CN103772275B - Singulair di-n-propylamine salt crystal formation and preparation method and application - Google Patents

Singulair di-n-propylamine salt crystal formation and preparation method and application Download PDF

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Publication number
CN103772275B
CN103772275B CN201310754013.3A CN201310754013A CN103772275B CN 103772275 B CN103772275 B CN 103772275B CN 201310754013 A CN201310754013 A CN 201310754013A CN 103772275 B CN103772275 B CN 103772275B
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singulair
propylamine
crystal formation
salt crystal
propylamine salt
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CN103772275A (en
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蒲通
张飞飞
范一
陈恬
王乃星
杨建明
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Zhejiang Charioteer Pharmaceutical CO Ltd
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Zhejiang Charioteer Pharmaceutical CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/18—Halogen atoms or nitro radicals

Abstract

The invention discloses a kind of Singulair di-n-propylamine salt crystal formation and its preparation method and application, described crystal formation uses Cu-Ka radiation, has charateristic avsorption band to spend 2 θ represented at 7.55 ± 0.2,8.71 ± 0.2,9.88 ± 0.2,11.84 ± 0.2,15.10 ± 0.2,15.88 ± 0.2,17.21 ± 0.2,18.56 ± 0.2,19.73 ± 0.2,20.90 ± 0.2,21.84 ± 0.2,22.60 ± 0.2,23.52 ± 0.2,25.18 ± 0.2,26.44 ± 0.2,27.98 ± 0.2,28.86 ± 0.2 and 29.62 ± 0.2 places.The preparation method of described Singulair di-n-propylamine salt crystal formation is: montelukast acid is separated out with di-n-propylamine salify in organic solvent A, obtain Singulair di-n-propylamine salt crystal formation, described organic solvent A is the mixed solvent of toluene or C3-C5 ketone or toluene and C3-C5 ketone.Described Singulair di-n-propylamine salt crystal formation is applied to the highly purified Menglusitena of preparation.

