CN103570618A - Preparation method of montelukast sodium - Google Patents
Preparation method of montelukast sodium Download PDFInfo
- Publication number
- CN103570618A CN103570618A CN201310463503.8A CN201310463503A CN103570618A CN 103570618 A CN103570618 A CN 103570618A CN 201310463503 A CN201310463503 A CN 201310463503A CN 103570618 A CN103570618 A CN 103570618A
- Authority
- CN
- China
- Prior art keywords
- singulair
- montelukast
- salt
- dicyclohexyl amine
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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 preparation method of a montelukast sodium, and the preparation method comprises the following steps: step A, transforming a montelukast free acid into a montelukast dicyclohexylamine salt; step B, transforming the montelukast dicyclohexylamine salt into a montelukast di-n-propylamine salt; step C, transforming the montelukast di-n-propylamine salt into a montelukast sodium salt. The preparation method of the montelukast sodium salt disclosed by the invention has the advantages of simplicity in operation, high yield, high product purity and the like.
Description
(1) technical field
The present invention relates to a kind of preparation method of MONTELUKAST sodium salt.
(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) cyclopropyl sodium acetate, structural formula is as follows:
This compound can be used for treating respiratory disease, as asthma and allergic rhinitis etc.The patent US5565473 of Merck & Co., Inc. discloses chemical structural formula of Singulair and preparation method thereof, the Singulair oily matter that it prepares is after column chromatography purification, become the soluble in water and freeze-drying of sodium salt, because of intermediate and final product all needed post purify and yield low, so this preparation method is not suitable for scale operation.In its technique patent CN1046712C, also mentioned above-mentioned defect, and disclose through dicyclohexyl amine salt purifying and prepared the method for Menglusitena.But we find can not effectively remove Singulair oxidation impurities (American Pharmacopeia impurity C) and terminal olefin impurity (American Pharmacopeia impurity B) through dicyclohexyl amine salt purifying in test.
Patent CN101679268A discloses and has a kind ofly prepared Singulair tert-butylamine salt and make it reach the process for purification of pharmaceutical purity.The method relates to a large amount of extractions, cleaning solvent, and complicated operation and dust removal rate are very low.
Along with market is more and more higher to the specification of quality of bulk drug (API), meet merely standards of pharmacopoeia and be not enough to meet the demands, be badly in need of the method that exploitation is applicable to suitability for industrialized production high quality MONTELUKAST sodium salt.
(3) summary of the invention
The object of the present invention is to provide the preparation method of the Menglusitena that a kind of simple to operate, good impurity removing effect and yield are high, can make single assorted Menglusitena of 0.10% that is less than.
The preparation method who the invention provides a kind of MONTELUKAST sodium salt, comprising:
A, make montelukast free acid be converted into Singulair dicyclohexyl amine salt;
B, make Singulair dicyclohexyl amine salt be converted into Singulair di-n-propylamine salt;
C, make Singulair di-n-propylamine salt be converted into MONTELUKAST sodium salt.
In the present invention, montelukast free acid can be obtained by disclosed prior art, recommends to be reacted and obtain with the methanesulfonates of 2-(2-(3-(2-(the chloro-2-quinolyl of 7-)-ethenylphenyl)-3-hydroxypropyl) phenyl)-2-propyl alcohol (abbreviation glycol) by 1-(mercapto methyl) cyclopropyl acetic acid two negatively charged ion two lithiums.
Steps A of the present invention is specifically according to carrying out as follows: montelukast free acid is suspended in suspension reagent A, adds dicyclohexyl amine, stir molten clearly, 0-40 ℃ is stirred 8-24h, filters, and obtains Singulair dicyclohexyl amine salt; Described suspension reagent A is the ketone of toluene or C3-C5.Wherein, the molar ratio of montelukast free acid and dicyclohexyl amine is 1:1.0-1.5, is preferably 1:1.1; The volume add-on of suspension reagent A is counted 5～25mL/g with the quality of montelukast free acid, is preferably 10mL/g.
Further, in steps A, suspension reagent A is preferably toluene.
Further, in steps A, whipping temp is preferably 20-40 ℃, the preferred 16-24h of churning time.
