CN105294556A

CN105294556A - Method for preparing montelukast acid

Info

Publication number: CN105294556A
Application number: CN201410250475.6A
Authority: CN
Inventors: 李金亮; 赵楠; 王子坤
Original assignee: SHANGHAI DESANO PHARMACEUTICAL CO Ltd; SHANGHAI DISAINUO CHEMICAL PHARMACEUTICAL CO Ltd
Current assignee: SHANGHAI DESANO PHARMACEUTICAL CO Ltd; SHANGHAI DISAINUO CHEMICAL PHARMACEUTICAL CO Ltd; Shanghai Desano Chemical Pharmaceutical Co Ltd
Priority date: 2014-06-06
Filing date: 2014-06-06
Publication date: 2016-02-03

Abstract

The invention discloses a method for preparing montelukast acid. The method comprises a reaction b or a reaction a to a reaction b in the following synthetic route: the formula is shown in the description. The method disclosed by the invention can be used for preparing montelukast acid and salts thereof with low cost and high yield by means of simple operations by using low-cost and easily available raw materials, and is of significance and has practical value to prepare montelukast acid and salts thereof with low cost on a large scale.

Description

A kind of method preparing montelukast acid

Technical field

The present invention relates to a kind of method preparing montelukast acid, belong to field of pharmaceutical chemistry technology.

Background technology

Montelukast acid or its pharmacy acceptable salt is capable of blocking or suppress the synthesis of leukotrienes and activity thereof, what it was commercially available at present is sodium salt.Montelukast acid or sodium salt are the prevention being used for the treatment of more than 15 and 15 years old Adults Asthma and the long-term treatment of first being researched and developed listing by Merck, and its chemical structural formula is such as formula shown in I:

At present about the preparation of this compound, mainly contain following several route:

Following route is disclosed in European patent EP 480717:

Above-mentioned route makes 1-(thiopurine methyltransferase) cyclopropylacetate and methylsulfonyl intermediate generation linked reaction obtain methyl compound, and wherein the hydroxyl of methylsulfonyl intermediate is subject to the protection of tetrahydropyrans; Hydrolysis methyl compound is to obtain corresponding free acid, and it is converted into MONTELUKAST sodium salt.Because aforesaid method needs upper protecting group, goes the complex operations such as protecting group and column chromatography for separation, so that the total recovery of end product is low, is not suitable for industrialization production requirements.

Following route is disclosed in European patent EP 737186:

This route uses with the mesyl compound of unprotected hydroxyl and 1-(thiopurine methyltransferase) cyclopropaneacetic acid generation linked reaction; again dicyclohexyl amine is joined in linked reaction the dicyclohexyl amine salt obtaining montelukast acid, then obtain MONTELUKAST sodium salt with NaOH process.Owing to employing the n-Butyl Lithium of easy spontaneous combustion in this route, and the mesyl compound with unprotected hydroxyl used in linked reaction is difficult to preparation, and therefore this route is also not suitable for industrialization production requirements.

Chinese patent ZL200880109004.6 disclose a kind of in the basic conditions, prepare the method for montelukast acid in ionic liquid medium, as follows:

The reaction under ionic liquid exists of linked reaction described in the method is quick, and the present inventor does not all produce coupled product by test of many times.Illustrate that the method exploitativeness is less, and owing to have employed the ionic liquid very easily absorbed water, make the operation of reaction very difficult, aftertreatment is also cumbersome, and in addition, ionic liquid is expensive, and therefore, this method is also not suitable for suitability for industrialized production.

Summary of the invention

For the problems referred to above that prior art exists, the present invention aims to provide a kind of method preparing montelukast acid, to meet the industrial requirement of montelukast acid or its salt.

For achieving the above object, the technical solution used in the present invention is as follows:

Prepare a method for montelukast acid, the b comprised in following synthetic route reacts or a reaction ~ b reacts:

Preferably, described a reaction comprises following operation: be dissolved in organic solvent A by formula IV compound, then adds organic bases at 0 ~ 40 DEG C and drips diphenyl phosphoryl chlorine, more at room temperature stirring reaction 2 ~ 8 hours, obtains formula III compound.

As further preferred version, described organic solvent A is selected from least one in methylene dichloride, toluene, benzene.

