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    • 9. 发明申请
    • NOVEL PROCESS FOR PREPARATION OF DULOXETINE HYDROCHLORIDE
    • 用于制备DOROXETINE氢氯化物的新方法
    • US20100105925A1
    • 2010-04-29
    • US12530214
    • 2008-03-05
    • Rajinder Singh SiyanSunil Kumar Vinubhai GohelGirij Pal Singh
    • Rajinder Singh SiyanSunil Kumar Vinubhai GohelGirij Pal Singh
    • C07D333/20C07C51/42
    • C07D333/20
    • An improved process for synthesis of duloxetine hydrochloride (1) having chiral purity greater than 99.9% that is characterized by the following: (i) preparation of racemic condensed compound (RS)—N,N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (4) by reaction of racemic hydroxy compound (2) with 1-fluoronaphthalene (3) in presence of a base such as sodamide, potassium amide or potassium bis(trimethylsilyl)amide (KHDMS) in polar aprotic solvent, (ii) optical resolution of racemic condensed compound (5a+5b) with di-benzoyl-L-tartaric acid (7, DBTA, R═H) or di-para-anisoyl-L-tartaric acid (7, DATA, R═OCH3) to obtain crude (S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine dibenzoyl tartarate salt (8a) or (S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine di-p-anisoyl tartarate salt (9a) respectively, (iii) optionally purification of crude tartarate salts (8a or 9a) by crystallization, (iv) optionally purification of duloxetine hydrochloride (1) by crystallization and (v) racemization of undesired (R)—N,N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5b) by treatment with base potassium bis(trimethylsilyl)amide (KHDMS) to obtain racemic mixture of condensed compounds (5a and 5b).
    • 具有手性纯度大于99.9%的改进的度洛西汀盐酸盐(1)的改进方法,其特征在于:(i)制备外消旋缩合化合物(RS)-N,N-二甲基-3-(1-萘氧基 )3-(2-噻吩基)丙胺(4),通过外消旋羟基化合物(2)与1-氟萘(3)在碱如Sodamide,氨基化钾或双(三甲基甲硅烷基)氨基钾(KHDMS)的存在下反应, 在极性非质子溶剂中,(ii)用二苯甲酰基-L-酒石酸(7,DBTA,R = H)或二对甲氧基苯甲酰基-L-酒石酸(7)的外消旋缩合化合物(5a + 5b) ,DATA,R = OCH 3),得到粗(S)-N,N-二甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺二苯甲酰酒石酸盐(8a)或(S)-N,N (3-萘基氧基)-3-(2-噻吩基)丙胺二对茴香酰酒石酸盐(9a),(iii)任选地通过结晶纯化粗酒石酸盐(8a或9a),(iv )任选地通过哭泣来纯化度洛西汀盐酸盐(1) (R)-N,N-二甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺(5b)通过用双(三甲基甲硅烷基)氨基钾酰胺(KHDMS)处理 ),得到缩合化合物(5a和5b)的外消旋混合物。
    • 10. 发明授权
    • Process for preparation of perindopril and salts thereof
    • 培哚普利及其盐的制备方法
    • US07521566B2
    • 2009-04-21
    • US10547243
    • 2003-02-28
    • Debashish DattaGirij Pal SinghHimanshu Madhav GodboleRajinder Singh Siyan
    • Debashish DattaGirij Pal SinghHimanshu Madhav GodboleRajinder Singh Siyan
    • C07D209/42
    • C07D209/42C07C227/32C07C227/34C07C229/12
    • A process for preparation of perindopril of formula (II) and salts thereof which is simple, safe, convenient and cost-effective. The process involves reaction of compound of formula (I), wherein X is chlorine or bromine with compound of formula (VII) wherein A signifies that the six-membered ring of the bicyclic system is either saturated or unsaturated to give compound of formula (VIII), wherein A is as defined above, followed by catalytic hydrogenation of the compound of formula (VIII) thus obtained to give the perindopril of formula (II). The above process for the manufacture of perindopril would specifically avoid the use of harmful chemicals like phosgene or costly coupling agents like dicyclohexylcarbodiimide and 1-hydroxybenxotriazole usually used for such manufacture. The process would also not require any intervention of a catalyst and does not require any alkaline or acidic reaction conditions. Importantly, the process provides for manufacture of perindopril with high stereoselectively giving perindopril (II) having (S)-configuration in all the five chiral centres of the molecule, conforming to pharmacoepeial specifications. The invention also relates to a method for preparation of the compound of formula (I) and also to a method for preparation of N-[(S)-1-carbethoxybutyl]-(S)-alanine of formula (III) used in the process.
    • 一种制备式(II)培哚普利及其盐的方法,其简单,安全,方便和具有成本效益。 该方法包括式(I)化合物,其中X是氯或溴与式(Ⅶ)化合物反应,其中A表示双环系统的六元环是饱和或不饱和的,得到式(Ⅷ)化合物 ),其中A如上所定义,然后将由此获得的式(VIII)化合物进行催化氢化,得到式(II)的培哚普利。 上述制造培哚普利的方法将特别避免使用通常用于制造的有害化学物质如光气或昂贵的偶联剂如二环己基碳二亚胺和1-羟基苯并三唑。 该方法也不需要任何催化剂的干预,并且不需要任何碱性或酸性反应条件。 重要的是,该方法提供了高度立体选择性地给予符合药代动力学规范的在分子的所有五个手性中心具有(S) - 构型的培哚普利(II)的培哚普利的培哚普利。 本发明还涉及制备式(I)化合物的方法,还涉及制备式(III)化合物的N - [(S)-1-乙酯基丁基] - (S) - 丙氨酸的方法, 处理。