Step B of the present invention is specifically according to carrying out as follows: by Singulair dicyclohexyl amine salt add in ethyl acetate, methylene dichloride or chloroform, stir molten clear after, acidifying, washing, boil off solvent, add again suspension reagent B to stir, add di-n-propylamine, stir molten clearly, stir 8-24h in 0-40 ℃, filtering drying obtains Singulair di-n-propylamine salt; Described suspension reagent B is the ketone of toluene or C3-C5.Wherein the molar weight that feeds intake of di-n-propylamine be preparation described Singulair dicyclohexyl amine salt required montelukast free acid molar weight 1.0-1.5 doubly, be preferably 1:1.1-1.2; The volume add-on of suspension reagent B is counted 5～25mL/g to prepare the quality of the required montelukast free acid of described Singulair dicyclohexyl amine salt, is preferably 10mL/g.
Further, in step B, suspension reagent B is preferably toluene.
Further, in step B, whipping temp is preferably 20-40 ℃, the preferred 16-24h of churning time.
In above-mentioned steps A and step B, add stir after corresponding amine salt molten clear after, can add crystal seed, be conducive to the generation of respective objects product.
Step C of the present invention is specially: in alcoholic solvent, Singulair di-n-propylamine salt is reacted with sodium hydroxide, separation obtains MONTELUKAST sodium salt.The alcohol of the preferred C1～C4 of described alcoholic solvent, more preferably methyl alcohol or ethanol.Described step C is popular response, wherein Singulair di-n-propylamine salt and sodium hydroxide for etc. mole feed intake, the volume that adds of alcoholic solvent does not have special requirement.After having reacted, adopting routine operation is the separable MONTELUKAST sodium salt that obtains, and such as reaction mixture is first boiled off to solvent, it is molten clear that crude product adds toluene or methylene dichloride etc. to stir, then add normal hexane or normal heptane analysis of material; Or obtain adding acetonitrile to stir analysis of material after crude product; Then filter, dry and can obtain MONTELUKAST sodium salt.
The present invention is concrete recommends described preparation method according to carrying out as follows:
A, montelukast free acid is suspended in the ketone of toluene or C3-C5, adds dicyclohexyl amine, stir molten clearly, 20-40 ℃ is stirred 16-24h, filters, and obtains Singulair dicyclohexyl amine salt; Wherein, the molar ratio of montelukast free acid and dicyclohexyl amine is 1:1.0-1.5, and the volume add-on of the ketone of toluene or C3-C5 is counted 5～25mL/g with the quality of montelukast free acid;
B, by Singulair dicyclohexyl amine salt add in ethyl acetate, methylene dichloride or chloroform, stir molten clear after, acid adjustment, washing, boil off solvent, the ketone that adds again toluene or C3-C5, stir, add di-n-propylamine, stir molten clear, in 20-40 ℃ of stirring 16-24h, filtering drying obtains Singulair di-n-propylamine salt; Wherein the molar weight that feeds intake of di-n-propylamine be preparation described Singulair dicyclohexyl amine salt required montelukast free acid molar weight 1.0-1.5 doubly, the volume add-on of the ketone of toluene or C3-C5 is counted 5～25mL/g to prepare the quality of the required montelukast free acid of described Singulair dicyclohexyl amine salt;
C, in alcoholic solvent, Singulair di-n-propylamine salt is reacted with sodium hydroxide, separation obtains MONTELUKAST sodium salt; Described alcoholic solvent is selected from the alcohol of C1～C4.
Compared with prior art, the preparation method of the MONTELUKAST sodium salt that the present invention reports, can effectively remove impurity through the operation of steps A and step B, have simple to operate, yield is high, product purity advantages of higher.
(4) accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of the Menglusitena that makes of embodiment 1.
(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 to this:
Embodiment 1
In 500ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 200ml toluene, nitrogen replacement 2 times, add dicyclohexyl amine 7.45ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 25 ℃ are stirred 24h, filter to obtain Singulair dicyclohexyl amine salt wet feed 30g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml ethyl acetate, and nitrogen replacement 2 times, adds 2.5% glacial acetic acid aqueous solution 100ml, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase dried over mgso, filters, and boils off solvent; Add toluene 200ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 25 ℃ are stirred 24h.Filter, dry.Obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 20g, yield 85.3%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 100ml methyl alcohol, nitrogen replacement 3 times.Add sodium hydrate methanol solution (20ml methyl alcohol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 50ml toluene, dissolve limpid after, splash into analysis of material in 500ml normal heptane, filter, dry, obtain and be singly assortedly less than 0.1% Menglusitena finished product 8.5g, yield 96.0%, content 99.7%, Fig. 1 is shown in by HPLC collection of illustrative plates.