Description

Singulair di-n-propylamine salt crystal formation and preparation method and application
(1) technical field
The present invention relates to crystal formation of a kind of Singulair di-n-propylamine salt and its preparation method and application
(2) background technology
The chemical name of Menglusitena (Montelukast Sodium) is: 1-(((1-(R)-(3-(2-(the chloro-2-quinolyl of 7-) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) sulfenyl)) methyl) cyclopropaneacetic acid sodium, structural formula is as follows:
This compound can be used for treating respiratory disease, as asthma and allergic rhinitis etc.Chemical structural formula of the open Menglusitena of Merck & Co., Inc. patent US5565473 and preparation method thereof, the wherein said montelukast acid be obtained by reacting is oily matter, after column chromatography purification, become sodium salt soluble in water and freeze-drying, because of intermediate and final product all needed post purify and yield is low, so this preparation method is not suitable for scale operation.Existing patent and non-patent literature report makes various organic amine salt (as dicyclohexyl amine, di-n-propylamine, TERTIARY BUTYL AMINE, Isopropylamine etc.) and an alkali metal salt montelukast acid, for removing organic impurity, last again with sodium hydroxide salify, obtain pharmaceutical grade Menglusitena.The invention provides new crystal of a kind of Singulair di-n-propylamine salt and its preparation method and application.Merck technique patent CN1046712 discloses through dicyclohexyl amine salt purifying and prepares the method for Menglusitena.But we find effectively to remove Singulair oxidation impurities and terminal olefin impurity through dicyclohexyl amine salt purifying in test.Patent CN101679268 discloses and a kind ofly prepares Montelukast tert-butylamine salt and make it reach the process for purification of pharmaceutical purity.The method relates to a large amount of extracting and washing, and operation is too complicated and dust removal rate is very low.
The invention provides a kind of Singulair di-n-propylamine salt crystal formation and its preparation method and application.
(3) summary of the invention
The object of this invention is to provide new crystal of a kind of Singulair di-n-propylamine salt and its preparation method and application, described salt can be used for preparing highly purified Menglusitena.
For achieving the above object, the present invention adopts following technical scheme:
On the one hand, the invention provides a kind of Singulair di-n-propylamine salt crystal formation, described crystal formation uses Cu-Ka radiation, has charateristic avsorption band to spend 2 θ represented at 7.55 ± 0.2,8.71 ± 0.2,9.88 ± 0.2,11.84 ± 0.2,15.10 ± 0.2,15.88 ± 0.2,17.21 ± 0.2,18.56 ± 0.2,19.73 ± 0.2,20.90 ± 0.2,21.84 ± 0.2,22.60 ± 0.2,23.52 ± 0.2,25.18 ± 0.2,26.44 ± 0.2,27.98 ± 0.2,28.86 ± 0.2 and 29.62 ± 0.2 places.
Further, the DSC endothermic transition of described Singulair di-n-propylamine salt crystal formation is at 87 DEG C ~ 90 DEG C.
Further, described Singulair di-n-propylamine salt crystal formation surveys infrared absorption spectrum at 3212cm with KBr pressed disc method -1, 3022cm -1, 2972cm -1, 2859cm -1, 2540cm -1, 1624cm -1, 1608cm -1, 1591cm -1, 1494cm -1, 1409cm -1, 1374cm -1, 1338cm -1, 1282cm -1, 1181cm -1, 1137cm -1, 1066cm -1, 1018cm -1, 964cm -1, 861cm -1, 833cm -1, 757cm -1, 734cm -1, 695cm -1there is charateristic avsorption band at place.
On the other hand, the invention provides a kind of method preparing Singulair di-n-propylamine salt new crystal, comprising:
Montelukast acid is separated out with di-n-propylamine salify in organic solvent A, and obtain Singulair di-n-propylamine salt crystal formation, described organic solvent A is the mixed solvent of toluene or C3-C5 ketone or toluene and C3-C5 ketone.
Further, described method is specially: make montelukast acid be suspended in organic solvent A, and add di-n-propylamine and stir clearly molten, stir 8-32h in 0-40 DEG C, filtering drying obtains Singulair di-n-propylamine salt crystal formation; Wherein the volumetric usage of organic solvent A counts 5 ~ 25mL/g with the quality of montelukast acid, and the molar ratio of montelukast acid and di-n-propylamine is 1:1.0-1.5.
Further, the volumetric usage of organic solvent A counts 10-15mL/g with the quality of montelukast acid.
Further, the molar ratio of montelukast acid and di-n-propylamine is 1:1.1.
Further, after adding di-n-propylamine, stir 16-24 hour in 25-30 DEG C.
Again further, described method is specially: make montelukast acid be suspended in organic solvent A, and add di-n-propylamine and stir clearly molten, stir 16-24h in 25-30 DEG C, filtering drying obtains Singulair di-n-propylamine salt crystal formation; Wherein the volumetric usage of organic solvent A counts 10-15mL/g with the quality of montelukast acid, and the molar ratio of montelukast acid and di-n-propylamine is 1:1.1.
In the present invention, montelukast acid can be obtained by disclosed prior art, recommends to be obtained by reacting by the methanesulfonates of 1-(mercapto methyl) cyclopropaneacetic acid two negatively charged ion two lithium and 2-(2-(3-(2-(the chloro-2-quinolyl of 7-)-ethenylphenyl)-3-hydroxypropyl) phenyl)-2-propyl alcohol (abbreviation glycol).
