CN106565467A - 一种抗过敏新药比拉斯汀中间体的制备方法 - Google Patents
一种抗过敏新药比拉斯汀中间体的制备方法 Download PDFInfo
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- CN106565467A CN106565467A CN201610961880.8A CN201610961880A CN106565467A CN 106565467 A CN106565467 A CN 106565467A CN 201610961880 A CN201610961880 A CN 201610961880A CN 106565467 A CN106565467 A CN 106565467A
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- Prior art keywords
- compound
- preparation
- halogen
- bilastine
- reaction
- Prior art date
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- ACCMWZWAEFYUGZ-UHFFFAOYSA-N bilastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ACCMWZWAEFYUGZ-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960004314 bilastine Drugs 0.000 title claims abstract description 17
- 230000003266 anti-allergic effect Effects 0.000 title claims abstract description 6
- 239000003814 drug Substances 0.000 title abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 22
- -1 halogen carbon Anion Chemical class 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000007792 addition Methods 0.000 claims description 6
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 5
- 239000002547 new drug Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000004224 protection Effects 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 235000014121 butter Nutrition 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims 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 claims 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 238000007259 addition reaction Methods 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical group [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 239000003863 metallic catalyst Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001007 flame atomic emission spectroscopy Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
本发明公开了一种抗过敏新药比拉斯汀中间体的制备方法,利用温和的加成反应构建比较难的季碳原子,用非常便宜易得的原料在室温下引入羧基基团,同时利用羧基酸特有的两相性对其纯化进行的研究,使得在合成过程中避免的昂贵的金属催化剂,也避免了苛刻的实施条件,从而提供了一条反应条件温和,操作简便,合成成本低廉,适合大规模生产的Bilastine中间体的制备方法。
Description
技术领域
本发明涉及一种医药中间体,特别涉及一种抗过敏新药比拉斯汀中间体的制备方法。
背景技术
比拉斯汀(又名吡拉斯汀bilastine)原料及片剂”为西班牙FAES制药公司开发的第2代组胺H1受体拮抗剂,比拉斯汀于2012年8月21日被欧盟批准用于治疗过敏性鼻膜炎和荨麻疹,同时在美国进行Ⅱ期临床研究。
