CN105646344B - A kind of purification process of montelukast - Google Patents
A kind of purification process of montelukast Download PDFInfo
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- CN105646344B CN105646344B CN201610111300.6A CN201610111300A CN105646344B CN 105646344 B CN105646344 B CN 105646344B CN 201610111300 A CN201610111300 A CN 201610111300A CN 105646344 B CN105646344 B CN 105646344B
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- montelukast
- cleaning solution
- mother liquor
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- solid
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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 present invention relates to a kind of purification process of montelukast, and ethanol water is added in montelukast solid, are heated to whole dissolvings, slow cooling, and crystallization filters, and filter cake is washed with ethanol water；Cleaning solution merges concentration with mother liquor, and such as upper type crystallization, suction filtration, washing, gained cleaning solution merges with mother liquor to be concentrated to dryness, and montelukast solid is obtained.The present invention is good to impurity removal effect, high income, is suitble to the montelukast purification of industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of purification process of montelukast.
Background technology
Montelukast is 1- [[[(1R) -1- [3- [(1E) -2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- [2- (1-
Hydroxyl -1- Methylethyls) phenyl] propyl] sulfanyl] methyl] cyclopropaneacetic acid (CAS：International Nonproprietary 158966-92-8)
Title.MONTELUKAST sodium salt (CAS：151767-02-1) it is currently used for treating asthma, inflammation, angina, brain spasm, glomerulus
Property ephritis, hepatitis, endotoxemia, uveitis and allograft rejection.
The structure of MONTELUKAST sodium salt corresponds to following formula：
In general, montelukast and its officinal salt are obtained by complicated building-up process, these processes are secondary anti-due to competition
Several by-products should be resulted in.These methods need lengthy and tedious post-processing operation to detach montelukast and its intermediate, and
Therefore cause the time cycle long, this is again so that the cost higher of these methods and environment friendly are lower.Known montelukast
Purifying be troublesome and complicated, it is difficult to obtain the montelukast of high-purity, because montelukast and its precursor are fast to causing
The oxygen and light of prompt drop solution are unstable.
Montelukast includes a variety of impurity during preparing and storing:The catabolite of Montelukast Sodium is mainly Meng
Lu Site cis-isomers (impurity G) and montelukast sulfoxide (impurity C).Experiment shows under illumination condition, solution state
Montelukast Sodium is easy to that molecular rearrangement occurs, and generates its cis-isomer；The Montelukast Sodium of solid state is easy oxidation, raw
At montelukast sulfoxide and montelukast sulfone.Montelukast -one (impurity F) by-product is unstable, with the extension in reaction time
It gradually decreases, this is also the better method for making its content reduce.In addition to this, montelukast impurity further includes montelukast methyl
Styrene (impurity B).Wherein impurity montelukast sulfoxide, montelukast -one, montelukast methyl styrene are difficult to remove.
The method that some purification of montelukast have been described in this field, shape of these methods based on montelukast salt
At.Therefore, EP737186 is related to preparing montelukast or the method for its salt, and this method includes making 1- (mercapto methyl)-cyclopropane-
Corresponding mesylate alcohol ((2- (2- (2- (3 (S)-(3- (2- (the chloro- 2- quinolyls-of 7-)-second of acetic acid
Alkenyl) phenyl) -3- (mesyl oxygroup)-propyl) phenyl) -2- propyl alcohol) reaction, to obtain montelukast.Crude acid passes through
Its dicyclohexyl amine salt is formed to be purified.
Invention content
It is difficult to remove in view of montelukast impurity, and different impurities processing method is different, the present invention provides a kind of Mengs
The purification process of Lu Site.
Present invention is generally directed to impurity be montelukast methyl styrene (EP impurity Bs)：CAS:918972-54-0.
Specifically, the present invention is realized by following technology:
Montelukast solid is added ethanol water, is heated to whole dissolvings, delayed by a kind of purification process of montelukast
Slow cooling, crystallization filter, and filter cake is washed with ethanol water；Cleaning solution merges concentration with mother liquor, as upper type crystallization, suction filtration,
Washing, gained cleaning solution merges with mother liquor to be concentrated to dryness, and montelukast solid is obtained.
The montelukast purification process can carry out 3~4 crystallizations, suction filtration, washings to cleaning solution and mother liquor.
