WO2010010412A2 - Procédé de préparation de dérivés de n-méthyl-aryloxy-propanamine - Google Patents

Procédé de préparation de dérivés de n-méthyl-aryloxy-propanamine Download PDF

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Publication number
WO2010010412A2
WO2010010412A2 PCT/HU2009/000063 HU2009000063W WO2010010412A2 WO 2010010412 A2 WO2010010412 A2 WO 2010010412A2 HU 2009000063 W HU2009000063 W HU 2009000063W WO 2010010412 A2 WO2010010412 A2 WO 2010010412A2
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formula
group
carbon atoms
compound
methyl
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PCT/HU2009/000063
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WO2010010412A3 (fr
WO2010010412A8 (fr
Inventor
GYÓGYSZERGYÁR Nilvánosan Müködö EGIS
Tibor Mezei
Györgyi KOVÁNYINÉ LAX
József Barkóczy
Baklázs VOLK
Márta PORCS-MAKKAY
Enikö MOLNAR
László Józsefné KOCSIS
Gy]Orgy Krasznai
Imre KÖHEGYI
Judit Broda
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LUKÁCS, Gyula
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Publication of WO2010010412A2 publication Critical patent/WO2010010412A2/fr
Publication of WO2010010412A3 publication Critical patent/WO2010010412A3/fr
Publication of WO2010010412A8 publication Critical patent/WO2010010412A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups

Definitions

  • the present invention relates to a method for the preparation of N- methyl-aryloxy-propanamine derivatives of the Formula (I)
  • Q and P independently represents a phenyl, naphtyl or thienyl group optionally substituted by a halogen, an alkyl group containing 1 to 6 carbon atoms, an alkoxy group containg an alkyl group having 1 to 6 carbon atoms, which comprises demethylation of the N,N- dimethyl analogue thereof.
  • the method according to the present invention can be advantageously used for the preparation of several pharmaceutically active ingredients widely used in the medicine for the treatment of diseases or disorders of the central nervous system including the compound (+)-(S)-N- methyl-3-(l-naphtyloxy)-3-(2-thienyl)-propyl-amin known by the International Nonproprietary Name (INN) duloxetine of the Formula
  • SSNRI selective serotonine- norepinephrine reuptake inhibitors
  • An economic and ecologically viable approch suitable for the synthesis of an N-methyl-propylamine derivative of the Formula (I) under industrial conditions involves the preparation of said structural unit starting from N-methyl-N-benzyl-propylamine analogue, which can be easily transformed into the product by removing the benzyl group by catalytic hydrogenation using palladium-charcoal catalyst.
  • the process is simple, provides high yield and only toluene is produced as a by-product.
  • the catalyst can be regenerated and recycled into the process, therefore minute amounts of byproducts are formed only and the environmental impact is low.
  • the benzyl compound of the Formula (VII) can also be transformed into a different alkyl-carbamate, i.e. methyl- or ethyl-carbamate of the general Formulae (XXII) or (XXIII), wherein R represents the corresponding alkyl group, e.g. methyl or ethyl.
  • R 1 C-O JU. and fluoxetine methylcarbamate thus obtained is subjected to alkaline hydrolysis in an aqueous medium.
  • the yield of the two step mentioned above is 65%.
  • fluoxetine of the Formula (III) can be practically produced starting from the alkyl- or arylcarbamate derivatives thereof,, since fluoxetine is a racemic compound, which is not sensitive to racemization or decomposition under the conditions of alkaline or acidic hydrolysis.
  • the N-methyl- propylamin structural unit is usually synthesized from the N,N- dimethyl-propylamine unit.
  • Such starting compound containing the N,N-dimethyl-propylamine structural unit is N,N-dimethyl-3-(l- naphtyloxy)-3-(2-thienyl)-propylamine of the Formula (IV).
