CN103864629A - Refining method of Salmeterol xinafoate - Google Patents
Refining method of Salmeterol xinafoate Download PDFInfo
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- CN103864629A CN103864629A CN201210543817.4A CN201210543817A CN103864629A CN 103864629 A CN103864629 A CN 103864629A CN 201210543817 A CN201210543817 A CN 201210543817A CN 103864629 A CN103864629 A CN 103864629A
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Abstract
The invention provides a refining method of Salmeterol xinafoate. The method is characterized in that a mixed solvent containing 5-40 parts by volume of alcohol, 10 parts by volume of ester and 0-10 parts by volume of ether is used to recrystallize.
Description
Technical field:
The present invention relates to a kind of process for purification of anti-asthmatic medicament, relate in particular to the process for purification of SALMETEROL XINAFOATE.
Background technology:
Salmeterol is a kind of selectivity long-acting (12 hours) beta-2-adrenoreceptor agonists.Compared with traditional fugitive broxaterol of recommended dose; the pharmacological property of Salmeterol can provide the provide protection of the more effective bronchoconstriction for histamine induction; and produce the more lasting bronchiectatic activity that at least continues 12 hours, for asthma (comprising Nocturnal and exercise-induced asthma), asthmatic bronchitis and Reversible airway obstruction.
The chemistry of SALMETEROL XINAFOATE 4-hydroxyl-alpha by name-[[[6-(4-benzene butoxy) hexyl] amino] methyl]-1,3-xylyl alcohol, 1-hydroxy-2-naphthoic acid (salt), structural formula is as follows:
Be different from other bronchiectasis medicine, SALMETEROL XINAFOATE has higher lipotropy and unique drug effect characteristic, its preparation consumption is very little, therefore the purity requirement of SALMETEROL XINAFOATE is very high, for example European Pharmacopoeia EP7.0 requires the total assorted of SALMETEROL XINAFOATE to be 0.9% to the maximum, impurity D is 0.3% to the maximum, and impurity A, F, G are 0.2% to the maximum, and impurity B, C, E and other single mixing are 0.1% to the maximum.Impurity B, C, D are for preparing the impurity of introducing in midbody compound (7a) process, more difficult removing.
About the existing many sections of bibliographical informations of preparation method of SALMETEROL XINAFOATE, but the preparation method of some bibliographical information need to utilize vacuum distilling or column chromatography to carry out purifying, is difficult to realize industrialization (GB2176476; US4992474; Tetrahedron Letters, V35(50), P9375 ~ 9378,1994; Indian Journal of Chemistry, V34B, P629 ~ 631,1995; East China Normal University's journal (natural science edition), the 3rd phase P102 ~ 104 in 2003).World patent WO2007/045857 exceedes 99.5% Salmeterol in order to obtain purity, the purity of midbody compound (7a) need to be brought up to more than 99.5%, increases cost, reduces yield, complex operation.
Summary of the invention:
The present invention is directed to the deficiency in prior art, a kind of process for purification of SALMETEROL XINAFOATE is provided, utilize this method just can obtain more than 99% SALMETEROL XINAFOATE by simple recrystallization, neither needing that the purity of compound (7a) is proposed to special requirement does not need to utilize vacuum distilling or column chromatography to carry out purifying yet.
The invention provides a kind of process for purification of SALMETEROL XINAFOATE, it is characterized in that adopting according to volume ratio and calculate, the mixed solvent of the isopropyl ether of the methyl alcohol that contains 5 ~ 40 parts, 10 parts of ethyl acetate and 0 ~ 10 part carries out recrystallization.
The process for purification of described a kind of SALMETEROL XINAFOATE, is characterized in that adopting according to volume ratio and calculates, and the mixed solvent of the isopropyl ether of the methyl alcohol that contains 20 ~ 30 parts, 10 parts of ethyl acetate and 5 ~ 10 parts carries out recrystallization.
The process for purification of described a kind of SALMETEROL XINAFOATE, is characterized in that adopting according to volume ratio and calculates, and the mixed solvent of the isopropyl ether of the methyl alcohol that contains 25 parts, 10 parts of ethyl acetate and 8 parts carries out recrystallization.
The process for purification of described a kind of SALMETEROL XINAFOATE, is characterized in that SALMETEROL XINAFOATE to be dissolved in described mixed solvent, is heated to whole dissolvings, with the speed of 3 ~ 7 DEG C of coolings per hour, is cooled to 5 ~ 25 DEG C, and filtration obtains.
The process for purification of described a kind of SALMETEROL XINAFOATE, is characterized in that SALMETEROL XINAFOATE to be dissolved in described mixed solvent, is heated to whole dissolvings, with the speed of 3 ~ 7 DEG C of coolings per hour, is cooled to 5 ~ 10 DEG C, and filtration obtains.
