WO2010091877A2 - Procédé de production d'ambrisentan - Google Patents

Procédé de production d'ambrisentan Download PDF

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Publication number
WO2010091877A2
WO2010091877A2 PCT/EP2010/000885 EP2010000885W WO2010091877A2 WO 2010091877 A2 WO2010091877 A2 WO 2010091877A2 EP 2010000885 W EP2010000885 W EP 2010000885W WO 2010091877 A2 WO2010091877 A2 WO 2010091877A2
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WIPO (PCT)
Prior art keywords
formula
ambrisentan
compound according
dimethyl
process according
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PCT/EP2010/000885
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English (en)
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WO2010091877A3 (fr
Inventor
Ramesh Matioram Gidwani
Christian Janssen
Alexandre Mathieu
Wolfgang Albrecht
Frank Lehmamnn
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Ratiopharm Gmbh
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Priority claimed from DE200920009917 external-priority patent/DE202009009917U1/de
Application filed by Ratiopharm Gmbh filed Critical Ratiopharm Gmbh
Publication of WO2010091877A2 publication Critical patent/WO2010091877A2/fr
Publication of WO2010091877A3 publication Critical patent/WO2010091877A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom

Definitions

  • the invention relates to a process for producing Ambrisentan (I) comprising the step of reacting (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid (II) with a 4,6-dimethyl- pyrimidine derivative (HI).
  • the invention relates to Ambrisentan in crystalline form R.
  • Ambrisentan (Gilead, US trade name Letairis ® ; EU trade name Volibris ® ) functions as an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It was approved for sale by the U.S. Food and Drug Administration (FDA) on June 15, 2007 for the once-daily treatment of pulmonary arterial hypertension. It was later approved by the European Medicines Agency for use in the EU on April 2008.
  • FDA U.S. Food and Drug Administration
  • WO 96/ 1 1914 generally relates to carboxylic derivatives and their use as endothelin receptor antagonists.
  • Ambrisentan is mentioned in a long list of compounds (see compound I- 100). Neither an explicit synthesis nor any physical data of Ambrisentan are disclosed.
  • a subject of the present invention is a process for producing Ambrisentan (I)
  • residue L is a leaving group, preferably a leaving group comprising a sulfonyl moiety.
  • a further subject of the present invention is Ambrisentan, obtainable by the process according to the invention, having an optical purity of 99.7 % ee or more and a residual solvent content of less than 1500 ppm, preferably in crystalline form R as described below in the second aspect of the present invention.
  • the process of the present invention comprises reacting a compound according to formula (II) with a compound according to formula (III). Said reaction is preferably carried out in the presence of a base.
  • MNR 1 R 2 wherein M is lithium (Li), sodium (Na) or potassium (K), N is nitrogen and R 1 and R 2 are independently hydrogen or C 1 to C 10 alkyl, are preferably used as bases. More preferably, M is lithium. Furthermore, more preferably R 1 and R 2 are hydrogen or R 1 and R 2 are isopropyl.
  • Suitable examples are butyllithium, sec-butyllithium, tert-butyllithium, isopropyllithium, isobutyllithium, l ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo- [5.4.0]undec-7-ene, lithium bis(trimethylsilyl)amide, lithium tert-butoxide, lithium diethylamide, lithium diisopropylamide, lithium dimethylamide, lithium ethoxide, lithium isopropoxide, lithium methoxide, methyllithium, potassium bis(trimethylsilyl)amide, potassium ethoxide, potassium methoxide, potassium tert- butoxide.
  • lithium amide (LiNH 2 ) is used as base.
  • reaction of the compound according to formula (II) with the compound according to formula (III) may be carried out in usual organic solvents, preferably inert organic solvents and at usual temperatures.
  • organic solvents preferably inert organic solvents and at usual temperatures.
  • dimethyl formamide may be used as suitable solvent.
  • the reaction of the compound according to formula (II) with the compound according to formula (III) is usually carried out at temperatures below 45 0 C, preferably below 35 °C, more preferably below 30 0 C, in particular below 20 0 C, e.g. from -20 0 C to 30 0 C, more preferably from 0 0 C to 20 0 C.
