CN1171873C - Preparation method of Menlust sodium and its preparation intermediate - Google Patents
Preparation method of Menlust sodium and its preparation intermediate Download PDFInfo
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Abstract
The present invention provides a novel method for synthesizing Montelukast sodium compounds and the preparation of intermediates of the Montelukast sodium compounds. 2-(2-(3(R)-(3-(2-(7-chlorine-2-quinolyl)-(E)vinyl)phenyl)-3-hydroxypropyl)phenyl formic ether is used as raw materials, the 2-(2-(3(R)-(3-(2-(7-chlorine-2-quinolyl)-(E)vinyl)phenyl)-3-hydroxypropyl)phenyl formic ether with leaving groups reacts with carbothioic acids or carbothioic salts. The reaction products react with Grignard reagents to generate tertiary alcohol and react with 2-(1-methyl cyclopropyl bromide) acetate to obtain 1-(((1-(R)-(3-(2-(7-chlorine-2-quinolyl)-vinyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid methyl ester. The obtained cyclopropyl acetate is converted into cyclopropaneacetic acid under the action of alkali, and the cyclopropaneacetic acid is further converted into the target compound of Montelukast sodium.
Description
The invention belongs to organic chemistry and pharmaceutical chemistry field, particularly, the present invention relates to the new preparation method of Menglusitena.
The chemical name of Menglusitena (Montelukast Sodium) is: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl sodium acetate, this compound can be used as Zhichuan agent, anti-allergic agent etc.This compound is at first synthetic by Canadian Mike's fluorine Luo Site company, and disclosed structure of this compound and preparation method thereof in CN1061407A by the said firm, the method for disclosed synthetic Menglusitena is with 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(hydroxyl) propyl group) phenyl) propyl alcohol and 1-(thiopurine methyltransferase)-cyclopropaneacetic acid ester prepared in reaction in CN1061407A.
The method of another kind of synthetic Menglusitena is disclosed among the CN1139429A, this method is improving one's methods of the disclosed synthetic method of CN1061407A, this method at first generates 1-(thiopurine methyltransferase)-cyclopropaneacetic acid two negatively charged ion two lithiums with 1-(thiopurine methyltransferase)-cyclopropaneacetic acid and a kind of lithium alkali reaction in organic solvent, obtain target compound with two negatively charged ion, two lithium compounds and with 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(hydroxyl) propyl group) phenyl) the propyl alcohol prepared in reaction that goes up leavings group then.
The inventor is devoted for years in the research of the synthetic method of Menglusitena compound, and has found the new synthetic method of synthetic Singulair sodium compound.
The method that the purpose of this invention is to provide a kind of synthetic Singulair sodium compound newly.
Method of the present invention is that (2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl manthanoate is a raw material, is with after the leavings group it and R with 2-
1The COSM reaction; M is H or alkalimetal ion; obtain 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl manthanoate; after the above-mentioned phenyl manthanoate and the form reagent react generation tertiary alcohol; obtain 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl acetic ester with the reaction of 2-(1-brooethyl cyclopropyl) acetic ester, the above-mentioned cyclopropyl acetic ester that obtains is changed into cyclopropyl acetate and further changes into the target compound Menglusitena under the alkali effect.
Synthetic route of the present invention is as follows:
R wherein
1Be H, C
1-5Alkyl or aryl, R, R
2Can be identical or different, can represent C respectively
1-5Alkyl, preferable methyl; L is a leavings group, preferred methylsulfonyl or p-toluenesulfonyl; Y is Cl, Br, I or O-L, and wherein L such as front define.
