CN104119270A - Method for preparing Montelukast sodium - Google Patents
Method for preparing Montelukast sodium Download PDFInfo
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- CN104119270A CN104119270A CN201410394089.4A CN201410394089A CN104119270A CN 104119270 A CN104119270 A CN 104119270A CN 201410394089 A CN201410394089 A CN 201410394089A CN 104119270 A CN104119270 A CN 104119270A
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- salt
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- propylamine
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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
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Abstract
The invention provides a method for preparing and purifying Montelukast sodium. The method comprises the following steps: A. preparing a disodium salt of 2-[1-(mercapto methyl) cyclopropyl] acetic acid; B. preparing an Montelukast free acid; C. preparing an Montelukast di-n-propylamine salt; D. preparing an Montelukast dicyclohexylamine salt; E. converting the Montelukast dicyclohexylamine salt into an Montelukast sodium salt. The synthesis method is simple in process conditions, good in impurity removal effect and small in risk factor, the sulfoxide impurity is less than 0.1%, other impurities are less than 0.05%, and even a certain impurity cannot be detected, and the purity of the Montelukast sodium is larger than 99.8%. All impurities of the Montelukast sodium can be effectively controlled to be less than 0.05%.
Description
Technical field
The present invention relates to a kind of preparation method of Menglusitena, with to its purifying further.
Background technology
Menglusitena (Montelukast sodium) is the selectivity LTRA of new generation that Merck company researches and develops for many years, be the optimal drug for the treatment of in the world asthma and allergic rhinitis at present, listing keeps annual more than 10% sale amplification so far certainly.
Menglusitena (Montelukast sodium) chemical name is (+)-1-［ ［ ［ (1R)-1-［ 3-［ the chloro-2-quinolyl of (1E)-2-(7-)-vinyl ］ phenyl ］-3-［ 2-(1-hydroxyl-1-methylethyl) phenyl ］ propyl group ］ sulphur ］ methyl ］ cyclopropaneacetic acid sodium, its structural formula is as follows:
Ⅰ
The entire industries that discloses Menglusitena in the patent that Merck company is 1139429 at publication number is combined to method, but there is defect aspect several impurity of control Menglusitena in its technique, wherein (American Pharmacopeia impurity a), two sulphur impurity (American Pharmacopeia impurity c and d), vinylbenzene impurity (American Pharmacopeia impurity f) all can not well remove for sulfoxide impurity, and along with the world market of Menglusitena in recent years expands gradually, the lifting of quality product has become the problem that must solve.
Summary of the invention
Technical problem to be solved by this invention is: the Menglusitena preparation method that a kind of high-quality, efficient, low-cost, easy industrialization is provided.
Technical solution of the present invention is: a kind of preparation method of Menglusitena of following formula I, comprising:
Ⅰ
A, 2-[1-(mercapto methyl) cyclopropyl] the double sodium salt preparation of acetic acid: the carboxyl in the compound of formula II and sulfydryl are become to active double sodium salt, obtain the compound of formula III;
Ⅱ Ⅲ
B, montelukast free acid preparation: the compound 2-of formula IV (2-(3S)-(3-(2-(the chloro-2-quinolyl of 7-)-vinyl-phenyl)-3-hydroxypropyl) phenyl) methanesulfonates of-2-propyl alcohol reacts with the compound of formula III the MONTELUKAST sodium salt that obtains low-purity, reacts and obtains montelukast free acid with weak acid;
Ⅳ
C, the preparation of Singulair di-n-propylamine salt: montelukast free acid is reacted with di-n-propylamine, through concentrated, crystallization, centrifugal, the dry Singulair di-n-propylamine salt that obtains;
D, the preparation of Singulair dicyclohexyl amine salt: by the acidifying of Singulair di-n-propylamine salt, after washing, react with dicyclohexyl amine, through crystallization, centrifugal, the dry Singulair dicyclohexyl amine salt that obtains;
E, MONTELUKAST sodium salt preparation: by the acidifying of Singulair dicyclohexyl amine salt, washing, becomes sodium salt with alkali, through concentrated, crystallization, the dry MONTELUKAST sodium salt that obtains.
Technique effect of the present invention is: processing condition simply, are easily gone, removed in Merck & Co. Inc. such as more difficult controlling such as " cross polarization microtechniques "; Good impurity removing effect, the Menglusitena quality product the obtaining super former drug quality of grinding far away, can make sulfoxide impurity and be less than 0.1%, and all the other impurity are less than 0.05%, and even indivedual impurity inspections do not measure, and Menglusitena purity is greater than 99.8%.; Danger coefficient is little, has removed as the use of the inflammable and explosive materials such as n-Butyl Lithium; Pollute littlely, reduced the consumption of water, with low poison solvent, replaced acetonitrile, the tetrahydrofuran (THF) equal solvent that toxicity is stronger.