The process for purification of described a kind of SALMETEROL XINAFOATE, is characterized in that SALMETEROL XINAFOATE to be dissolved in described mixed solvent, is heated to whole dissolvings, with the speed of 5 DEG C of coolings per hour, is cooled to 10 DEG C, and filtration obtains.
The SALMETEROL XINAFOATE that utilizes above-mentioned mixed solvent to carry out recrystallization just can to obtain for 1 ~ 3 time content 99% ~ 99.9%, method is simple, and easily industrialization neither needs to control the purity of intermediate, has also improved yield.We also find in recrystallization process under study for action, and the speed of lowering the temperature by control can improve product yield.
The crude product that we utilize several frequently seen Salmeterol preparation method to prepare the Salmeterol of different content all can adopt the method for this patent protection to refine.
Embodiment:
Below will by embodiment, the invention will be further described, these descriptions are not that content of the present invention is further limited.Person skilled should be understood that the replacement that is equal to that technical characterictic of the present invention is done, or improves accordingly, within still belonging to protection scope of the present invention.
We are according to the preparation method of three kinds of different Salmeterol former times naphthoic acids of the Li Li of document Guangxi University the moon " the synthetic and analysis of chiral drug Salmeterol " 8 ~ 9 pages of reports of Master's thesis, obtained Salmeterol former times naphthoic acid crude product I(HPLC content 95%), crude product II(HPLC content 94%) and crude product III(HPLC content 96%), for refining research below.
Embodiment 1:
By gained SALMETEROL XINAFOATE crude product I5g, be dissolved in the mixed solvent of 10ml methyl alcohol and 20ml ethyl acetate, be heated to all dissolve 20 DEG C of rear coolings per hour and be down to 35 DEG C, filter, obtain SALMETEROL XINAFOATE fine work 3.8g, HPLC content 99.0%.Adopt identical method to continue recrystallization to obtain for 2 times the SALMETEROL XINAFOATE fine work of HPLC content 99.9%, three recrystallization total recoverys 69.6%.
Embodiment 2:
By gained SALMETEROL XINAFOATE crude product II5g, be dissolved in the mixed solvent of 10ml methyl alcohol and 20ml ethyl acetate, after being heated to all dissolve, 3 DEG C of coolings per hour are down to 20 DEG C, filter, and obtain HPLC content and be 99.2% SALMETEROL XINAFOATE.Adopt identical method to continue recrystallization to obtain for 2 times the SALMETEROL XINAFOATE fine work of HPLC content 99.9%, three recrystallization total recoverys 74.8%.
Embodiment 3:
By gained SALMETEROL XINAFOATE crude product III5g, be dissolved in the mixed solvent of 10ml methyl alcohol and 20ml ethyl acetate, after being heated to all dissolve, 5 DEG C of coolings per hour are down to 10 DEG C, filter, and obtain HPLC content and be 99.0% SALMETEROL XINAFOATE.Adopt identical method to continue recrystallization to obtain for 2 times the SALMETEROL XINAFOATE fine work of HPLC content 99.9%, three recrystallization total recoverys 80.1%.
Embodiment 4:
By gained SALMETEROL XINAFOATE crude product I5g, be dissolved in the mixed solvent of 10ml methyl alcohol, 20ml ethyl acetate and 10ml isopropyl ether, after being heated to all dissolve, 10 DEG C of coolings per hour are down to 35 DEG C, filter, and obtain HPLC content and be 99.1% SALMETEROL XINAFOATE.Adopt identical method to continue recrystallization to obtain for 2 times the SALMETEROL XINAFOATE fine work of HPLC content 99.9%, three recrystallization total recoverys 69.8%.
Embodiment 5:
By gained SALMETEROL XINAFOATE crude product II5g, be dissolved in the mixed solvent of 10ml methyl alcohol, 20ml ethyl acetate and 10ml isopropyl ether, after being heated to all dissolve, 7 DEG C of coolings per hour are down to 20 DEG C, obtain HPLC content and be 99.2% SALMETEROL XINAFOATE.Adopt identical method to continue recrystallization to obtain for 2 times the SALMETEROL XINAFOATE fine work of HPLC content 99.9%, three recrystallization total recoverys 74.5%.
Embodiment 6:
By gained SALMETEROL XINAFOATE crude product III5g, be dissolved in the mixed solvent of 10ml methyl alcohol, 20ml ethyl acetate and 10ml isopropyl ether, after being heated to all dissolve, 5 DEG C of coolings per hour are down to 10 DEG C, obtain HPLC content and be 99.1% SALMETEROL XINAFOATE.Adopt identical method to continue recrystallization to obtain for 2 times the SALMETEROL XINAFOATE fine work of HPLC content 99.9%, three recrystallization total recoverys 80.3%.