Below method of the present invention is further specified:
Method of the present invention comprises the following steps:
(a). the hydroxyl in formula (II) compound is changed into leavings group, obtain formula (III compound):
Wherein R is C
1-5Alkyl, preferable methyl, L is a leavings group, preferred methylsulfonyl or p-toluenesulfonyl;
(b). with formula (III) compound and R
1The COSM reaction obtains formula (IV) compound:
R wherein
1Be H, C
1-5Alkyl, Ar, preferable methyl, M is H or alkalimetal ion, preferred M is H or K ion;
(c). formula (IV) compound and grignard reagent MeMgX reaction are obtained the formula V compound:
Wherein X is Cl, Br or I, and preferred X is Br or I;
(d). the compound reaction of formula V compound and formula (VI) is obtained formula (VII) compound:
R wherein
2Be C
1-5Alkyl, preferable methyl, Y is Cl, Br, I or O-L, and preferred Y is Br, and wherein L such as front define;
(e). formula (VII) compound is obtained formula (VIII) compound under the alkali effect:
(f). formula (VIII) compound is obtained formula (I) compound under the sodium hydroxide effect:
Formula in the reaction scheme of the present invention (IV) and formula V compound are new compounds.
The preferred synthetic method of the present invention comprises the following steps:
(a). with the 2-of formula (II ') (2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl methyl-formiate compound and methylsulfonyl chloride reaction obtain formula (III ') compound:
Wherein L such as front define;
(b). with formula (III ') compound and CH
3COSM reaction obtain formula (IV ') 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl methyl-formiate compound:
Wherein M is H or alkalimetal ion,
(c). formula (IV ') compound and grignard reagent MeMgI reaction are obtained 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(mercapto alcohol radical) propyl group) phenyl) propanol compounds of formula V:
(d). 2-(1-brooethyl cyclopropyl) the methyl acetate reaction of formula V compound and formula (VI ') is obtained 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) the cyclopropyl methyl acetate compound of formula (VII '):
(e). formula (VII ') compound is able to formula (VIII) compound under the sodium hydroxide effect:
(f). formula (VIII) compound is obtained formula (I) compound under the sodium hydroxide effect:
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.
Embodiment 1: preparation 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulphur) propyl group) phenyl methyl-formiate
Method 1:
Install reaction unit while hot, feed nitrogen and be cooled to room temperature, the lucifuge operation adds 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl methyl-formiate (45.8 grams, 0.1 mole, [α]
D 18-=+ 28.9 (c=4.21, CHCl
3)) and pyridine (400 milliliters), stirring is all dissolved solid, bathes with cryosel and is cooled to-15 ℃, drips methylsulfonyl chloride (27.2 milliliters, 0.35 mole), 45 minutes times spent, slowly is warming up to 20 ℃ of reactions, until reacting completely.Reactant is poured in the frozen water (1000 milliliters), stirred, with ethyl acetate (4 * 300 milliliters) extraction, merge,, add dried over mgso with 10% salt solution (3 * 200 milliliters) washing, the rotation solvent evaporated, oil pump vacuum drying at room temperature 4 hours gets brown oily matter.Under nitrogen protection, oily matter with dimethyl sulfoxide (DMSO) (400 milliliters) dissolving, is stirred adding triethylamine (27 milliliters, 0.19 mole), drip thioacetic acid (10 milliliters, 0.14 mole), heat 45 ℃ of reactions, until reacting completely.Reactant is poured in the frozen water (1000 milliliters), stirred, extract with ethyl acetate (4 * 300 milliliters), merge, with 10% salt solution (3 * 200 milliliters) washing, add dried over mgso, the rotation solvent evaporated gets brown oily matter.Through silica gel column chromatography purification (eluent: sherwood oil: ethyl acetate=4: 1), get 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl methyl-formiate (16.3 gram).[α]
D 23=+110.3 (c=1.87, CHCl
3); MS (m/z): 518,516 (M+1);
1H NMR (CD
3OD-d
4): δ 8.25 (d, 1H), 7.95 (d, 1H), 7.82 (dd, 2H), 7.81 (dd, 2H), 7.53 (d, 1H), 7.63 (brs, 1H), 7.54 (d, 1H), 7.49 (dd, 1H), 7.42 (td, 1H), 7.39 (s, 1H), 7.36 (t, 1H), 7.30 (d, 1H), 7.25 (td, 1H), 7.21 (d, 1H), 4.63 (t, 1H), 3.81 (s, 3H), 3.00-2.94 (m, 1H), 2.90-2.84 (m, 1H), 2.29 (s, 3H), 2.28-2.19 (m, 2H);
13CNMR (CD
3OD-d
4): δ 196.20,169.497, and 158.672,149.341,143.994,143.730,133.271,132.224,131.726,130.862,130.518,130.283,129.705,129.155,128.247,127.961,127.441,127.354,120.820,52.523,38.871,33.656,30.404; IR (KBr): 3022,2946,1718 (C=O), 1686,1606,1593,1496,1431,1409,1259,1129,1079,1067,963,937,837,752,695,631,472; Ultimate analysis: molecular formula: C
30H
26ClNO
3S: calculated value: C, 69.84; H, 5.04, N, 2.72, O, 9.31, S, 6.21, Cl, 6.89; Experimental value: C, 70.36, H, 5.64, N, 2.40, Cl, 6.78, S, 5.8 3.