The third aspect, the invention provides described Singulair di-n-propylamine salt crystal formation and is preparing the application in Menglusitena, described in be applied as: in alcoholic solvent, Singulair di-n-propylamine salt and sodium hydroxide are reacted, be separated obtain MONTELUKAST sodium salt.The alcohol of the preferred C1 ~ C4 of described alcoholic solvent, more preferably methyl alcohol or ethanol.Describedly be applied as popular response, wherein Singulair di-n-propylamine salt and sodium hydroxide for etc. mole to feed intake, the volume that adds of alcoholic solvent does not specially require.After having reacted, adopt routine operation and separablely obtain MONTELUKAST sodium salt, such as reaction mixture first being boiled off solvent, crude product adds toluene or methylene dichloride etc. and stirs clearly molten, then adds normal hexane or normal heptane analysis of material; Or add acetonitrile after obtaining crude product and stir analysis of material; Then filter, dry and can obtain MONTELUKAST sodium salt.
Compared with prior art, beneficial effect of the present invention is: present invention obtains a kind of Singulair di-n-propylamine salt crystal formation, the preparation of this crystal formation is simple, and preparation-obtained Singulair di-n-propylamine purity salt is high, yield is high, utilizes it can prepare highly purified Menglusitena.
(4) accompanying drawing explanation
Fig. 1 is the infared spectrum of the Singulair di-n-propylamine salt that embodiment 1 obtains.
Fig. 2 is the DSC figure of the Singulair di-n-propylamine salt that embodiment 1 obtains.
Fig. 3 is the XRD figure of the Singulair di-n-propylamine salt that embodiment 1 obtains.
(5) embodiment
With specific embodiment, technical scheme of the present invention is described further below, but protection scope of the present invention is not limited thereto:
Embodiment 1
By 20g(0.034 mole) montelukast acid adds 500ml acetone, nitrogen replacement 2 times, add di-n-propylamine 6.97ml(0.051 mole), be stirred to feed liquid clearly molten, add crystal seed, stir 16h in 0 DEG C, filter, dry to obtain Singulair di-n-propylamine salt crystal formation 21.4g, content 99.6%, yield 91.3%.
The infared spectrum of Singulair di-n-propylamine salt crystal formation, DSC collection of illustrative plates, XRD figure spectrum, as shown in Figure 1, Figure 2 and Fig. 3
Embodiment 2
By 20g(0.034 mole) montelukast acid adds toluene 200ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid clearly molten, add crystal seed, stir 24h in 25 DEG C.Filter, dry.Obtain single assorted Singulair di-n-propylamine salt crystal formation 21.5g being less than 0.1%, content 99.8%, yield 91.7%.
Embodiment 3
By 20g(0.034 mole) montelukast acid adds toluene 100ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 4.65ml(0.034 mole), be stirred to feed liquid clearly molten, stir 32h in 30 DEG C.Filter, dry.Obtain single assorted Singulair di-n-propylamine salt crystal formation 19.5g being less than 0.1%, content 99.6%, yield 83.2%.
Embodiment 4
By 20g(0.034 mole) montelukast acid adds pentanone 300ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 4.65ml(0.034 mole), be stirred to feed liquid clearly molten, add crystal seed, stir 24h in 40 DEG C.Filter, dry.Obtain single assorted Singulair di-n-propylamine salt 19.2g being less than 0.1%, content 99.5%, yield 81.9%.
Embodiment 5
By 20g(0.034 mole) montelukast acid adds in the mixing solutions of 100ml toluene and 100ml acetone, stirs, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid clearly molten, stir 8h in 30 DEG C.Filter, dry.Obtain single assorted Singulair di-n-propylamine salt crystal formation 19.5g being less than 0.1%, content 99.8%, yield 83.2%.
Embodiment 6
The 10g(0.015 mole that above-described embodiment is prepared) Singulair di-n-propylamine salt add 100ml ethanol making beating, nitrogen replacement 3 times.Add sodium hydroxide ethanolic soln (20ml ethanol+0.6g sodium hydroxide+0.6ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 200ml acetonitrile, stir analysis of material, filter, dry, obtain single assorted Menglusitena finished product 8.1g being less than 0.1%, yield 91.5%, content 99.8%.
Embodiment 7
The 10g(0.015 mole that above-described embodiment is prepared) Singulair di-n-propylamine salt add 150ml methyl alcohol making beating, nitrogen replacement 3 times.Add sodium hydrate methanol solution (20ml methyl alcohol+0.6g sodium hydroxide+0.6ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 200ml acetonitrile, stir analysis of material, filter, dry, obtain single assorted Menglusitena finished product 8.0g being less than 0.1%, yield 90.4%, content 99.6%.
Embodiment 8
The 10g(0.015 mole that above-described embodiment is prepared) Singulair di-n-propylamine salt add 150ml Virahol making beating, nitrogen replacement 3 times.Add sodium hydroxide aqueous isopropanol (20ml Virahol+0.6g sodium hydroxide+0.6ml water), stir 40 minutes.Pressure reducing and steaming solvent.Add 50ml toluene, after dissolving, analysis of material in instillation 500ml normal heptane, filters, dries.Obtain single assorted Menglusitena finished product 8.0g being less than 0.1%, yield 90.4%, content 99.7%.