Embodiment 2
In 500ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 100ml acetone, nitrogen replacement 2 times, add dicyclohexyl amine 10.15ml(0.051 mole), be stirred to feed liquid molten clear, add crystal seed, 35 ℃ are stirred 20h, filter to obtain Singulair dicyclohexyl amine salt wet feed 30g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml ethyl acetate, and nitrogen replacement 2 times, adds the aqueous tartaric acid solution 100ml of 0.5M, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase anhydrous sodium sulfate drying, filters, and boils off solvent; Add toluene 200ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 20 ℃ are stirred 20h.Filter, dry, obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 19.8g, yield 84.4%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 50ml ethanol, nitrogen replacement 3 times.Add sodium hydroxide ethanolic soln (20ml ethanol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 50ml toluene, dissolve limpid after, splash into analysis of material in 500ml normal hexane, filter, dry, obtain single assorted be less than 0.1% Menglusitena finished product 8.3g, yield 93.8%, content 99.6%.
Embodiment 3
In 500ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 200ml toluene, nitrogen replacement 2 times, add dicyclohexyl amine 7.45ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 25 ℃ are stirred 24h, filter to obtain Singulair dicyclohexyl amine salt wet feed 30g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml methylene dichloride, and nitrogen replacement 2 times, adds 2.5% glacial acetic acid aqueous solution 100ml, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase dried over mgso, filters, and boils off solvent; Add toluene 200ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 25 ℃ are stirred 24h.Filter, dry.Obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 20g, yield 85.3%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 100ml Virahol, nitrogen replacement 3 times.Add sodium hydroxide aqueous isopropanol (20ml Virahol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 50ml toluene, dissolve limpid after, splash into analysis of material in 500ml normal heptane, filter, dry, obtain single assorted be less than 0.1% Menglusitena finished product 8.4g, yield 94.9%, content 99.7%.
Embodiment 4
In 500ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 180ml pentanone, nitrogen replacement 2 times, add dicyclohexyl amine 7.45ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 20 ℃ are stirred 24h, filter to obtain Singulair dicyclohexyl amine salt wet feed 30g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml chloroform, and nitrogen replacement 2 times, adds 2.5% glacial acetic acid aqueous solution 120ml, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase dried over mgso, filters, and boils off solvent; Add pentanone 200ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 25 ℃ are stirred 24h.Filter, dry.Obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 19.6g, yield 83.6%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 100ml Virahol, nitrogen replacement 3 times.Add sodium hydroxide aqueous isopropanol (20ml Virahol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 50ml methylene dichloride, dissolve limpid after, splash into analysis of material in 500ml normal hexane, filter, dry, obtain single assorted be less than 0.1% Menglusitena finished product 8.3g, yield 93.8%, content 99.5%.
Embodiment 5
In 500ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 100ml toluene, nitrogen replacement 2 times, add dicyclohexyl amine 7.45ml(0.0374 mole), be stirred to feed liquid molten clear, 40 ℃ are stirred 24h, filter to obtain Singulair dicyclohexyl amine salt wet feed 28g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml ethyl acetate, and nitrogen replacement 2 times, adds 2.5% glacial acetic acid aqueous solution 120ml, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase dried over mgso, filters, and boils off solvent; Add acetone 100ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 15 ℃ are stirred 24h.Filter, dry.Obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 19.8g, yield 84.4%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 100ml methyl alcohol, nitrogen replacement 3 times.Add sodium hydrate methanol solution (20ml methyl alcohol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 50ml methylene dichloride, dissolve limpid after, splash into analysis of material in 500ml normal hexane, filter, dry, obtain single assorted be less than 0.1% Menglusitena finished product 8.4g, yield 94.9%, content 99.5%.
Embodiment 6
In 500ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 100ml toluene, nitrogen replacement 2 times, add dicyclohexyl amine 7.45ml(0.0374 mole), be stirred to feed liquid molten clear, 25 ℃ are stirred 24h, filter to obtain Singulair dicyclohexyl amine salt wet feed 31.4g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml chloroform, and nitrogen replacement 2 times, adds 2.5% glacial acetic acid aqueous solution 120ml, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase dried over mgso, filters, and boils off solvent; Add toluene 500ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 7.00ml(0.051 mole), be stirred to feed liquid molten clear, 25 ℃ are stirred 24h.Filter, dry.Obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 19.4g, yield 82.7%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 100ml methyl alcohol, nitrogen replacement 3 times.Add sodium hydrate methanol solution (20ml methyl alcohol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 50ml toluene, dissolve limpid after, splash into analysis of material in 500ml acetonitrile, filter, dry, obtain single assorted be less than 0.1% Menglusitena finished product 8.4g, yield 94.9%, content 99.7%.
