WO2010084514A2 - Procédé de préparation de (5s)-(n)-[[3-[3-fluoro-4-(4-morpholinyl)phényl]-2-oxo-5-oxazolidinyl]méthyl]acétamide - Google Patents

Procédé de préparation de (5s)-(n)-[[3-[3-fluoro-4-(4-morpholinyl)phényl]-2-oxo-5-oxazolidinyl]méthyl]acétamide Download PDF

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Publication number
WO2010084514A2
WO2010084514A2 PCT/IN2009/000751 IN2009000751W WO2010084514A2 WO 2010084514 A2 WO2010084514 A2 WO 2010084514A2 IN 2009000751 W IN2009000751 W IN 2009000751W WO 2010084514 A2 WO2010084514 A2 WO 2010084514A2
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formula
compound
oxazolidinyl
oxo
fluoro
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PCT/IN2009/000751
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English (en)
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WO2010084514A3 (fr
Inventor
Arul Ramakrishnan
Kashyap Ravindrabhai Wadekar
Gobind Singh Kapkoti
Venugopala Rao Narayana
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Neuland Laboratories Ltd.
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Publication of WO2010084514A2 publication Critical patent/WO2010084514A2/fr
Publication of WO2010084514A3 publication Critical patent/WO2010084514A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms

Definitions

  • the present invention relates to a novel, industrially viable and cost effective process for manufacturing (5S)-N-[[3-[3 -Fluoro-4-(4-morpholinyl)phenyl] -2-oxo-5 -oxazolidinyl] methyl] acetamide.
  • WO2007116284 describes a process for the preparation of Linezolid as shown in Scheme II below which comprises coupling of substituted imine moiety of formula VI with a carbamate of formula VII in presence of base and an aprotic solvent to give compound of formula VIII,
  • WO2006008754 describes a process, which comprises the reaction of 3-fluoro-4- morpholinyl aniline with epichlorohydrin to give compound of formula X which is treated with potassium phthalamide to give a compound of formula XII.
  • 3-fiuoro-4-morpholinyl aniline can react with phthalimido oxiranyl compound of formula XI to give N-[3-pthalimido-2- (R)-hydroxypropyl]-3-fluoro-4-morpholinylaniline of formula XII
  • the compound of formula XII is further carbonylated to give (S)-N-[[3-fluoro-4-(4- morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methylphthalimide of formula XIII which is deprotected with hydrazine hydrate or aqueous methylamine to give (S)-N-[[3-[3-fluoro-4-[4- morpholinyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula V.
  • the amine of formula V is acylated in presence of acetyl chloride or acetic anhydride in presence of solvent such as toluene or acetone to give Linezolid of Formula I.
  • (5R)-5- (chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone of formula XFV reacts with potassium phthalamide to give (5S)-(N)-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl] methyl]phthalamide of formula XIII which is converted to (5S)-(N)-[[3-[3-fluoro-4- (4-morpholinyl)phenyl-2-oxo-5-oxazolidinyl] methylamine of formula V.
  • the amine of formula V undergoes acylation with acetyl chloride or acetic anhydride in presence of solvent such as ethyl acetate or methylene dichloride to give Linezolid of Formula I.
  • US2007021417 describes a process for the preparation of Linezolid intermediate as shown in Scheme V. This process comprises the reduction of (5R)-[[N-(4-morpholinyl -3-fluorophenyl)-2- oxo-5-oxazolidinyl]methyl]azide of formula IV in presence of suitable reducing agents, solvent, base and phase transfer catalyst to give (5S)-(N)-(4-morpholinyl-3-fiuorophenyl)-2-oxo-5- oxazolidinyl]methyl] amine of formula V.
  • US5837870 discloses a process for the preparation of Linezolid as shown in scheme VI.
  • compound of formula VII is reacted with (S)-(+)-3-chloro-l, 2-propane- diol to give (5R)-N-[3-(3-fluoro-4-(4-mo ⁇ holinylphenyl)-2-oxo-5-oxazolidinyl]methanol of formula II which is further reacted with 4-nitrobenzene sulphonyl chloride, followed by quenching with hydrochloric acid to give (5R)-(N)-[[3-3-fluoro-4-mo ⁇ holinylphenyl]-2-oxo-5-oxazolidinyl]methanol-4- nitrobenzenesulfonate ester of formula XV.
