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WO2012022217A1 - Dérivés de n-[4-méthyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phényl]benzamide, leur procédé de préparation et leur utilisation pour la synthèse de l'imatinib - Google Patents

Dérivés de n-[4-méthyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phényl]benzamide, leur procédé de préparation et leur utilisation pour la synthèse de l'imatinib Download PDF

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Publication number
WO2012022217A1
WO2012022217A1 PCT/CN2011/077652 CN2011077652W WO2012022217A1 WO 2012022217 A1 WO2012022217 A1 WO 2012022217A1 CN 2011077652 W CN2011077652 W CN 2011077652W WO 2012022217 A1 WO2012022217 A1 WO 2012022217A1
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group
phenyl
compound
formula
chloride
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Chinese (zh)
Inventor
姬建新
金毅
胡晓玉
郭娜
杜锋田
左承森
张强
李伯刚
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Chengdu Diao Pharmaceutical Group Co Ltd
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Chengdu Diao Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicinal chemistry. Specifically relates to N-[4-mercapto-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]benzamide derivatives and preparation thereof, and the synthesis thereof in imatinib Applications.
  • BACKGROUND OF THE INVENTION Imatinib sulfonate, trade name "Glivec” is the first anticancer drug developed by Novartis to be rationally designed according to the mechanism of action of cancer cells.
  • imatinib 4-[(4-mercapto-1-piperazine)indolyl]-N-[4-indolyl-3-[[4-(3-pyridine)-2-pyrimidine]amino Phenyl]-benzamide, whose chemical structure is as follows:
  • the key to the synthesis of imatinib is to find a simple method to synthesize key intermediates through reverse synthesis analysis, and to construct imatinib by splicing reaction of key intermediates.
  • the currently reported synthetic methods of imatinib and its key intermediates mainly include the following:
  • imatinib is reacted with 4-(4-mercaptopiperazinyl)-benzoyl chloride to give imatinib.
  • the yield of imatinib in the final step of the method is only 20%, and it needs to be purified by column chromatography, which is extremely unfavorable for industrial production.
  • the key intermediate (V) is prepared by the reaction with p-nonanoyl chloride chloride, but the reaction between the benzyl chloride and the acid chloride is coordinated with the amino group, so that the reaction has more by-products, so the yield is not high. And it brings difficulties to the purification of the product, resulting in high production cost and large post-processing workload, so the method still needs to be improved.
  • Chinese patent CN1630648A discloses the method of making Yinmatinib (Scheme 3): taking CN coupling reaction as the core, directly 3-bromo-4-indenyl group in the presence of trisyl aluminum in the presence of benzene solution
  • the aniline and the ethyl 4-(4-mercapto-piperazin-1-ylindenyl) benzoate are linked by an amino group to give N-(4-mercapto-3-bromo-phenyl)-4-(4) - mercapto-piperazin-1-ylindenyl)benzamide, followed by 4-(3-pyridyl)-2 in the presence of heavy metal catalyst Pd 2 (dba) 3 *CHCl 3 and rac-BINAP ligand - Pyrimidine amine reacts to form imatinib.
  • the disadvantages of this route are: 1) Aluminum trichloride, which is an amide condensing agent, is a flammable chemical that can cause flammable explosive reactions when in contact with water, which poses a potential hazard to large-scale production; 2) The use of precious metal catalysts (Pd 2 (dba) 3 ) and organophosphorus ligands ( rac-BINAP ) increases the difficulty of separating products and increases labor and cost; 3) 10% of the isomers present in the final product need to be removed by repeated chromatography, which increases the difficulty of purification and is not suitable for industrial production.
  • a major disadvantage of this preparation method is that high temperature reflux operation is required in the preparation of the key intermediate IV, the energy consumption is relatively large, and the reaction time is too long (overnight reaction), and the yield is low, only about 60.5%, and finally In the step of producing imatinib, it is necessary to heat and reflux in a solvent such as trichloromethane for 15 hours to form imatinib.
  • a solvent such as trichloromethane
  • the present invention provides a novel intermediate for the synthesis of imatinib: a compound of formula (I), N-[4-mercapto-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzene
  • the present invention also provides a process for the preparation thereof, and the use of the intermediate in the synthesis of imatinib.
  • the present inventors have creatively proposed a novel synthetic strategy for the synthesis of imatinib and its analogs for the synthesis of the compound of formula (I) and subsequent transformation steps.
  • This strategy is of great significance for improving the synthesis efficiency of imatinib and its analogues.