Method 2:
Install reaction unit while hot, feed nitrogen and be cooled to room temperature, the lucifuge operation adds 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl methyl-formiate (45.8 grams, 0.1 mole) and pyridine (400 milliliters), stirring is all dissolved solid, bathes with cryosel and is cooled to-15 ℃, drips (27.2 milliliters of methylsulfonyl chlorides, 0.35 mole), 45 minutes times spent, slowly be warming up to 20 ℃ of reactions, until reacting completely.Reactant is poured in the frozen water (1000 milliliters), stirred, with ethyl acetate (4 * 300 milliliters) extraction, merge,, add dried over mgso with 10% salt solution (3 * 200 milliliters) washing, the rotation solvent evaporated, oil pump vacuum drying at room temperature 4 hours gets brown oily matter.Under nitrogen protection, oily matter with dimethyl sulfoxide (DMSO) (400 milliliters) dissolving, is stirred, add thioacetic acid potassium (22.8 grams, 0.20 mole) in batches, be heated to 45 ℃ of reactions, until reacting completely.Reactant is poured in the frozen water (1000 milliliters), stirred, extract with ethyl acetate (4 * 300 milliliters), merge, with 10% salt solution (3 * 200 milliliters) washing, add dried over mgso, the rotation solvent evaporated gets brown oily matter.Column chromatography purification (eluent: sherwood oil: ethyl acetate (4: 1)), get 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl methyl-formiate (15.7 gram).
Method 3:
Install reaction unit while hot, feed nitrogen and be cooled to room temperature, the lucifuge operation adds 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl methyl-formiate (45.8 grams, 0.1 mole) and pyridine (400 milliliters), stirring is all dissolved solid, bathes with cryosel and is cooled to-15 ℃, drips (27.2 milliliters of methylsulfonyl chlorides, 0.35 mole), 45 minutes times spent, slowly be warming up to 20 ℃ of reactions, until reacting completely.Reactant is poured in the frozen water (1000 milliliters), stirred, with ethyl acetate (4 * 300 milliliters) extraction, merge,, add dried over mgso with 10% salt solution (3 * 200 milliliters) washing, the rotation solvent evaporated, oil pump vacuum drying at room temperature 4 hours gets brown oily matter.In dry three-necked bottle (500 milliliters), feed nitrogen, add thioacetic acid (10 milliliters, 0.14 mole) and tetrahydrofuran (THF) (200 milliliters), stir, be cooled to-40 ℃, drip n-Butyl Lithium hexane solution (1.0N with dry ice/acetone, 154 milliliters, 0.154 mole), 1 hour time spent.-10 ℃ of reactions 30 minutes, with tetrahydrofuran (THF) (100 milliliters) dissolving ,-10 ℃ of droppings, 30 minutes times spent, the stirring at room reaction was until reacting completely with above-mentioned oily matter.Reactant is poured in the frozen water (1000 milliliters), stirred, extract with ethyl acetate (4 * 300 milliliters), merge, with 10% salt solution (3 * 200 milliliters) washing, add dried over mgso, the rotation solvent evaporated gets brown oily matter.Through silica gel column chromatography purification (eluent: sherwood oil: ethyl acetate=4: 1), get 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl methyl-formiate (16.3 gram).
