CN102442948B - Method for preparing montelukast sodium intermediate - Google Patents
Method for preparing montelukast sodium intermediate Download PDFInfo
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- CN102442948B CN102442948B CN 201110340278 CN201110340278A CN102442948B CN 102442948 B CN102442948 B CN 102442948B CN 201110340278 CN201110340278 CN 201110340278 CN 201110340278 A CN201110340278 A CN 201110340278A CN 102442948 B CN102442948 B CN 102442948B
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Abstract
The invention relates to a method for preparing montelukast sodium intermediate which is shown as a formula III. The method comprises the following steps of: (1), in a solvent, with the action of alkali, carrying out sulfonylation reaction of secondary hydroxyl in a compound II with a sulfonylation agent; and (2), directly carrying out halogenated reaction of reaction liquid obtained in the step (1) with a halogenated reagent, obtaining the montelukast sodium intermediate, wherein the X is C1, Br, or I. The method for preparing the montelukast sodium intermediate disclosed by the invention isgentle in reaction condition, simplex in product, simple and convenient in purification; in addition, the obtained intermediate is high in optical purity and higher in productivity, and more suitablefor industrial production.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, be specifically related to the preparation method of montelukast sodium intermediate.
Background technology
The chemistry of Menglusitena (Montelukast Sodium) is by name: 2-(1-((1 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-(2-(2-hydroxyl-2 propyl group) phenyl) rosickyite base) methyl) cyclopropyl) sodium acetate, this compound can be used as Zhichuan agent, anti-allergic agent etc.This compound is at first synthetic by Canadian Merk Frosst company, and structure of this compound and preparation method thereof is disclosed in CN1061407A by the said firm, its synthetic method is with 1 (S)-(3-(2-(7-chloroquinoline-2-yl)-(E) vinyl) phenyl)-3-(2-(2-hydroxyl-2-propyl group) phenyl) propyl alcohol and 2-(1-(thiopurine methyltransferase) cyclopropyl) acetic ester reaction preparation.
Another kind of Menglusitena synthetic method is disclosed among the CN1428335A, the method is as raw material take 2-(3-(3-(2-(7-chloro-2 quinolyls)-(E) vinyl) phenyl)-3 (R)-hydroxypropyls) methyl benzoate, hydroxyl is converted into the leavings group sulphonate, then obtain 2-(3-(3-(2-(7-chloro-2 quinolyls)-(E) vinyl) phenyl)-3 (R)-(acetyl mercapto) propyl group) methyl benzoate with the thioacetic acid reactant salt, and then Yu Geshi reagent react, obtain the sulfydryl tertiary alcohol, then obtain 2-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-(hydroxyl-2-propyl group) phenyl) propyl group) sulfenyl) methyl with the reaction of 2-(1-brooethyl) cyclopropyl acetic ester) the cyclopropyl acetic ester, the cyclopropyl acetic ester is obtained cyclopropyl acetic acid under the alkali effect, then further act on sodium hydroxide and obtain the target compound Menglusitena.
Summary of the invention
Technical problem to be solved by this invention is: complicated in order to overcome preparation Menglusitena pilot process, and severe reaction conditions, side reaction is many, the defective that purification processes is loaded down with trivial details, and the preparation method of montelukast sodium intermediate is provided.Preparation method's reaction conditions of the present invention is gentle, and product is single, and it is easy to purify, and the intermediate optical purity height and the productive rate that obtain are higher, more are applicable to suitability for industrialized production.The intermediate that the present invention makes can further be used for preparing the various compounds that contain this intermediate structure fragment.
The invention provides a kind of preparation method of the montelukast sodium intermediate shown in formula III, 1. it comprise the following steps: under the effect of alkali, the secondary hydroxyl among the Compound I I and sulfonylation agent to be carried out sulfonylation in the solvent; 2. the reaction solution that 1. step is obtained directly and halogenating agent carry out halogenating reaction, get final product;
Wherein, X is Cl, Br or I.
Among the present invention, the reaction conditions of described sulfonylation can be conventional sulfonylation condition, but such as reference literature WO2008/126075A1,2008; Reaction conditions among the Page column 12.Following each reaction conditions is the special reaction conditions of selecting of the present invention.