The montelukast purification process, ethanol water a concentration of 85%~95%.
The montelukast purification process, recrystallization temperature are -10~0 DEG C.
The montelukast purification process, crystallization time are 8~10h.
The montelukast purification process, cleaning solution merges with mother liquor is concentrated into 1/2~2/3 volume.
A kind of purification process of montelukast of the present invention is compared to the prior art：It is difficult to solve impurity B in montelukast
The problem of to remove.
Specific implementation mode
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration,
It does not limit the scope of the invention, while the obvious change and modification that those of ordinary skill in the art are made according to the present invention
It is also contained within the scope of the invention.
Embodiment 1：
10g montelukast solids are added into single port bottle, is added in the ethyl alcohol of 200ml95%, is heated to whole dissolvings, delay
It is slow to be down to -10 DEG C, crystallization 10h, it filters, filter cake is washed with a small amount of 95% ethyl alcohol.Cleaning solution is incorporated into 2/3 volume with mother liquor.
Such as upper type crystallization, suction filtration, washing, cleaning solution is incorporated into 2/3 volume with mother liquor, such as upper type crystallization, suction filtration, washing, washing
Liquid merges with mother liquor to be concentrated to dryness, and is obtained solid 9.42g, B impurity peak area ratio and is dropped to 0.013% by original 0.297%,
Yield 94.2%.
Embodiment 2：
10g montelukast solids are added into single port bottle, is added in 200ml absolute ethyl alcohols, is heated to whole dissolvings, slowly
It is down to 0 DEG C of crystallization 8h, is filtered, filter cake is washed with a small amount of absolute ethyl alcohol.Cleaning solution is incorporated into 2/3 volume with mother liquor.Such as upper type
Crystallization, suction filtration, washing, cleaning solution is incorporated into 2/3 volume with mother liquor, such as upper type crystallization, suction filtration, washing, cleaning solution and mother liquor
Merging is concentrated to dryness, and is obtained solid 8.76g, B impurity peak area ratio and is dropped to 0.016% by original 0.297%, yield
87.6%.
Embodiment 3：
10g montelukast solids are added into single port bottle, is added in the ethyl alcohol of 200ml90%, is heated to whole dissolvings, delay
It is slow to be down to -10 DEG C, crystallization 8h, it filters, filter cake is washed with a small amount of 90% ethyl alcohol.Cleaning solution is incorporated into 2/3 volume with mother liquor.Such as
Upper type crystallization, washs 3 times suction filtration, and cleaning solution merges with mother liquor to be concentrated to dryness, and solid 9.61g, B impurity peak area ratio is obtained
0.022% is dropped to by original 0.297%, yield 96.1%.
Embodiment 4：
10g montelukast solids are added into single port bottle, is added in the ethyl alcohol of 200ml85%, is heated to whole dissolvings, delay
Slowly -10 DEG C of crystallization 10h are down to, filtered, filter cake is washed with a small amount of 85% ethyl alcohol.Cleaning solution is incorporated into 2/3 volume with mother liquor.Such as
Upper type crystallization, suction filtration, washing, cleaning solution is incorporated into 2/3 volume with mother liquor, such as upper type crystallization, suction filtration, washing, cleaning solution
Merge with mother liquor and be concentrated to dryness, obtains solid 9.03g, B impurity peak area ratio and drop to 0.054% by original 0.297%, receive
Rate 90.3%.
Embodiment 5：
10g montelukast solids are added into single port bottle, is added in the methanol of 200ml95%, is heated to whole dissolvings, delay
It is slow to be down to -10 DEG C, crystallization 10h, it filters, filter cake is washed with a small amount of 95% methanol.Cleaning solution is incorporated into 2/3 volume with mother liquor.
Such as upper type crystallization, suction filtration, washing, cleaning solution is incorporated into 2/3 volume with mother liquor, such as upper type crystallization, suction filtration, washing, washing
Liquid merges with mother liquor to be concentrated to dryness, and is obtained solid 5.14g, B impurity peak area ratio and is dropped to 0.014% by original 0.297%,
Yield 51.4%.