Method 4:
Install reaction unit while hot, feed nitrogen and be cooled to room temperature, the lucifuge operation adds 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl methyl-formiate (45.8 grams, 0.1 mole) and pyridine (400 milliliters), stirring is all dissolved solid, bathes with cryosel and is cooled to-15 ℃, drips (27.2 milliliters of methylsulfonyl chlorides, 0.35 mole), 45 minutes times spent, slowly be warming up to 20 ℃ of reactions, until reacting completely.Pour reactant into frozen water (1000 milliliters) and stir, (4 * 300mL) extractions merge organic phase with ethyl acetate, (3 * 300mL) washings add anhydrous magnesium sulfate drying, and decompression steams solvent with 10% salt solution, room temperature vacuum-drying 3 hours gets brown oily matter.Under nitrogen protection, oily matter with dimethyl sulfoxide (DMSO) (400 milliliters) dissolving, is stirred adding triethylamine (54 milliliters, 0.38 mole), add thiobenzoic acid (28 grams, 0.2 mole), heat 45 ℃ of reactions, until reacting completely.Reactant is poured in the frozen water (1000 milliliters), stirred, filter, solid ethyl acetate (1000 milliliters) dissolving with 10% salt solution (3 * 200 milliliters) washing, adds dried over mgso, and the rotation solvent evaporated gets brown oily matter.Through silica gel column chromatography purification (eluent: sherwood oil: ethyl acetate=4: 1), get 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(benzoyl sulfenyl) propyl group) phenyl methyl-formiate (24.5 gram).[α]
D 24＝+108.9(c＝3％，CHCl
3)；
1H?NMR(CD
3OD-d
4)：δ8.30(d，1H)，7.99(d，1H)，7.95(dd，2H)，7.93(dd，2H)，7.90(q，1H)，7.83(m，1H)，7.79(s，1H)，7.74(brs，1H)，7.61-7.58(m，1H)，7.51(dd，1H)，7.48-7.41(m，6H)，7.28-7.25(m，2H)，4.08(t，1H)，3.82(s，3H)，3.09-3.034(m，1H)，3.00-2.94(m，1H)，2.41-2.35(m，2H)；
Embodiment 2: preparation 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl methyl acetate step 1:
Install reaction unit while hot, feed nitrogen and be cooled to room temperature, the lucifuge operation; add 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl methyl-formiate (10.4 grams; 0.02 mole) and toluene (250 milliliters), stir, bathe with cryosel and be cooled to-14 ℃; drip methyl iodate magnesium solution (1.0 mol; 120 milliliters, 0.12 mole), 35 minutes times spent; slowly be warming up to 10 ℃ of reactions, until reacting completely.Reactant is poured in 10% ammonium acetate solution (800 milliliters), stir, separatory, water merges with ethyl acetate (2 * 300 milliliters) extraction, wash with 10% salt solution (3 * 200 milliliters), add dried over mgso, rotation solvent evaporated, oil pump vacuum drying at room temperature 4 hours, getting 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(mercapto alcohol radical) propyl group) phenyl) propyl alcohol is brown oily matter, oil pump vacuum drying at room temperature 4 hours.MS(m/z)：472(M+)，454，439，421，379，325，310，291，227，176，130，114，90；
1H?NMR(CD
3OD-d
4)：δ8.18(d，1H)，7.91(d，1H)，7.78(dd，2H)，7.71(d，1H)，7.65(brs，1H)，7.52-7.51(m，1H)，7.43(dd，1H)，7.38-7.30(m，4H)，7.09(d，2H)，7.06-7.05(m1H)，3.85(td，1H)，3.13-3.07(td，1H)，2.84-2.78(td，1H)，2.25-1.89(m，2H)，1.52(s，3H)，1.51(s，3H)；
Step 2:
