CN105541817A - Method for preparing amorphous canagliflozin through heat treatment - Google Patents
Method for preparing amorphous canagliflozin through heat treatment Download PDFInfo
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- CN105541817A CN105541817A CN201610093744.1A CN201610093744A CN105541817A CN 105541817 A CN105541817 A CN 105541817A CN 201610093744 A CN201610093744 A CN 201610093744A CN 105541817 A CN105541817 A CN 105541817A
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- gelie
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- unformed
- canagliflozin
- clean
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing amorphous canagliflozin through heat treatment. The method includes the steps that a canagliflozin bulk drug is heated to 80 DEG C -130 DEG C, the temperature is kept for 0.5-10 h, and then the canagliflozin bulk drug is cooled to room temperature and smashed properly to obtain the target product-amorphous form canagliflozin. XRPD (X ray powder diffraction) detection shows that the target product is in amorphous peak patterns and is free of other crystal form characteristic peaks, and the yield can reach 99.0% or above. HPLC (high performance liquid chromatography) detection shows that no new impurities are generated, impurity content does not change, and the purity can reach 99.9%. Amorphous canagliflozin obtained through the provided preparing method has the advantages of being high in stability, simple in technology, high in yield and purity, short in production cycle, suitable for industrial mass production, small in environment protection pressure and the like.
Description
Technical field
The present invention relates to medical manufacturing technology field, particularly one prepares the clean unformed method of Ka Gelie by thermal treatment.
Background technology
Ka Gelie clean (canagliflozin), chemical name: (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl]-D-Glucose alcohol), molecular formula C
24h
25fO
5s, molecular weight is 444.52, and its structural formula is as follows:
Ka Gelie is a kind of selectivity II type sodium glucose cotransporter (SGLT2) inhibitor medicaments only, within 2013, obtain FDA (Food and Drug Adminstration) (FDA) approval, be used for the treatment of Adult type II diabetes, there is good glycemic control.Meanwhile, the clean antiobesity action of Ka Gelie is remarkable, and compared with glimepiride, the hypoglycemic event that Ka Gelie causes only much less far away.Therefore, Ka Gelie has broad application prospects and researching value only.
Disclose a kind of semihydrate crystal formation that Ka Gelie is clean in Chinese patent CN101573368A, the method for application precipitation or recrystallize obtains, and this semihydrate crystal formation is listing preparation crystal formation.
Disclose a kind of Ka Gelie in Chinese patent CN104119323A only unformed and preparation method thereof, its preparation is characterised in that dissolves only by Ka Gelie in suitable solvent, is then joined by solution in suitable anti-solvent, stirs, crystallization.The suitable good solvent used is selected from ethyl acetate, toluene, ethanol, methyl alcohol, acetone, methylene dichloride, tetrahydrofuran (THF) and their mixtures, and its anti-solvent is selected from normal hexane, hexanaphthene, normal heptane, sherwood oil, methyl tertiary butyl ether, isopropyl ether and their mixtures.The specification sheets part of this patent points out that generally obtaining unformed method has spraying dry, melting and solidification and fast evaporating solvents to solidify simultaneously, and wherein melting and solidification condition is violent, larger to the quality influence of product.
The activeconstituents of amorphous forms often has the dissolution rate higher than crystalline forms, higher dissolution rate can cause supersaturation, thus can cause having higher bioavailability, therefore, be necessary to develop a kind of technique simple, there is the preparation method that the unformed Ka Gelie of cost advantage is clean.
Summary of the invention
The advantages such as the invention provides and a kind of prepare the clean unformed method of Ka Gelie by thermal treatment, it is simple that it has technique, and purity is high, the production cycle is shorter, be applicable to industrialized production and environmental protection pressure is little.
The present invention is achieved through the following technical solutions: the clean unformed preparation method of a kind of Ka Gelie, clean for Ka Gelie bulk drug to be heated under 80 ~ 130 DEG C of conditions insulation 0.5 ~ 10 hour, takes out sample and is cooled to room temperature to obtain Ka Gelie only unformed.The clean bulk drug of Ka Gelie adopts the qualified product of chemical purity, HPLC purity more than 95%, preferably 99% and more than.Bulk drug can be Ka Gelie other crystal formation mixture clean of any ratio.
Preferably, heat-processed can adopt the mode of uncovered, airtight, nitrogen protection or decompression.When adopting heating under reduced pressure mode, the pressure selected is 0MPa ~-0.09MPa.
