CN105315184B - A kind of fertile Preparation Method And Their Intermediate for Xi Ting - Google Patents
A kind of fertile Preparation Method And Their Intermediate for Xi Ting Download PDFInfo
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- CN105315184B CN105315184B CN201510363588.1A CN201510363588A CN105315184B CN 105315184 B CN105315184 B CN 105315184B CN 201510363588 A CN201510363588 A CN 201510363588A CN 105315184 B CN105315184 B CN 105315184B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 100
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 239000002904 solvent Substances 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 12
- 238000009835 boiling Methods 0.000 claims abstract description 11
- XEIHTUKQICDYLA-UHFFFAOYSA-N 2,2-dichloroethanamine Chemical compound NCC(Cl)Cl XEIHTUKQICDYLA-UHFFFAOYSA-N 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 238000006731 degradation reaction Methods 0.000 claims description 34
- 238000006460 hydrolysis reaction Methods 0.000 claims description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 31
- 230000007062 hydrolysis Effects 0.000 claims description 30
- 238000006467 substitution reaction Methods 0.000 claims description 28
- 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 27
- 239000003513 alkali Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 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 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- 150000001298 alcohols Chemical class 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000000376 reactant Substances 0.000 claims description 9
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 9
- 229910021645 metal ion Inorganic materials 0.000 claims description 8
- 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 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims description 2
- ORQYPOUSZINNCB-UHFFFAOYSA-N potassium;hypobromite Chemical compound [K+].Br[O-] ORQYPOUSZINNCB-UHFFFAOYSA-N 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical group [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- RMVRSNDYEFQCLF-UHFFFAOYSA-N phenyl mercaptan Natural products SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 59
- 239000000047 product Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 125000004802 cyanophenyl group Chemical group 0.000 description 14
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- 238000010792 warming Methods 0.000 description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical group COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 3
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 2
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical compound Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- PNJYPDSNILRAGQ-UHFFFAOYSA-N CC1=C(C=CC=C1)C.S1C=CC(=C1)O Chemical compound CC1=C(C=CC=C1)C.S1C=CC(=C1)O PNJYPDSNILRAGQ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- TTYGYMLSPHRTOD-UHFFFAOYSA-N Cc(cc1C)ccc1Sc1ccccc1C#N Chemical compound Cc(cc1C)ccc1Sc1ccccc1C#N TTYGYMLSPHRTOD-UHFFFAOYSA-N 0.000 description 1
- ITYBYVIMIWXRDQ-UHFFFAOYSA-N Cc(cc1C)ccc1Sc1ccccc1C(N)OC Chemical compound Cc(cc1C)ccc1Sc1ccccc1C(N)OC ITYBYVIMIWXRDQ-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940081709 brintellix Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical class CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of fertile Preparation Method And Their Intermediate for Xi Ting.The invention provides a kind of fertile preparation method for Xi Ting, which comprises the steps：(1) according to the preparation method of above-mentioned compound V, compound V is obtained；(2) in high boiling solvent, by described compound V, ring-closure reaction is carried out with Dichloroethyl amine or its salt, be obtained fertile for western spit of fland；Described high boiling solvent is solvent of the boiling point more than 120 DEG C under normal pressure.The present invention preparation method low cost, gentle, simple to operate reaction condition, safety and environmental protection, high income, suitable for industrialized production..
Description
Technical field
The present invention relates to a kind of fertile Preparation Method And Their Intermediate for Xi Ting.
Background technology
Fertile is a kind of antidepressants developed jointly by Lundbeck (Lundbeck) and force field (Takeda) for Xi Ting, trade name
For Brintellix, FDA approval listings are obtained within 30th in September in 2013, be clinically used for major depressive disorder (MDD) and generalized anxiety disorder
The treatment of disease adult patient, the molecular structure of its main active is 1- [2- (2,4- methylphenyl-sulfanyl) phenyl] piperazine, knot
Structure formula is as follows：
The initial preparation method of compound (WO2003/029232A1) is the piperazine and o-dichlorohenzene protected with resin
Ferrocene complex carries out nucleophilic substitution, and nucleophilic displacement of fluorine, then Jing visible ray light are subsequently carried out with 2,4- thiophenol dimethyl benzenes
Crude product being obtained according to solution complexation, resin fracture, finally purification being prepared with LC-MS and ion exchange resin, total recovery is only 4%,
It is cumbersome and used ferrocene etc. danger toxic reagent.