  • the N,N- dimethylamino group can be converted into a carbamate by reacting said group with alkyl or aryl chloroformates. In this way, for example, the aryl carbamate compound of the Formula (XII)
  • XlI is obtained by reacting the compound of the Formula (IV) with phenyl chloroformate of the Formula (VIII), or the alkyl carbamate of the Formula (XIV)
  • N,N-dimethylamine compound of the Formula (IV) reacts easily at a temperature between 40 and 100 0 C with alkyl- or aryl- chloroformates, which are available commercially. Practically, three chloroformic esters are used for the preparation of duloxetine.
  • the hydrolysis is carried out at a temperature between 5 to 25 0 C with a chort reaction time in acidic-aqueous medium in the presence of zinc powder.
  • Alkyl (methyl- and ethyl-) chloroformates of the Formulae (XII) and (XIV) used as intermediates in the second and third method for the preparation of duloxetine of the Formula (II), can be converted into said product by hydrolysis in aqueous-alkaline medium.
  • racemization of the optically active duloxetine occurs at temperatures above 30 0 C.
  • the rate of racemization increases with the temperature, therefore the reaction conditions for the hydrolysis of the carbamate has to be chosen to limit the reaction rate of racemization.
  • the major disadvantage of the first method (Reaction A) using 2,2,2- trichloroethyl-chloroformate reagent resides in the fact that the conversion of the intermediate 2,2,2-trichloroethyl-carbamate compound of the Formula (XVII) into duloxetine of the Formula (II) can not be carried without using zinc.
  • zinc salt and zinc hydroxide are formed, which are toxic and harmful for the environment. Removal of zinc ions from the waste water to meet the environmental limit concentration is very costly, therefore the method is not economically viable.
  • a further disadvantage of the process resides in the fact that during the production of the carbamate of the Formula (XVII) from the compound of the Formula (IV), the etremely costly, toxic and unstable reagent, 2,2,2-trichloroethyl chloroformate of the Formula (XVIII)
  • the crude carbamate is converted to duloxetine of the Formula (II) in the mixture of N,N-dimethyl formamide and formic acid in the presence of 2.0-2.5 molar equivalents of zinc at the temperature of 15 0 C.
  • the reaction time is approximately 30 minues. Thereafter the reaction mixture is stirred overnight, the next day the duloxetine base is isolated, the solvents are removed and the crude product is purified by column chromatography, resulting in a product of oily appearence.
  • the yield is 51%.
  • Duloxetine base thus obtained is further purified by conversion into the oxalate salt thereof. No yield has been disclosed for the step of salt formation.
  • a further difficulty resides in the removal of solvents from the waste water, since one of the solvents of the carbamate cleveage is N,N-dimethyl formamide, which is miscible with water. Said solvent can be removed from the aqeous waste by distillation, which further increases the costs of the production.
  • a further problem during the use of Reaction B resides in the fact that during the alkaline hydrolysis of the carbamate group of the compound of the Formula (XII), a simultaneous side reaction may accur resulting in the ether hydrolysis of the naphtyl ether as well as partial racemization of the asymmetric carbon atom.
  • the first reaction is indicated by the presence of 1-naphtol besides phenol in the crude product.
  • the racemic phenylcarbamate of the Formula (XII) is stirred in 50-fold volume of propylene glycol in the presence of 5 M sodium hydroxide for 75 minutes at the temperature of 110 0 C, the reaction mixture is evaporated, diluted with water, the product is extracted with diethylether, the extract is dryed and evaporated. The residue is converted into oxalate salt, which is purified by two recrystallization. The yield of the reaction is 41.3 %.
  • Hungarian Patent No. 206309 is not suitable for the preparation of optically active duloxetine, since due to the high reaction temperature (110 0 C), the proportion of the racemic product is high. Furthermore, the reaction has low yield and complicated purification involving the oxalate salt, which has to be converted later into a pharmaceutically acceptable hydrochloride salt.
  • the solvent diethylether used during the isolation of the product is flammable and explosive, therefore its use need special precautions.
  • the hydrolysis of the carbamate takes 18 hours at the temperature of 50 0C, while in the method of the above-mentioned International Patent Application, said reaction is performed in 12 hours at the temperature between 40 and 45 0 C.
