CN103980226A - Acotiamide hydrochloride hydrate crystal form and preparation method thereof - Google Patents

Acotiamide hydrochloride hydrate crystal form and preparation method thereof Download PDF

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Publication number
CN103980226A
CN103980226A CN201410194795.4A CN201410194795A CN103980226A CN 103980226 A CN103980226 A CN 103980226A CN 201410194795 A CN201410194795 A CN 201410194795A CN 103980226 A CN103980226 A CN 103980226A
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CN
China
Prior art keywords
examining
hydrochloric acid
amine
type crystallization
amine hydrate
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Pending
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CN201410194795.4A
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Chinese (zh)
Inventor
杜焕达
丁建圣
郑阳峰
王万青
刘艳华
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Hangzhou Xin Bosi Biological Medicine Co Ltd
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Hangzhou Xin Bosi Biological Medicine Co Ltd
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Priority to CN201410194795.4A priority Critical patent/CN103980226A/en
Publication of CN103980226A publication Critical patent/CN103980226A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

The invention relates to a crystal form of an acotiamide hydrochloride hydrate shown as a chemical formula (I) and a preparation method thereof. Specifically, the present invention discloses an acotiamide hydrochloride hydrate of crystal form A and a preparation method thereof, and the XRPD characteristic peak is shown as in a figure 1. The preparation method of the acotiamide hydrochloride hydrate of crystal form A provided by the invention is safe, simple and strongly operable, the prepared acotiamide hydrochloride hydrate of crystal form A has single crystal form, stable property and good repeatability, and suitable for drug development.

