WO2011153923A1 - 决奈达隆及其盐的制备方法 - Google Patents
决奈达隆及其盐的制备方法 Download PDFInfo
- Publication number
- WO2011153923A1 WO2011153923A1 PCT/CN2011/075255 CN2011075255W WO2011153923A1 WO 2011153923 A1 WO2011153923 A1 WO 2011153923A1 CN 2011075255 W CN2011075255 W CN 2011075255W WO 2011153923 A1 WO2011153923 A1 WO 2011153923A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dronedarone
- dronedarone hydrochloride
- solvent
- producing
- ether
- Prior art date
Links
- ZJZKLBXEGZKOBW-UHFFFAOYSA-N CCCCc1c(C(c(cc2)ccc2O)=O)c2cc([N+]([O-])=O)ccc2[o]1 Chemical compound CCCCc1c(C(c(cc2)ccc2O)=O)c2cc([N+]([O-])=O)ccc2[o]1 ZJZKLBXEGZKOBW-UHFFFAOYSA-N 0.000 description 1
- WYALRXZJYXWYGR-UHFFFAOYSA-N CCCCc1c(C(c(cc2)ccc2OC)=O)c2cc([N+]([O-])=O)ccc2[o]1 Chemical compound CCCCc1c(C(c(cc2)ccc2OC)=O)c2cc([N+]([O-])=O)ccc2[o]1 WYALRXZJYXWYGR-UHFFFAOYSA-N 0.000 description 1
- YIYARJKYRBMMJG-UHFFFAOYSA-N CCCCc1c(C(c(cc2)ccc2OCCCN(CCCC)CCCC)=O)c(cc(cc2)[N+]([O-])=O)c2[o]1 Chemical compound CCCCc1c(C(c(cc2)ccc2OCCCN(CCCC)CCCC)=O)c(cc(cc2)[N+]([O-])=O)c2[o]1 YIYARJKYRBMMJG-UHFFFAOYSA-N 0.000 description 1
- SPIIBUQYWNFELT-UHFFFAOYSA-N CCCCc1c(C(c(cc2)ccc2OCCCN(CCCC)CCCC)=O)c2cc(N)ccc2[o]1 Chemical compound CCCCc1c(C(c(cc2)ccc2OCCCN(CCCC)CCCC)=O)c2cc(N)ccc2[o]1 SPIIBUQYWNFELT-UHFFFAOYSA-N 0.000 description 1
- OTHGZZYPCZCVDK-SECBINFHSA-N CCC[C@@H](C)c1cc2cc([N+]([O-])=O)ccc2[o]1 Chemical compound CCC[C@@H](C)c1cc2cc([N+]([O-])=O)ccc2[o]1 OTHGZZYPCZCVDK-SECBINFHSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
Definitions
- the present invention relates to 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-methylsulfonylamino-benzofuran (Dreondarone) and A new method of preparing salt for treating diseases of the cardiovascular system.
- Background technique 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-methylsulfonylamino-benzofuran
- Dronedarone (SR33589) is a benzofuran derivative and is a newly developed therapeutic arrhythmia drug.
- the structure and characteristics are similar to those of the cardiovascular drug amiodarone, which is iodine-free and has low lipophilicity.
- Dronedarone maintains the efficacy of amiodarone and has no extracardiac adverse reactions to amiodarone, so it is hopeful that it will be safer and better patient tolerant. It is one of the drugs to replace amiodarone in the treatment of arrhythmia. .
- With the continuous acceleration of social modernization people are under increasing social pressure.
- the number of cardiovascular diseases in China is also increasing. Cardiovascular diseases are listed as one of the top ten causes of death. Therefore, the development of Dronedarone will bring better economic and social benefits.
- the chemical structure of dronedarone is shown in formula I:
- compound A is acylated with methanesulfonyl chloride to easily form a bismethylsulfonyl by-product (referred to herein as a compound of formula la), which requires purification by column chromatography, which is industrialized. Production is very uneconomical.
- the preparation of dronedarone hydrochloride requires a salt-forming process, which requires the use of more reaction equipment, while reducing the yield of the entire route and increasing the production cost.
- US2005049302 discloses a process for the preparation of compound II from 5-amino-2-butyl-benzofuran without obtaining compound Il a .