  • the yield of the crude duloxetine hydrochloride is only 42.6% in the process of WO2006/126213, calculated on the basis of the starting compound of the Formula (IV).
  • the yield of the crude duloxetine hydrochloride is 73.3 %. No chemical or optical purity data are disclosed for duloxetine base, which is obtained as an oil.
  • duloxetine hydrochloride has been repeated according to Example 3 of International Patent Application WO WO2006/126213 and we have found that there is a significant degree of racemization during the reaction (see Reference Example 1).
  • the crude base was analyzed using enantioselective high-performance liquid chromatography coupled to mass spectrometry (enantioselective HPLC/MS), the crude base consisted of 85.4% by weight of (+)- duloxetine of the Formula (II), 2.4% of (-)-duloxetine, 4.5 % starting compound of the Formula (IV) and 5.2 % by weight phenol.
  • duloxetine hydrochloride with the yield of 45.3 %, calculated for the basis of the amount of the compound of the Formula (IV).
  • Duloxetine hydrochloride thus obtained contained 0.25 % phenol as well.
  • the hydrochloride could be used for the manufacture of a medicament containing duloxetine hydrochloride only after several recrystallizations, whereby the phenol impurity is removed.
  • Reaction B resides in that the method comprises several steps and carrying out said reactions takes long time.
  • the compound of the Formula (IV) is dissolved in toluene, diisopropyl- ethyl amine is added, the reaction mixture is heated to a temperature between 50 and 55 0 C, phenyl chloroformate is added in 1.5 hours and the reaction mixture is stirred for one and a half hours. Subsequently the mixture is washed with 1 weight% sodium bicarbonate solution, 0.5 M aqueous hydrochloric acid solution and 1 weight% sodium bicarbonate solution and finally evaporated.
  • the reaction time is 12 hours at a temperature between 40 and 45 0 C, while according to the method of Hungarian Patent No. 220673, said reaction time is 18 hours at the temperature of 50 0 C.
  • the reaction mixture is diluted with water, the pH is adjusted to 5.7 by the addition of acetic acid, the aqeous-organic solution is washed with hexane. After separation, the organic layer is discarded and the aqueous layer is adjusted to pH 10.5.
  • the product is extracted with ethylacetate, the solvent is evaporated, the residue is redissolved in ethylacetate, U2009/000063
  • Reaction A is the most suitable for the preparation of a product having acceptable quality for manufacturing medicaments.
  • the product obtained according to Reaction A has the highest optical and chemical purity.
  • the reason for this is the low reaction temperature (15 0 C) and mild reaction conditions (anhydrous solvent, presence of an organic acid, short reaction time) applied to the cleveage of the 2,2,2-trichloroethyl carbamate.
  • the carbamate of the Formula (XVII) can be cleaved in presence of zinc 2009/000063
  • Reactions B and C the hydrolysis is performed at higher temperature between 40 and 110 0 C in the mixture of dimethyl sulfoxide and aqueous alkali metal hydroxide. Under these conditions, the product of the Formula (II) is converted at least partly to the racemate. Furthermore, there occurs the partial cleveage of the naphtyl ether bond, which is indicated by the presence of 1-naphtol in the reaction mixture. 1-naphtol can be detected in the reaction mixture even at the temperature of 25 0 C after a few minute reaction time using thin layer chromatography.
  • the objective of our research was to provide a method for the preparation of N-methyl-aryloxy-propanamine derivatives of the Formula (I), especially for the production of duloxetine of the Formula (II), which does not require the use of heavy metals, such as zinc, which is environmentally safe and which can be carried out using mild reaction conditions, wherein the rate of racemization of chiral groups is low and involves the lowest possible amount of byproducts.
  • the present invention is based on the surprising recognition that the compound of the general Formula (XXIV)
  • S represents an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 6 carbon atoms or an aryl group
  • X represents halogen, yielding the formation of an aryl-oxy-propylamine derivative of the general Formula (I).
