CN102442948A - Method for preparing montelukast sodium intermediate - Google Patents
Method for preparing montelukast sodium intermediate Download PDFInfo
- Publication number
- CN102442948A CN102442948A CN201110340278XA CN201110340278A CN102442948A CN 102442948 A CN102442948 A CN 102442948A CN 201110340278X A CN201110340278X A CN 201110340278XA CN 201110340278 A CN201110340278 A CN 201110340278A CN 102442948 A CN102442948 A CN 102442948A
- Authority
- CN
- China
- Prior art keywords
- preparation
- alkali
- reaction
- compound
- chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title abstract description 12
- 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 abstract description 5
- 229960001951 montelukast sodium Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 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
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- 230000002140 halogenating effect Effects 0.000 claims description 13
- -1 Phenylsulfonic acid acid anhydride Chemical class 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 150000001340 alkali metals Chemical class 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 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
- 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
- 239000000543 intermediate Substances 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 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
- 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
- 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
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 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
- 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
- 125000003944 tolyl group Chemical group 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 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 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
- 235000019439 ethyl acetate Nutrition 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
- 239000012141 concentrate Substances 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000000043 antiallergic agent 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
- 238000004519 manufacturing process Methods 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
- 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
- 125000003368 amide group Chemical group 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
- 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
- OZYHLCOUAISLLG-UHFFFAOYSA-N cyclopropyl acetate Chemical compound CC(=O)OC1CC1 OZYHLCOUAISLLG-UHFFFAOYSA-N 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
- 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 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 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
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 is gentle 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 suitable for industrial production.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, be specifically related to the Menglusitena intermediates preparation.
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 compound method is with 1 (S)-(3-(2-(7-SN-7618-2-yl)-(E) vinyl) phenyl)-3-(2-(2-hydroxyl-2-propyl group) phenyl) propyl alcohol and 2-(1-(thiopurine methyltransferase) cyclopropyl) acetic ester prepared in reaction.
Another kind of Menglusitena compound method is disclosed among the CN1428335A; This method is to be raw material with 2-(3-(3-(2-(7-chloro-2 quinolyls)-(E) vinyl) phenyl)-3 (R)-hydroxypropyls) oil of Niobe; Hydroxyl is converted into the leavings group sulphonate; Obtain 2-(3-(3-(2-(7-chloro-2 quinolyls)-(E) vinyl) phenyl)-3 (R)-(acetyl mercapto) propyl group) oil of Niobe with the thioacetic acid reactant salt then; And then Yu Geshi reagent react; Obtain the sulfydryl tertiary alcohol; 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 then) the cyclopropyl acetic ester, the cyclopropyl acetic ester is obtained cyclopropyl acetate under the alkali effect, further act on sodium hydroxide then 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 Menglusitena intermediates preparation is provided.Preparing method's reaction conditions of the present invention is gentle, and product is single, and it is easy to purify, and the midbody optical purity height and the productive rate that obtain are higher, more are applicable to suitability for industrialized production.The midbody that the present invention makes can further be used for preparing and contain the segmental all cpds of this intermediate structure.
The invention provides a kind of Menglusitena intermediates preparation shown in formula III, 1. it comprise the following steps: under the effect of alkali, 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 like 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 thing or alkali-metal hexamethyl two silica-based aminated things; Described tertiary amine preferably is diisopropyl ethyl amine, triethylamine, TERTIARY BUTYL AMINE or 1, and 8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU) etc. are diisopropyl ethyl amine best; Described alkali-metal trimethyl carbinol thing preferably is sodium tert-butoxide or potassium tert.-butoxide; Described alkali-metal hexamethyl two silica-based aminated things preferably are hexamethyl two silica-based amido lithiums (LiHMDS), sodium hexamethyldisilazide (NaHMDS) or potassium hexamethyldisilazide (KHMDS) etc.; Described mineral alkali preferably is alkali-metal hydrogenate; Described alkali-metal hydrogenate 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 methylsulfonyl chloride, benzene sulfonyl chloride and the substituted benzene sulfonyl chloride of contraposition alkyl, more preferably is methylsulfonyl chloride; Described sulphonic acid anhydride preferably is one or more in the substituted Phenylsulfonic acid acid anhydride of ether, 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 like reference literature Journal of the American Chemical Society, 1952, vol.74, p.5851, the reaction conditions in 5852,5853,5857.The reactions condition is the special reaction conditions of selecting of the present invention.
