CN104003958A - Novel acotiamide hydrochloride hydrate crystal form and preparation method thereof - Google Patents
Novel acotiamide hydrochloride hydrate crystal form and preparation method thereof Download PDFInfo
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- CN104003958A CN104003958A CN201410237023.4A CN201410237023A CN104003958A CN 104003958 A CN104003958 A CN 104003958A CN 201410237023 A CN201410237023 A CN 201410237023A CN 104003958 A CN104003958 A CN 104003958A
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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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel acotiamide hydrochloride hydrate crystal form shown in a chemical formula (I) and a preparation method thereof, and particularly discloses a B-type crystal acotiamide hydrochloride hydrate and a preparation method thereof. An X-ray powder diffraction (XRPD) characteristic peak is shown in a figure 1. The B-type crystal acotiamide hydrochloride hydrate prepared by the method is stable in crystal form, good in solubleness, and applicable to drug development, and the used preparation method is safe, simple and convenient, and strong in maneuverability.
Description
Technical field
The present invention relates to medical technical field, be specifically related to hydrochloric acid Ah examining for amine hydrate novel crystal form and preparation method thereof.
Background technology
On June 6th, 2013, hydrochloric acid Ah the examining that Japanese Ze Li new drug Co., Ltd. and An Sitelaisi drugmaker develop jointly is for amine trihydrate, and in Japan's listing, 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 trihydrate, be functional dyspepsia medication, be mainly used in epigastric discomfort, feel sick, prevention and the treatment of vomiting, pyrosis, apocleisis, abdominal distension gas, chronic gastritis, reflux esophagitis and dumping syndrome.
Along with the change of environment and dietary structure, maldigestion sickness rate raises year by year.The maldigestion patient's in the whole world PMR approaches, and accounts for 19%～41%.Functional dyspepsia belongs to the symptom that a kind of chronic or intermittent upper digestive tract infects, it ill without organic reason, cardinal symptom is epigastric discomfort, pain, early full, nauseating and vomiting and heartburn, because illness can continue or repetitious appearance, makes people quite painful, endure ailing torment to the fullest extent, have a strong impact on patient's quality of life.
Hydrochloric acid Ah examining is the medicine of first functional dyspepsia of whole world approval for amine trihydrate, there is good curative effect and high security, change the treatment present situation of global functional dyspepsia, to patients with functional dyspepsia, brought new treatment to select.
At present, existing many pieces of reported in literature preparation and the application of hydrochloric acid Ah examining for amine trihydrate.As: CN1063442C, WO9858918/EP0994108/CN1084739C, WO2012077673/CN103237781A/TW201229024A, CN101006040B, CN 102125551A etc.
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 monohydrate, the spectral response curve of more not mentioned relevant its crystal formation.
As everyone knows, for medicinal compound, solvability is extremely important, directly affects bioavailability and the curative effect of medicine, and the crystal formation of researching and developing favourable medicinal feature is significant.
The invention provides a kind of hydrochloric acid Ah examining for amine hydrate novel crystal form and preparation method thereof, the resulting Type B crystallization of this method hydrochloric acid Ah examining is stable for amine hydrate crystal forms, we investigate for the solubleness of amine hydrate B crystal formation hydrochloric acid Ah examining, and obtain following result:
table 1 hydrochloric acid Ah examining is for the saturation solubility (37 ℃) of amine hydrate B crystal formation
| Name of product | pH1.0 | pH6.8 |
| Hydrochloric acid Ah examining is for amine hydrate B crystal formation | 1.54mg/ml | 46.18mg/ml |
Above result shows that hydrochloric acid Ah examining of the present invention has good solubility for amine hydrate B crystal formation, is conducive to the absorption of medicine, and the while is investigated up-to-standard through long-term and accelerated stability, be applicable to drug development.
Summary of the invention
The object of the present invention is to provide a kind of Type B crystallization hydrochloric acid Ah examining for amine hydrate, it is characterized in that: its powder x-ray diffraction collection of illustrative plates is in 2 θ=6.25 ± 0.2 °, 9.69 ± 0.2 °, 11.13 ± 0.2 °, 12.45 ± 0.2 °, 14.45 ± 0.2 °, 15.20 ± 0.2 °, 18.20 ± 0.2 °, 19.36 ± 0.2 °, 20.72 ± 0.2 °, 23.13 ± 0.2 °, 23.74 ± 0.2 °, 24.87 ± 0.2 °, 26.29 ± 0.2 °, 27.32 ± 0.2 °, located characteristic peak for 27.85 ± 0.2 ° and 29.12 ± 0.2 °, (wherein " ± 0.2 ° " measuring error scope for allowing) as shown in Figure 1.
Described Type B crystallization hydrochloric acid Ah examining located fusing endotherm(ic)peak for the differential thermal analysis collection of illustrative plates (DSC) of amine hydrate at 173-181 ℃, preferably at 175-179 ℃, located fusing endotherm(ic)peak (heating rate is 10.00 ℃/min), as shown in Figure 2.
Described Type B crystallization hydrochloric acid Ah examining for amine hydrate DSC-TGA trace the 100-190 ℃ of weightlessness of locating 3.0%-5.0%, as shown in Figure 3.
