WO2016078108A1 - Method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate - Google Patents
Method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate Download PDFInfo
- Publication number
- WO2016078108A1 WO2016078108A1 PCT/CN2014/092277 CN2014092277W WO2016078108A1 WO 2016078108 A1 WO2016078108 A1 WO 2016078108A1 CN 2014092277 W CN2014092277 W CN 2014092277W WO 2016078108 A1 WO2016078108 A1 WO 2016078108A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diazabicyclo
- octane
- compound
- methyl
- synthesizing
- Prior art date
Links
- SYYSPESGSRLVFX-MXLSIXORSA-N CN(C1)CC2C1CN(Cc1ccc(CC(C3)[C@H]3C3N(C)CC4C3CNC4)cc1)C2 Chemical compound CN(C1)CC2C1CN(Cc1ccc(CC(C3)[C@H]3C3N(C)CC4C3CNC4)cc1)C2 SYYSPESGSRLVFX-MXLSIXORSA-N 0.000 description 1
- SLEWLTIVHNDEEP-UHFFFAOYSA-N CN(CC1C(N2Cc3ccccc3)=O)CC1C2=O Chemical compound CN(CC1C(N2Cc3ccccc3)=O)CC1C2=O SLEWLTIVHNDEEP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention relates to a method for synthesizing a pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane.
- the invention provides a method for synthesizing a pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane to solve the defects in the prior art.
- the technical scheme of the present invention is a method for synthesizing a pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane, which comprises the following steps:
- Step (1) cyclization reaction: N-methylglycine, dimethyl maleate in toluene heated to reflux to prepare compound a;
- Step (2) Compound a is reacted with benzylamine to prepare compound b;
- Step (3) under the protection of argon, compound b is reduced by lithium aluminum hydride to form compound c;
- Step (4) obtaining 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate by hydrogenation deprotection;
- the reaction time of the step (1) is 2 to 4 hours.
- the reaction solvent of the step (2) is anhydrous ethanol.
- the reaction solvent of the step (3) is anhydrous tetrahydrofuran.
- the catalyst used in the step (4) is a palladium catalyst.
- the method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane, a pharmaceutical intermediate provided by the invention utilizes low cost and easily obtained dimethyl maleate and N-methylglycine As a raw material, after three steps of reaction, 3-methyl-3,7-diazabicyclo[3.3.0]octane was obtained.
- the method has the advantages that the raw materials are easy to obtain, the cost is low, the reaction is simple, the control is easy, the treatment is simple, the yield is high, and the production is easy to be enlarged.
- a method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane of the formula I which comprises the following steps:
- Step (1) cyclization reaction: N-methylglycine, dimethyl maleate in toluene heated to reflux to prepare compound a;
- Step (2) Compound a is reacted with benzylamine to prepare compound b;
- Step (3) under the protection of argon, compound b is reduced by lithium aluminum hydride to form compound c;
- Step (4) Hydrodeprotection to obtain 3-methyl-3,7-diazabicyclo[3.3.0]octane drug intermediate.
- the method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane, a pharmaceutical intermediate provided by the invention utilizes low cost and easily obtained dimethyl maleate and N-methylglycine As a raw material, after three steps of reaction, 3-methyl-3,7-diazabicyclo[3.3.0]octane was obtained.
- the method has the advantages that the raw materials are easy to obtain, the cost is low, the reaction is simple, the control is easy, the treatment is simple, the yield is high, and the production is easy to be enlarged.
- the invention provides a practical and feasible method for synthesizing pharmaceutical intermediates for green chemicals.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Provided is a method for synthesizing the pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane, containing the following steps: (1) a cyclization reaction, in which N-methylglycine and dimethyl maleate are heated under reflux in toluene to prepare a compound a; (2) the compound a undergoes a reaction with benzylamine to yield a compound b; (3) under an argon atmosphere, the compound b is reduced by lithium aluminum hydride to generate a compound c; (4) the compound c is deprotected by hydrogenation to yield the pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane. The starting materials of the method are readily available; the method is low-cost, and the reaction is simple and easy to control; processing is simple, the yield is high, and large-scale production is readily achieved.