Preferably, Heating temperature is 90 ~ 105 DEG C.
Preferably, soaking time is 1 ~ 5 hour.
Preferably, cooling sample to room temperature obtain Ka Gelie only unformed after can pulverize only unformed for Ka Gelie further, by with mortar grinder, powder beaten by machinery or air-flow beats the modes such as powder.
Target product detects through XRPD, is unformed peak type, and not containing the characteristic peak of other crystal formation, it is only unformed that starting raw material is converted into Ka Gelie completely, sees Fig. 1.
Target product detects through differential scanning calorimeter (DSC), and result has endotherm(ic)peak at 40 ~ 90 DEG C, sees Fig. 2.
Target product through thermogravimetric analyzer (TGA) detect, result have an appointment before 105 DEG C 1.0% weightlessness, see Fig. 3.
Target product detects through the infrared pellet technique of Fourier (IR), and charateristic avsorption band is shown in collection of illustrative plates 4.
Target product is through polarized light microscope observing, and sample powder size is 40 ~ 100um, sees Fig. 5.
Target product detects through HPLC, does not produce new impurity, and foreign matter content is substantially unchanged, and purity can reach more than 99.9%, sees Fig. 6.
Compared with prior art, the invention provides and a kind of prepare the clean unformed method advantage of Ka Gelie by thermal treatment and be:
1. do not relate to any organic solvent, without the need to investigating the impact of residual solvent, environmental protection pressure is little.
2. postmenstruation many experiments and Optimizing Process Parameters, detected by HLPC, find that the clean unformed quality of Ka Gelie obtained is unaffected, Ka Gelie is only unformed does not produce new impurity, and foreign matter content is unchanged, and purity can reach more than 99.9%.
3. and the starting material material medicine used can be Ka Gelie other crystal formation mixture clean of any ratio, production efficiency is high.
4., in whole preparation process, without the need to using specific installation, production cost is low, is suitable for industrialized production.
Comprehensively known, it is low that the inventive method prepares the clean unformed process costs of Ka Gelie, and easily control, environmental protection pressure is little; And the constant product quality obtained, yield is high; In whole preparation process, preparation cycle is shorter, substantially increases production efficiency, is applicable to industrialized production.
Accompanying drawing explanation
Fig. 1 is unformed X-ray powder diffraction figure (XRPD) prepared by the present invention.
Fig. 2 is unformed means of differential scanning calorimetry figure (DSC) prepared by the present invention.
Fig. 3 is unformed thermogravimetric analysis figure (TGA) prepared by the present invention.
Fig. 4 is unformed infrared spectrogram (IR) prepared by the present invention.
Fig. 5 is unformed polarizing microscope figure prepared by the present invention.
Fig. 6 is unformed high-efficient liquid phase chromatogram (HPLC) prepared by the present invention.
Embodiment
Comparative example 1:
Card taking lattice arrange clean bulk drug 5g and are placed in watch-glass, open wide heating 26 hours, be cooled to room temperature, suitably grind in 70 ~ 75 DEG C of baking ovens, detect through XRPD, the characteristic peak containing former crystal formation in collection of illustrative plates.Show, former crystal formation does not change into unformed completely.Temperature not or preparation time need be longer.
Comparative example 2:
Card taking lattice arrange clean bulk drug 5g and are placed in watch-glass, in 130 ~ 135 DEG C of baking ovens, be decompressed to-0.09MPa, open wide heating 1 hour, be cooled to room temperature, suitable grinding, detect through XRPD, it is only unformed that former crystal formation all changes Ka Gelie into, yield about 99.1%, detect through HPLC, data show that foreign matter content has increase trend, and purity is about 99.70%.Temperature is too high, causes foreign matter content to increase.
Embodiment 1
Card taking lattice arrange clean bulk drug 5g and are placed in watch-glass, open wide heating 2.5 hours, be cooled to room temperature, suitably grind in 95 ~ 105 DEG C of baking ovens, and detect through XRPD, it is only unformed that former crystal formation all changes Ka Gelie into, yield about 99.3%.Detect through HPLC, purity is about 99.94%.
Embodiment 2
Card taking lattice arrange clean bulk drug 10g and are placed in watch-glass, in 90 ~ 95 DEG C of baking ovens, are decompressed to-0.09MPa, open wide heating 2 hours, are cooled to room temperature, suitably grind, and detect through XRPD, it is only unformed that former crystal formation all changes Ka Gelie into, yield about 99.6%.Detect through HPLC, purity is about 99.96%.