  • the reaction time may vary from 10 minutes to 20 hours.
  • the reaction is carried out in two steps. Firstly, the starting compounds are reacted for 10 minutes to 1 hour at a temperature below 25 0 C, more preferably of 20 0 C or below, e.g. between 20 0 C and 5 0 C. Subsequently, the reaction is continued for 1 hour to 20 hours at a temperature of 20 0 C to 35 0 C, more preferably 25 0 C to 35 0 C.
  • the obtained crude product may be recrystallized. It has been found that a solvent system comprising an alcohol and water is useful for achieving a final product having a high purity and low residual solvent content.
  • ethanol or isopropanol are used as alcohols, wherein isopropanol is particularly preferred.
  • the weight ratio of alcohol to water ranges from 15 : 85 to 70 : 30, more preferably from 25 : 75 to 50 : 50.
  • the residue L is a leaving group.
  • the term "leaving group” comprises any group suitable of detaching itself from the remaining molecule.
  • suitable leaving groups are -NO 2 , -OR, -NR 3 + , -OAr, -SO 2 R, SR or a halogen atom, wherein R represents alkyl and Ar represents aryl.
  • Specific examples of leaving groups are, F, tosylate, -SOPh, Cl, Br, I, N 3 , -O-phenyl or -S-CH,.
  • the leaving group comprises a sulfonyl moiety (-SO 2 -).
  • the leaving group is a methylsufonyl moiety.
  • the compound according to formula (III) is 4,6-dimethyl-2-(methylsulfonyl)pyrimidine as represented by formula (Ilia)
  • the compound according to formula (II) is obtained by optical resolution of a compound according to formula (IV)
  • optical resolution can be achieved by methods known in the art.
  • optical resolution is achieved by a crystallisation step using a chiral substance, preferably a chiral amine.
  • a chiral substance preferably a chiral amine.
  • (S)-l-(4-chlorophenyl)ethylamine, (S)-l-(4-nitrophenyl)ethylamine and/or (R)-I- (phenyl)ethylamine is used a chiral substance.
  • L-proline methylester can be used.
  • a molar ratio of racemic acid (IV) : chiral substance of about 2 : 1 is preferred.
  • the use of a 1 : 1 ratio usually does not increase the yield of enantiomerically pure acid (II).
  • the chiral amine is recycled.
  • the chiral amine may be recycled from a hydrochloric acid phase, preferably by basification (e.g. with 2 M sodium hydroxide solution) and subsequent extraction with an organic solvent, e.g. extraction with dichloromethane or TBME.
  • the compound according to formula (II) is obtained by a Sharpless epoxidation reaction comprising the steps of reacting a compound according to formula (VI)
  • the Sharpless reaction may be carried out in the presence of an catalyst, e.g. OsO 4 or K 2 OsO 2 (OH).
  • the catalyst is usually used in amounts of from 0.1 to 4 mol % and preferably from 0.2 to 2.5 mol %, based on the substrate of formula (VI).
  • the reaction is carried out in the presence of a Sharpless ligand.
  • Sharpless ligands are compounds which are chiral, possess a nitrogen-containing six-membered heterocycle and bind to the catalyst.
  • Such Sharpless ligands are preferably hydroquinine and hydroquinidine derivatives, e.g. hydroquinine-( 1 ,4-phthalazine-diyl diether) (DHQ) 2 PHAL.
  • the compound according to formula (II) can be obtained by optical resolution of a compound according to formula (IV). Furthermore, wherein the compound according to formula (IV) can be obtained by hydrolyzing a compound according to formula (V)
  • the compound according to formula V is obtainable by reacting a compound of formula X with a Lewis acid, e.g. BF 3 .
  • the compound according formula X may be prepared by a Darzen's reaction, comprising reacting benzophenone with chloromethyl acetate. It is preferred that the inner temperature of the exothermic Darzen's reaction is maintained below 20 0 C by cooling, e.g. by cooling the reaction vessel with ice /salt and by adding the chloromethyl acetate slowly.
  • the residual benzophenone present throughout the sequence is preferably separated off by washing the basic solution with an inert organic solvent, preferably tert-butyl methyl ether (TBME), e.g. in the last step.
