CN104761458A - S-metoprolol succinate crystal form and preparation method thereof - Google Patents
S-metoprolol succinate crystal form and preparation method thereof Download PDFInfo
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- CN104761458A CN104761458A CN201510193165.XA CN201510193165A CN104761458A CN 104761458 A CN104761458 A CN 104761458A CN 201510193165 A CN201510193165 A CN 201510193165A CN 104761458 A CN104761458 A CN 104761458A
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- metoprolol succinate
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Abstract
The invention belongs to the field of pharmaceuticals and particularly relates to an S-metoprolol succinate crystal form and a preparation method thereof. The X-ray powder diffraction spectrum of the S-metoprolol succinate crystal form has a characteristic peak in the following d values: 9.873, 7.443, 6.672, 5.661, 5.202, 4.579, 4.277, 4.147, 4.041 and 3.552. The preparation method comprises the following steps: dissolving the S-metoprolol succinate crystal form in an organic solvent, and crystallizing to obtain the crystal form. The novel crystal form is good in stability, preparation method controllability and reproducibility and is suitable for large scale pharmaceutical production.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to a kind of S-metoprolol succinate crystal formation and preparation method thereof.
Background technology
Metoprolol (metoprolo1) is one optionally β1receptor blocker, chemistry 1-[4-(2-methylethyl) phenoxy group]-3-isopropylamino propyl alcohol by name.Metoprolol is the chiral molecules of tool 1 chiral carbon atom, is divided into R and S configuration thus, pharmaceutically mainly uses its tartrate, is clinically mainly used in that treatment is light, moderate hypertension, stable angina pectoris and irregular pulse.
And S-metoprolol succinate has significant curative effect to hypertension, stenocardia, myocardial infarction, irregular pulse etc., show that its drug effect is remarkable by external case, far above the curative effect of metoprolol and S-metoprolol tartrate.
Summary of the invention
The invention provides a kind of S-metoprolol succinate crystal formation and preparation method thereof, described new crystal good stability, its preparation method controllability is good, favorable reproducibility, is suitable for mass-producing pharmaceutical manufacturing.
For solving the problem, the present invention by the following technical solutions:
Design a kind of S-metoprolol succinate crystal formation, the X-ray powder diffraction of described crystal formation has characteristic peak in following d value: 9.873,7.443,6.672,5.661,5.202,4.579,4.277,4.147,4.041,3.552.
Preferably, the X-ray powder diffraction of described crystal formation also has characteristic peak in following d value: 4.894,4.699,3.626.
Preferred, the X-ray powder diffraction of described crystal formation as shown in Figure 1.
The present invention also designs a kind of preparation method of above-mentioned S-metoprolol succinate crystal formation: be dissolved in organic solvent by S-metoprolol succinate, carry out crystallization, obtain described crystal formation.
Described organic solvent is preferably acetonitrile.
Preferred, S-metoprolol succinate is added in acetonitrile, is heated to backflow, after stirring 0.5 ~ 1.5h, naturally cool to 25 DEG C, crystallization, filter, acetonitrile wash twice, collect filter cake, dry and get final product.
Preferred, described acetonitrile content is 10 ~ 15 times of S-metoprolol succinate weight.
positive beneficial effect of the present invention:
The different crystal forms of same medicine may have remarkable difference in outward appearance, solubleness, fusing point, dissolution rate, biological effectiveness etc., thus have impact on the stability of medicine, bioavailability and curative effect, this kind of phenomenon shows particularly evident in oral solid formulation.Polymorph in pharmaceuticals phenomenon is one of important factor affecting drug quality and clinical efficacy.S-metoprolol succinate stability of crystal form of the present invention is good, and bioavailability is high, and its preparation method controllability is good, favorable reproducibility, is suitable for mass-producing pharmaceutical manufacturing.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) collection of illustrative plates of S-metoprolol succinate crystal formation of the present invention.
Fig. 2 is differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates of S-metoprolol succinate crystal formation of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in more detail.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
S-metoprolol succinate crude product used in following examples of the present invention, also prepare by following methods by commercial:
(1) synthesis of (S)-3-isopropylamino-1.2-propylene glycol: add 69.0g Anhydrous potassium carbonate in 1L there-necked flask, 13.5g water, 222.4g Virahol, stirred at ambient temperature 1 hour.Add 206.5g Isopropylamine, the chloro-1.2-propylene glycol of 65.0gR-3-, reflux 10h, TLC detection reaction is complete, stopped reaction, is cooled to room temperature, crosses and filters Repone K etc., be spin-dried for solvent, add 100mL Virahol and be spin-dried for, obtain 66.5g pale yellow oily liquid body.