Accompanying drawing explanation
Fig. 1 is that Singulair di-n-propylamine salt related substance detects collection of illustrative plates;
Fig. 2 is that Singulair dicyclohexyl amine salt related substance detects collection of illustrative plates;
Fig. 3 is that Singulair dicyclohexyl amine salt related substance detects collection of illustrative plates;
Fig. 4 is that MONTELUKAST sodium salt related substance detects collection of illustrative plates;
Fig. 5 is that MONTELUKAST sodium salt related substance detects collection of illustrative plates.
Embodiment
Below by embodiment, further illustrate the present invention.The preparation method who it should be understood that the embodiment of the present invention is only used for illustrating the present invention, rather than limitation of the present invention, under design prerequisite of the present invention, preparation method's of the present invention improvement is all belonged to the scope of protection of present invention.
A preparation method for the Menglusitena of following formula I, comprising:
Ⅰ
A, 2-[1-(mercapto methyl) cyclopropyl] the double sodium salt preparation of acetic acid: the carboxyl in the compound of formula II and sulfydryl are become to active double sodium salt, obtain the compound of formula III.
Ⅱ Ⅲ
Described steps A be by the compound dissolution of formula II in tetrahydrofuran (THF) or toluene or C3-C5 solvent, be cooled to-40～0 ℃, add alkaline sodium ,-40～0 ℃ of reaction 0.5～10 hour, obtains the double sodium salt of the compound of formula II.
Described alkaline sodium is sodium hydroxide ethanolic soln or sodium methoxide solution.
The compound of formula II preferentially selects tetrahydrofuran (THF) to dissolve, and temperature of reaction is preferentially selected-10～0 ℃, and alkaline sodium is preferentially selected sodium methoxide solution, and the reaction times is preferentially selected 0.5～3 hour.
B, montelukast free acid preparation: the compound 2-of formula IV (2-(3S)-(3-(2-(the chloro-2-quinolyl of 7-)-vinyl-phenyl)-3-hydroxypropyl) phenyl) methanesulfonates of-2-propyl alcohol reacts with the compound of formula III the MONTELUKAST sodium salt that obtains low-purity, reacts and obtains montelukast free acid with weak acid.
Ⅳ
Described step B is added to the compound of formula IV in the solution of compound of formula III ,-40～0 ℃ of reaction 1～20 hour, then obtain montelukast free acid after processing with tartrate, standby with nitrogen protection after ethyl acetate or dichloromethane extraction.
The preparation of the methanesulfonates of 2-(2-(3S)-(3-(2-(the chloro-2-quinolyl of 7-)-vinyl-phenyl)-3-hydroxypropyl) phenyl)-2-propyl alcohol can be with reference to patent 1139429 preparations, temperature of reaction is preferentially selected-10～0 ℃, preferential selection of reaction times 1～10 hour, extraction solvent is selected ethyl acetate or methylene dichloride.
C, the preparation of Singulair di-n-propylamine salt: montelukast free acid is reacted with di-n-propylamine, through concentrated, crystallization, centrifugal, the dry Singulair di-n-propylamine salt that obtains.
Described step C will add di-n-propylamine in the ethyl acetate of montelukast free acid or dichloromethane solution, 0～40 ℃ is reacted 10 minutes to 6 hours, add Singulair di-n-propylamine salt crystal seed, crystallization, centrifugal, dryly obtain highly purified Singulair di-n-propylamine salt.
The mol ratio of described montelukast free acid and di-n-propylamine is 1:2.0～2.5.
Temperature of reaction is preferential selects 10～30 ℃, and the reaction times preferentially selects 10 minutes～and 2 hours, the mol ratio of montelukast free acid and di-n-propylamine is preferentially selected 1:2.1.
D, the preparation of Singulair dicyclohexyl amine salt: by the acidifying of Singulair di-n-propylamine salt, after washing, react with dicyclohexyl amine, through crystallization, centrifugal, the dry Singulair dicyclohexyl amine salt that obtains.
Described step D is after by Singulair di-n-propylamine, for salt, toluene, ethyl acetate or methylene dichloride dissolve, acidifying, separatory obtain montelukast free acid, add dicyclohexyl amine, 0～40 ℃ is reacted 10 minutes to 6 hours, add Singulair dicyclohexyl amine salt crystal seed, crystallization, centrifugal, dryly obtain highly purified Singulair dicyclohexyl amine salt.