As further preferred version, described organic bases is selected from the one in triethylamine, diisopropylethylamine, DMAP, imidazoles, pyridine.

As further preferred version, the mol ratio of formula IV compound and organic bases is 1:1 ~ 1:3.

Preferably, described b reaction comprises following operation: be dissolved in organic solvent B by formula II compound, then add alkali at 0 ~ 40 DEG C, in stirred at ambient temperature 0.5 ~ 3 hour, then add formula III compound, in stirred at ambient temperature reaction 2 ~ 8 hours, the cancellation that adds water is reacted, extraction, collects organic phase, carry out concentrating under reduced pressure, drying, obtain formula I.

As further preferred version, described organic solvent B is selected from least one in methyl-sulphoxide, DMF, N-methylmorpholine, toluene, tetrahydrofuran (THF).

As further preferred version, described alkali is selected from the one in sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, sodium amide, salt of wormwood, sodium carbonate, cesium carbonate.

As further preferred version, the mol ratio of formula II compound and described alkali is 1:1 ~ 1:6.

Formula IV compound involved in the present invention is the important intermediate of synthesis montelukast acid, can be prepared by method disclosed in EP0480717.

Montelukast acid prepared in the present invention obtains MONTELUKAST sodium salt by traditional method sodium hydroxide, sodium methylate or sodium tert-butoxide process.

Compared with prior art, the present invention has following unusual effect:

1. present invention, avoiding and adopt the larger methane sulfonyl chloride of toxicity, low toxicity, the acquisition montelukast acid of high yield and salt thereof can be realized;

2. present invention, avoiding the ionic liquid that employing very easily absorbs water, make operation simple, be applicable to large-scale production;

3. present invention, avoiding employing low-temp reaction, not high to the operational requirement of reaction, can high yield, simple operations realization preparation high purity montelukast acid.

4. traditional method preparing Singulair, the compound adopted in text CN1139429A as open in Chinese patent application: 2-(2-(3 (S)-(3-(2-(the chloro-2-quinolyl of 7-) vinyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propyl alcohol, it is unstable, is very easy to eliminate; And the compound adopted in the present invention: 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolyl) vinyl) phenyl)-3-two phenoxy group phosphonato propyl group) phenyl)-2-propyl alcohol is at room temperature highly stable, so the present invention can realize the synthesis montelukast acid of high yield.

In a word, the present invention can realize utilizing raw material cheap and easy to get, low cost, high yield, simple operations to prepare montelukast acid and salt thereof, and to realizing low cost, montelukast acid is prepared in mass-producing and salt is significant and practical value.

Embodiment

Below in conjunction with embodiment, technical scheme of the present invention is described in further detail.

Embodiment 1: the preparation of formula III compound

Formula IV compound (50g, 0.11mol) is dissolved in 200mL methylene dichloride, adds triethylamine (13.1g, 0.13mol), diphenyl phosphoryl chlorine (32.3g, 0.12mol) is dripped under room temperature, again in stirred at ambient temperature 2 ~ 8 hours, add 250mL saturated sodium bicarbonate aqueous solution, extraction, collect organic phase, carry out concentrating under reduced pressure, vacuum-drying, obtain formula III compound 68.72g, molar yield is 91.2%, HPLC purity is 99.8%.

Embodiment 2: the preparation of formula III compound

Formula IV compound (50g, 0.11mol) is dissolved in 200mL toluene, adds 4-dimethylaminopyridine (26.8g, 0.22mol), diphenyl phosphoryl chlorine (32.3g, 0.12mol) is dripped under room temperature, again in stirred at ambient temperature 2 ~ 8 hours, add 250mL saturated sodium bicarbonate aqueous solution, extraction, collect organic phase, carry out concentrating under reduced pressure, vacuum-drying, obtain formula III compound 70.3g, molar yield is 92.6%, HPLC purity is 99.6%.

Embodiment 3: the preparation of formula I

By formula II compound (12.4g, 0.08mol) join in 270mL methyl-sulphoxide, add sodium tert-butoxide (16.3g at 20 ~ 25 DEG C in batches, 0.17mol), stirred at ambient temperature 0.5 ~ 3 hour, add formula III compound (45g again, 0.07mol), then in stirred at ambient temperature reaction 2 ~ 8 hours, the cancellation that adds water is reacted, extraction, collect organic phase, carry out concentrating under reduced pressure, vacuum-drying, obtain formula I 37.5g, molar yield is 98.3%, HPLC purity is 99.4%.

