CN106397255A - Method for preparing safinamide mesylate in novel crystal form - Google Patents
Method for preparing safinamide mesylate in novel crystal form Download PDFInfo
- Publication number
- CN106397255A CN106397255A CN201610794816.5A CN201610794816A CN106397255A CN 106397255 A CN106397255 A CN 106397255A CN 201610794816 A CN201610794816 A CN 201610794816A CN 106397255 A CN106397255 A CN 106397255A
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- Prior art keywords
- fce
- mesylate
- ethyl acetate
- added
- preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a method for preparing safinamide mesylate in a novel crystal form, and relates to the technical field of medicine preparing. Compared with an existing crystal form, the prepared crystal form has better stability and solubility in a water containing system, the dissolution rate is good, and the bioavailability of the prepared crystal form is improved; the preparing method is easy, convenient, high in yield, convenient to operate and easy to industrially produce.
Description
Technical field
The present invention relates to technical field of medicine preparation is and in particular to a kind of preparation side of FCE-26743A mesylate novel crystal forms
Method.
Background technology
Parkinson's (Parkinson ' sdisease, PD) are a kind of lifelong diseases, once illness, need life-long therapy,
Drug therapy is still topmost method at present.MAO-B (MAO-B) inhibitor is suffered from usually as single therapy early stage PD
Person, or be added in the therapeutic scheme of late period PD patient so that symptom can be better controled over and reduces other required Parkinsons
The dosage of medicine.Chinese Medical Association's neurology branch Parkinson's and the Chinese handkerchief gold of dyskinesia group release in 2014
It is recommended that MAO-B inhibitor is as the choice drug treating Parkinson's early stage in gloomy disease treatment guidelines (third edition).
FCE-26743A (safinamide) is grand by the drugmaker's knob being devoted to developing central nervous system disease medicine
(Newron) and its marketing partner praise nation (Zambon) joint research and development exploitation, be mainly used in treat Parkinson's, act on machine
System is mainly the reuptake suppressing MAO-B, and other mechanism include blocking calcium channel, block sodium channels, suppress taking the photograph again of dopamine
Take, suppress the release of glutamic acid.Existing FCE-26743A mesylate bulk drug solid existence and stability difference and dissolution rate are relatively
Low defect, bioavilability is low.
Content of the invention
For the deficiencies in the prior art, the invention provides a kind of stability and the high FCE-26743A first sulphur of bioavilability
The preparation method of hydrochlorate novel crystal forms.
For realizing object above, the present invention is achieved by the following technical programs：
A kind of preparation method of FCE-26743A mesylate, step is as follows：
1) at 35-40 DEG C, FCE-26743A is added in ethyl acetate and the mixed solution of DMF, stirs to dissolving；
2) under normal temperature, Loprazolam is added in ethyl acetate, stirs to dissolving；
3) at 45-50 DEG C, by step 2) Loprazolam solution be added drop-wise to step 1) FCE-26743A solution in,
Back flow reaction 1-1.5h at 45-50 DEG C, then it is added thereto to acetonitrile, continue back flow reaction 0.5-1h, crystallization of lowering the temperature, filters, obtains
Filter cake；
4) wash filter cake 2-3 time with ethyl acetate, low-temperature vacuum drying, to constant weight, obtains final product white solid powder and produces for target
Thing.
Preferably, described step 1) in the mass ratio of FCE-26743A and mixed solution be 1：20-25.
Preferably, in described mixed solution, the mass ratio of ethyl acetate and DMF is 2：2-3.
Preferably, described step 2) in Loprazolam and ethyl acetate mass ratio be 1：15-20.
Preferably, described step 3) in FCE-26743A and Loprazolam mol ratio be 1：1-2.
Beneficial effect of the present invention：The invention provides a kind of preparation method of FCE-26743A mesylate novel crystal forms, relatively
In existing crystal formation, prepared novel crystal forms have more preferable stability and solubility in Aquo System, and dissolution rate preferably, carries
Its bioavilability high, and preparation method is simple, high income, are easy to operation it is easy to industrialized production.
Specific embodiment
Purpose, technical scheme and advantage for making the embodiment of the present invention are clearer, below in conjunction with the embodiment of the present invention,
Technical scheme in the embodiment of the present invention is clearly and completely described it is clear that described embodiment is the present invention one
Divide embodiment, rather than whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art are not making
The every other embodiment being obtained under the premise of creative work, broadly falls into the scope of protection of the invention.