  • TBME tert-butyl methyl ether
  • residue X (of the chiral amine) is hydrogen or halogen, preferably chlorine, or a nitro group.
  • residue R is a C 2 to C 6 alkyl group, preferably ethyl.
  • the process according to the present invention results in Ambrisentan having high optical purity, preferably an optical purity of more than 99 % enantiomeric excess (ee), more preferably of at last least 99.7 % ee and having a low residual solvent content, preferably of less than 1500 ppm, more preferably of less than 500 ppm.
  • the present invention relates to a process for producing compound Ilia.
  • a further subject of the present invention is a process for producing 4,6-dimethyl-2-(methyl- sulfonyl)pyrimidine as represented by formula (Ilia) comprising the steps of
  • step b) methylating agents known in the art can be used.
  • methyl iodide is used.
  • oxidizing agents known in the art can be used.
  • MCPBA meta- chloroperbenzoic acid
  • the resulting 4,6-dimethyl-2-(methylsulfonyl)pyrimidine is preferably used in the process of the present invention for producing Ambrisentan, i.e. it is reacted with a compound according to formula (II).
  • a preferred embodiment of the process for producing 4,6-dimethyl-2-(methylsulfonyl)pyrimidine can be summarized as follows:
  • a second aspect of the present invention relates to Ambrisentan in a specific crystalline form (hereinafter referred to as "form R"), obtainable in particular from (2S)-2-hydroxy-3-methoxy-3,3-diphenyl-propanoic acid or (S)-2-(4,6-dimethyl-pyrimidine-2-yloxy)-3-methoxy-3,3-diphenyl-propanoic acid benzyl ester.
  • the second aspect of the invention relates to Ambrisentan in a specific crystalline form (hereinafter referred to as "form R").
  • Crystalline form R of Ambrisentan can advantageously be used in pharmaceutical formulations, in particular with regard to processability, in-vitro and in-vivo dissolution properties, bioavailability and /or stability, especially stability during shelf life.
  • Ambrisentan is preferably prepared by a method shown in Scheme 1 below:
  • the S-enantiomer 2 is obtained by reacting racemic acid with a chiral base and subsequently separating the salt.
  • Suitable chiral bases are, for example, L-proline methylester, (S)- l-(4-nitrophenyl)-ethylamine and (S)-l -(4-chlorophenyl ⁇ -ethylamine (see WO 2000/26170).
  • Ambrisentan can be prepared by a method shown in Scheme 2 below:
  • the S-enantiomer 3 can be synthesized pursuant to the specifications of WO 96/ 1 1914.
  • R is an organic residue, preferably methyl, methoxy, trifluoromethyl.
  • the residue R is especially located at para position.
  • the benzyl ester 3a can be deprotected, preferably by HBr, e.g. by 33 % HBr in AcOH.
  • the hydrogenation transfer preferably could be achieved by using ammonium formate, e.g. in the presence of 10 % Pd / C.
  • ammonium formate e.g. in the presence of 10 % Pd / C.
  • the p-methoxy- benzyl group can also be removed oxidatively, using 2,3-dichloro-5,6-dicyano- benzoquinone (DDQ).
  • Form R Ambrisentan can be obtained by crystallization of Ambrisentan, preferably of Ambrisentan prepared in accordance with Scheme 1 or 2, in an organic solvent.
  • form R Ambrisentan is crystallized from organic ethers, in particular, from diethyl ether.
  • Ambrisentan is preferably prepared in accordance with Scheme 2.
  • form R Ambrisentan is crystallized from a mixture containing an organic solvent and water, more preferably an alcohol and water, in particular, isopropanol and water.
  • the water content in the mixture typically is 10 to 90 w/w%, preferably 40 to 80 w/w%.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • the samples were analyzed, using a D8 Advance Powder X-Ray Diffractometer (Bruker ® -AXS, Düsseldorf, Germany). The measuring conditions were as follows:
  • the measurements were performed using a Mettler ® Toledo DSC 822E device, coupled with a Mettler ® Toledo gas flow controller TS0800GC1 (Mettler ® -Toledo GmbH, Gie ⁇ en, Germany). A 40 ⁇ L aluminum crucible, having a perforated lid, was used.