Description

Hydrochloric acid Ah examining is for amine hydrate crystal forms and preparation method thereof
Technical field
The present invention relates to medical technical field, be specifically related to hydrochloric acid Ah examining for amine hydrate new crystal and preparation method thereof.
Background technology
Hydrochloric acid Ah examining, for amine hydrate, developed jointly by Japanese Ze Li new drug Co., Ltd. and An Sitelaisi drugmaker, on June 6th, 2013, takes the lead in Japan's listing, and commodity are called Acofide.Chemistry is by name: N-[2-(two isopropylamino) ethyl]-2-[(2-hydroxyl-4,5-dimethoxy benzoyl) amino]-4-thiazole carboxamides hydrochloride hydrate.Its structure is as shown in the formula (I):
Hydrochloric acid Ah examining for amine hydrate indication be epigastric discomfort, feel sick, prevention and the treatment of vomiting, pyrosis, apocleisis, abdominal distension gas, chronic gastritis, reflux esophagitis and dumping syndrome.
Functional dyspepsia is modal a kind of digestive system function disorder disease clinically.In recent years, functional dyspepsia sickness rate raises year by year.American-European epidemiology survey shows, person accounts for 19%～41% in general population, to have indigestion symptom.In China, indigestion symptom person accounts for Digestive System Department patient's 40%, accounts for 19% of normal population.Have a strong impact on daily life, become gradually the major issue that modern society pays close attention to.
Hydrochloric acid Ah examining is the medicine of first functional dyspepsia of whole world approval for amine hydrate.The clinical test results of Japan proves, hydrochloric acid Ah examining has good treatment validity for amine hydrate, and without serious adverse reaction.
At present, existing many pieces of reported in literature preparation and the application of hydrochloric acid Ah examining for amine hydrate.CN1063442C be hydrochloric acid Ah examining for amine hydrate in Chinese compound patent, protection hydrochloric acid Ah examining is for amine hydrate and it is for digesting the purposes of prevention and the treatment of dyskinesis.Meanwhile, the two kind general synthetic methods of preparation Ah examining for amine or its salt in patent, have also been mentioned.
WO9858918/EP0994108/CN1084739C has reported the preparation of Ah examining for amine.
WO2012077673/CN103237781A/TW201229024A has reported the preparation method of hydrochloric acid Ah examining for amine hydrate.
CN101006040B discloses Ah examine'ing preparation for amine hydrate for amine and hydrochloric acid Ah examining.
CN 102125551A discloses hydrochloric acid Ah examining and for amine hydrate, has been used for the treatment of stomach and holds obstacle.
Not yet there is up to now document to mention that hydrochloric acid Ah examining is for crystal formation and the preparation method of amine hydrate, the spectral response curve of more not mentioned relevant crystal formation.
Drug crystal forms research and the solid-state pharmacy industry that is characterized in of medicine have very important meaning.For medicinal compound, its physics, chemical stability under different conditions of storage is extremely important, and different crystal formations is in stability, solubleness, biochemical property aspect may there were significant differences with bioavailability etc., thereby affect the curative effect of medicine.Therefore, research and develop the crystal formation of favourable medicinal feature significant.
The invention provides a kind of hydrochloric acid Ah examining for amine hydrate new crystal and preparation method thereof, the resulting A type of this method crystallization hydrochloric acid Ah examining is single for amine hydrate crystal forms, stable in properties, through long-term and accelerated stability, investigates up-to-standard; And In Vitro Dissolution is good, be conducive to the absorption of medicine, be applicable to drug development.
Summary of the invention
The object of the present invention is to provide a kind of A type crystallization hydrochloric acid Ah examining for amine hydrate, it is characterized in that: its powder x-ray diffraction collection of illustrative plates in 2 θ=6.18 ± 0.2 °, 11.80 ± 0.2 °, 12.42 ± 0.2 °, 14.62 ± 0.2 °, 18.24 ± 0.2 °, 23.06 ± 0.2 °, 23.68 ± 0.2 °, 25.96 ± 0.2 ° and 28.56 ± 0.2 ° located characteristic peak, (wherein " ± 0.2 ° " measuring error scope for allowing) as shown in Figure 1.
Described A type crystallization hydrochloric acid Ah examining for amine hydrate infrared absorption spectrum at about 3488(cm -1), 3300(cm -1), 3095(cm -1), 2950(cm -1), 2672(cm -1), 1649(cm -1), 1566(cm -1), 1543(cm -1), 1522(cm -1), 1444(cm -1), 1342(cm -1), 1269(cm -1), 1168(cm -1), 815(cm -1) and 781(cm -1) located absorption peak, as shown in Figure 2.
Described A type crystallization hydrochloric acid Ah examining at 70-95 ℃, 140-160 ℃, located fusing endotherm(ic)peak (heating rate is 10.00 ℃/min) for 160-170 ℃, as shown in Figure 3 for the differential thermal analysis collection of illustrative plates (DSC) of amine hydrate.
Described A type crystallization hydrochloric acid Ah examining has two weightless platforms for amine hydrate DSC-TGA trace, locates weightless 7%, 90-170 ℃ and locates weightlessness 3%, as shown in Figure 4 at 30-80 ℃.