  • This synthetic strategy constructs the fragment (1) by efficiently coupling the alcohol-hydroxy protected fragment (II) with the fragment (III), followed by simple deprotection to obtain the fragment (IV), and then activates the IV hydroxyl group. It is then coupled with a nitrogen-containing compound to construct imatinib and its analogs.
  • the present invention provides a novel compound, N-[4-indolyl-3-(4-pyridin-3-yl-pyrimidin-2-yl) of the following formula (I) )phenyl]benzamide derivatives:
  • Pg is a hydroxy protecting group, wherein -op g constitutes an ester or an ether, or P g is another protecting group for the protection of an alcoholic hydroxyl group, preferably Pg is an alkanoyl group, an aralkanoyl group, an aroyl group, an alkyloxanium group Acyl, aryloxycarbonyl, nitrate, borate, sulfate, alkylsulfonyl, arylsulfonyl, etc.; and alkyl, aryl, alkylsilyl, arylsilyl, etc., but not limited Protection groups in these categories.
  • P g is preferably selected from the group consisting of: acetyl, propionyl, butyryl, valeryl, hexanoyl, benzoyl, phenylacetyl, oxime oxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, oxime oxime , tetrahydropyranyl, tert-butyl, allyl, propargyl, phenyl, p-chlorophenyl, p-nonyloxyphenyl, 2,4-dinitrophenyl, benzyl, palladium Oxybenzyl, p-nitrobenzyl, triphenylsulfonyl, trimethylsilyl, tert-butyldiphenylsilyl, tert-butylphosphonylphenylsilyl, tribenzyl-1-carbyl, Triphenylsilyl, nitrate, decyl,
  • Protecting group When the organic compound with multifunctional group is reacted, in order to make the reaction only occur at the desired functional group, and other groups are prevented from being affected, other groups are protected before the reaction, when the reaction is completed. Then resume.
  • the group introduced on the group is referred to as a protecting group.
  • the protecting group (P g ) of the compound (I ) and the compound (II ) of the present invention means Esters and ethers, as well as all other protecting groups that can be used for the protection of alcoholic hydroxyl groups, see Greene's Protective Groups in Organic Synthesis (4th. Edition Theodora W. Greene, pl 6 ⁇ 366).
  • the present invention provides a preferred N-[4-indolyl-3-(4-pyridin-3-yl-pyrimidin-2-yl)phenyl]benzamide of the general formula (I) Derivatives, including: (1) ⁇ [4-indolyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]-4-acetoxynonylbenzamide, (2) N-[4-indolyl-3-(4-pyridin-3-yl-pyrimidin-2-yl ⁇ )phenyl]-4-butyryloxymercaptobenzoic acid amide, (3) N-[4- ⁇ 3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]-4-(tert-butoxycarbonyl)nonylbenzamide, (4) N-[4-fluorenyl -3-(4-Pyridin-3-yl-pyrimidin-2-ylamino
  • the invention provides the preparation of N-[4-mercapto-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]phenylhydrazine of formula (I)
  • a method of amide derivatives which comprises subjecting a compound of formula II to a condensation reaction of a compound of formula III in a polar solvent at a temperature in a molar ratio,
  • Pg is as defined above; X is selected from C1 or Br.
  • the polar solvent is selected, for example, from tetrahydrofuran, dioxane, C1 to C4 alkyl alcohol, Cl to C4 chlorinated alkane, benzene or mercapto substituted benzene, N,N-dimercaptoamide, and acetonitrile; Tetrahydrofuran.
  • the reaction temperature can be varied within a wide range, generally -20. C to 150. C, preferably at -10 ° C to 100 ° C.
  • the molar ratio of the compound of the formula (II) to the compound of the formula (III) is from 1:0.2 to 1:5.0, preferably from 1:0.5 to 1:3.0.
  • the invention provides the use of a compound of formula (I) for the synthesis of imatinib. Includes the following steps: (1) using a compound of formula I as a starting material, and performing a deprotection reaction in a polar solvent to obtain a compound of formula IV;
  • Lg in the formula V is selected from the group consisting of Cl, Br, I, OTs, OMs, OTf, p-nitrobenzenesulfonyloxy, 2,5-dichlorobenzenesulfonyloxy, 4-chlorobenzenesulfonyloxy and the like.
  • the polar solvent in the step (1) is selected from the group consisting of water, decyl alcohol, ethanol, tert-butanol, n-butanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, 1,2- Dichloroethane, or any combination thereof.
  • the base used in the step (1) for deprotection to remove the P g group is selected from the group consisting of: sodium hydroxide, hydrazine hydroxide, sodium carbonate, carbonic acid clock, sodium decylate, sodium ethoxide, sodium t-butoxide, t-butanol clock, etc.
  • the acid used for deprotection to remove the Pg group is selected from the group consisting of trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • a preferred method of debenzylation is to catalytically remove the benzyl group using palladium on carbon under a hydrogen atmosphere.
  • the sulfonylating agent used in the step (2) is selected from the group consisting of: sulfonyl chloride, benzoquinonesulfonyl chloride, p-toluenesulfonyl chloride, trifluorosulfonyl chloride, trifluorosulfonate anhydride, p-nitrobenzenesulfonyl chloride, 2 , 5-dichlorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, and the like.