Wherein, described alkali preferably is organic bases or mineral alkali; Described organic bases preferably is tertiary amine, alkali-metal trimethyl carbinol compound or alkali-metal hexamethyl two silica-based amido compounds; Described tertiary amine preferably is diisopropyl ethyl amine, triethylamine, TERTIARY BUTYL AMINE or 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU) etc., is diisopropyl ethyl amine best; Described alkali-metal trimethyl carbinol compound preferably is sodium tert-butoxide or potassium tert.-butoxide; Described alkali-metal hexamethyl two silica-based amido compounds preferably are LHMDS (LiHMDS), sodium hexamethyldisilazide (NaHMDS) or potassium hexamethyldisilazide (KHMDS) etc.; Described mineral alkali preferably is alkali-metal hydride; Described alkali-metal hydride preferably is sodium hydride, potassium hydride KH or lithium hydride.
Wherein, the mol ratio of described alkali and formula II compound preferably is 1～4: 1, more preferably is 2～3: 1, is 2.5: 1 best.
Wherein, described sulfonylation agent preferably is SULPHURYL CHLORIDE and/or sulphonic acid anhydride; Described SULPHURYL CHLORIDE preferably is one or more in the benzene sulfonyl chloride that replaces of methylsulfonyl chloride, benzene sulfonyl chloride and contraposition alkyl, more preferably is methylsulfonyl chloride; Described sulphonic acid anhydride preferably is one or more in the Phenylsulfonic acid acid anhydride that replaces of methylsulfonic acid acid anhydride, trifluoromethanesulfanhydride anhydride, Phenylsulfonic acid acid anhydride and contraposition alkyl; Described alkyl is C
1～C
5The straight or branched alkyl, preferably be C
1～C
3The straight or branched alkyl.
Wherein, the mol ratio of described sulfonylation agent and formula II compound preferably is 1～3: 1, more preferably is 2～2.8: 1, is 2.5: 1 best.
Wherein, the temperature of reaction of described sulfonylation preferably is-35 ℃～0 ℃, more preferably is-30 ℃～-5 ℃, is-25 ℃～-10 ℃ best.
Among the present invention, the reaction conditions of described halogenating reaction can be conventional halogenating reaction condition, but such as reference literature Journal of the American Chemical Society, 1952, vol.74, p.5851, the reaction conditions in 5852,5853,5857.Following reaction conditions is the special reaction conditions of selecting of the present invention.
Wherein, described halogenating agent preferably is one or more in the hydrochloride of the hydrochloride of lithium chloride, tetrabutylammonium chloride, diisopropyl ethyl amine and triethylamine, more preferably is lithium chloride and/or tetrabutylammonium chloride.
Wherein, the mol ratio of described halogenating agent and formula II compound preferably is 0～9: 1, more preferably is 1～5: 1, is 3: 1 best.
Wherein, the temperature of reaction of described halogenating reaction preferably is-10 ℃～30 ℃, more preferably is 0 ℃～25 ℃, is 10 ℃～20 ℃ best.
Among the present invention, described preferred solvents ground is toluene, acetonitrile, N, in dinethylformamide (DMF), methylene dichloride and the tetrahydrofuran (THF) one or more, more preferably be toluene, acetonitrile and N, in the dinethylformamide (DMF) one or more, be DMF (DMF) and/or toluene best.
Among the present invention, the consumption of described solvent preferably is 5mL/g formula II compound～25mL/g formula II compound, more preferably is 10mL/g formula II compound～20mL/g formula II compound, is 15mL/g formula II compound best.
Among the present invention, used aftertreatment can be the post-treating method of this area routine after described sulfonylation halogenating reaction finished, preferably for adding frozen water; behind the ethyl acetate extraction; use successively saturated aqueous common salt and water washing, organic phase anhydrous sodium sulfate drying, concentrated getting final product.
Among the present invention, described preparation method preferably also is included under the protection of inert gas and reacts, and described rare gas element is the conventional rare gas element that uses in this area, preferably is nitrogen and/or argon gas.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available getting all.
Positive progressive effect of the present invention is:
1. preparation method's reaction conditions of the present invention is gentle, and product is single, and it is easy to purify, and the intermediate optical purity height and the productive rate that obtain are higher, more are applicable to suitability for industrialized production.
2. the intermediate that makes of the present invention can further be used for preparing the various compounds that contain this intermediate mechanism fragment, synthetic as for the synthesis of as the Menglusitena of Zhichuan agent and anti-allergic agent.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
The preparation of embodiment 1 formula III compound
The preparation method of 2-(2-(3 (S)-chloro-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol.