Another object of the present invention has been to provide above-mentioned A type crystallization hydrochloric acid Ah examining the preparation method for amine hydrate, it is characterized in that, comprises the following steps:
(1) hydrochloric acid Ah examining is placed in to appropriate solvent for amine anhydride or hydrochloric acid Ah examining for amine hydrate, reflux is dissolved;
(2) cooling, crystallization thing;
(3) crystalline solid that filtering separation obtains from step (2), forced air drying is placed under room temperature or high humidity (humidity is greater than 60%) condition, obtains A type crystallization hydrochloric acid Ah examining for amine hydrate.
Solvent in described method steps (1) is selected from the mixture of water or water and organic solvent, is preferably the mixture of water and organic solvent.Wherein organic solvent be selected from 5 carbon atoms with interior ketone, 8 carbon atoms with interior ether, 4 carbon atoms with interior alcohol or polar organic solvent.Be preferably, ketone is acetone, butanone; Ether is tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane; Alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol; Polar organic solvent is acetonitrile, DMF, DMSO.In the mixture of water and polar organic solvent, the volume ratio of water and polar organic solvent, for being greater than 0.1, is preferably 0.25-0.75.
In the step of described method (3), the crystalline solid that filtering separation obtains from step (2), and forced air drying is until moisture <8% obtains solid.Under room temperature or high humidity (humidity is greater than 60%) condition, place, until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate.
Another object of the present invention is to provide a kind of A type crystallization hydrochloric acid Ah examining can become pharmaceutical composition with pharmaceutically acceptable auxiliary material or vehicle group for amine hydrate.
A type crystallization hydrochloric acid Ah examining provided by the invention is single for amine hydrate crystal forms, stable in properties, favorable repeatability, is applicable to drug development.
Accompanying drawing explanation
Fig. 1 is that A type crystallization hydrochloric acid Ah examining provided by the invention is for the X-ray powder diffraction of amine hydrate.
Fig. 2 is that A type crystallization hydrochloric acid Ah examining provided by the invention is for the infrared spectra (KCl compressing tablet) of amine hydrate.
Fig. 3 is that A type crystallization hydrochloric acid Ah examining provided by the invention is for the DSC collection of illustrative plates of amine hydrate.
Fig. 4 is that A type crystallization hydrochloric acid Ah examining provided by the invention is for the DSC-TGA collection of illustrative plates of amine hydrate.
Embodiment
Below by embodiment, further describe the present invention in detail, but not as limitation of the present invention.
Hydrochloric acid Ah examining in following examples is for amine anhydride or hydrochloric acid Ah examining for amine hydrate, and the method for describing according to patent CN101006040A is prepared gained.
Embodiment 1
Get 3.0g hydrochloric acid Ah examining and for amine hydrate, drop in the methanol aqueous solution of 12.0g 20%, reflux is to dissolving.Be cooled to 20 ℃, filter.Filter cake is in 50 ℃ of forced air dryings to moisture <8%.At room temperature in air, place, until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate 2.31 g, yield is 77.0%.
Embodiment 2
Get 2.0g hydrochloric acid Ah examining and for amine anhydride, drop in the isopropanol water solution of 8.0g 40%, reflux is to dissolving.Be cooled to 20 ℃, filter.Filter cake is in 50 ℃ of forced air dryings to moisture <8%.At room temperature in air, place until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate 2.0g, yield is 90.0%.
Embodiment 3
Get 3.0g hydrochloric acid Ah examining and for amine hydrate, drop in the acetonitrile solution of 12.0g 20%, reflux is to dissolving.Be cooled to 20 ℃, filter.Filter cake is in 50 ℃ of forced air dryings to moisture <8%.At room temperature in air, place until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate 2.59g, yield is 86.3%.
Embodiment 4
Get 3.0g hydrochloric acid Ah examining and for amine hydrate, drop in Isosorbide-5-Nitrae-dioxane aqueous solution of 12.0g 20%, reflux is to dissolving.Be cooled to 20 ℃, filter.Filter cake is in 50 ℃ of forced air dryings to moisture <8%.At room temperature in air, place until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate 2.60g, yield is 86.7%.
Embodiment 5
Get 3.0g hydrochloric acid Ah examining and for amine hydrate, drop in the DMF aqueous solution of 12.0g 20%, reflux is to dissolving.Be cooled to 20 ℃, filter.Filter cake is in 50 ℃ of forced air dryings to moisture <8%.At room temperature in air, place until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate 2.53g, yield is 84.3%.
Embodiment 6
Get 1.0g hydrochloric acid Ah examining and drop in the 20.0g aqueous solution for amine hydrate, reflux is to dissolving.Be cooled to 20 ℃, filter.Filter cake is in 50 ℃ of forced air dryings to moisture <8%.At room temperature in air, place until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate 0.52g, yield is 52.0%.

