃, insulation 1h, filters, and uses 30mL water washing, reclaims resolving agent to Methyl benzenesulfonyl amido-D-PG 12.5g.
Claims (9)
1. the chemistry of a S-configuration lyrica splits preparation method, it is characterized in that: step (1) salify, to Methyl benzenesulfonyl amido-D-PG or benzene sulfonamido-D-PG, it is resolving agent, in containing the alcoholic solution of water, with lyrica raceme salify, separate out Methyl benzenesulfonyl amido-D-PG or benzene sulfonamido-D-PG and S-configuration lyrica salt composite; Step (2) depolymerization, by obtain Methyl benzenesulfonyl amido-D-PG or benzene sulfonamido-D-PG and S-configuration lyrica salt composite are suspended in water, regulates pH depolymerization, obtains optically pure S-configuration lyrica.
2. the chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that: in step (1) salification process, the resolving agent of use is to Methyl benzenesulfonyl amido-D-PG or benzene sulfonamido-D-PG; The alcoholic solution that contains 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 chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that: in step (1) salification process, lyrica raceme is 1:1-1.5 with resolving agent amount ratio; Lyrica raceme quality is 1g:10-20mL with the alcoholic solution ratio that contains water.
4. the chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that, in step (1) salification process, resolving agent being added to heating for dissolving in the alcoholic solution that contains water, adds lyrica raceme; Salification process solvent temperature be room temperature to reflux temperature, salify recrystallization temperature is room temperature to 40 ℃; The crystallization time is 4-20h.
5. the chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that: in step (1) salification process, filter out salt composite, use 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 ℃ to 40 ℃ filtration.
6. the chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that: step (2) is separated in collecting 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; Fully stir, filter, reclaim resolving agent, recycle; After concentrated filtrate 1/2nd, with alkali, being neutralized to pH 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 chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that: step (2) is separated in collecting process, becoming salt composite to be dissolved in volume fraction with tolysulfonyl amido-D-PG S-configuration lyrica and benzene sulfonamido-D-PG salt composite or 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; With alkali, regulating pH is 6.0-7.0, and 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; Fully stir, filter, reclaim resolving agent, recycle.
8. the chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that: in step (1) salification process, filter out the mother liquor of salt composite, reclaim after alcohol, add water, with inorganic acid for adjusting pH, to 1-2, acid used is hydrochloric acid, sulfuric acid or phosphoric acid; Fully stir, filter, reclaim resolving agent, recycle.
9. the chemistry of a kind of S-configuration lyrica according to claim 1 splits preparation method, it is characterized in that wash filtrate is directly used in the salification process of step in next split process (1) in step (1) salification process.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980144A (en) * | 2014-05-16 | 2014-08-13 | 浙江华海药业股份有限公司 | Nesting method for pregabalin intermediate mother liquor |
| CN104193630A (en) * | 2014-08-07 | 2014-12-10 | 段希福 | Chemical resolution preparation method of S-pregabalin |
| CN106432056A (en) * | 2016-09-17 | 2017-02-22 | 青岛辰达生物科技有限公司 | Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate |
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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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980144A (en) * | 2014-05-16 | 2014-08-13 | 浙江华海药业股份有限公司 | Nesting method for pregabalin intermediate mother liquor |
| CN103980144B (en) * | 2014-05-16 | 2018-08-17 | 浙江华海药业股份有限公司 | A kind of using method of pregabalin intermediate mother liquor |
| CN104193630A (en) * | 2014-08-07 | 2014-12-10 | 段希福 | Chemical resolution preparation method of S-pregabalin |
| CN104193630B (en) * | 2014-08-07 | 2015-09-30 | 陈红 | A kind of chemical resolution preparation method of S-configuration lyrica |
| CN106432056A (en) * | 2016-09-17 | 2017-02-22 | 青岛辰达生物科技有限公司 | Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate |
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