  • Measuring conditions temperature range 30 °C to 300 °C, heating rate 10 °C/min, nitrogen flow: 50 ml/min, Software STARe version 8.10, interpretation: endothermal.
  • Figure 1 shows an X-ray powder diffraction pattern of crystalline form R Ambrisentan with reflections at 8.9°, 11.1°, 12.3°, 13.1°, 17.9°, 26.9°, 14.1°, 15.2°, 18.2° and 20.6° ⁇ 0.2° 2 ⁇ , which can be obtained by crystallization from isopropanol / water.
  • Figure 2 shows an X-ray powder diffraction pattern of crystalline form R Ambrisentan with reflections at essentially the same 2 ⁇ -values, but with clearly lower peak intensities. Ambrisentan in accordance with Figure 2 can be obtained by crystallization from diethyl ether.
  • the object of the present invention also comprises mixtures containing different proportions of crystalline form R Ambrisentan and amorphous Ambrisentan.
  • the invention relates to a mixture containing
  • Method A Column: Agilent Zorbax SB-C18, 1.8 ⁇ m, 4.6 x 50 mm
  • Injection volume and concentration 5 ⁇ l of approximately 0.5-2 mg/ml solutions prepared in 100 % MeOH.
  • HPLC system Waters HPLC with UV detector
  • HPLC system Waters HPLC with PDA detector
  • buffer pH 3.0 0.68 g KH 2 PO 4 dissolved in 1000 ml milli-Q water. pH adjusted to 3.0 +/-0.05 with dilute orthophosphoric acid. Filter through 0.45 ⁇ m filter paper.
  • Sample preparation 10 mg Ambrisentan dissolved in and diluted to 20 ml acetonitrile (500 ppm Ambrisentan).
  • the yellowish slurry was cooled using an ice /salt bath at -5 °C.
  • 107 ml (0.99 mol) chloromethyl acetate was added over the period of 30 min while the internal temperature was kept between 5 and 18 0 C. Stirring continued for another 30 min.
  • the reaction mixture was kept at -18 0 C for 17 h in a freezer.
  • the mixture was poured onto 500 ml of water and extracted with 250 ml tert- butyl methyl ether (hereinafter referred to as TBME) twice each.
  • TBME 250 ml tert- butyl methyl ether
  • the precipitate was filtered off, washed with 100 ml TBME, and dried at 50 0 C/ 1 mbar for 3 h to yield 19.0 g (0.044 mol, 53 % of the theory) of the salt.
  • the salt was dissolved in 250 ml water and the solution was acidified by addition of 20 ml concentrated HCl, which resulted in precipitation.
  • the mixture was extracted with 150 ml EA three times.
  • the combined organic phases were washed with 60 ml 1 M HCl, 100 ml water, 100 ml brine, dried with sodium sulphate, evaporated, and dried at 50 0 C/ 1 mbar to yield 12.0 g (0.044 mol, 26.6 % yield) of the liberated acid.
  • Chiral HPLC 100 %.
  • the chiral amine is recovered from the hydrochloric acid phase, e.g. by basification with 2 M sodium hydroxide solution and subsequent extraction with dichloromethane or TBME.
  • the TBME phase was washed with brine and dried.
  • TBME extract was analysed by HPLC for content of S- l-(4-chlorophenyl)ethylamine and this extract was used directly for the next run of resolution. This recovery of amine makes a process eco friendly and more cost effective.
  • the chiral HPLC of recovered amine indicates 100 % purity.
  • the crude 4,6-dimethylpyrimidine-2-thiol was placed in a three-neck 1 -litre flask with mechanical stirring and was dissolved in 750 ml 2 M aqueous sodium hydroxide solution. 49 ml (0.79 mol) methyl iodide was added and the solution was stirred at room temperature for 1 h, kept at room temperature for 17 h, stirred for another 10 h, and kept at room temperature for another 17 h. LCMS indicated completion of the reaction.
  • the reaction mixture was extracted twice with 200 ml DCM. The combined organic layers were washed twice with 200 ml water, 200 ml brine, dried and evaporated.