Claims (10)

1.A type crystallization hydrochloric acid Ah examining is for amine hydrate, it is characterized in that, its powder x-ray diffraction collection of illustrative plates in 2 θ=6.18 ± 0.2 °, 11.80 ± 0.2 °, 12.42 ± 0.2 °, 14.62 ± 0.2 °, 18.24 ± 0.2 °, 23.06 ± 0.2 °, 23.68 ± 0.2 °, 25.96 ± 0.2 ° and 28.56 ± 0.2 ° located characteristic peak.
2. A type crystallization hydrochloric acid Ah examining according to claim 1, for amine hydrate, is characterized in that: its infrared absorption spectrum is at about 3488(cm -1), 3300(cm -1), 3095(cm -1), 2950(cm -1), 2672(cm -1), 1649(cm -1), 1566(cm -1), 1543(cm -1), 1522(cm -1), 1444(cm -1), 1342(cm -1), 1269(cm -1), 1168(cm -1), 815(cm -1) and 781(cm -1) located absorption peak.
3. A type crystallization hydrochloric acid Ah examining according to claim 1 is for amine hydrate, it is characterized in that: described A type crystallization hydrochloric acid Ah examining at 70-95 ℃, 140-160 ℃, located fusing endotherm(ic)peak (heating rate is 10.00 ℃/min) for the differential thermal analysis collection of illustrative plates (DSC) of amine hydrate for 160-170 ℃.
4. A type crystallization hydrochloric acid Ah examining according to claim 1, for amine hydrate, is characterized in that: described A type crystallization hydrochloric acid Ah examining has two weightless platforms for amine hydrate DSC-TGA trace, locates weightless 7%, 90-170 ℃ locate weightless 3% at 30-80 ℃.
According to A type crystallization hydrochloric acid Ah the examining described in claim 1-4 for amine hydrate, it is characterized in that: described hydrochloric acid Ah examining is that hydrochloric acid Ah examining is for amine trihydrate for amine hydrate.
6. preparation A type crystallization hydrochloric acid Ah examining as claimed in claim 1, for the method for amine hydrate, comprises the following steps:
(1) hydrochloric acid Ah examining is placed in to appropriate solvent for amine anhydride or hydrochloric acid Ah examining for amine hydrate, reflux is dissolved;
(2) cooling, crystallization thing;
(3) crystalline solid that filtering separation obtains from step (2), forced air drying is placed under room temperature or high humidity (humidity is greater than 60%) condition, obtains A type crystallization hydrochloric acid Ah examining for amine hydrate.
7. method according to claim 6, is characterized in that: in method steps (1), described solvent is selected from the mixture of water or water and organic solvent, is preferably the mixture of water and organic solvent; Wherein organic solvent be selected from 5 carbon atoms with interior ketone, 8 carbon atoms with interior ether, 4 carbon atoms with interior alcohol or polar organic solvent; Be preferably, ketone is acetone, butanone; Ether is tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane; Alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol; Polar organic solvent is acetonitrile, DMF, DMSO.
8. method according to claim 7, is characterized in that: in the mixture of water and organic solvent, the volume ratio of water and polar organic solvent, for being greater than 0.1, is preferably 0.25-0.75.
9. method according to claim 6, is characterized in that: in the step of described method (3), and the crystalline solid that filtering separation obtains from step (2), and forced air drying is until moisture <8% obtains solid; Under room temperature or high humidity (humidity is greater than 60%) condition, place, until moisture is 9.8%-10.5%, obtain A type crystallization hydrochloric acid Ah examining for amine hydrate.
10. a pharmaceutical composition, A type crystallization hydrochloric acid Ah the examining that it contains significant quantity is for amine hydrate and pharmaceutically acceptable auxiliary material or carrier.
CN201410194795.4A 2014-05-10 2014-05-10 Acotiamide hydrochloride hydrate crystal form and preparation method thereof Pending CN103980226A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105481791A (en) * 2015-12-09 2016-04-13 北京科莱博医药开发有限责任公司 Acotiamide hydrochloride dihydrate crystal, and preparation method and applications thereof
CN105753807A (en) * 2014-12-16 2016-07-13 四川海思科制药有限公司 Acotiamide hydrochloride hydrate compound
CN107176934A (en) * 2017-07-11 2017-09-19 湖南七纬科技有限公司 One kind treats dyspeptic drug hydrate and preparation method thereof
CN107235928A (en) * 2017-07-11 2017-10-10 湖南七纬科技有限公司 It is a kind of to treat medical compounds of functional dyspepsia FD and preparation method thereof
CN107266389A (en) * 2017-07-11 2017-10-20 湖南七纬科技有限公司 It is a kind of to treat medicine times semihydrate of enterogastric diseases and preparation method thereof
CN113121466A (en) * 2019-12-31 2021-07-16 成都迪康药业股份有限公司 Recrystallization solvent of acotiamide hydrochloride and refining method thereof