Description
本发明涉及一种药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法。The invention relates to a method for synthesizing a pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane.
近年来,3-甲基-3,7-二氮杂双环[3.3.0]辛烷成为众多新药的重要的中间体,现有技术中的合成方法合成路线较长,收率较低,后处理烦琐困难,原料成本高,三废多,污染大。因此科研人员仍在不断寻求更为简易的合成方法。In recent years, 3-methyl-3,7-diazabicyclo[3.3.0]octane has become an important intermediate for many new drugs. The synthesis method in the prior art has a long synthetic route and a low yield. Handling cumbersome difficulties, high raw material costs, more waste, and greater pollution. Therefore, researchers are still continually seeking simpler synthetic methods.
发明内容Summary of the invention
本发明提供一种药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,以解决现有技术中的缺陷。The invention provides a method for synthesizing a pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane to solve the defects in the prior art.
为了达到上述目的,本发明的技术方案是:一种药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,该方法包含下列步骤:In order to achieve the above object, the technical scheme of the present invention is a method for synthesizing a pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane, which comprises the following steps:
步骤(1):环化反应:将N-甲基甘氨酸、马来酸二甲酯在甲苯中加热回流制备化合物a;Step (1): cyclization reaction: N-methylglycine, dimethyl maleate in toluene heated to reflux to prepare compound a;
步骤(2):化合物a与苄胺反应制备化合物b;Step (2): Compound a is reacted with benzylamine to prepare compound b;
步骤(3):氩气保护下,化合物b被氢化铝锂还原生成化合物c;Step (3): under the protection of argon, compound b is reduced by lithium aluminum hydride to form compound c;
步骤(4):经氢化脱保护制得3-甲基-3,7-二氮杂双环[3.3.0]辛烷药物中间体;Step (4): obtaining 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate by hydrogenation deprotection;
作为优选,步骤(1)反应时间是2~4h。Preferably, the reaction time of the step (1) is 2 to 4 hours.
作为优选,步骤(2)反应溶剂是无水乙醇。Preferably, the reaction solvent of the step (2) is anhydrous ethanol.
作为优选,步骤(3)反应溶剂是无水四氢呋喃。Preferably, the reaction solvent of the step (3) is anhydrous tetrahydrofuran.
作为优选,步骤(4)中使用的催化剂是钯催化剂。Preferably, the catalyst used in the step (4) is a palladium catalyst.
本发明提供的药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,利用成本低,容易获得的马来酸二甲酯和N-甲基甘氨酸为原料,经过四步反应,得到3-甲基-3,7-二氮杂双环[3.3.0]辛烷。本方法原料易得,成本低,反应简单,易于控制,处理简单,收率高,并且易于放大生产。The method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane, a pharmaceutical intermediate provided by the invention, utilizes low cost and easily obtained dimethyl maleate and N-methylglycine As a raw material, after three steps of reaction, 3-methyl-3,7-diazabicyclo[3.3.0]octane was obtained. The method has the advantages that the raw materials are easy to obtain, the cost is low, the reaction is simple, the control is easy, the treatment is simple, the yield is high, and the production is easy to be enlarged.
下面结合具体实施例对本发明作进一步详述。
The invention will be further described in detail below with reference to specific embodiments.