  • the halogenating agent used in the step (2) is selected from the group consisting of hydrogen halides, halogenated sulfoxides, phosphorus halides, organic phosphine halides, N-haloamides, halogenated salts and the like, but is not limited to these classes of halogenating agents.
  • the halogenating agent is preferably chlorine gas, dichlorosulfoxide, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, oxychlorination Phosphorus, hydrochloric acid, hydrogen chloride, triphenylphosphine chloride, bromine, phosphorus tribromide, N-bromosuccinimide, triphenylphosphine bromide, N-iodosuccinimide and elemental iodine, but It is not limited to these halogenated reagents.
  • the reaction temperature in the step (3) is -10. C to 100. C, the molar ratio of the compound V to the N-decylpyrazine is 1:0.2 to 1:5.0; the preferred reaction temperature is 20 ° C to 50 ° C, and the preferred molar ratio is 1:0.5 to 1:3.0.
  • the invention also provides a process for the preparation of a compound of formula V below;
  • Lg is Cl, Br or I, and is included in -20. C to 100.
  • the compound of formula V is prepared by subjecting a compound of formula IV to a halogenation reaction under C conditions:
  • the halogenating agent used is selected from the group consisting of hydrogen halides, sulfoxides, phosphorus halides, organophosphorus halides, N-haloamides/halogenated salts, but is not limited to these classes of halogenating agents.
  • Preferred halogenating agents are selected from the group consisting of chlorine, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, hydrochloric acid, hydrogen chloride, triphenylphosphine chloride, bromine, phosphorus tribromide.
  • the technical solution of the present invention has at least one of the following advantages:
  • the yield of V and the final product imatinib is greatly improved (see Table 1 and Table 3 for details).
  • the inventors have found an effective synthon for the synthesis of the intermediate compound of the formula I by inverse synthesis analysis and multiple experiments: a compound of the formula II and a compound of the formula III. That is, the present invention uses a novel coupling method to synthesize a key intermediate (I) of imatinib by coupling simple and easily available fragments (II) and (III) under room temperature reaction conditions, The deprotection treatment of the compound (I) at room temperature gave a higher yield (96%) of another key intermediate (IV); while the yield of the intermediate IV reported in the CN101735197A patent was only 60.5%, which was significantly lower. In the present invention.
  • the yield of the synthetic route of imatinib is high (63% ⁇ 82%), while the total yield of synthetic imatinib of CN101735197A is only 32% ⁇ 47%.
  • the synthesis method of the present invention from the intermediates IV to V is very simple, and the compound of the formula V can be obtained by directly using the compound of the formula IV through a halogenation reaction in a higher yield (85% - 93%), and the similar intermediate disclosed in WO2004108699A1.
  • the yield can only reach about 67%, which is obviously lower than the present invention; and the invention uses the intermediate (I) as a starting material to prepare imatinib, and the three-step reaction can obtain the final product imatinib, the total yield. Up to 66%, and the total yield of the two-step reaction from the preparation of intermediate V to the synthesis of imatinib in WO2004108699A1 was only 42%.
  • the production cost of imatinib is greatly reduced. Due to the low price of the raw materials of the invention, the synthetic route is scientific and reasonable, the operation is simple (for example, room temperature is 25. C, the reaction time is greatly shortened), and the use of expensive chemical reagents is avoided, and the yield of imatinib is greatly improved, thereby The production cost of imatinib is greatly reduced. (See Table 1 and Table 2)
  • the preparation route is simple, and the starting materials of the reaction are highly toxic cyanamide compounds.
  • N-(3-Aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine 5.55 g, 20 mmol
  • 3 mL of triethylamine (20 mmol) was added, and then,
  • 4-chlorodecanoyl-benzyl acetate 4.24 g, 20 mmol
  • 15 mL of tetrahydrofuran was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour.
  • the solvent was evaporated under reduced pressure, dissolved in 30 mL of dichloromethane, and then adjusted to pH 4 with dilute hydrochloric acid.
  • N- (3- aminophenyl) -4- (3-pyrazol 11) -2-ethyl 1 ⁇ was dissolved in 50mL dioxane, 3mL was added triethylamine (20mmol), then To the reaction system, 4-chlorodecanoyl-benzyl acetate (12.8 g, 60 mmol) dissolved in 15 mL of dioxane was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure, dissolved in 30 mL of dichloromethane, and then adjusted to pH 4 with dilute hydrochloric acid.
