CN102442948B - Method for preparing montelukast sodium intermediate - Google Patents
Method for preparing montelukast sodium intermediate Download PDFInfo
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- CN102442948B CN102442948B CN 201110340278 CN201110340278A CN102442948B CN 102442948 B CN102442948 B CN 102442948B CN 201110340278 CN201110340278 CN 201110340278 CN 201110340278 A CN201110340278 A CN 201110340278A CN 102442948 B CN102442948 B CN 102442948B
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- 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 title claims abstract description 10
- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 16
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 15
- 230000006103 sulfonylation Effects 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 23
- -1 alkali-metal trimethyl carbinol compound Chemical class 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 230000002140 halogenating effect Effects 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical group ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 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 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940095102 methyl benzoate Drugs 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102000004377 Thiopurine S-methyltransferases Human genes 0.000 description 1
- 108090000958 Thiopurine S-methyltransferases Proteins 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 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 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
Abstract
The invention relates to a method for preparing montelukast sodium intermediate which is shown as a formula III. The method comprises the following steps of: (1), in a solvent, with the action of alkali, carrying out sulfonylation reaction of secondary hydroxyl in a compound II with a sulfonylation agent; and (2), directly carrying out halogenated reaction of reaction liquid obtained in the step (1) with a halogenated reagent, obtaining the montelukast sodium intermediate, wherein the X is C1, Br, or I. The method for preparing the montelukast sodium intermediate disclosed by the invention isgentle in reaction condition, simplex in product, simple and convenient in purification; in addition, the obtained intermediate is high in optical purity and higher in productivity, and more suitablefor industrial production.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, be specifically related to the preparation method of montelukast sodium intermediate.
Background technology
The chemistry of Menglusitena (Montelukast Sodium) is by name: 2-(1-((1 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-(2-(2-hydroxyl-2 propyl group) phenyl) rosickyite base) methyl) cyclopropyl) sodium acetate, this compound can be used as Zhichuan agent, anti-allergic agent etc.This compound is at first synthetic by Canadian Merk Frosst company, and structure of this compound and preparation method thereof is disclosed in CN1061407A by the said firm, its synthetic method is with 1 (S)-(3-(2-(7-chloroquinoline-2-yl)-(E) vinyl) phenyl)-3-(2-(2-hydroxyl-2-propyl group) phenyl) propyl alcohol and 2-(1-(thiopurine methyltransferase) cyclopropyl) acetic ester reaction preparation.
Another kind of Menglusitena synthetic method is disclosed among the CN1428335A, the method is as raw material take 2-(3-(3-(2-(7-chloro-2 quinolyls)-(E) vinyl) phenyl)-3 (R)-hydroxypropyls) methyl benzoate, hydroxyl is converted into the leavings group sulphonate, then obtain 2-(3-(3-(2-(7-chloro-2 quinolyls)-(E) vinyl) phenyl)-3 (R)-(acetyl mercapto) propyl group) methyl benzoate with the thioacetic acid reactant salt, and then Yu Geshi reagent react, obtain the sulfydryl tertiary alcohol, then obtain 2-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-(hydroxyl-2-propyl group) phenyl) propyl group) sulfenyl) methyl with the reaction of 2-(1-brooethyl) cyclopropyl acetic ester) the cyclopropyl acetic ester, the cyclopropyl acetic ester is obtained cyclopropyl acetic acid under the alkali effect, then further act on sodium hydroxide and obtain the target compound Menglusitena.
Summary of the invention
Technical problem to be solved by this invention is: complicated in order to overcome preparation Menglusitena pilot process, and severe reaction conditions, side reaction is many, the defective that purification processes is loaded down with trivial details, and the preparation method of montelukast sodium intermediate is provided.Preparation method's reaction conditions of the present invention is gentle, and product is single, and it is easy to purify, and the intermediate optical purity height and the productive rate that obtain are higher, more are applicable to suitability for industrialized production.The intermediate that the present invention makes can further be used for preparing the various compounds that contain this intermediate structure fragment.
The invention provides a kind of preparation method of the montelukast sodium intermediate shown in formula III, 1. it comprise the following steps: under the effect of alkali, the secondary hydroxyl among the Compound I I and sulfonylation agent to be carried out sulfonylation in the solvent; 2. the reaction solution that 1. step is obtained directly and halogenating agent carry out halogenating reaction, get final product;
Wherein, X is Cl, Br or I.
Among the present invention, the reaction conditions of described sulfonylation can be conventional sulfonylation condition, but such as reference literature WO2008/126075A1,2008; Reaction conditions among the Page column 12.Following each reaction conditions is the special reaction conditions of selecting of the present invention.