一种结构式为I药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,该方法包含下列步骤:A method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane of the formula I, which comprises the following steps:
步骤(1):环化反应:将N-甲基甘氨酸、马来酸二甲酯在甲苯中加热回流制备化合物a;Step (1): cyclization reaction: N-methylglycine, dimethyl maleate in toluene heated to reflux to prepare compound a;
具体如下:将5.2g(0.05mol,1.5eq)N-甲基甘氨酸、4.2g(0.034mol,1eq)马来酸二甲酯和3g(0.1mol,3eq)加到60ml的甲苯中,加热回流,搅拌2h,TLC检测,反应完全,旋干,在残夜中加入50mL乙酸乙酯,用饱和食盐水洗涤(3*50mL),硫酸镁干燥,旋干得化合物a(8.8g,80%)。Specifically, as follows: 5.2 g (0.05 mol, 1.5 eq) of N-methylglycine, 4.2 g (0.034 mol, 1 eq) of dimethyl maleate and 3 g (0.1 mol, 3 eq) were added to 60 ml of toluene and heated to reflux. The mixture was stirred for 2 h, and the mixture was evaporated to dryness. EtOAc (EtOAc)
步骤(2):化合物a与苄胺反应制备化合物b;Step (2): Compound a is reacted with benzylamine to prepare compound b;
具体如下:将4.02g(20mmol,1eq)化合物a和2.15g(20mmol,1eq)苄胺加入到40mL无水乙醇中,加热回流过夜,TLC检测终点,旋干得4g化合物b,收率81%Specifically, as follows: 4.02 g (20 mmol, 1 eq) of compound a and 2.15 g (20 mmol, 1 eq) of benzylamine were added to 40 mL of absolute ethanol, and the mixture was heated to reflux overnight, and the end of TLC was taken to yield 4 g of compound b, yield 81%.
步骤(3):氩气保护下,化合物b被氢化铝锂还原生成化合物c;Step (3): under the protection of argon, compound b is reduced by lithium aluminum hydride to form compound c;
具体如下:氩气保护下,在250mL三瓶中加入6.6g锂铝氢(0.18mol,3eq)和180mL无水THF,冰水浴下将14g化合物b(0.058mo1)溶解在70mL无水THF中,滴加到反应瓶中,滴加完毕后,自然升至室温,搅拌40min,然后回流5h,冷却至0度,依次滴加6.6g水、13.3g15%氢氧化钠水溶液和6.6g水,过滤,滤饼用乙醚洗涤3次,每次使用200mL乙醚,滤液用乙醚萃取3次,每次使用200mL乙醚,用硫酸镁干燥,过滤旋干,减压蒸馏得化合物c(7g,58%)Specifically, under argon protection, 6.6 g of lithium aluminum hydrogen (0.18 mol, 3 eq) and 180 mL of anhydrous THF were added to 250 mL of three bottles, and 14 g of compound b (0.058 mol) was dissolved in 70 mL of anhydrous THF under ice water bath. Add to the reaction flask, after the addition is completed, naturally rise to room temperature, stir for 40 min, then reflux for 5 h, cool to 0 °, and then add 6.6 g of water, 13.3 g of 15% aqueous sodium hydroxide solution and 6.6 g of water, filter, filter The cake was washed with diethyl ether three times, each time using 200 mL of diethyl ether, and the filtrate was extracted with diethyl ether three times, each time using 200 mL of diethyl ether, dried over magnesium sulfate, filtered and dried, and evaporated to give compound c (7 g, 58%)
步骤(4):经氢化脱保护制得3-甲基-3,7-二氮杂双环[3.3.0]辛烷药物中间体。Step (4): Hydrodeprotection to obtain 3-methyl-3,7-diazabicyclo[3.3.0]octane drug intermediate.
具体如下:在100mL的单口瓶中将8g化合物c溶解在80mL甲醇中,0.8gPd/C(10%w/w)加入到反应液中,用氢气置换三次,室温搅拌过夜,TLC检测反应完毕,过滤,浓缩,得得到3-甲基-3,7-二氮杂双环[3.3.0]辛烷(4.2g,93%),纯度GC>98.0%。Specifically, as follows: 8 g of the compound c was dissolved in 80 mL of methanol in a 100 mL single-mouth bottle, 0.8 g of Pd/C (10% w/w) was added to the reaction solution, and the mixture was replaced with hydrogen three times, stirred at room temperature overnight, and the reaction was completed by TLC. Filtration and concentration gave 3-methyl-3,7-diazabicyclo[3.3.0]octane (4.2 g, 93%).