Embodiment 6：
10g montelukast solids are added into single port bottle, is added in the normal propyl alcohol of 200ml95%, is heated to whole dissolvings,
- 10 DEG C, crystallization 10h are slowly dropped to, is filtered, filter cake is washed with a small amount of 95% normal propyl alcohol.Cleaning solution is incorporated into 2/3 body with mother liquor
Product.Such as upper type crystallization, suction filtration, washing, cleaning solution is incorporated into 2/3 volume with mother liquor, such as upper type crystallization, suction filtration, washing, washes
It washs liquid and merges with mother liquor and be concentrated to dryness, obtain solid 8.01g, B impurity peak area ratio and dropped to by original 0.297%
0.063%, yield 80.1%.
Comparative example 1：
10g montelukast solids are added into single port bottle, is added in 50ml ethyl acetate, is heated to whole dissolvings, slowly
- 10 DEG C, crystallization 10h are down to, is filtered, filter cake is washed with a small amount of cold ethyl acetate.Obtain solid 4.12g, B impurity peak area ratio
0.292% is faded to by original 0.297%, yield 41.2%.
Comparative example 2：
10g montelukast solids are added into single port bottle, is added in 50ml dichloromethane, is heated to whole dissolvings, slowly
It is down to 0 DEG C, crystallization 8h, is filtered, filter cake is washed with a small amount of dichloromethane.Solid 3.45g, B impurity peak area ratio is obtained by original
0.297% fade to 0.257%, yield 34.5%.
Comparative example 3：
10g montelukast solids are added into single port bottle, is added in 50ml chloroforms, is heated to whole dissolvings, slowly
- 10 DEG C, crystallization 8h are down to, is filtered, filter cake is washed with a small amount of chloroform.Solid 3.67g, B impurity peak area ratio is obtained by original
0.297% come fades to 0.303%, yield 36.7%.
Comparative example 4：
10g montelukast solids are added into single port bottle, is added in 50ml toluene, is heated to whole dissolvings, be slowly dropped to-
It 10 DEG C, crystallization 10h, filters, filter cake is washed with a small amount of toluene.Solid 7.21g, B impurity peak area ratio is obtained by original
0.297% fades to 0.296%, yield 72.1%.
Comparative example 5：
10g montelukast solids are added into single port bottle, are added in 100ml ether, 20~30 DEG C of mashing filter, filter cake
It is washed with a small amount of ether.It obtains solid 9.58g, B impurity peak area ratio and is increased to 0.365% by original 0.297%, yield
95.8%.
Comparative example 6：
10g montelukast solids are added into single port bottle, is added in 50ml acetonitriles, is heated to whole dissolvings, be slowly dropped to-
It 10 DEG C, crystallization 10h, filters, filter cake is washed with a small amount of acetonitrile.Solid 5.23g, B impurity peak area ratio is obtained by original
0.297% fades to 0.308%, yield 52.3%.
Comparative example 7：
10g montelukast acid solids are added into single port bottle, is added in 50ml tetrahydrofurans, is heated to whole dissolvings, delay
It is slow to be down to -10 DEG C, crystallization 10h, it filters, filter cake is washed with a small amount of tetrahydrofuran.Solid 4.75g, B impurity peak area ratio by
0.297% originally fades to 0.260%, yield 47.5%.
Claims (5)
1. a kind of purification process of montelukast, which is characterized in that ethanol water is added in montelukast solid, is heated to complete
Portion is dissolved, slow cooling, crystallization, is filtered, and filter cake is washed with ethanol water；Cleaning solution merges with mother liquor is concentrated into 2/3 volume,
Such as upper type crystallization, suction filtration, washing, gained cleaning solution merges with mother liquor to be concentrated to dryness, and montelukast solid is obtained；Ethanol water
The one kind of concentration in 85%, 90%, 95% and 100%；Recrystallization temperature is -10 DEG C or 0 DEG C;The crystallization time is 8h or 10h.
2. purification process according to claim 1, which is characterized in that 95% ethanol water is added in montelukast solid,
Whole dissolvings are heated to, slow cooling is filtered to -10 DEG C, crystallization 10h, and filter cake is washed with 95% ethanol water；Cleaning solution with
Mother liquor merging is concentrated into 2/3 volume, and such as upper type crystallization, suction filtration, washing, gained cleaning solution merges with mother liquor to be concentrated to dryness, and is obtained
Montelukast solid.