Under nitrogen protection; the lucifuge operation; 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(mercapto alcohol radical) propyl group) phenyl) propyl alcohol is dissolved in N; dinethylformamide (100 milliliters); be cooled to-15 ℃ with the cryosel bath; drip (4.6 milliliters of sodium methoxide solutions; 0.024 mole);-15 ℃ of following stirring reactions 30 minutes, slowly drip the N of 2-(1-brooethyl cyclopropyl) methyl acetate (5.0 grams, 0.024 mole); dinethylformamide (40 milliliters) solution; then, slowly be warming up to 5 ℃ of reactions, until reacting completely.Reactant is poured in the frozen water (1000 milliliters), stir, extract with ethyl acetate (4 * 200 milliliters), merge organic phase,, add anhydrous magnesium sulfate drying with 10% salt solution (3 * 200 milliliters) washing, filter out sal epsom, the rotation solvent evaporated, decompression (0.1mmHg) drying at room temperature 4 hours gets brown oily matter.Through silica gel column chromatography purification (eluent: sherwood oil: ethyl acetate=3: 1), get 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl methyl acetate (7.55 gram), yield is 63%.。MS(m/z)：599(M+)，581，454，422，310，292，221，180，163，131，81；
1H?NMR(CD
3Cl-d
1)：δ8.083(d，1H)，8.079(brs，1H)，8.061-7.620(m，4H)，7.51(dd，1H)，7.423-7.333(m，5H)，7.175-7.109(m，3H)，3.941(t，1H)，3.59(s，3H)，3.17-3.115(td，1H)，2.887-2.827(td，1H)2.526-2.470(dd，2H)，2.436-2.365(dd，2H)，2.26-2.147(m，2H)，1.604(s，3H)，1.585(s，3H)，0.513-0.378(m，4H)；
13C?NMR(CD
3Cl-d
1)：δ172.700，156.733，148.471，145.292，143.520，140.048，136.342，136.078，135.419，135.009，131.523，128.857，128.593，128.461，127.992，126.982，126.762，126.000，125.531，125.297，119.437，73.440，51.365，50.222，39.924，39.778，39.118，32.219，31.721，16.735，12.619，12.238.
Embodiment 3: preparation 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl acetate
Under nitrogen protection; the lucifuge operation; in 250 milliliters of three-necked bottles, add 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl methyl acetate (6.0 grams; 0.01 mole), tetrahydrofuran (THF) (35 milliliters) and methyl alcohol (50 milliliters); stir, slowly add sodium hydroxide solution (1.ON, 20 milliliters; 0.02 mole), the stirring at room reaction is 24 hours.Reactant is poured in 10% salt solution (200 milliliters) and ethyl acetate (200 milliliters) mixture, stirred 10 minutes, separatory, organic layer is used tartaric acid solution (0.5N, 100 milliliters) and water (100 milliliters) washing respectively, uses anhydrous magnesium sulfate drying 2 hours, after filtering out sal epsom, rotate solvent evaporated, after with ethyl acetate (50 milliliters) solid being dissolved, add normal hexane (50 milliliters).Put into a crystal seed, placed 20 hours in the room temperature lucifuge.Separate out yellow prism-shaped crystal, lucifuge filters out crystal, wash secondary (2 * 100 milliliters) with normal hexane, get 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl acetate (5.21 gram) after the vacuum-drying, yield is 89%.Fusing point: 148-150 ℃.MS (m/z): 589,588,586 (M+1), 569,568,524,422;
1H NMR (CD
3OD-d
4): δ 8.25 (d, 1H), 7.95 (d, 1H), 7.85 (dd, 2H), 7.76 (d, 1H), 7.70 (s, 1H), 7.55-7.53 (m1H), 7.48 (dd, 1H), and 7.39-7.36 (m, 4H), 7.12 (d, 2H), and 7.08-7.04 (m, 1H), 4.02 (t, 1H), and 3.14-3.08 (td, 1H), 2.85-2.79 (td, 1H), and 2.54-2.47 (dd, 2H), 2.44-2.37 (dd, 2H), and 2.25-2.19 (m, 1H), 2.17-2.10 (m, 1H), 1.52 (s, 3H), 1.51 (s, 3H), and 0.54-0.35 (m, 4H)
13CNMR (CD
3OD-d
4): δ 176.050,158.745, and 149.235,147.017,145.417,141.279,138.246,137.751,137.416,136.913,132.509,130.520,130.146,130.032,128.798,128.241,128.180,127.921,127.845,127.266,127.228,126.565,126.519,73.918,51.438,41.212,40.747,40.100,33.493,31.847,17.841,13.308,12.911.IR (KBr): 3574 (OH), 3442,3100,2989,2920,2861,1715 (C=O), 1638,1609,1500,1486,1441,1409,1347,1316,1249,1224,1202,1173,1148,1135,1075,1050,1015,985,966,951,934,766,699; Ultimate analysis: molecular formula: C
35H
36ClNO
3S: calculated value: C, 71.71; H, 6.19, N, 2.39, O, 8.19, S, 5.47, Cl, 6.05; Experimental value: C, 71.76, H, 6.18, N, 2.59, Cl, 6.06, S, 5.51.