Embodiment 1：
A kind of preparation method of FCE-26743A mesylate, step is as follows：
1) at 40 DEG C, by FCE-26743A according to solvents mass ratio be 1：22 are added in organic solvent, and described have
Machine solvent is 2 by mass ratio：3 ethyl acetate and DMF mixing composition, stir to dissolving；
2) under normal temperature by Loprazolam according to solvents mass ratio be 1：18 are added in ethyl acetate, stir to molten
Solution；
3) at 50 DEG C, by step 2) Loprazolam solution be added drop-wise to step 1) FCE-26743A solution in, husky sweet smell acyl
The mol ratio of amine and Loprazolam is 1：1.5, back flow reaction 1.5h at 50 DEG C, then it is added thereto to acetonitrile, continue backflow anti-
Answer 0.5h, crystallization of lowering the temperature, filters, obtains filter cake；
4) wash filter cake 2 times with ethyl acetate, low-temperature vacuum drying, to constant weight, obtains final product white solid powder and produces for target
Thing.
Embodiment 2：
A kind of preparation method of FCE-26743A mesylate, step is as follows：
1) at 37 DEG C, by FCE-26743A according to solvents mass ratio be 1：20 are added in organic solvent, and described have
Machine solvent is 1 by quality：1 ethyl acetate and DMF mixing composition, stir to dissolving；
2) under normal temperature by Loprazolam according to solvents mass ratio be 1：15 are added in ethyl acetate, stir to molten
Solution；
3) at 45 DEG C, by step 2) Loprazolam solution be added drop-wise to step 1) FCE-26743A solution in, husky sweet smell acyl
The mol ratio of amine and Loprazolam is 1：1, back flow reaction 1h at 50 DEG C, then it is added thereto to acetonitrile, continue back flow reaction 1h,
Cooling crystallization, filters, obtains filter cake；
4) wash filter cake 3 times with ethyl acetate, low-temperature vacuum drying, to constant weight, obtains final product white solid powder and produces for target
Thing.
Embodiment 3：
A kind of preparation method of FCE-26743A mesylate, step is as follows：
1) at 35 DEG C, by FCE-26743A according to solvents mass ratio be 1：20 are added in organic solvent, and described have
Machine solvent is 2 by quality：3 ethyl acetate and DMF mixing composition, stir to dissolving；
2) under normal temperature by Loprazolam according to solvents mass ratio be 1：20 are added in ethyl acetate, stir to molten
Solution；
3) at 45 DEG C, by step 2) Loprazolam solution be added drop-wise to step 1) FCE-26743A solution in, husky sweet smell acyl
The mol ratio of amine and Loprazolam is 1：1.5, back flow reaction 1.5h at 48 DEG C, then it is added thereto to acetonitrile, continue backflow anti-
Answer 1h, crystallization of lowering the temperature, filters, obtains filter cake；
4) wash filter cake 2 times with ethyl acetate, low-temperature vacuum drying, to constant weight, obtains final product white solid powder and produces for target
Thing.
Embodiment 4：
A kind of preparation method of FCE-26743A mesylate, step is as follows：
1) at 40 DEG C, by FCE-26743A according to solvents mass ratio be 1：25 are added in organic solvent, and described have
Machine solvent is 1 by quality：1 ethyl acetate and DMF mixing composition, stir to dissolving；
2) under normal temperature by Loprazolam according to solvents mass ratio be 1：20 are added in ethyl acetate, stir to molten
Solution；
3) at 45 DEG C, by step 2) Loprazolam solution be added drop-wise to step 1) FCE-26743A solution in, husky sweet smell acyl
The mol ratio of amine and Loprazolam is 1：2, back flow reaction 1.5h at 45 DEG C, then it is added thereto to acetonitrile, continue back flow reaction
0.5h, crystallization of lowering the temperature, filters, obtains filter cake；
4) wash filter cake 3 times with ethyl acetate, low-temperature vacuum drying, to constant weight, obtains final product white solid powder and produces for target
Thing.