Embodiment 7
In 1000ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 500ml toluene, nitrogen replacement 2 times, add dicyclohexyl amine 7.45ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 25 ℃ are stirred 8h, filter to obtain Singulair dicyclohexyl amine salt wet feed 28g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml ethyl acetate, and nitrogen replacement 2 times, adds 2.5% glacial acetic acid aqueous solution 120ml, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase dried over sodium sulfate, filters, and boils off solvent; Add pentanone 100ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 5.11ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 30 ℃ are stirred 16h.Filter, dry.Obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 19.3g, yield 82.3%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 100ml ethanol, nitrogen replacement 3 times.Add sodium hydroxide ethanolic soln (20ml ethanol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 200ml acetonitrile, stir analysis of material, filter, dry, obtain single assorted be less than 0.1% Menglusitena finished product 8.5g, yield 96.0%, content 99.7%.
Embodiment 8
In 1000ml there-necked flask, drop into 20g(0.034 mole) montelukast acid, add 400ml acetone, nitrogen replacement 2 times, add dicyclohexyl amine 7.45ml(0.0374 mole), be stirred to feed liquid molten clear, add crystal seed, 0 ℃ is stirred 24h, filters to obtain Singulair dicyclohexyl amine salt wet feed 28.4g.
Above-mentioned Singulair dicyclohexyl amine salt is added in 200ml methylene dichloride, and nitrogen replacement 2 times, adds 2.5% glacial acetic acid aqueous solution 120ml, stirs 30 minutes, standing, branch vibration layer; Organic phase 100ml washes once, branch vibration layer.Organic phase dried over sodium sulfate, filters, and boils off solvent; Add acetone 500ml, stir, nitrogen replacement 2 times, adds di-n-propylamine 4.65ml(0.034 mole), be stirred to feed liquid molten clear, add crystal seed, 25 ℃ are stirred 18h.Filter, dry.Obtain single assorted be less than 0.1% Singulair di-n-propylamine salt 19.1g, yield 81.5%.
10g Singulair di-n-propylamine salt (0.017 mole) adds the making beating of 100ml Virahol, nitrogen replacement 3 times.Add sodium hydroxide aqueous isopropanol (20ml Virahol+0.68g sodium hydroxide+0.68ml water), stir 30 minutes.Pressure reducing and steaming solvent.Add 50ml methylene dichloride, dissolve limpid after, splash into analysis of material in 500ml normal heptane, filter, dry, obtain single assorted be less than 0.1% Menglusitena finished product 8.5g, yield 96%, content 99.7%.
Claims (11)
1. a preparation method for MONTELUKAST sodium salt, comprising:
A, make montelukast free acid be converted into Singulair dicyclohexyl amine salt;
B, make Singulair dicyclohexyl amine salt be converted into Singulair di-n-propylamine salt;
C, make Singulair di-n-propylamine salt be converted into MONTELUKAST sodium salt.
2. the preparation method of MONTELUKAST sodium salt as claimed in claim 1, it is characterized in that described steps A is specifically according to carrying out as follows: montelukast free acid is suspended in suspension reagent A, add dicyclohexyl amine, stir molten clear, 0-40 ℃ is stirred 8-24h, filter, obtain Singulair dicyclohexyl amine salt; Described suspension reagent A is the ketone of toluene or C3-C5.
3. the preparation method of MONTELUKAST sodium salt as claimed in claim 2, is characterized in that in described steps A, and the molar ratio of montelukast free acid and dicyclohexyl amine is 1:1.0-1.5; The volume add-on of suspension reagent A is counted 5～25mL/g with the quality of montelukast free acid.
4. the preparation method of MONTELUKAST sodium salt as claimed in claim 2, is characterized in that in described steps A, and the molar ratio of montelukast free acid and dicyclohexyl amine is 1:1.1; The volume add-on of suspension reagent A is counted 10mL/g with the quality of montelukast free acid.