Under room temperature (25-30 ℃) and argon shield; in reaction flask, add successively 2-(2-(3 (R)-hydroxyl-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (25.1g; 55mmol), DMF (400mL) and diisopropyl ethyl amine (17.74g; 137.5mmol), be stirred to fully dissolving.Cryosel is bathed and system is cooled to-10 ℃, drips methylsulfonyl chloride (15.6g, 137.5mmol) in 30 minutes, then reacts 10 hours under this temperature.(TLC or HPLC monitoring raw material reaction are complete); Disposable adding lithium chloride (11.7g, 275mmol) removes ice bath, naturally is back to room temperature, continues reaction 14 hours.It is complete that TLC follows the tracks of reaction.Add frozen water 300mL ethyl acetate (60mL * 3), merge organic phase.Use successively saturated aqueous common salt, the water washing organic phase.Anhydrous sodium sulfate drying.Concentrate organic phase to 1/5 of original volume, add sherwood oil 500mL and stir half an hour, then hold over night is filtered, dry 16.1g formula III compound white solid, the yield 61.5% of getting.
Ee value=92%
LC-MS：[M+H]
+＝476.1；
1H?NMR(400MHz，DMSO-d
6)：8.42(d，J＝8.8Hz，1H)，7.99～8.03(m，2H)，7.88～7.94(m，3H)，7.72(d，J＝7.2Hz，1H)，7.59(d，J＝8.8Hz，1H)，7.55(d，J＝16.8Hz，，1H)，7.45～7.52(m，2H)，7.38(d，J＝7.2Hz，1H)，7.09～7.22(m，3H)，5.28(t，J＝7.2Hz，1H)，4.98(s，1H)，3.20(m，1H)，2.92(m，1H)，2.43(m，2H)，1.50(s，3H)，1.49(s，3H)。
The preparation of embodiment 2 formula III compounds
The preparation method of 2-(2-(3 (S)-chloro-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol.
Under room temperature (25-30 ℃) and argon shield; in reaction flask, add successively 2-(2-(3 (R)-hydroxyl-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (4.58g; 10mmol), toluene (68mL) and diisopropyl ethyl amine (25mmol), be stirred to fully dissolving.Cryosel is bathed (calcium chloride/ice) and system is cooled to-25 ℃, drips methylsulfonyl chloride (25mmol) in 30 minutes, then reacts 10 hours under this temperature.(TLC or HPLC monitoring raw material reaction are complete); Disposable adding tetrabutylammonium chloride (50mmol) removes ice bath, naturally is back to room temperature, continues reaction 14 hours.It is complete that TLC follows the tracks of reaction.Add frozen water 300mL ethyl acetate (60mL * 3), merge organic phase.Use successively saturated aqueous common salt, the water washing organic phase.Anhydrous sodium sulfate drying.Concentrated, add sherwood oil 150mL, ethyl acetate 15mL stirs half an hour, and then hold over night is filtered, dry 3.0g formula III compound white solid, the yield 63% of getting.
Ee value=92%
LC-MS：[M+H]
+＝476.1；
1H?NMR(400MHz，DMSO-d
6)：8.42(d，J＝8.8Hz，1H)，7.99～8.03(m，2H)，7.88～7.94(m，3H)，7.72(d，J＝7.2Hz，1H)，7.59(d，J＝8.8Hz，1H)，7.55(d，J＝16.8Hz，，1H)，7.45～7.52(m，2H)，7.38(d，J＝7.2Hz，1H)，7.09～7.22(m，3H)，5.28(t，J＝7.2Hz，1H)，4.98(s，1H)，3.20(m，1H)，2.92(m，1H)，2.43(m，2H)，1.50(s，3H)，1.49(s，3H)。
The preparation of embodiment 3 formula V compounds
The preparation method of 2-(1-((1 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-(2-(2-hydroxyl-2 propyl group) phenyl) rosickyite base) methyl) cyclopropyl) methyl acetate.
Under the condition of ice-water bath (10 ℃) and argon shield; 2-(2-(3 (S)-chloro-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (16.1g; 33.8mmol); 1-thiopurine methyltransferase cyclopropyl-2-methyl acetate (5.4g; 33.8mmol); cesium carbonate (16.5g, 50.7mmol) is put among the DMF (200mL) and removes ice-water bath, and reaction system was reacted under room temperature 3 hours.TLC monitors reaction.React complete, the 1000mL saturated aqueous common salt is added in the system, and the usefulness ethyl acetate (3 * 50mL), anhydrous sodium sulfate drying.Concentrated, get the light yellow oily formula of 14.72g V compound, yield 72.5%.