  • the ester of formula XV is converted to (5S)-[N-3-[3- fiuoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl] methylamine salicylaldehyde imine of formula XVI.
  • the compound XVI is treated with 37% hydrochloric acid, toluene, acetic anhydride and solvent such as, methylene dichloride, ethyl acetate to give Linezolid of Formula I.
  • WO2002085849 reports a process for the preparation of Linezolid as shown in scheme VIII below.
  • This process comprises reaction of (N)-carbobenzoxy-3-fluoro-4-morpholinylaniline of formula XIX with (S)-(N)-[2-(acetyloxy)-3-chloropropyl]acetamide of formula VII in presence of N,N-dimethylformamide (or tetrahydrofuran), methanol, lithium t-butoxide, aq. ammonium chloride, water, sodium chloride (or acetic acid , water) and methylene dichloride to give Linezolid of Formula I .
  • Scheme VIII
  • EP 1255754 discloses Linezolid Form II and its process for its preparation. This patent provides a process for preparation of Form II of ' Linezolid by starting with Linezolid of enantiomeric purity more than 98%. The Linezolid of greater than 98% enantiomeric purity is mixed with ethyl acetate and stirred at a temperature below 80 0 C until crystals of Form II is obtained.
  • the principal aspect of present invention is to provide a novel process for the synthesis of Linezolid comprising: a) conversion of (5R)-(N)-[3-fluoro-(4-mo ⁇ holinylphenyl)-2-oxo-5-oxazolidinyl] methanol of formula II to give compound of formula XX; b) optional halogenation of compound of formula XX to give (5R)-(N)-[[3-fluoro-(4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]halide of formula XXI (where X is Cl, Br, I); c) amination of compound of formula XX or (5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2- oxo-5-oxazolidinyl]methyl]halide of formula XXI with substituted or unsubstituted benzylamine to obtain
  • the present invention provides novel intermediates of the formula XXIII
  • Z is O, S, SO or SO 2
  • the present invention provides novel intermediates of the formula XXIV and its acid addition salt
  • R is substituted or unsubstituted benzyl and Z is O, S, SO or SO 2.
  • the present invention provides novel crystalline form of hydrochloride salt of compound of formula V
  • novel crystalline Form of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methyl]amine hydrochloride is characterised by characterised by a powder X-Ray diffraction pattern with peaks at 2.8573, 3.8195, 5.6764, 6.0519, 11.3477, 13.5399, 14.2743,15.7351, 17.79.8, 18.4282, 19.1175, 19.4426, 20.8834, 22.6963, 23.2676, 24.4569, 25.1108, 25.2348, 25.7859, 26.6613, 27.2147, 28.4793, 29.1220, 30.4464, 32.2931, 33.4371, 34.3074, 35.3599, 37.2139, 38.4590, 40.2361, 43.2659, 44.0735, 45.4430, 46.3811 ⁇ 0.2 degree 2? or substantially as indicated in figure 1.
  • the present invention provides a novel hydrobromide salt of compound of formula V
  • the present invention provides a novel crystalline Form of (5S)-(N)-[[3- fluoro-(4- morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl]amine hydrobromide, which is characterised by a powder X-Ray diffraction pattern with peaks at 5.6150, 6.0556, 8.2863, 11.2256, 12.2041, 12.7626, 14.2995, 15.2086, 16.8592, 17.7950, 17.9146, 18.5177, 18.8185, 19.1798, 20.5387, 20.8364, 21.3311, 21.7952, 22.5113, 23.0950, 23.3384, 24.2757, 24.5123, 24.9863, 25.1603, 26.0177, 26.7433, 27.5435, 27.7923, 28.2463, 28.4927, 28.8051, 29.1759, 30.6270, 31.3431, 31.6763, 32.3296, 32.83
  • the present invention provides a novel crystalline Form (5R)-(N)-[[3- fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl]bromide characterised by a powder X- Ray diffraction pattern with peaks at 6.3630, 7.6550, 9.2030, 10.1346, 11.6263, 12.2634, 12.6984, 14.1651, 14.6063, 14.7231, 15.3214, 15.9823, 16.2150, 18.1013, 18.4042, 19.2656, 19.5033, 19.7863, 20.7208, 21.0278, 22.1026, 22.8345, 23.4240, 23.7016, 24.0825, 24.4004, 24.6478, 25.1561, 26.9171, 27.2141, 27.5442, 27.8006, 28.0430, 28.7220, 29.3398, 29.6282, 30.3864, 30.7562, 30.9434, 31.1