Embodiment 5：
A kind of preparation method of FCE-26743A mesylate, step is as follows：
1) at 40 DEG C, by FCE-26743A according to solvents mass ratio be 1：20 are added in organic solvent, and described have
Machine solvent is 2 by quality：3 ethyl acetate and DMF mixing composition, stir to dissolving；
2) under normal temperature by Loprazolam according to solvents mass ratio be 1：20 are added in ethyl acetate, stir to molten
Solution；
3) at 45 DEG C, by step 2) Loprazolam solution be added drop-wise to step 1) FCE-26743A solution in, husky sweet smell acyl
The mol ratio of amine and Loprazolam is 1：1, back flow reaction 1h at 50 DEG C, then it is added thereto to acetonitrile, continue back flow reaction
0.5h, crystallization of lowering the temperature, filters, obtains filter cake；
4) wash filter cake 2 times with ethyl acetate, low-temperature vacuum drying, to constant weight, obtains final product white solid powder and produces for target
Thing.
Above example only in order to technical scheme to be described, is not intended to limit；Although with reference to the foregoing embodiments
The present invention has been described in detail, it will be understood by those within the art that：It still can be to aforementioned each enforcement
Technical scheme described in example is modified, or carries out equivalent to wherein some technical characteristics；And these modification or
Replace, do not make the essence of appropriate technical solution depart from the spirit and scope of various embodiments of the present invention technical scheme.
Claims (5)
1. a kind of preparation method of FCE-26743A mesylate novel crystal forms is it is characterised in that step is as follows：
1) at 35-40 DEG C, FCE-26743A is added in ethyl acetate and the mixed solution of DMF, stirs to dissolving；
2) under normal temperature, Loprazolam is added in ethyl acetate, stirs to dissolving；
3) at 45-50 DEG C, by step 2) Loprazolam solution be added drop-wise to step 1) FCE-26743A solution in, in 45-50
Back flow reaction 1-1.5h at DEG C, then it is added thereto to acetonitrile, continue back flow reaction 0.5-1h, crystallization of lowering the temperature, filters, obtains filter cake；
4) wash filter cake 2-3 time with ethyl acetate, to constant weight, obtain final product white solid powder is target product to low-temperature vacuum drying.
2. the preparation method of FCE-26743A mesylate as claimed in claim 1 is it is characterised in that described step 1) in husky fragrant
Acid amides is 1 with the mass ratio of mixed solution：20-25.
3. the preparation method of FCE-26743A mesylate as claimed in claim 2 is it is characterised in that second in described mixed solution
The mass ratio of acetoacetic ester and DMF is 2：2-3.
4. the preparation method of FCE-26743A mesylate as claimed in claim 1 is it is characterised in that described step 2) in methane
The mass ratio of sulfonic acid and ethyl acetate is 1：15-20.
5. the preparation method of FCE-26743A mesylate as claimed in claim 1 is it is characterised in that described step 3) in husky fragrant
The mol ratio of acid amides and Loprazolam is 1：1-2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610794816.5A CN106397255A (en) | 2016-08-31 | 2016-08-31 | Method for preparing safinamide mesylate in novel crystal form |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610794816.5A CN106397255A (en) | 2016-08-31 | 2016-08-31 | Method for preparing safinamide mesylate in novel crystal form |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106397255A true CN106397255A (en) | 2017-02-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610794816.5A Pending CN106397255A (en) | 2016-08-31 | 2016-08-31 | Method for preparing safinamide mesylate in novel crystal form |
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| CN (1) | CN106397255A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014178083A1 (en) * | 2013-05-03 | 2014-11-06 | Council Of Scientific & Industrial Research | An improved synthesis of anti-parkinson agent |
| CN104546747A (en) * | 2014-11-20 | 2015-04-29 | 美吉斯制药（厦门）有限公司 | Pharmaceutical composition containing safinamide mesylate and preparation method of pharmaceutical composition |
-
2016
- 2016-08-31 CN CN201610794816.5A patent/CN106397255A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014178083A1 (en) * | 2013-05-03 | 2014-11-06 | Council Of Scientific & Industrial Research | An improved synthesis of anti-parkinson agent |
| CN104546747A (en) * | 2014-11-20 | 2015-04-29 | 美吉斯制药（厦门）有限公司 | Pharmaceutical composition containing safinamide mesylate and preparation method of pharmaceutical composition |
Non-Patent Citations (1)
| Title |
|---|
| 邢瑞娟等: ""沙芬酰胺的合成"", 《中国医药工业杂志》 * |
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| RJ01 | Rejection of invention patent application after publication | ||
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Application publication date: 20170215 |