Ee value=92%
LCMS：[M+H]
+＝600.2；
1H?NMR(400MHz，DMSO-d
6)：8.41(d，J＝8.8Hz，1H)，8.02(s，1H)，8.02(d，J＝2.0Hz，1H)，8.01(d，J＝8.8Hz，1H)，7.94(d，J＝8.8Hz，1H)，7.90(d，J＝16.0Hz，1H)，7.74(s，1H)，7.64(d，J＝7.6Hz，1H)，7.59(dd，J＝2.0Hz，8.4Hz，1H)，7.51(d，J＝16.0Hz，1H)，7.42(t，J＝7.2Hz，1H)，7.37(d，J＝8.0Hz，2H)，7.06～7.14(m，3H)，4.90(s，1H)，3.99(t，J＝7.2Hz，1H)，3.53(s，3H)，3.06(td，J＝4.8Hz，12.4Hz，1H)2.77(td，J＝4.8Hz，12.4Hz，1H)，2.49(s，2H)，2.38(q，J＝15.6Hz，2H)，2.15(m，2H)，1.44(s，6H)，0.42(m，4H)。
Claims (7)
1. 1. preparation method suc as formula the montelukast sodium intermediate shown in the III is characterized in that comprising the following steps: under the effect of alkali, the secondary hydroxyl in the compound ii and sulfonylation agent being carried out sulfonylation in the solvent; The temperature of reaction of described sulfonylation is-35 ℃～0 ℃; 2. the reaction solution that 1. step is obtained directly and halogenating agent carry out halogenating reaction, get final product; The temperature of reaction of described halogenating reaction is-10 ℃～30 ℃; Described sulfonylation agent is SULPHURYL CHLORIDE and/or sulphonic acid anhydride;
Wherein, X is Cl, Br or I.
2. preparation method as claimed in claim 1, it is characterized in that: described alkali is tertiary amine, alkali-metal hydride, alkali-metal trimethyl carbinol compound or alkali-metal hexamethyl two silica-based amido compounds; The mol ratio of described alkali and formula II compound is 1～4:1.
3. preparation method as claimed in claim 2, it is characterized in that: described tertiary amine is diisopropyl ethyl amine, triethylamine, TERTIARY BUTYL AMINE or 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene; Described alkali-metal hydride is sodium hydride, potassium hydride KH or lithium hydride; Described alkali-metal trimethyl carbinol compound is sodium tert-butoxide or potassium tert.-butoxide; Described alkali-metal hexamethyl two silica-based amido compounds are hexamethyldisilazane lithium, hmds base sodium or hmds base potassium.
4. preparation method as claimed in claim 1, it is characterized in that: the mol ratio of described sulfonylation agent and formula II compound is 1～3:1.
5. preparation method as claimed in claim 4 is characterized in that: described SULPHURYL CHLORIDE is one or more in the benzene sulfonyl chloride that replaces of methylsulfonyl chloride, benzene sulfonyl chloride and contraposition alkyl; Described sulphonic acid anhydride is one or more in the Phenylsulfonic acid acid anhydride that replaces of methylsulfonic acid acid anhydride, trifluoromethanesulfanhydride anhydride, Phenylsulfonic acid acid anhydride and contraposition alkyl; Described alkyl is C
1～C
5The straight or branched alkyl.
6. preparation method as claimed in claim 1 is characterized in that: described halogenating agent is one or more in the hydrochloride of the hydrochloride of lithium chloride, tetrabutylammonium chloride, diisopropyl ethyl amine and triethylamine; The mol ratio of described halogenating agent and formula II compound is 0～9:1.
7. preparation method as claimed in claim 1, it is characterized in that: described solvent is one or more in toluene, acetonitrile, DMF, methylene dichloride and the tetrahydrofuran (THF).
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032099A2 (en) * | 2006-09-15 | 2008-03-20 | Cipla Limited | Process for the preparation of montelukast, and intermediates therefor |
| CN101323589A (en) * | 2008-03-06 | 2008-12-17 | 台耀化学股份有限公司 | Novel compound and preparation method of montelukast sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090143590A1 (en) * | 2004-07-19 | 2009-06-04 | Matrix Laboratories Ltd. | Process for the Preparation of Montelukast and its Salts |
| ATE539061T1 (en) * | 2004-07-19 | 2012-01-15 | Matrix Lab Ltd | 2-Ä(3S)-Ä3-Ä(2E)-(7-CHLOROQUINOLIN-2-YL)ETHENYLÜPHENYLÜ-3- HALOPROPYLBENZOIC ACID METHYL ESTER |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032099A2 (en) * | 2006-09-15 | 2008-03-20 | Cipla Limited | Process for the preparation of montelukast, and intermediates therefor |
| CN101323589A (en) * | 2008-03-06 | 2008-12-17 | 台耀化学股份有限公司 | Novel compound and preparation method of montelukast sodium |
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