本发明提供的药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,利用成本低,容易获得的马来酸二甲酯和N-甲基甘氨酸为原料,经过四步反应,得到3-甲基-3,7-二氮杂双环[3.3.0]辛烷。本方法原料易得,成本低,反应简单,易于控制,处理简单,收率高,并且易于放大生产。本发明为绿色化工提供了一条切实可行的医药中间体的合成方法。The method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane, a pharmaceutical intermediate provided by the invention, utilizes low cost and easily obtained dimethyl maleate and N-methylglycine As a raw material, after three steps of reaction, 3-methyl-3,7-diazabicyclo[3.3.0]octane was obtained. The method has the advantages that the raw materials are easy to obtain, the cost is low, the reaction is simple, the control is easy, the treatment is simple, the yield is high, and the production is easy to be enlarged. The invention provides a practical and feasible method for synthesizing pharmaceutical intermediates for green chemicals.
本领域的技术人员可以对发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包括这些改动和变型在内。
A person skilled in the art can make various modifications and variations to the invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of the invention as claimed.
Claims (5)
- 一种药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,其特征在于,该方法包含下列步骤:A method for synthesizing a pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane, characterized in that the method comprises the following steps:步骤(1):环化反应:将N-甲基甘氨酸、马来酸二甲酯在甲苯中加热回流制备化合物a;Step (1): cyclization reaction: N-methylglycine, dimethyl maleate in toluene heated to reflux to prepare compound a;步骤(2):化合物a与苄胺反应制备化合物b;Step (2): Compound a is reacted with benzylamine to prepare compound b;步骤(3):氩气保护下,化合物b被氢化铝锂还原生成化合物c;Step (3): under the protection of argon, compound b is reduced by lithium aluminum hydride to form compound c;步骤(4):经氢化脱保护制得3-甲基-3,7-二氮杂双环[3.3.0]辛烷药物中间体;Step (4): obtaining 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate by hydrogenation deprotection;
- 根据权利要求1所述的药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,其特征在于,步骤(1)反应时间是2~4h。The method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane as a pharmaceutical intermediate according to claim 1, wherein the reaction time in the step (1) is 2 to 4 hours.
- 根据权利要求1所述的药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法,其特征在于,步骤(2)反应溶剂是无水乙醇。The method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane as a pharmaceutical intermediate according to claim 1, wherein the reaction solvent in the step (2) is anhydrous ethanol.
- 根据权利要求1所述的药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法其特征在于,步骤(3)反应溶剂是无水四氢呋喃。The method for synthesizing the 3-amino-3,7-diazabicyclo[3.3.0]octane as the pharmaceutical intermediate according to claim 1, wherein the reaction solvent in the step (3) is anhydrous tetrahydrofuran.
- 根据权利要求1所述的药物中间体3-甲基-3,7-二氮杂双环[3.3.0]辛烷的合成方法其特征在于,步骤(4)中使用的催化剂是钯催化剂。 The method for synthesizing the pharmaceutical intermediate 3-methyl-3,7-diazabicyclo[3.3.0]octane according to claim 1, wherein the catalyst used in the step (4) is a palladium catalyst.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410664648.9 | 2014-11-19 | ||
CN201410664648.9A CN104402891A (en) | 2014-11-19 | 2014-11-19 | Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016078108A1 true WO2016078108A1 (en) | 2016-05-26 |
Family
ID=52640571
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2014/092277 WO2016078108A1 (en) | 2014-11-19 | 2014-11-26 | Method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN104402891A (en) |
WO (1) | WO2016078108A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111363005A (en) * | 2018-12-26 | 2020-07-03 | 联宁(苏州)生物制药有限公司 | Synthetic method for antibody-coupled drug intermediate CLB-SN38 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101619064A (en) * | 2008-07-01 | 2010-01-06 | 韶远化学科技(上海)有限公司 | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates |
CN102101861A (en) * | 2008-07-01 | 2011-06-22 | 韶远化学科技(上海)有限公司 | Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate |
CN102180874A (en) * | 2008-07-01 | 2011-09-14 | 韶远化学科技(上海)有限公司 | Synthetic process method for azabicyclo medicinal intermediates |
CN102977105A (en) * | 2012-11-30 | 2013-03-20 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis method of 3(methyl),7-diazabicyclooctane |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5179090A (en) * | 1989-09-11 | 1993-01-12 | Klaus Rudolf | Condensed diazepinones and medicaments containing these compounds |
-
2014
- 2014-11-19 CN CN201410664648.9A patent/CN104402891A/en active Pending
- 2014-11-26 WO PCT/CN2014/092277 patent/WO2016078108A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101619064A (en) * | 2008-07-01 | 2010-01-06 | 韶远化学科技(上海)有限公司 | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates |
CN102101861A (en) * | 2008-07-01 | 2011-06-22 | 韶远化学科技(上海)有限公司 | Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate |
CN102180874A (en) * | 2008-07-01 | 2011-09-14 | 韶远化学科技(上海)有限公司 | Synthetic process method for azabicyclo medicinal intermediates |
CN102977105A (en) * | 2012-11-30 | 2013-03-20 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis method of 3(methyl),7-diazabicyclooctane |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111363005A (en) * | 2018-12-26 | 2020-07-03 | 联宁(苏州)生物制药有限公司 | Synthetic method for antibody-coupled drug intermediate CLB-SN38 |
CN111363005B (en) * | 2018-12-26 | 2021-08-17 | 联宁(苏州)生物制药有限公司 | Synthetic method for antibody-coupled drug intermediate CLB-SN38 |
Also Published As
Publication number | Publication date |
---|---|
CN104402891A (en) | 2015-03-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2016026380A1 (en) | Method for preparing idelalisib | |
CN104447443B (en) | A kind of Apremilast and the preparation method of intermediate thereof | |
CN109651225B (en) | Preparation method of 1-methyl-3-morphinyl-4-arylmercapto maleimide compound | |
KR20160094945A (en) | Process for large scale production of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1h-indole dimesylate monohydrate | |
AU2018366342A1 (en) | Method for preparing Baricitinib | |
CN103509025A (en) | Preparation method of epinastine hydrochloride and intermediate thereof | |
TR201807444T4 (en) | Preparation of amino acid compounds. | |
CN103183673B (en) | The synthetic method of (S, S)-2,8-diazabicyclo [4,3,0] nonane | |
CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
CN110272414A (en) | A kind of preparation method of zolpidem | |
WO2016078108A1 (en) | Method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate | |
CN108640884B (en) | 2-morpholinone salt, preparation method thereof and preparation method of 2-morpholinone | |
CN103467449B (en) | Piperidine derivative, and preparation method and application thereof in preparation of halofuginone | |
WO2022222913A1 (en) | Preparation method for l-nicotine | |
JP6733449B2 (en) | Method for producing berberine alkaloid | |
CN108727214B (en) | Synthetic method of anesthetic bupivacaine impurity | |
CN104804008B (en) | A kind of method of suitability for industrialized production methylsulfonic acid Telatinib | |
CN102702196B (en) | Method for synthesizing 3-methyl-7-diazaindene | |
CN108129414B (en) | Preparation method of mosapride citrate intermediate | |
CN111925310A (en) | 3-amino-4-arylseleno maleimide compound and preparation method thereof | |
CN111320622A (en) | Method for synthesizing moxifloxacin hydrochloride | |
CN105085526B (en) | A kind of improved silaenafil preparation method | |
CN108658961A (en) | A kind of preparation method of Azilsartan | |
CN106604921B (en) | The method that 1- isopropyl -3- { 5- [1- (3- methoxy-propyl) piperidin-4-yl]-[1,3,4] oxadiazoles -2- base } -1H- indazole oxalates is mass produced | |
CN108017576B (en) | Preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14906438 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 26.07.2017) |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14906438 Country of ref document: EP Kind code of ref document: A1 |