  • the prior art is silent about the cleveage of the compounds of the Formulae (XII), (XIV) es (XVII) by reacting said compounds with a Grignard-reagent. No reference in the state of the art is known for the process of preparation of N- methylamino compound by converting the corresponding N,N- dimethylamino compound into an uretane and subsequently cleaving said uretane with a Grignard reagent.
  • Q and P independently represents a phenyl, naphtyl or thienyl group substituted by a halogen, an alkyl group comprising 1 to 6 carbon atoms, an alkoxy group having an alkyl group comprising 1 to 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms or a trifluoromethyl group, which comprises reacting an uretane compound of the general Formula (XXIV), wherein the meaning of Q and P is the same as above, R represents an alkyl group havin 1 to 6 carbon atoms, an aryl group, an aralkyl group having 1 to 6 carbon atoms, a 2,2,2-trichloroethyl group at low to moderate temperature under mild reaction conditions with a Grignard reagent of the general Formula (XXV), wherein S represents an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 6 carbon atoms or an ary
  • a suitable Grignard reagent for the hydrolysis of the carbamate is widely used in industrial processes, inexpensive and commercially available.
  • the most suitable reagents available in the commercial circulation are methyl-magnesium-chloride and methyl-magnesium- bromide, but the somewhat more expensive methyl-magnesium-iodide can also be used with satisfactory results.
  • Transformation of the phenylcarbamate of the Formula (XII) into duloxetine of the Formula (II) can be carried out using methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide. No detectable amount of racemic product was observed with any of the above-mentioned Grignard reagents. Similar results were obtained when the reactions of the carbamates of the Formula (XIV) and (XVII) were studied.
  • the reaction can be carried out in any of the above-mentioned ether-type solvents or in an aprotic solvent, e.g. benzene, toluene.
  • an aprotic solvent e.g. benzene, toluene.
  • the reaction is completed in a few minutes even at the temperature of 0 0 C. No racemate is detectable under the reaction temperature of 50 0 C.
  • the reaction can be carried out the most advantageously at room temperature, where it is completed almost instantly.
  • the dried solution of the carbamate compound in toluene is mixed with 2 to 10 molar equivalents of the Grignard reagent and the product is isolated after a few minutes. Carbamates - similarly to esters or nitrile - react with two molar equivalents of the Grignard-reagent.
  • the isolation of the product can be carried out by adding concentrated aqeuous ammonium chloride solution to the reaction mixture dropwise, separating the layers and evaporating the organic layer.
  • the residue is dissolved in ethylacetate and using solution of hydrogen chloride in an organic solvent, e.g. in ethylacetate, a hydrochloride salt of duloxetine is produced and isolated by filtration.
  • the chemical and optical purity of the crude duloxetine hydrochloride of the Formula (II) obtained in this process is similar or better than that of the starting compound of the Formula (IV).
  • the advantage of the process according to the present invention resides in the fact that the conversion of the carbamates of the Formulae (XII), (XIV) and (XVII) can be easily carried out using any commercially available methyl-magnesium halogenide at low temperature. Since the reaction is carried out in a water-free solution, the rate of racemization is extremely low. Thus, the quality of duloxetine hydrochloride of the Formula (II) is better than that of the product obtained by the prior art process. Further aspects of the present invention are demonstrated by the following examples.
  • the mixture of 50 ml of saturated ammonium chloride solution and 10 ml of water is added dropwise to the reaction mixture at 35 0 C.
  • the layers are separated, the upper toluene layer is washed with 50 ml of 20 weight% sodium hydroxide solution, 50 ml of water and finally with 60 ml of saturated sodium chloride solution and evaporated at decreased pressure.
  • the evaporation residue (23.5 g of pale yellow oil) is dissolved in 200 ml of ethylacetate, chilled to 0 to 3 0 C and 50 ml of 5 % hydrogen chloride solution in ethylacetate are added ( to pH 6) dropwise.
  • the product precipitated during the addition of the acid is stirred for two hours at 5 0 C, filtered, washed with 30 ml of ethylacetate and dried at room temperature until constant weight.