Claims (10)

1. a Singulair di-n-propylamine salt crystal formation, it is characterized in that described crystal formation uses Cu-Ka radiation, have charateristic avsorption band to spend 2 θ represented at 7.55 ± 0.2,8.71 ± 0.2,9.88 ± 0.2,11.84 ± 0.2,15.10 ± 0.2,15.88 ± 0.2,17.21 ± 0.2,18.56 ± 0.2,19.73 ± 0.2,20.90 ± 0.2,21.84 ± 0.2,22.60 ± 0.2,23.52 ± 0.2,25.18 ± 0.2,26.44 ± 0.2,27.98 ± 0.2,28.86 ± 0.2 and 29.62 ± 0.2 places; The DSC endothermic transition of described Singulair di-n-propylamine salt crystal formation is from 85.11 DEG C to 92.51 DEG C.
2. Singulair di-n-propylamine salt crystal formation as claimed in claim 1, is characterized in that: described Singulair di-n-propylamine salt crystal formation surveys infrared absorption spectrum at 3212cm with KBr pressed disc method -1, 3022cm -1, 2972cm -1, 2859cm -1, 2540cm -1, 1624cm -1, 1608cm -1, 1591cm -1, 1494cm -1, 1409cm -1, 1374cm -1, 1338cm -1, 1282cm -1, 1181cm -1, 1137cm -1, 1066cm -1, 1018cm -1, 964cm -1, 861cm -1, 833cm -1, 757cm -1, 734cm -1, 695cm -1there is charateristic avsorption band at place.
3. Singulair di-n-propylamine salt crystal formation as claimed in claim 1, is characterized in that: the XRD figure that described crystal formation uses Cu-Ka radiation to obtain as shown in Figure 3.
4. prepare the method for Singulair di-n-propylamine salt crystal formation according to claim 1 for one kind, it is characterized in that described method is: make montelukast acid stir 8-32h salify with di-n-propylamine in 0-40 DEG C and separate out in organic solvent A, obtain Singulair di-n-propylamine salt crystal formation, described organic solvent A is the mixed solvent of toluene or C3-C5 ketone or toluene and C3-C5 ketone.
5. prepare the method for Singulair di-n-propylamine salt crystal formation as claimed in claim 4, it is characterized in that: described method is specially: make montelukast acid be suspended in organic solvent A, adding di-n-propylamine stirs clearly molten, stir 8-32h in 25-30 DEG C, filtering drying obtains Singulair di-n-propylamine salt crystal formation; Wherein the volumetric usage of organic solvent A counts 5 ~ 25mL/g with the quality of montelukast acid, and the molar ratio of montelukast acid and di-n-propylamine is 1:1.0-1.5.
6. prepare the method for Singulair di-n-propylamine salt crystal formation as claimed in claim 5, it is characterized in that: the volumetric usage of organic solvent A counts 10-15mL/g with the quality of montelukast acid.
7. prepare the method for Singulair di-n-propylamine salt crystal formation as claimed in claim 5, it is characterized in that: the molar ratio of montelukast acid and di-n-propylamine is 1:1.1.
8. prepare the method for Singulair di-n-propylamine salt crystal formation as claimed in claim 5, it is characterized in that: after adding di-n-propylamine, stir 16-24 hour in 25-30 DEG C.
9. prepare the method for Singulair di-n-propylamine salt crystal formation as claimed in claim 5, it is characterized in that described method is specially: make montelukast acid be suspended in organic solvent A, adding di-n-propylamine stirs clearly molten, stir 16-24h in 25-30 DEG C, filtering drying obtains Singulair di-n-propylamine salt crystal formation; Wherein the volumetric usage of organic solvent A counts 10-15mL/g with the quality of montelukast acid, and the molar ratio of montelukast acid and di-n-propylamine is 1:1.1.
10. Singulair di-n-propylamine salt crystal formation as claimed in claim 1 is preparing the application in Menglusitena, is applied as: in alcoholic solvent, Singulair di-n-propylamine salt and sodium hydroxide are reacted described in it is characterized in that, is separated and obtains MONTELUKAST sodium salt.
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JP2016020320A (en) * 2014-07-16 2016-02-04 大日本印刷株式会社 Method for manufacturing montelukast sodium

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004237A2 (en) * 2005-07-05 2007-01-11 Matrix Laboratories Ltd A process for the preparation of montelukast
CN101213177A (en) * 2005-07-05 2008-07-02 特瓦制药工业有限公司 Purification of montelukast
CN101679268A (en) * 2007-05-02 2010-03-24 波尔法玛制药工厂股份公司 The method of the sodium salt of preparation 1-(((1 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfane base) methyl) Cyclopropylacetic acid

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EP2053043A1 (en) * 2007-10-26 2009-04-29 Inke, S.A. Crystalline salt of montelukast

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004237A2 (en) * 2005-07-05 2007-01-11 Matrix Laboratories Ltd A process for the preparation of montelukast
CN101213177A (en) * 2005-07-05 2008-07-02 特瓦制药工业有限公司 Purification of montelukast
CN101679268A (en) * 2007-05-02 2010-03-24 波尔法玛制药工厂股份公司 The method of the sodium salt of preparation 1-(((1 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfane base) methyl) Cyclopropylacetic acid

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