- the invention synthesizes dronedarone by reacting compound II with compound III under the condition of tin tetrachloride (see scheme 3).
- the method has low yield and still undergoes complicated operation steps such as column chromatography purification, which is disadvantageous for industrial production. .
- One aspect of the invention relates to a method for preparing dronedarone hydrochloride, the method comprising 5- Synthesis of dronedarone hydrochloride by reaction of amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran (Compound A) with methanesulfonyl chloride
- the reaction is carried out without adding a catalyst; preferably, the reaction is carried out in a solvent or a mixed solvent of a plurality of solvents; preferably, after the crude dronedarone hydrochloride is obtained, a step of further purifying to obtain a pure product thereof is further included.
- Another aspect of the invention relates to a novel process for the preparation of dronedarone and a salt thereof which is not a hydrochloride salt.
- the method comprises: first reacting 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran (Compound A) with methanesulfonyl chloride to form a reaction
- Nidalon hydrochloride is then treated with an alkaline solution to prepare high purity dronedarone or converted to other pharmaceutically acceptable salts as needed. See scenario 4 for the route:
- the process for preparing dronedarone and its salts comprises the following steps: a) 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy Benzoyl)benzofuran
- the present inventors have unexpectedly found in the study of the acylation reaction that the compound A and the methanesulfonyl chloride can be smoothly subjected to the acylation reaction without adding any catalyst, and the bismethylsulfonyl by-product (compound la) is greatly inhibited.
- the formation of high-purity dronedarone hydrochloride can be directly obtained, thereby obtaining a new synthesis method for preparing dronedarone and its salt.
- the present inventors have found that in a solvent of a nitrile, a ketone, a halogenated hydrocarbon, an ether or an aromatic hydrocarbon or a mixed solvent composed of two or more of the above solvents, Compound A and A are added without adding a catalyst.
- the sulfonyl chloride can be smoothly subjected to the acylation reaction, and the high-purity dronedarone hydrochloride can be directly obtained without the cumbersome purification step and the salt-forming step of column chromatography, or Nidalon can be determined as needed.
- the hydrochloride salt is converted to other pharmaceutically acceptable salts.
- the catalyst referred to in the present invention means 5-amino-2-butyl-3-(4-[3-(dibutylamino)) Catalysts for the reaction of propoxy]benzoyl)benzofuran with methanesulfonyl chloride, such as acid adsorbents, including organic bases such as mercaptoamines such as triethylamine, dipropylamine, etc.; inorganic bases such as alkali metals and Its alkaline earth metal salt, such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, calcium hydroxide, barium hydroxide and the like.
- organic bases such as mercaptoamines such as triethylamine, dipropylamine, etc.
- inorganic bases such as alkali metals and Its alkaline earth metal salt, such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, calcium hydroxide, barium hydroxide and the like.
- the nitrile solvent used in the present invention is selected from the group consisting of C 2 to C 6 fatty nitriles such as acetonitrile, propionitrile, butyronitrile, etc., preferably acetonitrile.
- the ketone solvent used in the present invention is selected from the group consisting of C 3 to C 6 aliphatic ketones, preferably acetone.
- the 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxyl of the present invention is in the range of 0 to 15 times, preferably 4 to 10 times, more preferably 5 to 8 times the amount of acetone.
- the benzoyl)benzofuran is reacted with 1 to 5 equivalents, preferably 1.5 to 3.5 equivalents, more preferably 2 to 2.5 equivalents of methanesulfonyl chloride at room temperature to reflux temperature, preferably reflux temperature.
- the halogenated hydrocarbon solvent used in the present invention is selected from the group consisting of aliphatic halogenated hydrocarbons of the formula, and is usually chloroform, chloroform, carbon tetrachloride or the like, preferably dichloromethane.
- the obtained dronedarone is salted and crystallized with hydrochloric acid in acetone to obtain crude dronedarone hydrochloride, and then purified or treated with an aqueous alkali solution to prepare high-purity dronedarone or its hydrochloride, or according to Need to be converted to other pharmaceutically acceptable salts.
- the linear ether is selected from the group consisting of (e.g., a fatty ether, preferably ethylene glycol dimethyl ether; and the cyclic ether is selected from the group consisting of an aliphatic ring ether of c 2 to c 4 , preferably tetrahydrofuran. .