Wherein, described alkali preferably is organic bases or mineral alkali; Described organic bases preferably is tertiary amine, alkali-metal trimethyl carbinol compound or alkali-metal hexamethyl two silica-based amido compounds; Described tertiary amine preferably is diisopropyl ethyl amine, triethylamine, TERTIARY BUTYL AMINE or 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU) etc., is diisopropyl ethyl amine best; Described alkali-metal trimethyl carbinol compound preferably is sodium tert-butoxide or potassium tert.-butoxide; Described alkali-metal hexamethyl two silica-based amido compounds preferably are LHMDS (LiHMDS), sodium hexamethyldisilazide (NaHMDS) or potassium hexamethyldisilazide (KHMDS) etc.; Described mineral alkali preferably is alkali-metal hydride; Described alkali-metal hydride preferably is sodium hydride, potassium hydride KH or lithium hydride.
Wherein, the mol ratio of described alkali and formula II compound preferably is 1～4: 1, more preferably is 2～3: 1, is 2.5: 1 best.
Wherein, described sulfonylation agent preferably is SULPHURYL CHLORIDE and/or sulphonic acid anhydride; Described SULPHURYL CHLORIDE preferably is one or more in the benzene sulfonyl chloride that replaces of methylsulfonyl chloride, benzene sulfonyl chloride and contraposition alkyl, more preferably is methylsulfonyl chloride; Described sulphonic acid anhydride preferably is one or more in the Phenylsulfonic acid acid anhydride that replaces of methylsulfonic acid acid anhydride, trifluoromethanesulfanhydride anhydride, Phenylsulfonic acid acid anhydride and contraposition alkyl; Described alkyl is C
1～C
5The straight or branched alkyl, preferably be C
1～C
3The straight or branched alkyl.
Wherein, the mol ratio of described sulfonylation agent and formula II compound preferably is 1～3: 1, more preferably is 2～2.8: 1, is 2.5: 1 best.
Wherein, the temperature of reaction of described sulfonylation preferably is-35 ℃～0 ℃, more preferably is-30 ℃～-5 ℃, is-25 ℃～-10 ℃ best.
Among the present invention, the reaction conditions of described halogenating reaction can be conventional halogenating reaction condition, but such as reference literature Journal of the American Chemical Society, 1952, vol.74, p.5851, the reaction conditions in 5852,5853,5857.Following reaction conditions is the special reaction conditions of selecting of the present invention.
Wherein, described halogenating agent preferably is one or more in the hydrochloride of the hydrochloride of lithium chloride, tetrabutylammonium chloride, diisopropyl ethyl amine and triethylamine, more preferably is lithium chloride and/or tetrabutylammonium chloride.
Wherein, the mol ratio of described halogenating agent and formula II compound preferably is 0～9: 1, more preferably is 1～5: 1, is 3: 1 best.
Wherein, the temperature of reaction of described halogenating reaction preferably is-10 ℃～30 ℃, more preferably is 0 ℃～25 ℃, is 10 ℃～20 ℃ best.
Among the present invention, described preferred solvents ground is toluene, acetonitrile, N, in dinethylformamide (DMF), methylene dichloride and the tetrahydrofuran (THF) one or more, more preferably be toluene, acetonitrile and N, in the dinethylformamide (DMF) one or more, be DMF (DMF) and/or toluene best.
Among the present invention, the consumption of described solvent preferably is 5mL/g formula II compound～25mL/g formula II compound, more preferably is 10mL/g formula II compound～20mL/g formula II compound, is 15mL/g formula II compound best.
Among the present invention, used aftertreatment can be the post-treating method of this area routine after described sulfonylation halogenating reaction finished, preferably for adding frozen water; behind the ethyl acetate extraction; use successively saturated aqueous common salt and water washing, organic phase anhydrous sodium sulfate drying, concentrated getting final product.
Among the present invention, described preparation method preferably also is included under the protection of inert gas and reacts, and described rare gas element is the conventional rare gas element that uses in this area, preferably is nitrogen and/or argon gas.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available getting all.
Positive progressive effect of the present invention is:
1. preparation method's reaction conditions of the present invention is gentle, and product is single, and it is easy to purify, and the intermediate optical purity height and the productive rate that obtain are higher, more are applicable to suitability for industrialized production.
2. the intermediate that makes of the present invention can further be used for preparing the various compounds that contain this intermediate mechanism fragment, synthetic as for the synthesis of as the Menglusitena of Zhichuan agent and anti-allergic agent.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
The preparation of embodiment 1 formula III compound
The preparation method of 2-(2-(3 (S)-chloro-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol.