  • the reaction mixture is washed at room temperature twice with 200 ml of 5 weight% aqeuous sodium hydrogencarbonate solution each and thereafter with 200 ml of saturated aqeuous sodium chloride solution, the organic layer is separated and the solvent is evaporated.
  • the residue thus obtained is 101.5 g of thick yellow oil containing 10- 15 % toluene, 2-3 % phenyl chloroformate, 1.5 % by weight of the compound of the Formula (IV) and 0.5 % of phenol and having an (S)- enantiomer content of: 97.6 %.
  • (+)-enantiomer content (enantioselective HPLC): 99.6 %.
  • Example ; 4_ The procedure of Example ; 4_ is carried out with the difference that instead of diisopropylether, an equal volume of diethylether, instead of 3 M methylmagnesiumchloride solution, identical volume of 3 M methylmagnesiumbromide solution in diethylether were used. Yield, 15.4 g, white crystals (74.5 %, calculated on the basis of the amount of the compound of Formulaa (PV) ) Melting point, 141.0- 142.5 0 C (+)-enantiomer content (by stereoselective HPLC), 99.2 %.
  • the reaction mixture is stirred at the temperature of 40 0 C for 30 minutes.
  • the reaction mixture is cooled to room temperature and washed twice with 100 ml of 5 weight% aqueous sodium hydrogencarbonate solution each and subsequently with 100 ml of concentrated aqueous sodium chloride solution.
  • the organic layer is separated and in order to remove the water from the solution, 50 ml of toluene is distilled off in vacuo.
  • the remaining toluene solution is combined by the solution of methylmagnesium bromide at the temperature of 5 0 C by adding dropwise 40,0 ml (0.12 mol) of 3 M methylmagnesium chloride in tetrahydrofuran.
  • the reaction mixture is stirred at 25 0 C for half an hour, the mixture of 80 ml saturated aqueous ammonium chloride solution and 10 ml of water are added dropwise, the -on kevertetj ⁇ k, 80 ml telitett vizes amm ⁇ nium-klorid oldat es 10 ml viz elegyet csepegtetj ⁇ k hozza, a ketfazis ⁇ elegyet elvalasztjuk, a organic layer is separated, dried over anhydrous magnesium sulfate and evaporated.
  • the evaporation residue (26.5 g of pale yellow oil) is dissolved in 250 ml of ethylacetate and the solution is made acidic until pH 6 by adding 5 (m/v)% hydrogen chloride solution in ethylacetate at the temperature of 0 to 3 0 C.
  • the precipitated product is stirred for two hours after the end of the addition of acid at 0 0 C, filtered, washed with ethylacetate and dried at room temperature until constant weight.
  • reaction mixture is stirred at 40 0 C for 30 minutes. Thereofter the reaction mixture is cooled to room temperature,washed twice with 100 ml of 5 weight % sodium hydrogencarbonate solution each and once with 100 ml of concentrated aqueous sodium chloride solution, separated and the solvent is evaporated.
  • the title product is obtained in the form of a pale yellow oil.
  • the reaction mixture is stirred at the temperature of 80 to 85 0 C for one hour, cooled to room temperature and washed twice with 100 ml of 5 weight% aqueous sodium hydrogencarbonate solution and one with 100 ml of concentrated aqueous sodium chloride solution, the organic layer is separated and the remaining water is removed by distilling 50 ml toluene from the solution.
  • the remaining toluene solution is reacted by the Grignard reagent by adding dropwise 50 ml (0.15 M) 3 M methylmagnesiumchloride solution in tetrahydrofurane at the temperature of 5 0 C ml and stirring the reaction mixture at 50 0 C for half an hour.
  • the solution is cooled and the mixture of 80 ml of saturated ammonium chloride solution and 10 ml of water are added dropwise, the layers are separated and the organic phase is dried over magnesium sulfate.
  • the solvent is evaporated and the remaining pale yellow oil (23.5 g) is dissolved in 250 ml of ethylacetate.