3. purification process according to claim 1, which is characterized in that montelukast solid is added in absolute ethyl alcohol, adds
Heat is to whole dissolvings, and slow cooling is filtered to 0 DEG C, crystallization 8h, and filter cake is washed with absolute ethyl alcohol；Cleaning solution merges dense with mother liquor
It is reduced to 2/3 volume, such as upper type crystallization, suction filtration, washing, gained cleaning solution merges with mother liquor to be concentrated to dryness, and it is solid to obtain montelukast
Body.
4. purification process according to claim 1, which is characterized in that 90% ethanol water is added in montelukast solid,
Whole dissolvings are heated to, slow cooling is filtered to -10 DEG C, crystallization 8h, and filter cake is washed with 90% ethanol water；Cleaning solution and mother
Liquid merging is concentrated into 2/3 volume, and such as upper type crystallization, suction filtration, washing, gained cleaning solution merges with mother liquor to be concentrated to dryness, and Meng is obtained
Lu Site solids.
5. purification process according to claim 1, which is characterized in that 85% ethanol water is added in montelukast solid,
Whole dissolvings are heated to, slow cooling is filtered to -10 DEG C, crystallization 10h, and filter cake is washed with 85% ethanol water；Cleaning solution with
Mother liquor merging is concentrated into 2/3 volume, and such as upper type crystallization, suction filtration, washing, gained cleaning solution merges with mother liquor to be concentrated to dryness, and is obtained
Montelukast solid.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008087628A1 (en) * | 2007-01-15 | 2008-07-24 | Chemagis Ltd. | Process for preparing montelukast sodium containing controlled levels of impurities |
| US20080188664A1 (en) * | 2007-01-15 | 2008-08-07 | Chemagis Ltd. | Process for preparing montelukast sodium containing controlled levels of impurities |
| CN101490005A (en) * | 2006-08-09 | 2009-07-22 | 埃斯特维化学股份有限公司 | Process for the purification of montelukast |
| CN101501000A (en) * | 2006-08-09 | 2009-08-05 | 埃斯特维化学股份有限公司 | Purification process of Montelukast and its amine salts |
| WO2009098271A1 (en) * | 2008-02-06 | 2009-08-13 | Farmaprojects, S.A. | Process for the purification of montelukast by the preparation of acid addition salts and tert-amylamine salt |
| WO2009117381A2 (en) * | 2008-03-17 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Preparation of montelukast and its salts |
| WO2011076237A1 (en) * | 2009-12-23 | 2011-06-30 | Pharmathen S.A. | Improved process for the preparation of montelukast and salts thereof |
-
2016
- 2016-02-29 CN CN201610111300.6A patent/CN105646344B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101490005A (en) * | 2006-08-09 | 2009-07-22 | 埃斯特维化学股份有限公司 | Process for the purification of montelukast |
| CN101501000A (en) * | 2006-08-09 | 2009-08-05 | 埃斯特维化学股份有限公司 | Purification process of Montelukast and its amine salts |
| WO2008087628A1 (en) * | 2007-01-15 | 2008-07-24 | Chemagis Ltd. | Process for preparing montelukast sodium containing controlled levels of impurities |
| US20080188664A1 (en) * | 2007-01-15 | 2008-08-07 | Chemagis Ltd. | Process for preparing montelukast sodium containing controlled levels of impurities |
| WO2009098271A1 (en) * | 2008-02-06 | 2009-08-13 | Farmaprojects, S.A. | Process for the purification of montelukast by the preparation of acid addition salts and tert-amylamine salt |
| WO2009117381A2 (en) * | 2008-03-17 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Preparation of montelukast and its salts |
| WO2011076237A1 (en) * | 2009-12-23 | 2011-06-30 | Pharmathen S.A. | Improved process for the preparation of montelukast and salts thereof |
Non-Patent Citations (1)
| Title |
|---|
| 孟鲁司特钠合成路线图解;陈瀛等;《中国医药工业杂志》;20091231;第40卷(第1期);第64-66页 * |
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Denomination of invention: A purification method of montelukast Effective date of registration: 20211224 Granted publication date: 20180814 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016193 |
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Denomination of invention: A Purification Method of Monelukast Effective date of registration: 20221103 Granted publication date: 20180814 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980020531 |