比拉斯汀的合成极具难度,主要体现在如结构II所示化合物上,其独特的季碳原子非常难以构建,目前文献专利报道(WO2009/102155A2,2009;US2011/9636A1,2011)的合成从异丁酸酯出发,低温下构建不稳定的TMS保护的烯醇硅醚,随后与4-溴苯乙醇在绝对无水无氧的条件下进行金属催化的偶联反应,随后水解得到相应的结构II。
上述路线虽然成功的实现II结构的制备,但需要低温下构建不稳定的烯醇硅醚,同时需要价格昂贵的金属催化剂实现偶联,虽然收率中等偏上,但需要及其苛刻的条件(绝对无水无氧,长时间的高温)和处理条件(去除重金属),另外,关键的金属偶联反应一旦实施规模超过百克,收率急剧下降。众多因素结合使得该条路线虽然在小试时收率很高,但其实施成本,能耗都非常高,实施条件也非常苛刻,加之无法放大,使得改路线无法成为一条好的工艺化路线。
发明内容
本发明的目的在于针对现有Bilastine中间体的制备方法存在缺点,提供一种抗过敏新药比拉斯汀中间体的制备方法,本发明利用温和的加成反应构建比较难的季碳原子,用非常便宜易得的原料在室温下引入羧基基团,同时利用羧基酸特有的两相性对其纯化进行的研究,使得在合成过程中避免的昂贵的金属催化剂,也避免了苛刻的实施条件,从而提供了一条反应条件温和,操作简便,合成成本低廉,最关键是适合大规模生产的Bilastine中间体的制备方法。
本发明解决其技术问题所采用的技术方案是:
一种抗过敏新药比拉斯汀中间体的制备方法,比拉斯汀中间体为式II所示化合物,制备方法步骤如下:
其中,P1为羟基保护基;X为卤素;R1和R2为C1-C6烷基,或者R1和R2与所链接的碳原子一起形成5元环或者6元环;
(1)化合物V在卤素碳负离子交换后加成得到化合物IV;
(2)化合物IV经亲电氰化反应得到化合物III;
(3)化合物III水解后得到化合物II。
其中化合物V的合成可参考文献Organic Letters,2012,vol.14,#
3p.696–699。
作为优选,所述羟基保护基为TBS保护基。
作为优选,X为卤素Cl、Br、I中的一种。
作为优选,R1和R2均为甲基。
作为优选,步骤(1)化合物V在卤素碳负离子交换后与丙酮加成得到化合物IV。
作为优选,卤素碳负离子交换所使用反应试剂为正丁基锂、仲丁基锂或者异丙基格式试剂,反应温度为-78℃或者-20℃~0℃。异丙基格式试剂具体为异丙基溴化镁或者异丙基氯化镁。
作为优选,步骤(2)中亲电氰化反应所使用的氰化试剂为***、***或者三甲基氰基硅烷,使用的催化剂为三氯化铁、二氯化锡、四氯化锡或者二氯化锌,使用的溶剂为二氯甲烷、二氯乙烷、氯仿或者甲苯。化合物IV在路易斯酸存在下脱除羟基得到碳正离子,再与体系中的氰基结合生成化合物III。
作为优选,步骤(3)化合物III加碱水解后得到化合物II:所使用的碱为氢氧化钾、氢氧化钠或者氢氧化锂,水解的反应介质为甲醇、乙醇、异丙醇、乙二醇、乙二醇二甲醚或者乙二醇单甲醚,反应温度为80-140℃。
本发明的有益效果是:反应条件温和,操作简便,合成成本低廉,适合大规模生产。
具体实施方式
下面通过具体实施例,对本发明的技术方案作进一步的具体说明。
本发明中,若非特指,所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法,如无特别说明,均为本领域的常规方法。
比拉斯汀中间体为式II所示化合物,工艺路线如下:
其中,P1为羟基保护基;X为卤素;R1和R2为C1-C6烷基,或者R1和R2与所链接的碳原子一起形成5元环或者6元环;
制备方法步骤如下:
(1)化合物V在卤素碳负离子交换后加成得到化合物IV;
(2)化合物IV经亲电氰化反应得到化合物III;
(3)化合物III水解后得到化合物II。
在一个特别优选的方案中,本发明提供了如下合成路线:
该合成方法包括以下步骤:
1)如式Va所示化合物,碳负离子交换后加成得到如式IVa所示化合物;
2)如式IVa所示化合物,亲电氰化得到如式IIIa所示化合物;
3)如式IIIa所示化合物,水解得到如式II所示化合物。
本发明所使用术语,除有相反的表述外,具有如下含义。
“烷基”指饱和的脂肪烃基团,包括1-10个碳原子的直链和支链基团,优选包括1至6个碳原子。非限制实施例包括但不限于甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,仲丁基,正戊基,1,1-二甲基丙基,1,2-二甲基丙基,2,2-二甲基丙基,1-乙基丙基,2-甲基丁基,3-甲基丁基,正己基,1-乙基-2-甲基丙基,1,1,2-三甲基丙基,1,1-二甲基丁基,1,2-二甲基丁基,2,2-二甲基丁基,1,3-二甲基丁基,2-乙基丁基,2-甲基戊基,3-甲基戊基,4-甲基戊基,2,3-二甲基丁基等。烷基可以是取代的或者未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立的选自烷基,烯基,炔基,烷氧基,烷硫基,烷基氨基,卤素,硫醇,羟基,硝基,氰基,环氧基,杂环烷基,芳基,杂芳基,环烷氧基,杂环烷氧基,环烷硫基,杂环烷硫基,氧代。