  • the present invention provides a novel process for the purification of (5R)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol of formula II, comprising providing a solution or slurry of compound of formula II in a halogenated solvent or ester solvent preferably methylene dichloride, adding water; and precipitating or crystallizing by an ester solvent preferably ethyl acetate to obtain (5R)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methanol of formula II having higher HPLC or enantiomeric purity.
  • the present invention provides a novel process for the acetylation of compound of formula V or its acid addition salt in absence of any organic solvent and organic base to obtain Linezolid Form II
  • Yet another aspect of the present invention is to provide a process for purification of compound of formula V by making acid salt of it and further crystallizing and then basifying to get pure compound of formula V.
  • Fig 1 XRD of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl]amine hydrochloride of the present invention.
  • Fig 2 DSC thermogram of (5S)-(N)-[[3— fiuoro-(4-morpholinylphenyl)— 2-oxo-5-oxazolidinyl] methyl] amine hydrochloride of the present invention.
  • Fig 3 XRD of (5S)-(N)-[[3-fluoro-(4— morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl]amine hydrobromide of the present invention.
  • Fig 4 DSC thermogram of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)— 2-oxo-5-oxazolidinyl] methyl] amine hydrobromide of the present invention.
  • Figure 10 DSC thermogram of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] benzylamine hydrobromide
  • Figure 11 X-ray powder diffractogram of (5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methyljbromide
  • the present invention provides a novel process for the manufacturing of Linezolid
  • (5R)-(N)-[[3-fluoro-(4-morpholinyl phenyl)]-2-oxo-5-oxazolidinyl]methanol of formula II is converted to a compound of formula XX (where L is a leaving group) in the presence of reagents selected from methanesulfonyl chloride, p- toluenesulfonyl chloride, o-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4- bromobenzene sulfonyl chloride and trifluromethanesulfonyl chloride preferably methanesulfonyl chloride; in an organic solvent selected from methylene dichloride, ethylene dichloride, toluene, ethylacetate and acetonitrile, preferably methylene dichloride; and in presence of base such as pyridine, trimethylamine, di
  • the compound of formula XX is treated with alkali metal halide such as potassium bromide, sodium iodide and lithium bromide; haloacetamide such as bromoacetamide, iodoacetamide, chloroacetamide, preferably with alkali metal halide, more preferably with lithium bromide in presence of an organic solvent selected from tetrahydrofuran, acetonitrile, dimethylformamide and 1,4-dioxan, preferably in tetrahydrofuran to give (5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]halide of formula XXI.
  • alkali metal halide such as potassium bromide, sodium iodide and lithium bromide
  • haloacetamide such as bromoacetamide, iodoacetamide, chloroacetamide, preferably with alkali
  • (5R)-(N)-[3-fluoro-(4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]halide undergoes animation in presence of reagents selected from benzylamine, 4-(triflouromethyl)-benzylamine, 4- (trifluoromethyl)benzylamine,4-(trifluoromethoxy)benzylamine,3-methoxy- benzylamine and 4- methoxybenzylamine more preferably benzylamine at 150°C temperature.
  • the mixture is cooled to 4O 0 C to 45 0 C and organic solvent like acetone, ethyl acetate, toluene, cyclohexane, methylene dichloride, ethylene dichloride, preferably acetone is added to form clear solution and then water is added to obtain solid compound of formula XXII.
  • organic solvent like acetone, ethyl acetate, toluene, cyclohexane, methylene dichloride, ethylene dichloride, preferably acetone is added to form clear solution and then water is added to obtain solid compound of formula XXII.
  • (5R)-(N)-[3-fluoro-(4-morpholinylphenyl)- 2-oxo-5-oxazolidinyl]methyl]sulphonate undergoes amination in presence of reagents selected from benzylamine, 4-(triflouromethyl)-benzylamine, 4-(trifluoromethyl)benzylamine,4-