Wherein, described halogenating agent preferably is one or more in the hydrochloride of hydrochloride and triethylamine of lithium chloride, tetrabutylammonium chloride, diisopropyl ethyl amine, 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 THF one or more more preferably are toluene, acetonitrile and N, one or more in the dinethylformamide (DMF); Be N best, dinethylformamide (DMF) and/or toluene.
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, described sulfonylation halogenating reaction finishes the used aftertreatment in back and can be the conventional post-treating method in this area, preferably for adding frozen water; Behind the ethyl acetate extraction; Use saturated aqueous common salt and water washing successively, organic phase is used anhydrous sodium sulfate drying, concentrates to get 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.
On the basis of this area general knowledge, above-mentioned each optimum condition, but arbitrary combination promptly get each preferred embodiments of the present invention.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is:
1. preparing method's reaction conditions of the present invention is gentle, and product is single, and it is easy to purify, and the midbody optical purity height and the productive rate that obtain are higher, more are applicable to suitability for industrialized production.
2. the midbody that makes of the present invention can further be used for preparation and contains this segmental all cpds of midbody mechanism, as is used for synthesizing of synthetic Menglusitena as Zhichuan agent and anti-allergic agent.
Embodiment
Mode through embodiment further specifies the present invention below, 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 2-(2-(3 (R)-hydroxyl-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (25.1g successively; 55mmol), DMF (400mL) and diisopropyl ethyl amine (17.74g; 137.5mmol), be stirred to dissolving fully.Cryosel is bathed and system is cooled to-10 ℃, and (15.6g 137.5mmol), reacted 10 hours under this temperature then in 30 minutes, to drip methylsulfonyl chloride.(TLC or HPLC monitoring raw material reaction finish); (11.7g 275mmol), removes ice bath to disposable adding lithium chloride, is back to room temperature naturally, continues reaction 14 hours.TLC follows the tracks of reaction and finishes.Add frozen water 300mL ETHYLE ACETATE (60mL * 3), merge organic phase.Use saturated aqueous common salt successively, the water washing organic phase.Anhydrous sodium sulfate drying.Concentrated organic phase adds sherwood oil 500mL and stirs half a hour to 1/5 of original volume, and hold over night is filtered then, 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 2-(2-(3 (R)-hydroxyl-3-(3-(2-(7-chloro-2-quinolyl)-(E) vinyl) phenyl) propyl group) phenyl)-2-propyl alcohol (4.58g successively; 10mmol), toluene (68mL) and diisopropyl ethyl amine (25mmol), be stirred to dissolving fully.Cryosel is bathed (calcium chloride/ice) and system is cooled to-25 ℃, in 30 minutes, drips methylsulfonyl chloride (25mmol), under this temperature, reacts 10 hours then.(TLC or HPLC monitoring raw material reaction finish); Disposable adding tetrabutylammonium chloride (50mmol) removes ice bath, is back to room temperature naturally, continues reaction 14 hours.TLC follows the tracks of reaction and finishes.Add frozen water 300mL ETHYLE ACETATE (60mL * 3), merge organic phase.Use saturated aqueous common salt successively, the water washing organic phase.Anhydrous sodium sulfate drying.Concentrate, add sherwood oil 150mL, ETHYLE ACETATE 15mL stirs half a hour, and hold over night is filtered then, 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); (16.5g 50.7mmol) is removed ice-water bath among the input DMF (200mL) to cesium carbonate, and reaction system was reacted under room temperature 3 hours.TLC monitors reaction.Reaction finishes, and the 1000mL saturated aqueous common salt is added in the system, with ETHYLE ACETATE (3 * 50mL), anhydrous sodium sulfate drying.Concentrate, 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 (9)
1. 1. Menglusitena intermediates preparation shown in formula III is characterized in that comprising the following steps: under the effect of alkali, secondary hydroxyl among the compound I I and sulfonylation agent being 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.
