CN1420113A - Method for preparing Menglusitena and intermediate preparation thereof - Google Patents
Method for preparing Menglusitena and intermediate preparation thereof Download PDFInfo
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- CN1420113A CN1420113A CN 01134866 CN01134866A CN1420113A CN 1420113 A CN1420113 A CN 1420113A CN 01134866 CN01134866 CN 01134866 CN 01134866 A CN01134866 A CN 01134866A CN 1420113 A CN1420113 A CN 1420113A
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- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- -1 2-(3(S)-(3-(2-(7-chloro-2-quinolyl)- (E) vinyl) phenyl)-3-hydroxypropyl) phenyl Chemical group 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 5
- 150000003566 thiocarboxylic acids Chemical class 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 239000000376 reactant Substances 0.000 claims description 14
- 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 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- 229910001413 alkali metal ion Inorganic materials 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
- 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 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
- 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
- 229940125898 compound 5 Drugs 0.000 claims 1
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 abstract description 2
- 150000003509 tertiary alcohols Chemical class 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract 1
- 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 abstract 1
- QJXFOQUFBFSNGH-MGBGTMOVSA-N [1-[[(1r)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl] acetate Chemical compound S([C@H](CCC=1C(=CC=CC=1)C(C)(C)O)C=1C=C(C=CC=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)CC1(OC(=O)C)CC1 QJXFOQUFBFSNGH-MGBGTMOVSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 229910052708 sodium Inorganic materials 0.000 abstract 1
- 239000011734 sodium Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000012266 salt solution Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- OZYHLCOUAISLLG-UHFFFAOYSA-N cyclopropyl acetate Chemical compound CC(=O)OC1CC1 OZYHLCOUAISLLG-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 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
- 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 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
- 230000006837 decompression Effects 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
- 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
- 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
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [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 description 1
- 229960001951 montelukast sodium Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material 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
A process for preparing Menglusite sodium includes reaction of 2 (2-(3(S)-(3-(2-(7-chloro-2-quinolyl)- (E) vinyl) phenyl)-3-hydroxypropyl) phenyl formate with thiocarboxylic acid or its salt, reaction of its resultant with Grignard reagent to obtain tertiary alcohol, reaction with 2-(1-bromomethyl cyclopropyl) acetate to obtain 1-(((1-(R)-(3-(2-(7- chloro-2-quinolyl)-vinyl)phenyl)-3-(2-(1-hydroxy-1- methyl ethyl)phenyl)propyl)thio)methyl)cyclopropyl acetate, converting it to cyclopropyl acetic acid under action of alkali and further converting to desired product.
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.
Another object of the present invention provides the midbody compound of synthetic Menglusitena.
Method of the present invention is that (2-(3 (S)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-hydroxypropyl) phenyl manthanoate is a raw material with 2-; be with leavings group to obtain 2-(2-(3 (R)-(3-(2-(7-chloro-2-quinolyl)-vinyl) phenyl)-3-(ethanoyl sulfenyl) propyl group) phenyl manthanoate with thiocarboxylic acid or its reactant salt afterwards it; 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:
Wherein R, R
1, R
2Can be identical or different, 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 explanation is advanced-gone on foot to method of the present invention:
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 formula R
1The thiocarboxylic acid of COSM or its reactant salt obtain formula (IV) compound:
R wherein
1Be C
1-5Alkyl, 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 that the preferred Y of Cl, Br, I or O-L is Br, 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 (S)-(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 COSM or its reactant salt 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 (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 (S)-(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 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).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, 5.83. method 2:
Install reaction unit while hot, feed nitrogen and be cooled to room temperature, the lucifuge operation adds 2-(2-(3 (S)-(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 (S)-(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).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): δ 8.18 (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): δ 8.083 (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): δ 172.700,156.733, and 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 (1.0N, 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 40C.Leach gac, decompression (0.1mmHg/40 ℃) concentrated filtrate is approximately to 5 00 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
-13412,2976,2928,16 37 (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 formula R
1The thiocarboxylic acid of COSM or its reactant salt obtain formula
(IV) compound:
R wherein
1Be C
1-5Alkyl, 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 2, it is characterized in that comprising the following steps:
(a). with the 2-of formula (II ') (2-(3 (S)-(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. formula (IV) compound
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. formula V compound
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