  • the obtained product was washed with saturated brine to dryness and dried over anhydrous sodium sulfate. 8.16 g of the target product was obtained in a yield of 90%.
  • N- (3- aminophenyl) -4- (3-pyrazol 11) -2-ethyl 1 ⁇ (11.0 g, 40mmol) was dissolved in lOOmL of tetrahydrofuran, was added 6 mL of triethylamine (40mmol), then, in the Under the ice bath, 4-chlorodecanoyl-butyric acid benzyl ester (9.6 g, 40 mmol) dissolved in 25 mL of tetrahydrofuran was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure, and 100 is added.
  • the aqueous phase is extracted with dichloromethane to remove excess acid chloride.
  • the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the aqueous phase was extracted with dichloromethane to remove excess acid chloride, and the aqueous phase was adjusted to pH with dilute NaOH. And then, it is extracted with chloroform. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. g target product, yield 90%.
  • N- (3- aminophenyl) -4- (3-pyrazol 11) 2-pyrimidinamine (11.0 g, 40mmol) was dissolved in 100 mL of tetrahydrofuran, was added 6 mL of triethylamine (40mmol), then, in the Under the ice bath, benzyl 4-chlorodecanoyl-tert-butoxybenzoate (10.8 g, 40 mmol) dissolved in 25 mL of tetrahydrofuran was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • N-(3- ⁇ Phenyl)-4-(3-pyridyl)-2-pyrimidinamine 55.5 g, 200 mmol was dissolved in 500 mL of tetrahydrofuran, and 27.5 mL of triethylamine (200 mmol) was added, then 4-Benzoxyanthryl-benzoyl chloride (57.3 g, 220 m mol) dissolved in 150 mL of tetrahydrofuran was slowly added dropwise to the reaction system under ice cooling, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, dissolved in 300 mL of dichloromethane, and then adjusted to pH 4 with dilute hydrochloric acid.
  • N-(3- ⁇ Phenyl)-4-(3-pyridyl)-2-pyrimidinamine 55.5 g, 200 mmol was dissolved in 500 mL of acetonitrile, and 5.5 mL of triethylamine (40 mmol) was added, then 4-Benzyloxyindolyl-benzoyl chloride (26 g, 100 mmol) dissolved in 150 mL of acetonitrile was slowly added dropwise to the reaction system under ice bath at 50. The reaction was stirred at C for 30 minutes.
  • N-(3- ⁇ Phenyl)-4-(3-pyridyl)-2-pyrimidinamine 55.5 g, 200 mmol was dissolved in 500 mL of tetrahydrofuran, and 27.5 mL of triethylamine (200 mmol) was added, then 4-(tert-Butyldiphenylsilyloxy)decyl-benzoyl chloride (98.0 g, 220 mmol) dissolved in 150 mL of tetrahydrofuran was slowly added dropwise to the reaction system under ice-cooling, and the reaction was stirred at room temperature. hour.
  • reaction solution was diluted with 500 ml of dichloromethane, and then washed with 10% aqueous sodium hydrogencarbonate, and the aqueous phase was extracted three times with dichloromethane, and the organic phase was combined, dried over anhydrous Na2SO In addition to the solvent, it was recrystallized from ethanol to give a solid product of 53 g .
  • the rate is 94%.
  • N-[4-Mercapto-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]-4-acetoxynonylbenzamide (45.3 g, 100 mmol) was dissolved in 500 ml of hydrazine.
  • a 5% sterol/sodium decoxide solution was added dropwise to the reaction system at room temperature to adjust the pH to between 9 and 10, and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was made neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The obtained product was dried over anhydrous Na 2 SO 4 , evaporated to dryness under reduced pressure to yield a solid product 40.0 g , yield 98%.
  • reaction mixture was diluted with 500 ml of dichloromethane, and then washed with 10% aqueous sodium hydrogencarbonate, and the aqueous phase was extracted three times with dichloromethane, and the organic phase was combined and dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated under reduced pressure and the residue was crystallised from ethyl ether (yield: 40 g ).
  • N-[4-Mercapto-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]-4-benzyloxynonylbenzamide 50.1 g, 100 mmol was dissolved in 300 ml 1 , in a mixed solvent of 4-dioxane and 200 ml of decyl alcohol, 5 g of 10% wet palladium carbon was added to carry out hydrogen reaction at room temperature for 24 hours. After the reaction was completed, palladium carbon was filtered, concentrated to a small volume, and crystallized to obtain a solid product 39. g , yield 95%.
  • reaction mixture was diluted with 500 ml of dichloromethane, and then washed with 10% aqueous sodium hydrogencarbonate, and the aqueous phase was extracted three times with dichloromethane, and the organic phase was combined and dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated under reduced pressure, and then crystallised from ethyl ether to yield 45.9 g of product.
  • reaction mixture was diluted with 500 ml of dichloromethane, and then washed with 10% aqueous sodium hydrogencarbonate, and the aqueous phase was extracted three times with dichloromethane, and the organic phase was combined and dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated under reduced pressure and the residue was crystallised from EtOAc (EtOAc )