  • the compound of formula XXII or its acid salt is deprotected by hydrogenation in presence of catalyst such as palladium on carbon or platinum on carbon, preferably palladium on carbon in acidic medium such as acetic acid, formic acid, trifluoroacetic acid, acid salt of pyridine, N,N-dimethylamine, N,N-diethylamine and diphenylamine,preferably acetic acid and in solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethylacetate, toluene, acetic acid and butanol, preferably methanol at 5 to 6 Kg/cm 2 pressure to give (5S)-(N)-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl] methyl] amine of formula V or its acid salt.
  • catalyst such as palladium on carbon or platinum on carbon, preferably palladium on carbon in acid
  • the compound (5S)-(N)-[[3-fluoro-(4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] amine or its acid salts is acylated with acetyl halide or acetic anhydride in presence of base and solvent selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone (MEK), t-butanol, tetrahydrofuran, acetone, ethanol, ethylene dichloride, water or the mixture thereof.
  • the solvent is preferably selected from ethylacetate, water or the mixture of ethylacetate and water.
  • the base is selected from ammonia in liqiud or gaseous form, trialkylamine, pyridine, DMAP, metal hydroxide such as sodium hydroxide, potassium hydroxide, metal carbonate such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate preferably aqueous ammonia to give (5 S)-(N)- [[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide of formula I.
  • the present invention provides a process for the acetylation of compound of formula V or its acid addition salt in presence of water and absence of any organic solvent and organic base to obtain Linezolid Form II
  • (5R)-(N)-[3-fluoro-(4- morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol of formula II is purified by dissolving or slurring the compound of formula II in a halogenated solvent or ester solvent, preferably methylene dichloride, adding water; and precipitating or crystallizing by an ester solvent preferably ethyl acetate to obtain (5R)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol of formula II having higher HPLC or enantiomeric purity.
  • a halogenated solvent or ester solvent preferably methylene dichloride
  • the purification of compound of formula V is carried out in an organic solvent and acid to make an acid addition salt and further basifying it using a base preferably ammonia most preferably aqueous ammonia.
  • the organic solvent is selected from a halogenated solvent such as methylene dichloride, ethylene dichloride, and ester solvent such as ethyl acetate, isopropyl acetate preferably ethyl acetate.
  • this purified compound of formula V is further used for the preparation of Linezolid.
  • the present invention provides novel intermediates of the formula XXIII
  • Z is O, S, SO or SO 2
  • the present invention provides novel intermediates of the formula XXIV and its acid addition salt
  • R is substituted or unsubstituted benzyl and Z is O, S, SO or SO 2
  • Z is O, S, SO or SO 2
  • These compounds of formula XXIII and XXIV are ate key intermediates of for the preparation of oxazolidinone antibacterials.
  • the compounds of formula XXIII and XXIV and their acid addition salts are especially preferred when Z is oxygen, which are the preferred intermediates for the preparation of Linezolid.
  • Example-1 Preparation of (5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] sulphonate.
  • Example-2 Preparation of(5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] bromide (5R)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]sulphonate (1 mole eq, 100 g) and lithium bromide(2.0 mole eq, 46.36 g) were taken in tetrahydrofuran (1.0 L) under nitrogen at 27 - 30 0 C and heated to reflux for 8-9 hours. The reaction mixture was cooled to room temperature and distilled out completely. To the residue was added water (350 ml), stirred for lhr at room temperature, filtered, washed with water and dried to obtain the titled compound (Yield :
  • Example-5 Preparation of (5S)-(N)-[[3-fluoro-(4-m orpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] amine. Hydrochloride.
  • Example-6 Preparation of[(5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] amine]
  • Example-9 Purification of[(5S)-(N)-[[3—fluoro-(4—morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] amine]