- the aromatic hydrocarbon solvent employed in the present invention is selected from substituted or unsubstituted C 6 -C 1Q aromatic hydrocarbons commonly used in the art, such as toluene, ethylbenzene, cumene, preferably toluene.
- the mixed solvent selected in the present invention is a mixed solvent of two or more solvents of the same or different kinds of solvents in a nitrile, a ketone, a halogenated hydrocarbon, an ether or an aromatic hydrocarbon solvent, preferably an acetone-acetonitrile mixed solvent.
- the ratio of acetone/acetonitrile of the present invention is 0 to 5:1, preferably 0.2 to 3:1, more preferably 0.5 to 1:1, 5-amino-2-butyl-3-(4-[3- (Dibutylamino)propoxy]benzoyl)benzofuran with 1 to 5 equivalents, preferably 1.5 to 4 equivalents, more preferably 2 to 3 equivalents of methanesulfonyl chloride at room temperature to reflux temperature, preferably reflux temperature .
- the mixture is crystallized at -40 to 50 ° C, preferably -15 to 40 ° C, more preferably at -10 to 35 ° C to obtain crude dronedarone hydrochloride.
- High purity dronedarone or its hydrochloride salt can then be prepared by treatment with a purified or aqueous alkali solution, or converted to other pharmaceutically acceptable salts as needed.
- the solvent used for the purification of dronedarone hydrochloride of the present invention is acetone-water, preferably 30 to 5:1 (V/V) o
- the selected alkaline solution is prepared by subjecting the dronedarone hydrochloride to a purified or alkaline solution to prepare a pure product of dronedarone or a hydrochloride thereof, or converted into a pharmaceutically acceptable other salt.
- the base in the base is an inorganic base such as sodium hydroxide, sodium carbonate and sodium hydrogencarbonate, preferably sodium hydrogencarbonate.
- the present invention is in a single solvent or a mixed solvent such as a nitrile solvent of acetonitrile, such as a ketone solvent of acetone, such as a halogenated hydrocarbon of methylene chloride, without adding any catalyst, Compound A and A Sulfonyl chloride undergoes acylation without column chromatography and salt formation
- a mixed solvent such as a nitrile solvent of acetonitrile, such as a ketone solvent of acetone, such as a halogenated hydrocarbon of methylene chloride
- the method of the invention has the advantages of less steps, high yield, simple operation, low cost, and is suitable for industrial production, and has significant social and economic benefits. detailed description
- the method was the same as in the first step 1), the reaction temperature was 55 to 60 ° C, the reaction was carried out for 15 hours, the yield was 85.3%, and the HPLC purity was 99.0%.
- the method was the same as in the first step 1), the reaction temperature was 40 to 45 ° C, the reaction was carried out for 41 hours, the yield was 82.1%, and the HPLC purity was 98.3%.
- the method is the same as step 1 in the first step, the reaction temperature is 40 to 45 ° C, the reaction rate is 86.1% in 36 hours, and the HPLC purity is 98.8%.
- the oil obtained in the step 1) was dissolved in 12 mL of acetone, 2 mL of water was added, and 1 mL of a solution of 1 mL of concentrated sulfuric acid in 3 mL of acetone was slowly added dropwise at 10 to 15 ° C for about 20 minutes, and the mixture was stirred at 52 ° C for 1 hour. The mixture was stirred and crystallized for 3.5 hours under ice-water bath, filtered, and dried under vacuum at 50 ° C to give 5.5 g of product (yield: 84%). The HPLC purity was 99.85%.
- the method is the same as the step 10 in the implementation of 10).
- Step 2) Preparation of dronedarone mesylate
- the procedure was the same as in the step 2) of the example except that 1.5 g of methanesulfonic acid (99%) was used, the yield was 76%, and the HPLC purity was 99.83%.
- Example 12
- the method was the same as the step 2) in Example 1, the yield was 78.5%, the melting point was 140.5 to 142.5 ° C, and the HPLC purity was 98.9%.