2. preparation method as claimed in claim 1 is characterized in that: described alkali is tertiary amine, alkali-metal hydrogenate, alkali-metal trimethyl carbinol thing or alkali-metal hexamethyl two silica-based aminated things; The mol ratio of described alkali and formula II compound is 1～4: 1.
3. preparation method as claimed in claim 2 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 hydrogenate is sodium hydride, potassium hydride KH or lithium hydride; Described alkali-metal trimethyl carbinol thing is sodium tert-butoxide or potassium tert.-butoxide; Described alkali-metal hexamethyl two silica-based aminated things are hexamethyldisilazane lithium, hmds base sodium or hmds base potassium.
4. preparation method as claimed in claim 1 is characterized in that: described sulfonylation agent is SULPHURYL CHLORIDE and/or sulphonic acid anhydride; 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 methylsulfonyl chloride, benzene sulfonyl chloride and the substituted benzene sulfonyl chloride of contraposition alkyl; Described sulphonic acid anhydride is one or more in the substituted Phenylsulfonic acid acid anhydride of ether, 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: the temperature of reaction of described sulfonylation is-35 ℃～0 ℃.
7. preparation method as claimed in claim 1 is characterized in that: described halogenating agent is one or more in the hydrochloride of hydrochloride and triethylamine of lithium chloride, tetrabutylammonium chloride, diisopropyl ethyl amine; The mol ratio of described halogenating agent and formula II compound is 0～9: 1.
8. preparation method as claimed in claim 1 is characterized in that: the temperature of reaction of described halogenating reaction is-10 ℃～30 ℃.
9. preparation method as claimed in claim 1 is characterized in that: described solvent is toluene, acetonitrile, N, one or more in dinethylformamide, methylene dichloride and the THF.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110340278 CN102442948B (en) | 2011-11-01 | 2011-11-01 | Method for preparing montelukast sodium intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110340278 CN102442948B (en) | 2011-11-01 | 2011-11-01 | Method for preparing montelukast sodium intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102442948A true CN102442948A (en) | 2012-05-09 |
| CN102442948B CN102442948B (en) | 2013-10-16 |
Family
ID=46005930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110340278 Expired - Fee Related CN102442948B (en) | 2011-11-01 | 2011-11-01 | Method for preparing montelukast sodium intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102442948B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032099A2 (en) * | 2006-09-15 | 2008-03-20 | Cipla Limited | Process for the preparation of montelukast, and intermediates therefor |
| US20080275243A1 (en) * | 2004-07-19 | 2008-11-06 | Chava Satyanarayana | Process for the Preparation of Polymorphs, Solvates of Aripiprazole Using Aripiprazole Acid Salts |
| 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 |
| US20110137039A1 (en) * | 2004-07-19 | 2011-06-09 | Chava Satyanarayana | Process for the preparation of montelukast and its salts |
-
2011
- 2011-11-01 CN CN 201110340278 patent/CN102442948B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080275243A1 (en) * | 2004-07-19 | 2008-11-06 | Chava Satyanarayana | Process for the Preparation of Polymorphs, Solvates of Aripiprazole Using Aripiprazole Acid Salts |
| US20110137039A1 (en) * | 2004-07-19 | 2011-06-09 | Chava Satyanarayana | Process for the preparation of montelukast and its salts |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102442948B (en) | 2013-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2935601A1 (en) | 5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1h)-one and processes for their preparation | |
| CN104262344A (en) | A preparing method of Idelalisib | |