  • the crude dark brown product (85.0 g, 0.606 mol, quant.) was directly used for the next step.
  • MCPBA meta-chloroperbenzoic acid
  • the yellowish slurry was poured onto 600 ml crushed ice/water and 80 ml 2 M citric acid was added to form a white precipitate.
  • the reaction mixture was extracted three times with 200 ml DCM each.
  • the combined organic phases were washed with 200 ml brine, dried and evaporated.
  • the residual DMF was evaporated for 1 h at
  • DSC shows a small exothermic peak at 165.47 0 C, followed by an endothermic peak at 184.46 0 C.
  • the product can be isolated by filtration of the precipitate, resulting from quenching the reaction with ice /water and acidification with 2 M citric acid. This crude was recrystallised with EA/hexane. But both yield and purity improved using the extraction method described above.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé de production d'ambrisentan (I) consistant à faire réagir de l'acide (S)-2-hydroxy-3-méthoxy-3,3-diphénylpropanoïque (II) avec un dérivé de 4,6-diméthyl-pyrimidine (III). L'invention porte également sur de ambrisentan sous forme cristalline, caractérisé en ce que le schéma de diffraction de la poudre sous rayons X présente des réflexions d'environ 8,9°, 12,3°, 17,9° et 26,9°, à l'échelle 2-thêta.
PCT/EP2010/000885 2009-02-13 2010-02-12 Procédé de production d'ambrisentan WO2010091877A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN291/DEL/2009 2009-02-13
IN291DE2009 2009-02-13
DE202009009917.2 2009-07-21
DE200920009917 DE202009009917U1 (de) 2009-07-21 2009-07-21 Ambrisentan in spezifischer kristalliner Form

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WO2010091877A2 true WO2010091877A2 (fr) 2010-08-19
WO2010091877A3 WO2010091877A3 (fr) 2010-11-11

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011004402A3 (fr) * 2009-07-10 2011-03-10 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
CN102276536A (zh) * 2011-06-10 2011-12-14 中国科学院化学研究所 一种光学纯的（+）-安倍生坦和光学纯的（+）-达芦生坦的制备方法
EP2476670A1 (fr) 2011-01-07 2012-07-18 Zentiva, K.S. Seuls solides stabiles de l'ambrisentane
CN102627613A (zh) * 2012-02-27 2012-08-08 中国药科大学 一种2-[(4,6-二甲基嘧啶-2-)氧基]-3-腈基-3,3-二苯基丙酸光学异构体及其制备、方法医药用途
CN102887861A (zh) * 2011-07-18 2013-01-23 天津市医药集团技术发展有限公司 一种安贝生坦新晶型及其制备方法
WO2013057468A1 (fr) 2011-10-19 2013-04-25 Cipla Limited Procédé de préparation d'un antagoniste du récepteur de l'endothéline
CN103396370A (zh) * 2013-07-26 2013-11-20 浙江华海药业股份有限公司 一种安立生坦的纯化方法
CN103524424A (zh) * 2012-07-04 2014-01-22 天津药物研究院 一种安立生坦的晶型vi及其制备方法和应用
CN103524425A (zh) * 2012-07-04 2014-01-22 天津药物研究院 一种安立生坦的晶型v及其制备方法和应用
CN103709106A (zh) * 2013-12-06 2014-04-09 石家庄博策生物科技有限公司 一种立体选择性制备安立生坦的方法