(2) synthesis of (S)-5-methylol-3-sec.-propyl-2-oxazolidone: add 154.9g Virahol in 1L there-necked flask, 13.0g water, 79.3g Anhydrous potassium carbonate, 63.6g(S)-3-isopropylamine base-1.2-propylene glycol, stirred at ambient temperature 2h.With cryosel bath cooling, start to drip 65.0g Vinyl chloroformate, temperature controls below 10 DEG C.Drip off reaction 2h.Start to be heated to backflow, reaction 10h, TLC detect, and react complete, are chilled to room temperature.Filter, with 100mL washed with isopropyl alcohol filter cake.Filtrate is spin-dried for, and adds 200mL toluene and is spin-dried for, obtain semi-crystalline solid.
(3) synthesis of (S)-5-tolysulfonyl oxygen methyl-3-sec.-propyl-2-oxazolidone: add 66.0g(R in 1L there-necked flask)-5-methylol-3-sec.-propyl-2-oxazolidone, 58.8g triethylamine, 500mL methylene dichloride, add under cooling bath in batches 103.3g Tosyl chloride (PTSC) add be warming up to 35 DEG C reaction 2h.TLC detection reaction is complete.Add 100mL water, stir 20min, separatory, organic phase adds 5% sodium bicarbonate 50mL, stirs 20 minutes, separatory, organic phase adds water 40mL, regulates PH to be 2, separatory with concentrated hydrochloric acid 5mL, wash organic phase with saturated nacl aqueous solution, separatory, organic phase is spin-dried for, add Virahol 500mL stirring and crystallizing, filter, filter cake 100mL washed with isopropyl alcohol, vacuum-drying, obtains 92g white solid.
(4) (S)-5-is to the synthesis of methoxy ethyl phenylol-3-sec.-propyl-2-oxazolidone: add 54.2g Anhydrous potassium carbonate in 1L there-necked flask, 10.5g water, 700mL Virahol, stirs 2 hours.Add 59.6g to methoxy ethyl phenol, 91.0g(S)-5-tolysulfonyl oxygen methyl-3-sec.-propyl-2-oxazolidone, reflux 18h.TLC detection reaction is complete.Obtain reaction solution and be directly used in the next step.
(5) synthesis of (S)-metoprolol: add step reaction solution in 2L there-necked flask, adds 188g 10% potassium hydroxide solution, is heated to backflow, and reaction 22h, TLC detection reaction is complete.Stopped reaction, is cooled to room temperature, filters, filter cake washed with isopropyl alcohol, filtrate is spin-dried for, and adds 300mL toluene, and 100mL water stirs 1 hour, separatory, organic phase adds water 300mL, uses vitriol oil 12mL, regulate PH to be 2, separatory, aqueous phase adds toluene 300mL, adding sodium hydroxide 20g regulates PH to be 14, separatory, and organic phase saturated nacl aqueous solution washs, separatory, organic phase evaporate to dryness, adds 300mL petroleum ether and stirring crystallization.Filter, vacuum-drying, obtains 67.1g (S)-metoprolol.
(6) preparation of (S)-metoprolol succinate
Add 300mL acetonitrile in 500mL there-necked flask, 11.8g succsinic acid, reflux stirring and dissolving is complete, 53.4g(S) metoprolol is dissolved in 50mL acetonitrile (heating), to add in flask stirring (having solid to separate out) heating reflux reaction 4 hours.Cooling crystallization, filters, dry 54.6g white solid.
embodiment 1
A kind of preparation method of S-metoprolol succinate crystal formation, comprise the following steps: S-metoprolol succinate 30g is dissolved in acetonitrile 300g, be heated to backflow, stir 1h, naturally cool to room temperature (25 DEG C), crystallization, filters, acetonitrile wash, collect filter cake, dry to obtain white crystal 24.3g, as shown in Figure 1, its differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates as shown in Figure 2 for its X-ray powder diffraction (XRPD) collection of illustrative plates.
embodiment 2
A kind of preparation method of S-metoprolol succinate crystal formation, comprise the following steps: S-metoprolol succinate 30g is dissolved in acetonitrile 360g, be heated to backflow, stir 1h, naturally cool to room temperature, crystallization, filter, acetonitrile wash, collect filter cake, dry to obtain white crystal 23.1g, its X-ray powder diffraction (XRPD) collection of illustrative plates and differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates identical with embodiment 1.
embodiment 3
A kind of preparation method of S-metoprolol succinate crystal formation, comprise the following steps: S-metoprolol succinate 30g is dissolved in acetonitrile 450g, be heated to backflow, stir 1h, naturally cool to room temperature, crystallization, filter, acetonitrile wash, collect filter cake, dry to obtain white crystal 21.3g, its X-ray powder diffraction (XRPD) collection of illustrative plates and differential thermal/thermogravimetric analysis (DSC/TG) collection of illustrative plates identical with embodiment 1.