5. the preparation method of the MONTELUKAST sodium salt as described in one of claim 1～4, it is characterized in that described step B is specifically according to carrying out as follows: by Singulair dicyclohexyl amine salt add in ethyl acetate or methylene dichloride or chloroform, stir molten clear after, acid adjustment, wash, boil off solvent, add again suspension reagent B, stir, add di-n-propylamine, stir molten clear, in 0-40 ℃ of stirring 8-24h, filtering drying obtains Singulair di-n-propylamine salt; Described suspension reagent B is the ketone of toluene or C3-C5.
6. the preparation method of MONTELUKAST sodium salt as claimed in claim 5, it is characterized in that in described step B, the molar weight that feeds intake of di-n-propylamine is 1.0-1.5 times of the required montelukast free acid molar weight of the described Singulair dicyclohexyl amine salt of preparation, and the volume add-on of suspension reagent B is counted 5～25mL/g to prepare the quality of the required montelukast free acid of described Singulair dicyclohexyl amine salt.
7. the preparation method of MONTELUKAST sodium salt as claimed in claim 6, it is characterized in that in described step B, the molar weight that feeds intake of di-n-propylamine is the 1:1.1 of the required montelukast free acid molar weight of the described Singulair dicyclohexyl amine salt of preparation, and the volume add-on of suspension reagent B is counted 10mL/g to prepare the quality of the required montelukast free acid of described Singulair dicyclohexyl amine salt.
8. the preparation method of MONTELUKAST sodium salt as claimed in claim 5, is characterized in that described step C is specially: in alcoholic solvent, Singulair di-n-propylamine salt is reacted with sodium hydroxide, separation obtains MONTELUKAST sodium salt.
9. the preparation method of MONTELUKAST sodium salt as claimed in claim 8, is characterized in that in step C, and described alcoholic solvent is selected from the alcohol of C1～C4.
10. the preparation method of MONTELUKAST sodium salt as claimed in claim 8, is characterized in that in step C, and described alcoholic solvent is methyl alcohol or ethanol.
The preparation method of 11. MONTELUKAST sodium salt as claimed in claim 1, is characterized in that described preparation method is according to carrying out as follows:
A, montelukast free acid is suspended in the ketone of toluene or C3-C5, adds dicyclohexyl amine, stir molten clearly, 20-40 ℃ is stirred 16-24h, filters, and obtains Singulair dicyclohexyl amine salt; Wherein, the molar ratio of montelukast free acid and dicyclohexyl amine is 1:1.0-1.5, and the volume add-on of the ketone of toluene or C3-C5 is counted 5～25mL/g with the quality of montelukast free acid;
B, by Singulair dicyclohexyl amine salt add in ethyl acetate or methylene dichloride or chloroform, stir molten clear after, acid adjustment, wash, boil off solvent, the ketone that adds again toluene or C3-C5, stir, add di-n-propylamine, stir molten clearly, stir 16-24h in 20-40 ℃, filtering drying obtains Singulair di-n-propylamine salt; Wherein, the molar weight that feeds intake of di-n-propylamine is 1.0-1.5 times of the required montelukast free acid molar weight of the described Singulair dicyclohexyl amine salt of preparation, and the volume add-on of the ketone of toluene or C3-C5 is counted 5～25mL/g to prepare the quality of the required montelukast free acid of described Singulair dicyclohexyl amine salt;
C, in alcoholic solvent, Singulair di-n-propylamine salt is reacted with sodium hydroxide, separation obtains MONTELUKAST sodium salt; Described alcoholic solvent is selected from the alcohol of C1～C4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310463503.8A CN103570618A (en) | 2013-09-30 | 2013-09-30 | Preparation method of montelukast sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310463503.8A CN103570618A (en) | 2013-09-30 | 2013-09-30 | Preparation method of montelukast sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103570618A true CN103570618A (en) | 2014-02-12 |
Family
ID=50043410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310463503.8A Pending CN103570618A (en) | 2013-09-30 | 2013-09-30 | Preparation method of montelukast sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103570618A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119270A (en) * | 2014-08-12 | 2014-10-29 | 牡丹江恒远药业有限公司 | Method for preparing Montelukast sodium |
