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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- CN1171873C CN1171873C CNB011369469A CN01136946A CN1171873C CN 1171873 C CN1171873 C CN 1171873C CN B011369469 A CNB011369469 A CN B011369469A CN 01136946 A CN01136946 A CN 01136946A CN 1171873 C CN1171873 C CN 1171873C
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- 238000002360 preparation method Methods 0.000 title abstract description 13
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title 1
- 229910052708 sodium Inorganic materials 0.000 title 1
- 239000011734 sodium Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- -1 phenyl formic ether Chemical compound 0.000 claims abstract description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000000376 reactant Substances 0.000 claims description 12
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical class CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 9
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 201000010354 chronic purulent otitis media Diseases 0.000 claims 1
- OZYHLCOUAISLLG-UHFFFAOYSA-N cyclopropyl acetate Chemical compound CC(=O)OC1CC1 OZYHLCOUAISLLG-UHFFFAOYSA-N 0.000 abstract description 5
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical class [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 abstract description 4
- 229960001951 montelukast sodium Drugs 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000003509 tertiary alcohols Chemical class 0.000 abstract description 2
- 229920002554 vinyl polymer Polymers 0.000 abstract 3
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 abstract 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 238000003756 stirring Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000012266 salt solution Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000005406 washing Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- MNGVYFIQRJMEGV-UHFFFAOYSA-N C1(CC1)[Na].C(C)(=O)O Chemical compound C1(CC1)[Na].C(C)(=O)O MNGVYFIQRJMEGV-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000004377 Thiopurine S-methyltransferases Human genes 0.000 description 3
- 108090000958 Thiopurine S-methyltransferases Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- WIJKCDNTPKNICK-UHFFFAOYSA-N cyclopropylmethyl acetate Chemical compound CC(=O)OCC1CC1 WIJKCDNTPKNICK-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GWCVLQQBIZYDSS-UHFFFAOYSA-N [Mg].I(=O)(=O)OC Chemical compound [Mg].I(=O)(=O)OC GWCVLQQBIZYDSS-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 1
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- SDJHDRMYZQFJJO-UHFFFAOYSA-N ethanethioic s-acid;potassium Chemical compound [K].CC(S)=O SDJHDRMYZQFJJO-UHFFFAOYSA-N 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
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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| US20050107612A1 (en) * | 2002-12-30 | 2005-05-19 | Dr. Reddy's Laboratories Limited | Process for preparation of montelukast and its salts |
| WO2005040123A1 (en) * | 2003-10-10 | 2005-05-06 | Synhton B. V. | Solid-state montelukast |
| EP1760077A1 (en) | 2004-01-30 | 2007-03-07 | Teva Pharmaceutical Industries Ltd. | Montelukast free acid polymorphs |
| US7829716B2 (en) * | 2004-04-30 | 2010-11-09 | Synthon Pharmaceuticals, Inc. | Process for making montelukast and intermediates therefor |
| US7501517B2 (en) * | 2004-04-30 | 2009-03-10 | Synthon Ip, Inc. | Process for making montelukast and intermediates therefor |
| EP1904448B1 (en) | 2005-07-05 | 2011-02-02 | Teva Pharmaceutical Industries, Ltd. | Purification of montelukast |
| CN101356158B (en) * | 2005-11-18 | 2011-12-14 | 斯索恩有限公司 | Intermediates and related compounds for the preparation of montelukast |
| AR056815A1 (en) * | 2005-11-18 | 2007-10-24 | Synthon Bv | PROCESS TO PREPARE MONTELUKAST, INTERMEDIARIES OF THE SAME AND ITS ADDITION SALTS AND PROCEDURE OF PURIFICATION OF THESE AND MONTELUKAST |
| EP1968942A4 (en) * | 2005-12-23 | 2010-06-02 | Glade Organics Private Ltd | An improved 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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