“羟基保护基”为本领域已知的适当的用于羟基保护的基团,参见文献(“Protective groups in Organic Synthesis”,5th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例,优选的,所述的羟基保护基可以是(C1-C10烷基或者芳基)3硅烷基,如三乙基硅基,三异丙基硅基,叔丁基二甲基硅基,叔丁基二苯基硅基等。可以是C1-C10烷基或者取代烷基,如甲基,叔丁基,烯丙基,苄基,甲氧基甲基,乙氧基乙基,2-四氢吡喃基,可以是C1-C10烷基或者芳香基酰基,如甲酰基,乙酰基,苯甲酰基等等。缩写TBS叔丁基二甲基硅基,TMSCN三甲基氰基硅烷。
实施例:
1:化合物Va的合成
反应釜中加入4-溴苯乙醇(1.0kg,5.0mol),10倍体积的二氯甲烷溶解,加入三乙胺(1.01kg,10.0mol)和催化量的DMAP,分批量加入TBSCl(0.9kg,6.0mol)。室温反应至原料消失,水洗,饱和盐水洗,无水硫酸钠干燥后浓缩得无色油状液体化合物Va(1.5kg,95.5%),直接投入下一步反应。
2:化合物IVa的合成
反应釜中加入上述化合物Va(1.5kg,4.78mol),无水THF(10V)溶解,冷却至-78℃,慢慢滴加正丁基锂(2.5M,2.3L),滴加完毕,维持该温度反应2小时。慢慢滴加无水丙酮(0.55kg),耗时1小时。滴加完毕,慢慢升至室温反应至原料消失,饱和氯化铵淬灭后EA提取,水洗,饱和盐水洗,无水硫酸钠干燥后浓缩的化合物IVa(1.40kg,粗品),可直接投入下一步反应。3:化合物IIIa的合成
反应釜中加入上述化合物IVa(1.40kg,粗品),无水DCM(5V)溶解,加入TMSCN(1.41kg),冷却至0℃后慢慢滴加四氯化锡(0.86kg,3.33mol)的无水DCM溶液,加毕,反应至原料消失。将反应体系抽至所配置的氢氧化钠和氟化钾混合溶液中,控制温度低于30℃,向体系中加入1kg硅藻土,搅拌三十分钟过滤,分液后有机相浓缩,滤渣用乙酸乙酯洗涤,水相用乙酸乙酯萃取,和浓缩液合并用清水洗涤两次后,饱和食盐水洗涤两次,干燥后浓缩得所需化合物IIIa(1.35kg,粗品),可直接投入下一步反应。
4:化合物II的合成
反应釜中加入化合物IIIa(1.35kg,粗品),加入乙二醇4L,加入50%氢氧化钾溶液(1.92kg),加热至140℃反应至原料消失。冷却至室温后加水淬灭,用甲叔醚洗涤反应体系两遍,分液将水相用6N盐酸调成酸性,乙酸乙酯萃取后干燥,浓缩的灰褐色粉末状固体,PE/EA=3/1打浆可得纯度超过99%的白色粉末状固体化合物II(0.72kg,70%,4步)。1H-NMR(400MHz,CDCl3)δ7.35(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),3.86(t,J=6.4Hz,2H),3.74(brs,2H),2.86(t,J=6.4Hz,2H),1.59(s,6H)。
以上所述的实施例只是本发明的一种较佳的方案,并非对本发明作任何形式上的限制,在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (8)
1.一种抗过敏新药比拉斯汀中间体的制备方法,其特征在于,比拉斯汀中间体为式II所示化合物,制备方法步骤如下:
其中,P1为羟基保护基;X为卤素;R1和R2为C1-C6烷基,或者R1和R2与所链接的碳原子一起形成5元环或者6元环;
(1)化合物V在卤素碳负离子交换后加成得到化合物IV;
(2)化合物IV经亲电氰化反应得到化合物III;
(3)化合物III水解后得到化合物II。
2.根据权利要求1所述的制备方法,其特征在于,所述羟基保护基为TBS保护基。
3.根据权利要求1所述的制备方法,其特征在于,X为卤素Cl、Br、I中的一种。
4.根据权利要求1所述的制备方法,其特征在于,R1和R2均为甲基。
5.根据权利要求1-4任意一项所述的制备方法,其特征在于,步骤(1)化合物V在卤素碳负离子交换后与丙酮加成得到化合物IV。
6.根据权利要求5所述的制备方法,其特征在于,卤素碳负离子交换所使用反应试剂为正丁基锂、仲丁基锂或者异丙基格式试剂,反应温度为-78℃或者-20℃~0℃。
7.根据权利要求1-4任意一项所述的制备方法,其特征在于,步骤(2)中亲电氰化反应所使用的氰化试剂为***、***或者三甲基氰基硅烷,使用的催化剂为三氯化铁、二氯化锡、四氯化锡或者二氯化锌,使用的溶剂为二氯甲烷、二氯乙烷、氯仿或者甲苯。
8.根据权利要求1-4任意一项所述的制备方法,其特征在于,步骤(3)化合物III加碱水解后得到化合物II:所使用的碱为氢氧化钾、氢氧化钠或者氢氧化锂,水解的反应介质为甲醇、乙醇、异丙醇、乙二醇、乙二醇二甲醚或者乙二醇单甲醚,反应温度为80-140℃。
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