Embodiment 4: preparation 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl sodium acetate
The lucifuge operation.Under nitrogen protection; in an exsiccant three neck round-bottomed flasks (2000 milliliters); add 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl acetate (65 grams, 0.11 mole), toluene (1147 milliliters) respectively.Stir down, be added dropwise to ethanol (218 milliliters) solution of sodium hydroxide (4.58 grams, 0.11 mole), temperature is controlled at room temperature.Dropwise room temperature reaction 1 hour.At 40 ℃, be evaporated to 1/3 volume.Add toluene (800 milliliters) and gac (5 gram) then,, stirred 3 hours at 40 ℃.Leach gac, decompression (0.1mmHg/40 ℃) concentrated filtrate is approximately to 500 milliliters.Concentrated solution is splashed into normal heptane (1147 milliliters), and lucifuge is placed and is spent the night under nitrogen atmosphere.Lucifuge is filtered, and solid is washed secondary with normal heptane, after draining, in vacuum drying oven, in 40 ℃ of dryings 48 hours.Get 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropyl sodium acetate (61g), be white powder.Yield: 90%.MS (m/z): 610,608 (M+), 589,588,586,571,570,568;
1HNMR (CD
3OD-d
4): δ 8.28 (d, 1H), 7.98 (d, 1H), 7.89 (dd, 2H), 7.79 (d, 1H), 7.71 (s, 1H), 7.56 (d, 1H), 7.50 (dd, 1H), 7.42-7.37 (m, 4H), and 7.14-7.12 (m, 2H), 7.08-7.04 (m, 1H), 4.04 (t, 1H), 3.11-3.05 (td, 1H), 2.84-2.78 (td, 1H), 2.64 (d, 1H), 2.50 (d, 1H), 2.48 (d, 1H), 2.28 (d, 1H), 2.26-2.21 (m, 1H), 2.16 (m, 1H), 1.52 (s, 3H), 1.51 (s, 3H), 0.54-0.28 (m, 4H).
13C NMR (CD
3OD-d
4): δ 180.555,158.838, and 149.338,147.061,145.659,141.334,138.208,137.723,137.477,136.865,132.523,130.518,130.119,130.068,128.776,128.377,128.190,127.875,127.298,126.907,126.465,120.862,73.862,51.430,44.505,41.327,41.073,33.485,31.845,18.497,13.356,12.804; IR (KBr): cm
-13412,2976,2928,1637 (C=O), 1608,1595,1566,1497,1441,1409,1312,1270,1144,1132,1069,1018,964,864,837,762,698,622,474; Ultimate analysis: molecular formula: C
35H
35ClNNaO
3S calculated value: C, 69.12; H, 5.80; N, 2.30, O, 7.89; Experimental value: C, 69.38, H, 6.20, N, 2.46, O, 8.18.
Claims (6)
1. a method for preparing Menglusitena comprises the following steps:
(a). the hydroxyl in formula (II) compound is changed into leavings group, obtain formula (III) compound:
Wherein R is C
1-5Alkyl, L are leavings groups;
(b). with formula (III) compound and R
1The COSM reaction obtains formula (IV) compound:
R wherein
1Be H, C
1-5Alkyl or aryl, M are H or alkalimetal ion;
(c). formula (IV) compound and grignard reagent MeMgX reaction are obtained the formula V compound:
Wherein X is Cl, Br or I;
(d). the compound reaction of formula V compound and formula (VI) is obtained formula (VII) compound:
R wherein
2Be C
1-5Alkyl, Y are Cl, Br, I or O-L, and L such as front define;
(e). formula (VII) compound is obtained formula (VIII) compound under the alkali effect:
(f). formula (VIII) compound is obtained formula (I) compound under the sodium hydroxide effect:
2. according to the method for claim 1, it is characterized in that
In step (a), R is a methyl, and L is methylsulfonyl or p-toluenesulfonyl;
In step (b), R
1Be methyl, M is H or alkalimetal ion;
In step (c), X is Br or I;
In step (d), R
2Be methyl, Y is Br, I or O-L, and wherein L is methylsulfonyl or p-toluenesulfonyl.