Embodiment 4: the preparation of formula I

Formula II compound (12.4g, 0.08mol) is joined in 250mL tetrahydrofuran (THF), add sodium hydride (5.52g at 0 DEG C in batches, 0.24mol), stirred at ambient temperature 0.5 ~ 3 hour, then add formula III compound (45g, 0.07mol), then in stirred at ambient temperature reaction 2 ~ 8 hours, the cancellation that adds water is reacted, extraction, collect organic phase, carry out concentrating under reduced pressure, vacuum-drying, obtain formula I 40.47g, molar yield is 98.8%, HPLC purity is 99.3%.

Embodiment 5: the preparation of Menglusitena

By formula I (40g, 0.068mol) be dissolved in 200mL methyl alcohol, add 2 grams of gacs, stirred at ambient temperature 30min, filter, room temperature also drips the methanol solution (2.73gNaOH is dissolved in 95mL methyl alcohol) of sodium hydroxide under protection of inert gas in filtrate, after stirring 30min, pressure reducing and steaming solvent, residue is dissolved in 100mL toluene and stirs 15min, again remove solvent under reduced pressure, residue is dissolved in 120mL toluene, then slowly 400mL normal heptane is dripped, 2h is stirred again after dropwising, filter, solid is vacuum-drying 12h at 80-85 DEG C, obtain Menglusitena 38.2g, molar yield is 92%, HPLC purity is 99.3%.

Comparative example: (method described in Chinese patent CN101808998B)

14g bromo normal-butyl-N-methylpyrrole is dissolved in 60mL dimethyl sulfoxide (DMSO), add 2.7g1-(thiopurine methyltransferase) cyclopropaneacetic acid wherein, then, to fast drop potassium tert.-butoxide 4.0g in mixture under room temperature, then this mixture is stirred 30 minutes, add 5g [2-(2-(3-S-(2-(the chloro-2-quinolyl of 7-) vinyl) phenyl)-3-diphenyl phosphoester-oxygen propyl group) phenyl)-2-propyl alcohol] wherein, stir this mixture, non-compound of formula I.

Finally be necessary to herein means out: above embodiment is only for being described further technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.

Claims

1. prepare a method for montelukast acid, it is characterized in that, the b comprised in following synthetic route reacts or a reaction ~ b reacts:

2. the method for claim 1, it is characterized in that, described a reaction comprises following operation: be dissolved in organic solvent A by formula IV compound, then adds organic bases at 0 ~ 40 DEG C and drips diphenyl phosphoryl chlorine, at room temperature stirring reaction 2 ~ 8 hours again, obtains formula III compound.

3. method as claimed in claim 2, is characterized in that: described organic solvent A is selected from least one in methylene dichloride, toluene, benzene.

4. method as claimed in claim 2, is characterized in that: described organic bases is selected from the one in triethylamine, diisopropylethylamine, DMAP, imidazoles, pyridine.

5. method as claimed in claim 2, is characterized in that: the mol ratio of formula IV compound and organic bases is 1:1 ~ 1:3.

6. the method for claim 1, it is characterized in that, described b reaction comprises following operation: be dissolved in organic solvent B by formula II compound, then add alkali at 0 ~ 40 DEG C, in stirred at ambient temperature 0.5 ~ 3 hour, add formula III compound again, in stirred at ambient temperature reaction 2 ~ 8 hours, the cancellation that adds water was reacted, extraction, collect organic phase, carry out concentrating under reduced pressure, drying, obtain formula I.

7. method as claimed in claim 6, is characterized in that: described organic solvent B is selected from least one in methyl-sulphoxide, DMF, N-methylmorpholine, toluene, tetrahydrofuran (THF).

8. method as claimed in claim 6, is characterized in that: described alkali is selected from the one in sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, sodium amide, salt of wormwood, sodium carbonate, cesium carbonate.

9. method as claimed in claim 6, is characterized in that: the mol ratio of formula II compound and described alkali is 1:1 ~ 1:6.