Under room temperature (25-30 ℃) and argon shield; in reaction flask, add successively 2-(2-(3 (R)-hydroxyl-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (25.1g; 55mmol), DMF (400mL) and diisopropyl ethyl amine (17.74g; 137.5mmol), be stirred to fully dissolving.Cryosel is bathed and system is cooled to-10 ℃, drips methylsulfonyl chloride (15.6g, 137.5mmol) in 30 minutes, then reacts 10 hours under this temperature.(TLC or HPLC monitoring raw material reaction are complete); Disposable adding lithium chloride (11.7g, 275mmol) removes ice bath, naturally is back to room temperature, continues reaction 14 hours.It is complete that TLC follows the tracks of reaction.Add frozen water 300mL ethyl acetate (60mL * 3), merge organic phase.Use successively saturated aqueous common salt, the water washing organic phase.Anhydrous sodium sulfate drying.Concentrate organic phase to 1/5 of original volume, add sherwood oil 500mL and stir half an hour, then hold over night is filtered, dry 16.1g formula III compound white solid, the yield 61.5% of getting.
Ee value=92%
LC-MS：[M+H]
+＝476.1；
1H?NMR(400MHz，DMSO-d
6)：8.42(d，J＝8.8Hz，1H)，7.99～8.03(m，2H)，7.88～7.94(m，3H)，7.72(d，J＝7.2Hz，1H)，7.59(d，J＝8.8Hz，1H)，7.55(d，J＝16.8Hz，，1H)，7.45～7.52(m，2H)，7.38(d，J＝7.2Hz，1H)，7.09～7.22(m，3H)，5.28(t，J＝7.2Hz，1H)，4.98(s，1H)，3.20(m，1H)，2.92(m，1H)，2.43(m，2H)，1.50(s，3H)，1.49(s，3H)。
The preparation of embodiment 2 formula III compounds
The preparation method of 2-(2-(3 (S)-chloro-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol.
Under room temperature (25-30 ℃) and argon shield; in reaction flask, add successively 2-(2-(3 (R)-hydroxyl-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (4.58g; 10mmol), toluene (68mL) and diisopropyl ethyl amine (25mmol), be stirred to fully dissolving.Cryosel is bathed (calcium chloride/ice) and system is cooled to-25 ℃, drips methylsulfonyl chloride (25mmol) in 30 minutes, then reacts 10 hours under this temperature.(TLC or HPLC monitoring raw material reaction are complete); Disposable adding tetrabutylammonium chloride (50mmol) removes ice bath, naturally is back to room temperature, continues reaction 14 hours.It is complete that TLC follows the tracks of reaction.Add frozen water 300mL ethyl acetate (60mL * 3), merge organic phase.Use successively saturated aqueous common salt, the water washing organic phase.Anhydrous sodium sulfate drying.Concentrated, add sherwood oil 150mL, ethyl acetate 15mL stirs half an hour, and then hold over night is filtered, dry 3.0g formula III compound white solid, the yield 63% of getting.
Ee value=92%
LC-MS：[M+H]
+＝476.1；
1H?NMR(400MHz，DMSO-d
6)：8.42(d，J＝8.8Hz，1H)，7.99～8.03(m，2H)，7.88～7.94(m，3H)，7.72(d，J＝7.2Hz，1H)，7.59(d，J＝8.8Hz，1H)，7.55(d，J＝16.8Hz，，1H)，7.45～7.52(m，2H)，7.38(d，J＝7.2Hz，1H)，7.09～7.22(m，3H)，5.28(t，J＝7.2Hz，1H)，4.98(s，1H)，3.20(m，1H)，2.92(m，1H)，2.43(m，2H)，1.50(s，3H)，1.49(s，3H)。
The preparation of embodiment 3 formula V compounds
The preparation method of 2-(1-((1 (R)-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl)-3-(2-(2-hydroxyl-2 propyl group) phenyl) rosickyite base) methyl) cyclopropyl) methyl acetate.
Under the condition of ice-water bath (10 ℃) and argon shield; 2-(2-(3 (S)-chloro-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (16.1g; 33.8mmol); 1-thiopurine methyltransferase cyclopropyl-2-methyl acetate (5.4g; 33.8mmol); cesium carbonate (16.5g, 50.7mmol) is put among the DMF (200mL) and removes ice-water bath, and reaction system was reacted under room temperature 3 hours.TLC monitors reaction.React complete, the 1000mL saturated aqueous common salt is added in the system, and the usefulness ethyl acetate (3 * 50mL), anhydrous sodium sulfate drying.Concentrated, get the light yellow oily formula of 14.72g V compound, yield 72.5%.