Embodiment 3
Card taking lattice arrange clean bulk drug 30g and are placed in 250ml tri-mouthfuls of round-bottomed flasks, and stir under air tight condition and be warming up to 120 ~ 125 DEG C of insulations 1 hour, be cooled to room temperature, detect through XRPD, it is only unformed that former crystal formation all changes Ka Gelie into, yield about 99.1%.Detect through HPLC, purity is about 99.91%.
Above-mentionedly only the preferred embodiments of the present invention to be elaborated, the invention is not restricted to above-described embodiment, any all protection scope of the present invention is belonged to conversion of the present invention and modification.
Claims (7)
1. the clean unformed preparation method of Yi Zhong Ka Gelie, is characterized in that: clean for Ka Gelie bulk drug to be heated under 80 ~ 130 DEG C of conditions insulation 0.5 ~ 10 hour, after be cooled to room temperature to obtain Ka Gelie only unformed.
2. preparation method according to claim 1, is characterized in that: described Heating temperature is 90 ~ 105 DEG C.
3. preparation method according to claim 1, is characterized in that: described soaking time is 1 ~ 5 hour.
4. preparation method according to claim 1, is characterized in that: described heat-processed airtight, uncovered, decompression or nitrogen protection under carry out.
5. preparation method according to claim 4, is characterized in that: when adopting heating under reduced pressure mode, pressure is 0MPa ~-0.09MPa.
6. preparation method according to claim 1, is characterized in that: can pulverize only unformed for Ka Gelie further after cooling sample to room temperature.
7. preparation method according to claim 6, is characterized in that: described grinding mode for mortar grinder, powder beaten by machinery or air-flow beats powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610093744.1A CN105541817A (en) | 2016-02-20 | 2016-02-20 | Method for preparing amorphous canagliflozin through heat treatment |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610093744.1A CN105541817A (en) | 2016-02-20 | 2016-02-20 | Method for preparing amorphous canagliflozin through heat treatment |
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| CN105541817A true CN105541817A (en) | 2016-05-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610093744.1A Pending CN105541817A (en) | 2016-02-20 | 2016-02-20 | Method for preparing amorphous canagliflozin through heat treatment |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018149327A1 (en) | 2017-02-20 | 2018-08-23 | 浙江华海药业股份有限公司 | Method for preparing canagliflozin amorphous form |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119323A (en) * | 2013-04-28 | 2014-10-29 | 重庆医药工业研究院有限责任公司 | Amorphous substance of canagliflozin and preparation method of amorphous substance |
| WO2014195966A2 (en) * | 2013-05-30 | 2014-12-11 | Cadila Healthcare Limited | Amorphous form of canagliflozin and process for preparing thereof |
| CN104402946A (en) * | 2014-11-17 | 2015-03-11 | 连云港恒运医药科技有限公司 | Invokana intermediate and preparation method thereof in amorphous form |
| US20160002275A1 (en) * | 2014-07-03 | 2016-01-07 | Cadila Healthcare Limited | Process for preparation and purification of canagliflozin |
-
2016
- 2016-02-20 CN CN201610093744.1A patent/CN105541817A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119323A (en) * | 2013-04-28 | 2014-10-29 | 重庆医药工业研究院有限责任公司 | Amorphous substance of canagliflozin and preparation method of amorphous substance |
| WO2014195966A2 (en) * | 2013-05-30 | 2014-12-11 | Cadila Healthcare Limited | Amorphous form of canagliflozin and process for preparing thereof |
| US20160002275A1 (en) * | 2014-07-03 | 2016-01-07 | Cadila Healthcare Limited | Process for preparation and purification of canagliflozin |
| CN104402946A (en) * | 2014-11-17 | 2015-03-11 | 连云港恒运医药科技有限公司 | Invokana intermediate and preparation method thereof in amorphous form |
Non-Patent Citations (1)
| Title |
|---|
| 刘耀华著: "《有机化学中的选择性氧化作用》", 30 June 2008, 中国科学技术出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018149327A1 (en) | 2017-02-20 | 2018-08-23 | 浙江华海药业股份有限公司 | Method for preparing canagliflozin amorphous form |
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Application publication date: 20160504 |