Singulair di-n-propylamine salt is preferentially selected acetic acid ethyl dissolution, adds after dicyclohexyl amine that temperature of reaction is preferential selects 10～30 ℃, and the reaction times preferentially selects 10 minutes～and 2 hours.
E, MONTELUKAST sodium salt preparation: by the acidifying of Singulair dicyclohexyl amine salt, washing, becomes sodium salt with alkali, through concentrated, crystallization, the dry MONTELUKAST sodium salt that obtains.
Described step e is by toluene, ethyl acetate or the methylene dichloride dissolving for salt of Singulair dicyclohexyl amine, after acidifying, washing, separatory, add alkaline sodium to become sodium salt, join crystallization in sherwood oil, normal hexane or normal heptane after concentrated, centrifugal, dryly obtain highly purified MONTELUKAST sodium salt.
Singulair dicyclohexyl amine salt preferentially selects toluene to dissolve, the concentrated rear preferential crystallization in normal heptane of selecting.
2-[1-(mercapto methyl) cyclopropyl] the double sodium salt preparation of acetic acid:
Embodiment 1: in 500ml there-necked flask, add 2-[1-(mercapto methyl) cyclopropyl] acetic acid 20g (0.137mol), tetrahydrofuran (THF) 200ml, is cooled to-10 ℃ after stirring and dissolving, add sodium methylate 30g, and-10～0 ℃ of insulation reaction 3 hours is standby.
Embodiment 2: in 500ml there-necked flask, add 2-[1-(mercapto methyl) cyclopropyl] acetic acid 20g (0.137mol), toluene 200ml, is cooled to-10 ℃ after stirring and dissolving, add sodium methylate 30g, and-10～0 ℃ of insulation reaction 3 hours is standby.
Embodiment 3: in 500ml there-necked flask, add 2-[1-(mercapto methyl) cyclopropyl] acetic acid 20g (0.137mol), toluene 200ml, after stirring and dissolving, be cooled to-10 ℃, add sodium hydroxide ethanolic soln (11g sodium hydroxide, 200ml ethanol is prepared from),-10～0 ℃ of insulation reaction 3 hours, standby.
Montelukast free acid preparation:
Embodiment 4: in 1000ml there-necked flask, add 2-[1-(mercapto methyl) cyclopropyl preparing in embodiment 1] the double sodium salt solution of acetic acid, the methanesulfonates 54g(0.1mol that adds again 2-(2-(3S)-(3-(2-(the chloro-2-quinolyl of 7-)-vinyl-phenyl)-3-hydroxypropyl) phenyl)-2-propyl alcohol),-10～0 ℃ of insulation reaction 10 hours, add tartrate 40g, water 400ml, stir 30 minutes, add ethyl acetate 500ml, stir 30 minutes, standing separatory, obtain montelukast free acid, standby.
Embodiment 5: in 1000ml there-necked flask, add 2-[1-(mercapto methyl) cyclopropyl preparing in embodiment 1] the double sodium salt solution of acetic acid, the methanesulfonates 54g(0.1mol that adds again 2-(2-(3S)-(3-(2-(the chloro-2-quinolyl of 7-)-vinyl-phenyl)-3-hydroxypropyl) phenyl)-2-propyl alcohol),-10～0 ℃ of insulation reaction 10 hours, add tartrate 40g, water 400ml, stir 30 minutes, add methylene dichloride 500ml, stir 30 minutes, standing separatory, obtain montelukast free acid, standby.
The preparation of Singulair di-n-propylamine salt:
Embodiment 6: to the montelukast free acid solution that adds embodiment 2 preparations in 1000ml there-necked flask, add di-n-propylamine 24g, 10～30 ℃ are reacted 2 hours, add Singulair di-n-propylamine salt crystal seed 0.2g, 10～30 ℃ of insulation crystallizatioies 24 hours, filter, and 50 ℃ of filter cakes are dry obtains the Singulair di-n-propylamine salt 62g that single impurity is less than 0.1% for 6 hours, yield 86%, accompanying drawing 1 is shown in by HPLC collection of illustrative plates.
The preparation of Singulair dicyclohexyl amine salt:
Embodiment 7: in 500ml there-necked flask, add Singulair di-n-propylamine salt 20g, add ethyl acetate 150ml, stirring and dissolving, adds water 100ml, and glacial acetic acid 2.5g stirs standing separatory 30 minutes.Add dicyclohexyl amine 11g, 10～30 ℃ are reacted 2 hours, add 0.2g Singulair dicyclohexyl amine salt crystal seed, 10～30 ℃ are incubated crystallization 10 hours, filter, and 60 ℃ are dried 12 hours, obtain the Singulair dicyclohexyl amine salt 21g that single impurity is less than 0.1%, yield 94%, accompanying drawing 2 is shown in by HPLC collection of illustrative plates.