Embodiment 7 ~ embodiment 33:
Claims (6)
1. a process for purification for SALMETEROL XINAFOATE, is characterized in that adopting according to volume ratio and calculates, and the mixed solvent of the isopropyl ether of the methyl alcohol that contains 5 ~ 40 parts, 10 parts of ethyl acetate and 0 ~ 10 part carries out recrystallization.
2. the process for purification of a kind of SALMETEROL XINAFOATE as claimed in claim 1, is characterized in that adopting according to volume ratio and calculates, and the mixed solvent of the isopropyl ether of the methyl alcohol that contains 20 ~ 30 parts, 10 parts of ethyl acetate and 5 ~ 10 parts carries out recrystallization.
3. the process for purification of a kind of SALMETEROL XINAFOATE as claimed in claim 2, is characterized in that adopting according to volume ratio and calculates, and the mixed solvent of the isopropyl ether of the methyl alcohol that contains 25 parts, 10 parts of ethyl acetate and 8 parts carries out recrystallization.
4. the process for purification of any SALMETEROL XINAFOATE as described in claim 1 ~ 3, it is characterized in that SALMETEROL XINAFOATE to be dissolved in described mixed solvent, be heated to whole dissolvings, with the speed of 3 ~ 7 DEG C of coolings per hour, be cooled to 5 ~ 25 DEG C, filtration obtains.
5. the process for purification of a kind of SALMETEROL XINAFOATE as claimed in claim 4, is characterized in that SALMETEROL XINAFOATE to be dissolved in described mixed solvent, is heated to whole dissolvings, with the speed of 3 ~ 7 DEG C of coolings per hour, is cooled to 5 ~ 10 DEG C, and filtration obtains.
6. the process for purification of a kind of SALMETEROL XINAFOATE as claimed in claim 4, is characterized in that SALMETEROL XINAFOATE to be dissolved in described mixed solvent, is heated to whole dissolvings, with the speed of 5 DEG C of coolings per hour, is cooled to 10 DEG C, and filtration obtains.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201210543817.4A CN103864629A (en) | 2012-12-13 | 2012-12-13 | Refining method of Salmeterol xinafoate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210543817.4A CN103864629A (en) | 2012-12-13 | 2012-12-13 | Refining method of Salmeterol xinafoate |
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| CN103864629A true CN103864629A (en) | 2014-06-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016142582A1 (en) * | 2015-03-11 | 2016-09-15 | Fermion Oy | Process for the preparation of crystalline salmeterol and its xinafoate salt |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992474A (en) * | 1983-04-18 | 1991-02-12 | Glaxo Group Ltd. | Phenethanolamine derivatives |
| EP0947498A1 (en) * | 1996-12-02 | 1999-10-06 | Chisso Corporation | Optically active nitro alcohol derivatives, optically active amino alcohol derivates, and process for preparing the same |
| US20100009950A1 (en) * | 2008-06-30 | 2010-01-14 | Auspex Pharmaceuticals, Inc. | Substituted ethanolamines |
| WO2012032546A2 (en) * | 2010-09-08 | 2012-03-15 | Cadila Healthcare Limited | Process for the preparation of salmeterol and its intermediates |
-
2012
- 2012-12-13 CN CN201210543817.4A patent/CN103864629A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992474A (en) * | 1983-04-18 | 1991-02-12 | Glaxo Group Ltd. | Phenethanolamine derivatives |
| EP0947498A1 (en) * | 1996-12-02 | 1999-10-06 | Chisso Corporation | Optically active nitro alcohol derivatives, optically active amino alcohol derivates, and process for preparing the same |
| US20100009950A1 (en) * | 2008-06-30 | 2010-01-14 | Auspex Pharmaceuticals, Inc. | Substituted ethanolamines |
| WO2012032546A2 (en) * | 2010-09-08 | 2012-03-15 | Cadila Healthcare Limited | Process for the preparation of salmeterol and its intermediates |
Non-Patent Citations (4)
| Title |
|---|
| BREAM,ROBERT N.等: "A mild, enantioselective synthesis of (R)-salmeterol via sodium borohydride-calcium chloride asymmetric reduction of a phenacyl phenylglycinol derivative", 《JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS》 * |
| 伍晓春: "一种合成平喘药沙美特罗羟基萘甲酸盐的新方法", 《西南师范大学学报（自然科学版）》 * |
| 国泰 等: "沙美特罗羟基萘甲酸盐的研制", 《黑龙江医药》 * |
| 江志赶 等: "平喘新药沙美特罗的合成", 《华东师范大学学报（自然科学版）》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016142582A1 (en) * | 2015-03-11 | 2016-09-15 | Fermion Oy | Process for the preparation of crystalline salmeterol and its xinafoate salt |
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