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US5981557A (en) * 1995-05-18 1999-11-09 Zeria Pharmaceutical Co., Ltd. Aminothiazole derivative, medicament containing the same, and intermediate for preparation of said compound
CN1261357A (en) * 1997-06-24 2000-07-26 泽里新药工业株式会社 Process for producing 2-hydroxybenzamide derivatives
WO2003084537A1 (en) * 2002-04-08 2003-10-16 Zeria Pharmaceutical Co., Ltd. Therapeutic agent for food competence disorder in stomach
CN101006040A (en) * 2004-08-23 2007-07-25 泽里新药工业株式会社 Method for producing aminothiazole derivative and production intermediate
CN103665023A (en) * 2013-12-23 2014-03-26 华润赛科药业有限责任公司 Synthetic method of acotiamide hydrochloride
CN103709120A (en) * 2014-01-20 2014-04-09 华润赛科药业有限责任公司 Method for preparing acotiamide hydrochloride trihydrate
CN103709191A (en) * 2014-01-20 2014-04-09 华润赛科药业有限责任公司 Synthetic method of acotiamide hydrochloride hydrate
CN103896873A (en) * 2013-10-23 2014-07-02 山东诚创医药技术开发有限公司 Refining method for hydrochloride acid acotiamide

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981557A (en) * 1995-05-18 1999-11-09 Zeria Pharmaceutical Co., Ltd. Aminothiazole derivative, medicament containing the same, and intermediate for preparation of said compound
CN1261357A (en) * 1997-06-24 2000-07-26 泽里新药工业株式会社 Process for producing 2-hydroxybenzamide derivatives
WO2003084537A1 (en) * 2002-04-08 2003-10-16 Zeria Pharmaceutical Co., Ltd. Therapeutic agent for food competence disorder in stomach
CN101006040A (en) * 2004-08-23 2007-07-25 泽里新药工业株式会社 Method for producing aminothiazole derivative and production intermediate
CN103896873A (en) * 2013-10-23 2014-07-02 山东诚创医药技术开发有限公司 Refining method for hydrochloride acid acotiamide
CN103665023A (en) * 2013-12-23 2014-03-26 华润赛科药业有限责任公司 Synthetic method of acotiamide hydrochloride
CN103709120A (en) * 2014-01-20 2014-04-09 华润赛科药业有限责任公司 Method for preparing acotiamide hydrochloride trihydrate
CN103709191A (en) * 2014-01-20 2014-04-09 华润赛科药业有限责任公司 Synthetic method of acotiamide hydrochloride hydrate

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753807A (en) * 2014-12-16 2016-07-13 四川海思科制药有限公司 Acotiamide hydrochloride hydrate compound
CN105481791A (en) * 2015-12-09 2016-04-13 北京科莱博医药开发有限责任公司 Acotiamide hydrochloride dihydrate crystal, and preparation method and applications thereof
CN107176934A (en) * 2017-07-11 2017-09-19 湖南七纬科技有限公司 One kind treats dyspeptic drug hydrate and preparation method thereof
CN107235928A (en) * 2017-07-11 2017-10-10 湖南七纬科技有限公司 It is a kind of to treat medical compounds of functional dyspepsia FD and preparation method thereof
CN107266389A (en) * 2017-07-11 2017-10-20 湖南七纬科技有限公司 It is a kind of to treat medicine times semihydrate of enterogastric diseases and preparation method thereof
CN113121466A (en) * 2019-12-31 2021-07-16 成都迪康药业股份有限公司 Recrystallization solvent of acotiamide hydrochloride and refining method thereof
CN113121466B (en) * 2019-12-31 2023-12-15 成都迪康药业股份有限公司 Recrystallizing solvent of acotiamide hydrochloride and refining method thereof

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Application publication date: 20140813