Embodiment 8: in 500ml there-necked flask, add Singulair di-n-propylamine salt 20g, add toluene 150ml, stirring and dissolving, adds water 100ml, and glacial acetic acid 2.5g stirs standing separatory 30 minutes.Add dicyclohexyl amine 11g, 10～30 ℃ are reacted 2 hours, add 0.2g Singulair dicyclohexyl amine salt crystal seed, 10～30 ℃ are incubated crystallization 10 hours, filter, and 60 ℃ are dried 12 hours, obtain the Singulair dicyclohexyl amine salt 20.2g that single impurity is less than 0.1%, yield 90%, accompanying drawing 3 is shown in by HPLC collection of illustrative plates.
Menglusitena preparation:
Embodiment 9: in 250ml there-necked flask, add 10g Singulair dicyclohexyl amine salt, 60ml toluene, adds 100ml water after stirring and dissolving, and 2g glacial acetic acid stirs standing separatory 30 minutes.Add sodium hydroxide/ethyl alcohol solution (0.5g sodium hydroxide adds 15g ethanol and is prepared from), room temperature reaction 30 minutes, adds gac 1g, room temperature decolouring 30 minutes, filter, 50 ℃ of filtrates distill out and join in 100ml normal heptane crystallization after 20g solvent 2 hours, filter, 60 ℃ dry 24 hours, obtain sulfoxide impurity and be less than 0.1%, the Menglusitena 7.5g that all the other impurity are less than 0.05%, yield 95%, accompanying drawing 4 is shown in by HPLC collection of illustrative plates.
Embodiment 10: in 250ml there-necked flask, add 10g Singulair dicyclohexyl amine salt, 60ml toluene, adds 100ml water after stirring and dissolving, and 2g glacial acetic acid stirs standing separatory 30 minutes.Add sodium hydroxide/ethyl alcohol solution (0.5g sodium hydroxide adds 15g ethanol and is prepared from), room temperature reaction 30 minutes, adds gac 1g, room temperature decolouring 30 minutes, filter, 50 ℃ of filtrates distill out and join in 100ml normal hexane crystallization after 20g solvent 2 hours, filter, 60 ℃ dry 24 hours, obtain sulfoxide impurity and be less than 0.1%, the Menglusitena 7.6g that all the other impurity are less than 0.05%, yield 96%, accompanying drawing 5 is shown in by HPLC collection of illustrative plates.
Claims (8)
1. a preparation method for the Menglusitena of following formula I, is characterized in that, described method comprises:
Ⅰ
A, 2-[1-(mercapto methyl) cyclopropyl] the double sodium salt preparation of acetic acid: the carboxyl in the compound of formula II and sulfydryl are become to active double sodium salt, obtain the compound of formula III;
Ⅱ Ⅲ
B, montelukast free acid preparation: the compound 2-of formula IV (2-(3S)-(3-(2-(the chloro-2-quinolyl of 7-)-vinyl-phenyl)-3-hydroxypropyl) phenyl) methanesulfonates of-2-propyl alcohol reacts with the compound of formula III the MONTELUKAST sodium salt that obtains low-purity, reacts and obtains montelukast free acid with weak acid;
Ⅳ
C, the preparation of Singulair di-n-propylamine salt: montelukast free acid is reacted with di-n-propylamine, through concentrated, crystallization, centrifugal, the dry Singulair di-n-propylamine salt that obtains;
D, the preparation of Singulair dicyclohexyl amine salt: by the acidifying of Singulair di-n-propylamine salt, after washing, react with dicyclohexyl amine, through crystallization, centrifugal, the dry Singulair dicyclohexyl amine salt that obtains;
E, MONTELUKAST sodium salt preparation: by the acidifying of Singulair dicyclohexyl amine salt, washing, becomes sodium salt with alkali, through concentrated, crystallization, the dry MONTELUKAST sodium salt that obtains.
2. the preparation method of Menglusitena as claimed in claim 1, it is characterized in that, described steps A be by the compound dissolution of formula II in tetrahydrofuran (THF) or toluene or C3-C5 solvent, be cooled to-40～0 ℃, add alkaline sodium,-40～0 ℃ is reacted 0.5～10 hour, obtains the double sodium salt of the compound of formula II.
