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1. WO2020135508 - MINOCYCLINE(II) P-CHLOROBENZENE SULFONATE CRYSTAL FORM, PREPARATION METHOD THEREFOR AND USE THEREOF

Publication Number WO/2020/135508
Publication Date 02.07.2020
International Application No. PCT/CN2019/128333
International Filing Date 25.12.2019
IPC
C07C 237/26 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
237Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
24having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
26of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
C07C 231/12 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
231Preparation of carboxylic acid amides
12by reactions not involving the formation of carboxamide groups
CPC
C07B 2200/13
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
2200Indexing scheme relating to specific properties of organic compounds
13Crystalline forms, e.g. polymorphs
C07C 231/12
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
231Preparation of carboxylic acid amides
12by reactions not involving the formation of carboxamide groups
C07C 237/26
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
237Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
24having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
26of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
C07C 2603/46
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
2603Systems containing at least three condensed rings
02Ortho- or ortho- and peri-condensed systems
40containing four condensed rings
42containing only six-membered rings
44Naphthacenes; Hydrogenated naphthacenes
461,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
C07C 303/32
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
303Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
32of salts of sulfonic acids
C07C 309/39
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
309Sulfonic acids; Halides, esters, or anhydrides thereof
01Sulfonic acids
28having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
39containing halogen atoms bound to the carbon skeleton
Applicants
  • 浙江昌海制药有限公司 ZHEJIANG CHANGHAI PHARMACEUTICAL CO., LTD. [CN]/[CN]
  • 浙江医药股份有限公司新昌制药厂 ZHEJIANG MEDICINE CO., LTD. XINCHANG PHARMACEUTICAL FACORTY [CN]/[CN]
Inventors
  • 刘泺 LIU, Luo
  • 吴国锋 WU, Guofeng
  • 申向黎 SHEN, Xiangli
  • 余腾飞 YU, Tengfei
  • 金建青 JIN, Jianqing
  • 黎亮 LI, Liang
  • 谢斌 XIE, Bin
  • 李炜 LI, Wei
  • 陈龙 CHEN, Long
Agents
  • 浙江翔隆专利事务所(普通合伙) ZHEJIANG SHINE PATENT OFFICE (GENERAL PARTNER)
Priority Data
201811600460.226.12.2018CN
Publication Language Chinese (ZH)
Filing Language Chinese (ZH)
Designated States
Title
(EN) MINOCYCLINE(II) P-CHLOROBENZENE SULFONATE CRYSTAL FORM, PREPARATION METHOD THEREFOR AND USE THEREOF
(FR) FORME CRISTALLINE DE SULFONATE DE MINOCYCLINE(II) P-CHLOROBENZÈNE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
(ZH) 一种米诺环素二对氯苯磺酸盐晶型及其制备方法和应用
Abstract
(EN)
Disclosed are a minocycline(II) p-chlorobenzene sulfonate crystal form, a preparation method therefor and the use thereof. In the current preparation process of minocycline hydrochloride, the last step, i.e. the post-treatment and purification operations of a hydrogenation reaction, is the bottleneck part of the process. The preparation method for the minocycline(II) p-chlorobenzene sulfonate crystal form of the present invention comprises the following steps: dissolving a hydrogenation azo substance in an alcohol solvent, adding an acid and a palladium carbon catalyst, displacing same with nitrogen gas, and then subjecting same to a hydrogenation reaction, then adding formaldehyde at a mass percent of 35-40%, and continuously subjecting same to a hydrogenation reaction; and after the reaction is finished, displacing same with nitrogen gas, filtering the catalyst, adding p-chlorobenzenesulfonic acid for crystallization, slowly decreasing the temperature to an endpoint temperature, and filtering and drying same. The preparation method of the present invention is simple and convenient, and stable, is suitable for industrialization, and is also beneficial for subsequent filtering and drying operations. For the prepared minocycline(II) p-chlorobenzene sulfonate crystal form, the product quality thereof is sufficient for raw material drugs for preparing minocycline hydrochloride which meets required standards.
(FR)
L'invention concerne une forme cristalline de sulfonate de minocycline(II) p-chlorobenzène, son procédé de préparation et son utilisation. Dans le procédé de préparation de chlorhydrate de minocycline, la dernière étape, c'est-à-dire les opérations de post-traitement et de purification d'une réaction d'hydrogénation, est la partie la plus importante du procédé. Le procédé de préparation de la forme cristalline du sulfonate de minocycline(II) p-chlorobenzène selon la présente invention comprend les étapes suivantes consistant à : dissoudre une substance azoïque d'hydrogénation dans un solvant alcoolique, ajouter un acide et un catalyseur au palladium-carbone, déplacer celui-ci avec de l'azote gazeux, puis soumettre celui-ci à une réaction d'hydrogénation, ensuite ajouter du formaldéhyde à un pourcentage en masse de 35 à 40 %, et soumettre en continu celui-ci à une réaction d'hydrogénation ; après achèvement de la réaction, déplacer celui-ci avec de l'azote gazeux, filtrer le catalyseur, ajouter l'acide p-chlorobenzènesulfonique pour la cristallisation, diminuer lentement la température jusqu'à une température de point final, et filtrer et sécher celui-ci. Le procédé de préparation selon la présente invention est simple, pratique et stable, est approprié pour une industrialisation, et est également avantageux pour des opérations de filtration et de séchage ultérieures. La qualité de produit de la forme cristalline de sulfonate de minocycline(II) p-chlorobenzène préparée est suffisante pour des matières premières de médicaments afin de préparer du chlorhydrate de minocycline répondant aux normes requises.
(ZH)
本发明公开了一种米诺环素二对氯苯磺酸盐晶型及其制备方法和应用。目前的盐酸米诺环素制备工艺中,最后一步氢化反应的后处理和纯化操作是该工艺的瓶颈部分。本发明米诺环素二对氯苯磺酸盐晶型的制备方法,包含下列步骤:氢化偶氮物溶解在醇类溶剂,加入酸和钯碳催化剂,用氮气置换后,进行氢化反应,然后加入质量百分数为35-40%的甲醛,继续进行氢化反应;反应结束后,用氮气置换,过滤催化剂,加入对氯苯磺酸进行结晶,缓慢将温度降至终点温度,过滤,干燥。本发明的制备方法简便、稳定,适合产业化,也有利于于后续的过滤和干燥操作;制得的米诺环素二对氯苯磺酸盐晶型,其产品质量足以满足用来制备合格的盐酸米诺环素原料药。
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