3. according to the method for claim 1, it is characterized in that comprising the following steps:
(a). with the 2-of formula (II ') (2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl methyl-formiate compound and methylsulfonyl chloride reaction obtain formula (III ') compound:
(b). with formula (III ') compound and formula CH
3The thioacetic acid of CSOM or its reactant salt obtain 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-ethanoyl sulfenyl) propyl group) the phenyl methyl-formiate compound of formula (IV '):
Wherein M is H or K ion,
(c). formula (IV ') compound and grignard reagent MeMgI reaction are obtained 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) the phenyl)-3-mercapto alcohol radical) propyl group) phenyl of formula V) propanol compounds:
(d). 2-(1-brooethyl cyclopropyl) the methyl acetate reaction of formula V compound and formula (VI ') is obtained 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) the cyclopropyl methyl acetate compound of formula (VII '):
(e). formula (VII ') compound is able to formula (VIII) compound under the sodium hydroxide effect:
(f). formula (VIII) compound is obtained formula (I) compound under the sodium hydroxide effect:
4. the compound of formula IV
Wherein R and R
1Define as claim 1.
5. according to the compound of claim 4, it is 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl methyl-formiate.
6. the compound of formula V
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050107612A1 (en) * | 2002-12-30 | 2005-05-19 | Dr. Reddy's Laboratories Limited | Process for preparation of montelukast and its salts |
| ATE522507T1 (en) * | 2003-10-10 | 2011-09-15 | Synhton B V | MONTELUKAST IN A FIXED PHASE |
| EP1760077A1 (en) | 2004-01-30 | 2007-03-07 | Teva Pharmaceutical Industries Ltd. | Montelukast free acid polymorphs |
| US7501517B2 (en) * | 2004-04-30 | 2009-03-10 | Synthon Ip, Inc. | Process for making montelukast and intermediates therefor |
| US7829716B2 (en) * | 2004-04-30 | 2010-11-09 | Synthon Pharmaceuticals, Inc. | Process for making montelukast and intermediates therefor |
| JP2008510840A (en) | 2005-07-05 | 2008-04-10 | テバ ファーマシューティカル インダストリーズ リミティド | Purification of Montelukast |
| CN101356157B (en) * | 2005-11-18 | 2011-07-06 | 斯索恩有限公司 | Process for making montelukast and intermediates therefor |
| AR057909A1 (en) * | 2005-11-18 | 2007-12-26 | Synthon Bv | PROCESS TO PREPARE MONTELUKAST AND RELATED COMPOUNDS, USING AN INTERMEDIATE COMPOUND DERIVED FROM A SULFONIC ESTER. |
| US20090182148A1 (en) * | 2005-12-23 | 2009-07-16 | Harmander Singh Pal Chawla | Process for the manufacture of montelukast sodium |
| EP1886998A1 (en) | 2006-08-09 | 2008-02-13 | Esteve Quimica, S.A. | Purification process of montelukast and its amine salts |
| EP2287154A1 (en) | 2009-07-14 | 2011-02-23 | KRKA, D.D., Novo Mesto | Efficient synthesis for the preparation of montelukast |
| WO2011121091A1 (en) | 2010-03-31 | 2011-10-06 | Krka, D.D., Novo Mesto | Efficient synthesis for the preparation of montelukast and novel crystalline form of intermediates therein |
| CN103570619B (en) * | 2013-11-08 | 2015-12-09 | 南京靖龙药物研发有限公司 | A kind of preparation method of montelukast sodium derivative |
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