3. the preparation method of Menglusitena as claimed in claim 2, is characterized in that, described alkaline sodium is sodium hydroxide ethanolic soln or sodium methoxide solution.
4. the preparation method of Menglusitena as claimed in claim 1; it is characterized in that; described step B is added to the compound of formula IV in the solution of compound of formula III;-40～0 ℃ is reacted 1～20 hour; after processing with tartrate again, obtain montelukast free acid, standby with nitrogen protection after ethyl acetate or dichloromethane extraction.
5. the preparation method of Menglusitena as claimed in claim 1, it is characterized in that, described step C will add di-n-propylamine in the ethyl acetate of montelukast free acid or dichloromethane solution, 0～40 ℃ is reacted 10 minutes to 6 hours, add Singulair di-n-propylamine salt crystal seed, crystallization, centrifugal, dryly obtain highly purified Singulair di-n-propylamine salt.
6. the preparation method of Menglusitena as claimed in claim 5, is characterized in that, the mol ratio of described montelukast free acid and di-n-propylamine is 1:2.0～2.5.
7. the preparation method of Menglusitena as claimed in claim 1, it is characterized in that, described step D is after by Singulair di-n-propylamine, for salt, toluene, ethyl acetate or methylene dichloride dissolve, acidifying, separatory obtain montelukast free acid, add dicyclohexyl amine, 0～40 ℃ of reaction 10 minutes to 6 hours, adds Singulair dicyclohexyl amine salt crystal seed, crystallization, centrifugal, dryly obtains highly purified Singulair dicyclohexyl amine salt.
8. the preparation method of Menglusitena as claimed in claim 1, it is characterized in that, described step e is by toluene, ethyl acetate or the methylene dichloride dissolving for salt of Singulair dicyclohexyl amine, after acidifying, washing, separatory, add alkaline sodium to become sodium salt, join crystallization in sherwood oil, normal hexane or normal heptane after concentrated, centrifugal, dryly obtain highly purified MONTELUKAST sodium salt.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541711A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Preparation method of montelukast |
| CN105541710A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Synthesis method for montelukast |
| CN105585524A (en) * | 2016-02-29 | 2016-05-18 | 山东新时代药业有限公司 | Method for preparing montelukast sodium from montelukast acid |
| CN105924392A (en) * | 2016-02-29 | 2016-09-07 | 山东新时代药业有限公司 | Preparation method of montelukast sodium |
| CN106928138A (en) * | 2017-05-04 | 2017-07-07 | 威海迪素制药有限公司 | A kind of preparation method of montelukast sodium impurity D |
| CN111170939A (en) * | 2019-12-20 | 2020-05-19 | 牡丹江恒远药业股份有限公司 | Preparation method of high-purity montelukast sodium and intermediate thereof |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541711A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Preparation method of montelukast |
| CN105541710A (en) * | 2016-02-22 | 2016-05-04 | 齐鲁天和惠世制药有限公司 | Synthesis method for montelukast |
| CN105541711B (en) * | 2016-02-22 | 2018-06-19 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of montelukast |
| CN105541710B (en) * | 2016-02-22 | 2018-06-19 | 齐鲁天和惠世制药有限公司 | A kind of synthetic method of montelukast |
| CN105585524A (en) * | 2016-02-29 | 2016-05-18 | 山东新时代药业有限公司 | Method for preparing montelukast sodium from montelukast acid |
| CN105924392A (en) * | 2016-02-29 | 2016-09-07 | 山东新时代药业有限公司 | Preparation method of montelukast sodium |
| CN105924392B (en) * | 2016-02-29 | 2018-03-02 | 山东新时代药业有限公司 | A kind of Menglusitena preparation method |
| CN105585524B (en) * | 2016-02-29 | 2018-03-02 | 山东新时代药业有限公司 | A kind of method that Menglusitena is prepared by montelukast acid |
| CN106928138A (en) * | 2017-05-04 | 2017-07-07 | 威海迪素制药有限公司 | A kind of preparation method of montelukast sodium impurity D |
| CN106928138B (en) * | 2017-05-04 | 2019-08-16 | 威海迪素制药有限公司 | A kind of preparation method of montelukast sodium impurity D |
| CN111170939A (en) * | 2019-12-20 | 2020-05-19 | 牡丹江恒远药业股份有限公司 | Preparation method of high-purity montelukast sodium and intermediate thereof |
| CN112409252A (en) * | 2019-12-20 | 2021-02-26 | 牡丹江恒远药业股份有限公司 | Preparation method of high-purity montelukast sodium and intermediate thereof |
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