The present invention is not limited to above-mentioned embodiment, and those skilled in the art also can make multiple change accordingly, but to be anyly equal to the present invention or similar change all should be encompassed in the scope of the claims in the present invention.
Claims (7)
1. a S-metoprolol succinate crystal formation, is characterized in that: the X-ray powder diffraction of described crystal formation has characteristic peak in following d value: 9.873,7.443,6.672,5.661,5.202,4.579,4.277,4.147,4.041,3.552.
2. S-metoprolol succinate crystal formation according to claim 1, is characterized in that: the X-ray powder diffraction of described crystal formation also has characteristic peak in following d value: 4.894,4.699,3.626.
3. S-metoprolol succinate crystal formation according to claim 2, is characterized in that: the X-ray powder diffraction of described crystal formation as shown in Figure 1.
4. a preparation method for S-metoprolol succinate crystal formation described in claim 1, is characterized in that: be dissolved in organic solvent by S-metoprolol succinate, carries out crystallization, obtain described crystal formation.
5. preparation method according to claim 4, is characterized in that: described organic solvent is acetonitrile.
6. preparation method according to claim 5, is characterized in that, concrete steps are: add in acetonitrile by S-metoprolol succinate, is heated to backflow, after stirring 0.5 ~ 1.5h, naturally cool to 25 DEG C, crystallization, filter, acetonitrile wash twice, collects filter cake, dries and get final product.
7. preparation method according to claim 5, is characterized in that: described acetonitrile content is 10 ~ 15 times of S-metoprolol succinate weight.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083614A (en) * | 2016-06-07 | 2016-11-09 | 浙江永太药业有限公司 | A kind of preparation method of metoprolol salt |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083372A (en) * | 1995-07-18 | 2000-07-04 | Waters Investments Limited | Reagents and methods for performing electrokinetic chromatography |
| US20090247642A1 (en) * | 2005-12-23 | 2009-10-01 | Carmen Arnalot Aguilar | Synthesis and preparations of metoprolol and its salts |
| CN102633660A (en) * | 2011-11-03 | 2012-08-15 | 北京华禧联合科技发展有限公司 | New crystal form of metoprolol succinate |
| WO2013141437A1 (en) * | 2012-03-23 | 2013-09-26 | 주식회사 알에스텍 | Method for manufacturing high purity (s)-metoprolol |
| CN103508909A (en) * | 2012-06-25 | 2014-01-15 | 石药集团中奇制药技术（石家庄）有限公司 | Crystal form of metoprolol succinate and preparation method thereof |
| CN102295569B (en) * | 2011-07-04 | 2014-05-21 | 南京工业大学 | Method for preparing (S) -metoprolol succinate |
| CN104086450A (en) * | 2014-05-30 | 2014-10-08 | 安徽省新星药物开发有限责任公司 | Crystal form delta of metoprolol succinate, and preparation method and application thereof |
-
2015
- 2015-04-22 CN CN201510193165.XA patent/CN104761458A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083372A (en) * | 1995-07-18 | 2000-07-04 | Waters Investments Limited | Reagents and methods for performing electrokinetic chromatography |
| US20090247642A1 (en) * | 2005-12-23 | 2009-10-01 | Carmen Arnalot Aguilar | Synthesis and preparations of metoprolol and its salts |
| CN102295569B (en) * | 2011-07-04 | 2014-05-21 | 南京工业大学 | Method for preparing (S) -metoprolol succinate |
| CN102633660A (en) * | 2011-11-03 | 2012-08-15 | 北京华禧联合科技发展有限公司 | New crystal form of metoprolol succinate |
| WO2013141437A1 (en) * | 2012-03-23 | 2013-09-26 | 주식회사 알에스텍 | Method for manufacturing high purity (s)-metoprolol |
| CN103508909A (en) * | 2012-06-25 | 2014-01-15 | 石药集团中奇制药技术（石家庄）有限公司 | Crystal form of metoprolol succinate and preparation method thereof |
| CN104086450A (en) * | 2014-05-30 | 2014-10-08 | 安徽省新星药物开发有限责任公司 | Crystal form delta of metoprolol succinate, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| SWAPNIL P. SONAWANE ETAL: "Concise Synthesis of Two β-Adrenergic Blocking Agents in High Stereoselectivity Using the Readily Available Chiral Building Block (2S,20S,200S)-Tris-(2,3-epoxypropyl)-isocyanurate", 《ORG. PROCESS RES. DEV》 * |
| 狄潘潘等: "琥珀酸S-美托洛尔的合成工艺及其杂质控制研究", 《安徽医药》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083614A (en) * | 2016-06-07 | 2016-11-09 | 浙江永太药业有限公司 | A kind of preparation method of metoprolol salt |
| CN106083614B (en) * | 2016-06-07 | 2018-02-16 | 浙江永太药业有限公司 | A kind of preparation method of metoprolol salt |
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Application publication date: 20150708 |