Ee value=92%
LCMS：[M+H]
+＝600.2；
1H?NMR(400MHz，DMSO-d
6)：8.41(d，J＝8.8Hz，1H)，8.02(s，1H)，8.02(d，J＝2.0Hz，1H)，8.01(d，J＝8.8Hz，1H)，7.94(d，J＝8.8Hz，1H)，7.90(d，J＝16.0Hz，1H)，7.74(s，1H)，7.64(d，J＝7.6Hz，1H)，7.59(dd，J＝2.0Hz，8.4Hz，1H)，7.51(d，J＝16.0Hz，1H)，7.42(t，J＝7.2Hz，1H)，7.37(d，J＝8.0Hz，2H)，7.06～7.14(m，3H)，4.90(s，1H)，3.99(t，J＝7.2Hz，1H)，3.53(s，3H)，3.06(td，J＝4.8Hz，12.4Hz，1H)2.77(td，J＝4.8Hz，12.4Hz，1H)，2.49(s，2H)，2.38(q，J＝15.6Hz，2H)，2.15(m，2H)，1.44(s，6H)，0.42(m，4H)。
Claims (7)
1. 1. preparation method suc as formula the montelukast sodium intermediate shown in the III is characterized in that comprising the following steps: under the effect of alkali, the secondary hydroxyl in the compound ii and sulfonylation agent being carried out sulfonylation in the solvent; The temperature of reaction of described sulfonylation is-35 ℃～0 ℃; 2. the reaction solution that 1. step is obtained directly and halogenating agent carry out halogenating reaction, get final product; The temperature of reaction of described halogenating reaction is-10 ℃～30 ℃; Described sulfonylation agent is SULPHURYL CHLORIDE and/or sulphonic acid anhydride;
Wherein, X is Cl, Br or I.
2. preparation method as claimed in claim 1, it is characterized in that: described alkali is tertiary amine, alkali-metal hydride, alkali-metal trimethyl carbinol compound or alkali-metal hexamethyl two silica-based amido compounds; The mol ratio of described alkali and formula II compound is 1～4:1.
3. preparation method as claimed in claim 2, it is characterized in that: described tertiary amine is diisopropyl ethyl amine, triethylamine, TERTIARY BUTYL AMINE or 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene; Described alkali-metal hydride is sodium hydride, potassium hydride KH or lithium hydride; Described alkali-metal trimethyl carbinol compound is sodium tert-butoxide or potassium tert.-butoxide; Described alkali-metal hexamethyl two silica-based amido compounds are hexamethyldisilazane lithium, hmds base sodium or hmds base potassium.
4. preparation method as claimed in claim 1, it is characterized in that: the mol ratio of described sulfonylation agent and formula II compound is 1～3:1.
5. preparation method as claimed in claim 4 is characterized in that: described SULPHURYL CHLORIDE is one or more in the benzene sulfonyl chloride that replaces of methylsulfonyl chloride, benzene sulfonyl chloride and contraposition alkyl; Described sulphonic acid anhydride is one or more in the Phenylsulfonic acid acid anhydride that replaces of methylsulfonic acid acid anhydride, trifluoromethanesulfanhydride anhydride, Phenylsulfonic acid acid anhydride and contraposition alkyl; Described alkyl is C
1～C
5The straight or branched alkyl.
6. preparation method as claimed in claim 1 is characterized in that: described halogenating agent is one or more in the hydrochloride of the hydrochloride of lithium chloride, tetrabutylammonium chloride, diisopropyl ethyl amine and triethylamine; The mol ratio of described halogenating agent and formula II compound is 0～9:1.
7. preparation method as claimed in claim 1, it is characterized in that: described solvent is one or more in toluene, acetonitrile, DMF, methylene dichloride and the tetrahydrofuran (THF).
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| WO2008032099A2 (en) * | 2006-09-15 | 2008-03-20 | Cipla Limited | Process for the preparation of montelukast, and intermediates therefor |
| CN101323589A (en) * | 2008-03-06 | 2008-12-17 | 台耀化学股份有限公司 | Preparation of novel compound and montelukast sodium |
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| ATE539061T1 (en) * | 2004-07-19 | 2012-01-15 | Matrix Lab Ltd | 2-Ä(3S)-Ä3-Ä(2E)-(7-CHLOROQUINOLIN-2-YL)ETHENYLÜPHENYLÜ-3- HALOPROPYLBENZOIC ACID METHYL ESTER |
| ATE500225T1 (en) * | 2004-07-19 | 2011-03-15 | Matrix Lab Ltd | METHOD FOR PRODUCING MONTELUKAST AND SALTS THEREOF |
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| CN101323589A (en) * | 2008-03-06 | 2008-12-17 | 台耀化学股份有限公司 | Preparation of novel compound and montelukast sodium |
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