Abstract

La présente invention porte sur un nouveau procédé rentable, industriellement viable, permettant la fabrication de (5S)-(N)-[[3-[3-fluoro-4-(4-morpholinyl)phényl]-2-oxo-5-oxazolidinyl]méthyl]acétamide par le biais d'un nouvel intermédiaire de formule XXI et XXII.
PCT/IN2009/000751 2009-01-02 2009-12-30 Procédé de préparation de (5s)-(n)-[[3-[3-fluoro-4-(4-morpholinyl)phényl]-2-oxo-5-oxazolidinyl]méthyl]acétamide WO2010084514A2 (fr)

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Cited By (8)

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CN102229577A (zh) * 2011-05-11 2011-11-02 石药集团中诺药业（石家庄）有限公司 利奈唑胺中间体的制备及纯化方法
CN102491954A (zh) * 2011-12-06 2012-06-13 江苏正大丰海制药有限公司 利奈唑胺的制备方法
CN102617500A (zh) * 2011-01-31 2012-08-01 深圳信立泰药业股份有限公司 一种新的利奈唑胺中间体、其制备方法和利奈唑胺的新制备方法
CN102731336A (zh) * 2011-04-12 2012-10-17 浙江医药股份有限公司新昌制药厂 利奈唑胺中间体及合成利奈唑胺的方法
WO2013072923A1 (fr) 2011-09-19 2013-05-23 Cadila Healthcare Limited Procédé de préparation de linézolide cristallin
WO2013111048A1 (fr) 2012-01-24 2013-08-01 Jubilant Life Sciences Limited Procédé amélioré de préparation de la forme cristalline stable i du linézolide, pratiquement exempte de solvant résiduel
WO2014071990A1 (fr) 2012-11-09 2014-05-15 Synthon Bv Procédé de production de linézolide
CN104262280A (zh) * 2014-09-22 2015-01-07 山东华生化学股份有限公司 一种利奈唑酮的制备方法

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WO2007116284A1 (fr) * 2006-04-07 2007-10-18 Pfizer Products Inc. Procede de preparation du linezolide
WO2010031769A1 (fr) * 2008-09-16 2010-03-25 Unión Químico Farmacéutica, S. A. Procédé pour la préparation d’un agent antibactérien à base d’oxazolidinone et de ses intermédiaires

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WO2007116284A1 (fr) * 2006-04-07 2007-10-18 Pfizer Products Inc. Procede de preparation du linezolide
WO2010031769A1 (fr) * 2008-09-16 2010-03-25 Unión Químico Farmacéutica, S. A. Procédé pour la préparation d’un agent antibactérien à base d’oxazolidinone et de ses intermédiaires

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102617500A (zh) * 2011-01-31 2012-08-01 深圳信立泰药业股份有限公司 一种新的利奈唑胺中间体、其制备方法和利奈唑胺的新制备方法
CN102617500B (zh) * 2011-01-31 2016-07-13 山东信立泰药业有限公司 一种利奈唑胺中间体、其制备方法和利奈唑胺的制备方法
US8962827B2 (en) 2011-04-12 2015-02-24 Zhejiang Medicine Co. Ltd. Xinchang Pharmaceutical Factory Linezolid intermediate and method for synthesizing linezolid
CN102731336A (zh) * 2011-04-12 2012-10-17 浙江医药股份有限公司新昌制药厂 利奈唑胺中间体及合成利奈唑胺的方法
WO2012139505A1 (fr) * 2011-04-12 2012-10-18 浙江医药股份有限公司新昌制药厂 Intermédiaire du linézolide et procédé de synthèse du linézolide
CN102731336B (zh) * 2011-04-12 2014-05-07 浙江医药股份有限公司新昌制药厂 利奈唑胺中间体及合成利奈唑胺的方法
CN102229577A (zh) * 2011-05-11 2011-11-02 石药集团中诺药业（石家庄）有限公司 利奈唑胺中间体的制备及纯化方法
WO2013072923A1 (fr) 2011-09-19 2013-05-23 Cadila Healthcare Limited Procédé de préparation de linézolide cristallin
CN102491954A (zh) * 2011-12-06 2012-06-13 江苏正大丰海制药有限公司 利奈唑胺的制备方法
CN102491954B (zh) * 2011-12-06 2014-04-23 江苏正大丰海制药有限公司 利奈唑胺的制备方法
WO2013111048A1 (fr) 2012-01-24 2013-08-01 Jubilant Life Sciences Limited Procédé amélioré de préparation de la forme cristalline stable i du linézolide, pratiquement exempte de solvant résiduel
WO2014071990A1 (fr) 2012-11-09 2014-05-15 Synthon Bv Procédé de production de linézolide
CN104262280A (zh) * 2014-09-22 2015-01-07 山东华生化学股份有限公司 一种利奈唑酮的制备方法
CN104262280B (zh) * 2014-09-22 2016-07-20 山东华生化学股份有限公司 一种利奈唑酮的制备方法

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