CN103739557A (zh) * 2013-12-30 2014-04-23 黄河三角洲京博化工研究院有限公司 一种4,6-二甲基-2-甲磺酰基嘧啶的合成方法
CN104177300A (zh) * 2014-03-18 2014-12-03 上海美悦生物科技发展有限公司 一种安立生坦降解产物及其制备方法
CN104280480A (zh) * 2013-07-02 2015-01-14 天津药物研究院 一种分离检测安立生坦及其有关物质的方法
CN106093250A (zh) * 2016-08-27 2016-11-09 江苏嘉逸医药有限公司 一种高效液相色谱法测定安立生坦含量的方法
CN109705042A (zh) * 2017-10-26 2019-05-03 正大天晴药业集团股份有限公司 一种安立生坦的制备方法
CN110437063A (zh) * 2018-05-03 2019-11-12 江苏豪森药业集团有限公司 安立生坦关键中间体的制备方法

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Cited By (25)

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US8962832B2 (en) 2009-07-10 2015-02-24 Cadila Healthcare Limited Process for the preparation of ambrisentan and novel intermediates thereof
WO2011004402A3 (fr) * 2009-07-10 2011-03-10 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
EP2476670A1 (fr) 2011-01-07 2012-07-18 Zentiva, K.S. Seuls solides stabiles de l'ambrisentane
CN102276536B (zh) * 2011-06-10 2015-04-29 中国科学院化学研究所 一种光学纯的(+)-安倍生坦和光学纯的(+)-达芦生坦的制备方法
CN102276536A (zh) * 2011-06-10 2011-12-14 中国科学院化学研究所 一种光学纯的（+）-安倍生坦和光学纯的（+）-达芦生坦的制备方法
CN102887861A (zh) * 2011-07-18 2013-01-23 天津市医药集团技术发展有限公司 一种安贝生坦新晶型及其制备方法
CN102887861B (zh) * 2011-07-18 2015-04-15 天津市医药集团技术发展有限公司 一种安贝生坦新晶型及其制备方法
WO2013057468A1 (fr) 2011-10-19 2013-04-25 Cipla Limited Procédé de préparation d'un antagoniste du récepteur de l'endothéline
JP2015502916A (ja) * 2011-10-19 2015-01-29 シプラ・リミテッド エンドセリン受容体拮抗薬の調製法
CN102627613A (zh) * 2012-02-27 2012-08-08 中国药科大学 一种2-[(4,6-二甲基嘧啶-2-)氧基]-3-腈基-3,3-二苯基丙酸光学异构体及其制备、方法医药用途
CN103524425A (zh) * 2012-07-04 2014-01-22 天津药物研究院 一种安立生坦的晶型v及其制备方法和应用
CN103524424A (zh) * 2012-07-04 2014-01-22 天津药物研究院 一种安立生坦的晶型vi及其制备方法和应用
CN104280480B (zh) * 2013-07-02 2016-12-28 天津药物研究院有限公司 一种分离检测安立生坦及其有关物质的方法
CN104280480A (zh) * 2013-07-02 2015-01-14 天津药物研究院 一种分离检测安立生坦及其有关物质的方法
CN103396370A (zh) * 2013-07-26 2013-11-20 浙江华海药业股份有限公司 一种安立生坦的纯化方法
CN103396370B (zh) * 2013-07-26 2018-11-16 浙江华海药业股份有限公司 一种安立生坦的纯化方法
CN103709106A (zh) * 2013-12-06 2014-04-09 石家庄博策生物科技有限公司 一种立体选择性制备安立生坦的方法
CN103739557A (zh) * 2013-12-30 2014-04-23 黄河三角洲京博化工研究院有限公司 一种4,6-二甲基-2-甲磺酰基嘧啶的合成方法
CN103739557B (zh) * 2013-12-30 2015-10-21 黄河三角洲京博化工研究院有限公司 一种4,6-二甲基-2-甲磺酰基嘧啶的合成方法
CN104177300A (zh) * 2014-03-18 2014-12-03 上海美悦生物科技发展有限公司 一种安立生坦降解产物及其制备方法
CN106093250A (zh) * 2016-08-27 2016-11-09 江苏嘉逸医药有限公司 一种高效液相色谱法测定安立生坦含量的方法
CN109705042A (zh) * 2017-10-26 2019-05-03 正大天晴药业集团股份有限公司 一种安立生坦的制备方法
CN109705042B (zh) * 2017-10-26 2021-12-21 正大天晴药业集团股份有限公司 一种安立生坦的制备方法
CN110437063A (zh) * 2018-05-03 2019-11-12 江苏豪森药业集团有限公司 安立生坦关键中间体的制备方法
CN110437063B (zh) * 2018-05-03 2022-04-29 常州恒邦药业有限公司 安立生坦关键中间体的制备方法

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