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

Cette invention concerne un nouvel intermédiaire (I) utilisé dans la synthèse de l'imatinib, sa méthode de préparation et la méthode de synthèse de l'imatinib utilisant ce nouveau composé. Les matières premières utilisées dans le cadre de ladite méthode de synthèse de l'imatinib sont peu coûteuses, la préparation du segment structurel de ladite matière première est simple, la préparation dans son ensemble est scientifique et raisonnable, le rendement est élevé et le fonctionnement simple. Ladite méthode de synthèse permet, par ailleurs, d'éviter d'utiliser des réactifs chimiques coûteux et dangereux, elle réduit considérablement le coût de production et convient parfaitement à une production industrielle.
PCT/CN2011/077652 2010-08-20 2011-07-27 Dérivés de n-[4-méthyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phényl]benzamide, leur procédé de préparation et leur utilisation pour la synthèse de l'imatinib Ceased WO2012022217A1 (fr)

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CN201010258399 2010-08-20

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Cited By (1)

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CN111333598A (zh) * 2019-12-30 2020-06-26 武汉利昌医药科技有限公司 一种R-3-丙基-γ-丁内脂的合成方法

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CN103145693B (zh) * 2013-03-29 2015-04-29 成都百裕科技制药有限公司 伊马替尼的制备方法
CN115850258B (zh) * 2022-12-27 2024-09-24 东北林业大学 一种马赛替尼的合成方法

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CN101245061A (zh) * 2007-02-13 2008-08-20 天津天士力集团有限公司 N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-嘧啶胺类一氧化氮供体型衍生物，制备方法及其用途
CN101528700A (zh) * 2006-11-16 2009-09-09 意大利合成制造有限公司 用于制备伊马替尼的方法及其中间体
CN101735197A (zh) * 2009-12-18 2010-06-16 天津市炜杰科技有限公司 一种伊马替尼的合成方法

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WO2004108699A1 (fr) * 2003-06-06 2004-12-16 Natco Pharma Limited Nouveau procede de preparation du medicament anticancereux imatinibe et de nouveaux analogues de ce medicament
CN101528700A (zh) * 2006-11-16 2009-09-09 意大利合成制造有限公司 用于制备伊马替尼的方法及其中间体
CN101245061A (zh) * 2007-02-13 2008-08-20 天津天士力集团有限公司 N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-嘧啶胺类一氧化氮供体型衍生物，制备方法及其用途
CN101735197A (zh) * 2009-12-18 2010-06-16 天津市炜杰科技有限公司 一种伊马替尼的合成方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111333598A (zh) * 2019-12-30 2020-06-26 武汉利昌医药科技有限公司 一种R-3-丙基-γ-丁内脂的合成方法
CN111333598B (zh) * 2019-12-30 2023-07-07 武汉利昌医药科技有限公司 一种R-3-丙基-γ-丁内脂的合成方法

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