The above hydrochloric acid Ah examining refers to that for amine hydrate hydrochloric acid Ah examining is for amine monohydrate.
Another object of the present invention has been to provide above-mentioned Type B 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 trihydrate, 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 condition or high humidity (humidity is greater than 60%) condition, obtains Type B crystallization hydrochloric acid Ah examining for amine hydrate.
Organic solvent in described method steps (1) 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 described method steps (3), the crystalline solid that filtering separation obtains from step (2), and forced air drying are placed under room temperature or high humidity (humidity is greater than 60%) condition, until moisture is 3.0%-5.0%, obtain Type B crystallization hydrochloric acid Ah examining for amine hydrate.
Type B crystallization hydrochloric acid Ah examining provided by the invention is stable for amine hydrate crystal forms, solvability is good, is applicable to drug development.
Accompanying drawing explanation
Fig. 1 is that Type B crystallization hydrochloric acid Ah examining provided by the invention is for the X-ray powder diffraction of amine hydrate.
Fig. 2 is that Type B crystallization hydrochloric acid Ah examining provided by the invention is for the DSC collection of illustrative plates of amine hydrate.
Fig. 3 is that Type B 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 the examining who uses in following examples is for amine trihydrate, and the method for describing according to patent CN101006040A is prepared gained.
Embodiment 1
Get 3.0 g hydrochloric acid Ah examining and be dissolved in 12g DMF for amine trihydrate, reflux, to dissolving, is cooled to 20 ℃, filters.Filter cake, in 50 ℃ of forced air dryings, is at room temperature placed in air 24 hours, until moisture is 3.0%-5.0%, obtains Type B crystallization hydrochloric acid Ah examining for amine hydrate 1.75g, and yield is 62.5%.
Embodiment 2
Get 3.0 g hydrochloric acid Ah examining and be dissolved in 12g methyl alcohol for amine trihydrate, reflux, to dissolving, is cooled to 20 ℃, filters.Filter cake, in 50 ℃ of forced air dryings, is at room temperature placed in air 24 hours, until moisture is 3.0%-5.0%, obtains Type B crystallization hydrochloric acid Ah examining for amine hydrate 1.16g, and yield is 41.4%.
Claims (7)
1.B 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=6.25 ± 0.2 °, 9.69 ± 0.2 °, 11.13 ± 0.2 °, 12.45 ± 0.2 °, 14.45 ± 0.2 °, 15.20 ± 0.2 °, 18.20 ± 0.2 °, 19.36 ± 0.2 °, 20.72 ± 0.2 °, 23.13 ± 0.2 °, 23.74 ± 0.2 °, 24.87 ± 0.2 °, 26.29 ± 0.2 °, 27.32 ± 0.2 °, 27.85 ± 0.2 ° and 29.12 ± 0.2 ° located characteristic peak.
2. Type B crystallization hydrochloric acid Ah examining according to claim 1 is for amine hydrate, it is characterized in that: described Type B crystallization hydrochloric acid Ah examining located fusing endotherm(ic)peak for the differential thermal analysis collection of illustrative plates (DSC) of amine hydrate at 173-181 ℃, preferably at 175-179 ℃, located fusing endotherm(ic)peak (heating rate is 10.00 ℃/min).
3. Type B crystallization hydrochloric acid Ah examining according to claim 1, for amine hydrate, is characterized in that: described Type B crystallization hydrochloric acid Ah examining for the DSC-TGA trace of amine hydrate the 100-190 ℃ of weightlessness of locating 3.0%-5.0%.
According to Type B hydrochloric acid Ah the examining described in claim 1-3 for amine hydrate, it is characterized in that: described hydrochloric acid Ah examining is that hydrochloric acid Ah examining is for amine monohydrate for amine hydrate.
5. preparation Type B 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 trihydrate, 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 Type B crystallization hydrochloric acid Ah examining for amine hydrate.
6. method according to claim 5, is characterized in that: in method steps (1), described 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.
7. method according to claim 5, it is characterized in that: in the step of described method (3), the crystalline solid that filtering separation obtains from step (2), and forced air drying, under room temperature or high humidity (humidity is greater than 60%) condition, place, until moisture is 3.0%-5.0%, obtain Type B crystallization hydrochloric acid Ah examining for amine hydrate.
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| CN201410237023.4A CN104003958A (en) | 2014-05-30 | 2014-05-30 | Novel acotiamide hydrochloride hydrate crystal form and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006022252A1 (en) * | 2004-08-23 | 2006-03-02 | Zeria Pharmaceutical Co., Ltd. | Method for producing aminothiazole derivative and production intermediate |
| 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 |
| CN104447611A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Acotiamide compound |
-
2014
- 2014-05-30 CN CN201410237023.4A patent/CN104003958A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006022252A1 (en) * | 2004-08-23 | 2006-03-02 | Zeria Pharmaceutical Co., Ltd. | Method for producing aminothiazole derivative and production intermediate |
| CN104447611A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Acotiamide compound |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 陈琳萍: "首个功能性消化不良治疗药阿考替胺的研究进展", 《上海医药》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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: 20140827 |