  • reaction mixture is stirred at the temperature of 50 0 C for 30 minutes. Thereafter the reaction mixture is cooled to room temperature, washed with 100 ml of 5 weightt% aqueous sodium hydrogencarbonate solution and 100 ml of concentrated aqueous sodium chloride solution, separated carefully and evaporated. The residual pale yellow oil is dissolved in 200 ml of diethylether and after cooling to the temperature of 10 0 C, 40.0 ml (0.12 mol) of 3 M methylmagnesium-chloride solution in tetrahydrofurane are added dropwise.
  • reaction mixture is stirred for 30 minutes, 80 ml of aqueous saturated ammonium chloride solution are added, the layers are separated and the organic layer is dried over magnesium sulfate.
  • aqueous saturated ammonium chloride solution are added at the temperature of 5 to 10 0 C, 5 (m/v)% ethereal hydrogen chloride solution are added until pH 1 is reached.
  • the suspension is stirred for three hours at 0 0 C, filtered, washed with 50 ml ether and dried at room temperature until constant weight.
  • the assay was performed according to the provisions of the monograph of pharmacopoeia directed to the test for impurities.
  • the reaction mixture is cooled to the temperature of 40 0 C and washed with 440 ml of 1 weight% sodium hydrogencarbonate solution, 150 ml of 0.5 M aqueous hydrochloric acid solution and again with 150 ml 1 weight% sodium hydrogencarbonate solution, and the organic layer is evaporated.
  • the residue is dissolved in dimethyl sulfoxide (480 ml), 16.7 g of sodium hydroxide dissolved in 105 ml of water are added at the temperature of 35 0 C and stirred for 12 hours at 40 to 45 0 C.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de N-méthyl-aryloxy-propanamine, ledit procédé comprenant la réaction d'un dérivé d'uréthanne approprié de formule (XXIV) avec un réactif de Grignard.
PCT/HU2009/000063 2008-07-25 2009-07-24 Procédé de préparation de dérivés de n-méthyl-aryloxy-propanamine WO2010010412A2 (fr)

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HUP0800467 2008-07-25
HU0800467A HU230480B1 (hu) 2008-07-25 2008-07-25 Eljárás N-metil-ariloxi-propánamin származékok előállítására

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104163811A (zh) * 2013-05-16 2014-11-26 重庆圣华曦药业股份有限公司 一种制备度洛西汀盐酸盐的新方法

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DE169819C (fr) *
DE1044103B (de) * 1956-06-12 1958-11-20 Hoffmann La Roche Verfahren zur Herstellung von Xanthen- bzw. Thioxanthenderivaten
US3758620A (en) * 1969-11-06 1973-09-11 Nat Patent Dev Corp Process for the preparation of grignard reagents
EP0273658A1 (fr) * 1986-12-22 1988-07-06 Eli Lilly And Company Propanamines 3-aryloxy-3-substituées
EP0457559A2 (fr) * 1990-05-17 1991-11-21 Eli Lilly And Company Synthèse chirale des 1-aryl-3-aminopropan-1-ols
WO2006071868A2 (fr) * 2004-12-23 2006-07-06 Teva Pharmaceutical Industries Ltd. Processus de preparation de sels de duloxetine repondant aux normes pharmaceutiques et d'intermediaires de ceux-ci

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W. TSCHELINZEFF: "Ueber die Analogie zwischen den organischen Sauerstoff- und Stickstoff-Verbindungen" BERICHTE DER DEUTSCHEN CHEMISCHEN GESELLSCHAFT, vol. 37, no. 2, 1904, pages 2081-2085, XP002576036 DOI: 10.1002/cber.190403702129 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104163811A (zh) * 2013-05-16 2014-11-26 重庆圣华曦药业股份有限公司 一种制备度洛西汀盐酸盐的新方法

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HUP0800467A2 (en) 2011-03-28
WO2010010412A3 (fr) 2010-05-27
HU230480B1 (hu) 2016-07-28
HU0800467D0 (en) 2008-10-28
WO2010010412A8 (fr) 2010-07-22

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