| CN103254211B (en) | A kind of method preparing dimension card Gray and derivative thereof | |
| JP2006232802A (en) | Method for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane | |
| KR20220025790A (en) | Method for producing ether compound | |
| CN102442947B (en) | Preparation method of Montelukast Sodium intermediate | |
| CN103304567B (en) | Preparation method of ticagrelor | |
| CN102442948B (en) | Method for preparing montelukast sodium intermediate | |
| JPWO2012105263A1 (en) | Process for producing aminophenylpyrimidinyl alcohol derivative and synthetic intermediate thereof | |
| JP2016084348A (en) | Difluoroalkylbenzene derivative and method for producing the same | |
| JP6072247B2 (en) | Process for producing shikimic acid derivatives and intermediates | |
| CN109096186B (en) | Synthesis method of 2-arylsulfonyl quinoline derivative | |
| JP5663482B2 (en) | Method for producing pyrimidinylacetonitrile derivative and synthetic intermediate thereof | |
| KR101471047B1 (en) | Improved process for preparation of highly pure bosentan | |
| KR102434471B1 (en) | Posaconazole, composition, intermediate, preparation method therefor, and uses thereof | |
| EP2980079A1 (en) | Method of manufacturing pyridazinone compound | |
| KR20190006960A (en) | Process for preparing an herbicidal compound | |
| JP2002356488A (en) | Method for producing (dioxolenon-4-yl)methyl ester derivative | |
| JP4326471B2 (en) | Method for producing organic compound | |
| JP2014151285A (en) | New optically active imidazoline-phosphoric acid catalyst and derivative thereof | |
| JP2002220371A (en) | Method for producing n-vinyl carbazoles | |
| JP5034277B2 (en) | Of 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide Production method | |
| WO2010079813A1 (en) | Method for manufacturing inosine derivative | |
| CN102924375B (en) | Talnetant intermediate, preparation method and applications thereof | |
| JPWO2016013225A1 (en) | Process for producing diphenyl sulfide derivative and production intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 201203 Shanghai City Harley Road, Zhangjiang High Tech Park of Pudong New Area No. 998 building 4 Room 102 Patentee after: SHANGHAI YINGLI PHARMACEUTICAL Co.,Ltd. Address before: 201203 Shanghai City Harley Road, Zhangjiang High Tech Park of Pudong New Area No. 998 building 4 Room 102 Patentee before: SHANGHAI YINGLI SCIENCE AND TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20170124 Address after: 201400 Fengxian District, United North Road, No. 99, Shanghai Patentee after: Kaihui Pharmaceutical (Shanghai) Co.,Ltd. Address before: 201203 Shanghai City Harley Road, Zhangjiang High Tech Park of Pudong New Area No. 998 building 4 Room 102 Patentee before: SHANGHAI YINGLI PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170615 Address after: 201203 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road No. 3 Building No. 302 room 720 Patentee after: XDCEXPLORER (SHANGHAI) Co.,Ltd. Address before: 201400 Fengxian District, United North Road, No. 99, Shanghai Patentee before: Kaihui Pharmaceutical (Shanghai) Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180104 Address after: 201203 Shanghai City, Pudong New Area Zhangjiang road 576 No. 6 libing room No. 311 Patentee after: SHANGHAI YINGLI PHARMACEUTICAL Co.,Ltd. Address before: 201203 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road No. 3 Building No. 302 room 720 Patentee before: XDCEXPLORER (SHANGHAI) Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190506 Address after: Room 204, Building 576 Li Bing Road, 56 Faraday Road, China (Shanghai) Free Trade Pilot Area, Pudong New Area, Shanghai, 201210 Patentee after: XDCEXPLORER (SHANGHAI) Co.,Ltd. Address before: Room 311, Building 6, 576 Li Bing Road, Zhangjiang, Pudong New Area, Shanghai, 201203 Patentee before: SHANGHAI YINGLI PHARMACEUTICAL Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20131016 Termination date: 20211101 |