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/701,642 US8481763B2 (en) | 2010-06-09 | 2011-06-03 | Preparation process of dronedarone and its salts |
JP2013513534A JP5873484B2 (ja) | 2010-06-09 | 2011-06-03 | ドロネダロン及びその塩の製造方法 |
EP11791914.2A EP2581369A4 (en) | 2010-06-09 | 2011-06-03 | METHOD OF MANUFACTURING DRONEDARON AND ITS SALTS |
CN201180003259.6A CN102471302B (zh) | 2010-06-09 | 2011-06-03 | 决奈达隆及其盐的制备方法 |
TW100134530A TWI516483B (zh) | 2011-06-03 | 2011-09-26 | 決奈達隆及其鹽的製備方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201010195733.7 | 2010-06-09 | ||
CN2010101957337A CN102276561A (zh) | 2010-06-09 | 2010-06-09 | 决奈达隆及其盐的制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011153923A1 true WO2011153923A1 (zh) | 2011-12-15 |
Family
ID=45097533
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2011/075255 WO2011153923A1 (zh) | 2010-06-09 | 2011-06-03 | 决奈达隆及其盐的制备方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8481763B2 (zh) |
EP (1) | EP2581369A4 (zh) |
JP (1) | JP5873484B2 (zh) |
CN (2) | CN102276561A (zh) |
WO (1) | WO2011153923A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2428511A1 (en) * | 2010-09-09 | 2012-03-14 | USV Limited | Synthesis of dronedarone and salts thereof |
WO2012120544A3 (en) * | 2011-03-10 | 2012-11-01 | Sun Pharmaceutical Industries Ltd. | Process for the preparation of n- [2-n-butyl-3-[4-[3-[di-n-butylamino] propoxy] benzoyl] benzofuran-5-yl]methanesul fonamide hydrochloride |
WO2012153225A1 (en) * | 2011-05-09 | 2012-11-15 | Alembic Pharmaceuticals Limited | Improved processes for obtaining high purity of dronedarone hydrochloride |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2447256A1 (en) * | 2010-10-21 | 2012-05-02 | Laboratorios Lesvi, S.L. | Process for obtaining dronedarone |
CN103044369A (zh) * | 2012-12-21 | 2013-04-17 | 北京华禧联合科技发展有限公司 | 一种盐酸决奈达隆的精制方法 |
WO2014203058A1 (en) * | 2013-06-17 | 2014-12-24 | Aurobindo Pharma Limited | An improved process for preparing benzofuran compound |
CN107880003A (zh) * | 2016-09-30 | 2018-04-06 | 北京新领先医药科技发展有限公司 | 一种精制盐酸决奈达隆的新方法 |
CN112442003B (zh) * | 2020-12-17 | 2022-04-19 | 南京方生和医药科技有限公司 | 一种决奈达隆中间体杂质及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US522351A (en) | 1894-07-03 | phillips | ||
US5223510A (en) | 1990-08-06 | 1993-06-29 | Sanofi | Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them |
WO2003048144A2 (fr) | 2001-12-06 | 2003-06-12 | Rhodia Chimie | Procede de monosulfonylation d'un compose de type aminobenzofuranne. |
US20050049302A1 (en) | 2001-11-08 | 2005-03-03 | Arie Gutman | Process for the preparation of dronedarone |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2803846B1 (fr) * | 2000-01-17 | 2002-04-05 | Clariant France Sa | 3-(1-hydroxy-pentylidene)-5-nitro-3h-benzofuran-2-one, son procede de preparation et son utilisation |
CN101153012B (zh) * | 2006-09-29 | 2010-06-23 | 北京德众万全药物技术开发有限公司 | 一种决奈达隆关键中间体的新的制备方法 |
FR2915482B1 (fr) * | 2007-04-27 | 2009-11-27 | Finorga | Procede de preparation du 2-(n-butyl)-5-nitrobenzofurane. |
-
2010
- 2010-06-09 CN CN2010101957337A patent/CN102276561A/zh active Pending
-
2011
- 2011-06-03 US US13/701,642 patent/US8481763B2/en active Active
- 2011-06-03 WO PCT/CN2011/075255 patent/WO2011153923A1/zh active Application Filing
- 2011-06-03 CN CN201180003259.6A patent/CN102471302B/zh active Active