| JP2016020320A (en) * | 2014-07-16 | 2016-02-04 | 大日本印刷株式会社 | Method for manufacturing montelukast sodium |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5565473A (en) * | 1990-10-12 | 1996-10-15 | Merck Frosst Canada, Inc. | Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists |
| CN1139429A (en) * | 1993-12-28 | 1997-01-01 | 麦克公司 | Process for the preparation of leukotriene antagonists |
| US20050234241A1 (en) * | 2004-04-15 | 2005-10-20 | Venkataraman Sundaram | Process for the preparation of [R-(E)-1-[[[1-[3-[2-[7-chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (montelukast) and its pharmaceutically acceptable salts |
| CN101213177A (en) * | 2005-07-05 | 2008-07-02 | 特瓦制药工业有限公司 | 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 |
| 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 |
| CN101808998A (en) * | 2007-10-09 | 2010-08-18 | 韩美药品株式会社 | Method for the preparation of montelukast acid in ionic liquid medium |
| CN102164897A (en) * | 2008-09-26 | 2011-08-24 | 株式会社Lg生命科学 | Method for preparing montelukast sodium salts |
-
2013
- 2013-09-30 CN CN201310463503.8A patent/CN103570618A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5565473A (en) * | 1990-10-12 | 1996-10-15 | Merck Frosst Canada, Inc. | Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists |
| CN1139429A (en) * | 1993-12-28 | 1997-01-01 | 麦克公司 | Process for the preparation of leukotriene antagonists |
| US20050234241A1 (en) * | 2004-04-15 | 2005-10-20 | Venkataraman Sundaram | Process for the preparation of [R-(E)-1-[[[1-[3-[2-[7-chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (montelukast) and its pharmaceutically acceptable salts |
| CN101213177A (en) * | 2005-07-05 | 2008-07-02 | 特瓦制药工业有限公司 | 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 |
| 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 |
| CN101808998A (en) * | 2007-10-09 | 2010-08-18 | 韩美药品株式会社 | Method for the preparation of montelukast acid in ionic liquid medium |
| CN102164897A (en) * | 2008-09-26 | 2011-08-24 | 株式会社Lg生命科学 | Method for preparing montelukast sodium salts |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016020320A (en) * | 2014-07-16 | 2016-02-04 | 大日本印刷株式会社 | Method for manufacturing montelukast sodium |
| CN104119270A (en) * | 2014-08-12 | 2014-10-29 | 牡丹江恒远药业有限公司 | Method for preparing Montelukast sodium |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5411161B2 (en) | N- {1- [3- (2-Ethoxy-5- (4-ethylpiperazinyl) sulfonylphenyl) -4,5-dihydro-5-oxo-1,2,4-triazin-6-yl] ethyl } Butyramide, its preparation method and use | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| MX2008012119A (en) | Novel method for the synthesis of strontiuim ranelate and of hydrates thereof. | |
| JP2015500325A5 (en) | ||
| CN102010308B (en) | Preparation method of 8-hydroxyl caprylaldehyde of intermediate for synchronizing royaljelly acid | |
| JP2004527577A (en) | Synthesis of 4-phenylbutyric acid | |
| CN103570618A (en) | Preparation method of montelukast sodium | |
| CN102180892A (en) | Novel method for purifying cefmetazole sodium | |
| CN103304467A (en) | Method for preparing N-coffee acyl tryptamine by one-step process | |
| CN102898439B (en) | Preparation method of descarbamoyl cefuroxime lactone | |
| CN103145636A (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN101492411A (en) | Improved method for preparation of mitiglinide | |
| EP2981518B1 (en) | "an improved process for the preparation of fluvoxamine maleate" | |
| CN103772275B (en) | Singulair di-n-propylamine salt crystal formation and preparation method and application | |
| CN104926922A (en) | Preparation method for pidotimod | |
| CN105585524B (en) | A kind of method that Menglusitena is prepared by montelukast acid | |
| CN105924392B (en) | A kind of Menglusitena preparation method | |
| CN103539796B (en) | Preparation method of levo praziquantel as well as intermediate thereof | |
| CN105669475A (en) | Preparation method of dapoxetine and dapoxetine hydrochloride | |
| CN102477000B (en) | Method for synthesizing phenylethanolamines | |
| CN105924407B (en) | A kind of salifying method of S-1574 | |
| CN111320622A (en) | Method for synthesizing moxifloxacin hydrochloride | |
| CN102875399A (en) | D-valine preparation method | |
| CN110678075B (en) | Pyrazole amine reaction crystal | |
| WO2024022426A1 (en) | Method for preparing 4-(trimethylammonio)pentanoate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140212 |