- 2011-06-03 JP JP2013513534A patent/JP5873484B2/ja not_active Expired - Fee Related
- 2011-06-03 EP EP11791914.2A patent/EP2581369A4/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US522351A (en) | 1894-07-03 | phillips | ||
US5223510A (en) | 1990-08-06 | 1993-06-29 | Sanofi | Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them |
US20050049302A1 (en) | 2001-11-08 | 2005-03-03 | Arie Gutman | Process for the preparation of dronedarone |
WO2003048144A2 (fr) | 2001-12-06 | 2003-06-12 | Rhodia Chimie | Procede de monosulfonylation d'un compose de type aminobenzofuranne. |
Non-Patent Citations (2)
Title |
---|
HE, XIAOQING ET AL.: "Graphical Synthetic Routes of Dronedarone Hydrochloride.", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 41, no. 2, February 2010 (2010-02-01), CHINESE, pages 148 - 151, XP008140341 * |
See also references of EP2581369A1 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2428511A1 (en) * | 2010-09-09 | 2012-03-14 | USV Limited | Synthesis of dronedarone and salts thereof |
WO2012120544A3 (en) * | 2011-03-10 | 2012-11-01 | Sun Pharmaceutical Industries Ltd. | Process for the preparation of n- [2-n-butyl-3-[4-[3-[di-n-butylamino] propoxy] benzoyl] benzofuran-5-yl]methanesul fonamide hydrochloride |
WO2012153225A1 (en) * | 2011-05-09 | 2012-11-15 | Alembic Pharmaceuticals Limited | Improved processes for obtaining high purity of dronedarone hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
CN102471302B (zh) | 2014-03-26 |
EP2581369A4 (en) | 2014-01-22 |
CN102471302A (zh) | 2012-05-23 |
CN102276561A (zh) | 2011-12-14 |
EP2581369A1 (en) | 2013-04-17 |
JP2013530959A (ja) | 2013-08-01 |
JP5873484B2 (ja) | 2016-03-01 |
US8481763B2 (en) | 2013-07-09 |
US20130072697A1 (en) | 2013-03-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2011153923A1 (zh) | 决奈达隆及其盐的制备方法 | |
EP2428511A1 (en) | Synthesis of dronedarone and salts thereof | |
WO2016180033A1 (zh) | 一种前列环素受体激动剂的制备方法 | |
CN112062712A (zh) | 一种2-(5-溴-3-甲基吡啶-2-基)乙酸盐酸盐的制备方法 | |
JP2018512066A (ja) | デオキシコール酸の作製方法 | |
WO2016161826A1 (zh) | 一种4-异丙氨基-1-丁醇的制备方法 | |
WO2018214676A1 (zh) | 布格呋喃原料药及其制备方法和应用 | |
CN112062669A (zh) | 芳烃类化合物的制备方法 | |
US11325922B2 (en) | Process for the preparation of Crisaborole in a stable crystal form | |
WO2015085827A1 (zh) | 一种西洛多辛及其中间体的制备方法 | |
TWI516483B (zh) | 決奈達隆及其鹽的製備方法 | |
CN114685468A (zh) | 用于治疗子宫肌瘤的药物的中间体化合物及其制备方法 | |
WO2020125581A1 (zh) | 一种类酰胺类衍生物及其中间体的制备方法 | |
WO2012062109A1 (zh) | 阿利克仑的药物中间体的制备方法 | |
CN112250586A (zh) | 一种硫酸特布他林及其b晶型的制备方法 | |
CN111217709A (zh) | 一种(1-氟环丙基)甲胺盐酸盐的制备方法 | |
CN109942442A (zh) | 一种盐酸达泊西汀有关物质i的制备方法 | |
CN114685415B (zh) | 一种曲酸二聚体的合成方法 | |
CN110105361B (zh) | 一种Evodiakine及其衍生物的制备方法 | |
CN110218169B (zh) | 手性4-(n-苄氧羰基)吡咯烷酮的合成方法 | |
CN111349012B (zh) | 一种卤代芳烃类化合物的制备方法及其中间体 | |
CN108203396A (zh) | 一种脑啡肽酶抑制剂的合成 | |
CN112225739A (zh) | 一种氮杂环丁烷化合物的制备方法 | |
JP2022104572A (ja) | 1,3-ジアリール置換テトラゾロン内塩の合成方法 | |
CN117534613A (zh) | 一种3-氨基吡啶-2-羧酸甲酯的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201180003259.6 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11791914 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013513534 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13701642 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011791914 Country of ref document: EP |