Subsequent improved method (WO2007/144005A1；J.Med.Chem, 2011,54 (9), 3206-3221) for metal
The coupling reaction of palladium chtalyst, constructs C-S keys and C-N keys in the presence of metal palladium catalyst respectively, and these methods are both needed to use
Expensive palladium catalyst and Phosphine ligands, and the residue problem of metal deals with improperly and will have a strong impact on the quality of finished product.
It is not suitable for carrying out the problem of industrialized production, Zupancic (WO2014161976A1) for above several method
Reported in 2014 in succession with Cen Junda (Chinese Journal of Pharmaceuticals, 2014,45 (4), 301-303), with 2,4- dimethyl benzenes
Thiophenol and 2- chloronitrobenzenes (or 2- fluoronitrobenzenes) are raw material, first pass through substitution reaction and obtain 2- (2,4- thiophenol dimethyl benzene) nitre
Base benzene, restores and obtains 2- (2,4- thiophenol dimethyl benzene) aniline, subsequently generates with two (2- chloroethyls) amine hydrochlorate cyclization fertile
For Xi Ting.But in the reduction step of nitro, Zupancic uses ferrum/acetate system, Cen Junda to use hydrogen/palladium carbon body
System, the former post processing are loaded down with trivial details, and the latter's potential safety hazard is larger.Additionally, initiation material 2- chloronitrobenzenes (or 2- fluoronitrobenzenes) and 2,
4- thiophenol dimethyl benzene prices are higher.
In addition, synthesis, 2010,21,3602～3608. describe above-mentioned reaction, it use copper catalyst and match somebody with somebody
Body, condition are more harsh, and yield is only 57%.
Therefore, this area need badly gentle, simple to operate a kind of low cost, reaction condition, safety and environmental protection, high income, be suitable for
In the fertile preparation method for Xi Ting of industrialized production.
The content of the invention
The technical problem to be solved is to overcome the existing fertile preparation method high cost for replacing Xi Ting, reaction
Condition is harsh, cumbersome, dangerous, pollution environment, the low defect of yield and provide a kind of fertile preparation method for Xi Ting and
Its intermediate, the preparation method low cost of the present invention, gentle, simple to operate reaction condition, safety and environmental protection, high income, is applied to
Industrialized production.
The invention provides a kind of preparation method of compound V, which comprises the steps：Compound IV is carried out into Huffman
Degradation reaction, is obtained compound V；
The condition of described hoffman degradation reaction can be the conventional condition of this area hoffman degradation reaction, of the invention special
Not preferred following conditions：In water, in the presence of alkali and hypohalite, compound IV is carried out into hoffman degradation reaction, made
Obtain compound V.
In described hoffman degradation reaction, described water and the Molar ratio of described compound IV can be ability
The conventional Molar ratio of such reaction of domain, such as preferably 3L/mol～4L/mol, 3.5L/mol.
In described hoffman degradation reaction, described alkali can be the conventional alkali of such reaction of this area, preferably
Inorganic base is more preferably potassium hydroxide, one or more in sodium hydroxide, potassium carbonate and sodium carbonate, be most preferably hydroxide
The mol ratio of sodium and sodium carbonate composition is 1.2 alkali.
In described hoffman degradation reaction, described alkali can be somebody's turn to do for this area with the mol ratio of described compound IV
The conventional mol ratio of class reaction, preferably 15～25, it is most preferably 16～22.
In described hoffman degradation reaction, described hypohalite can be the conventional hypohalogenous acids of such reaction of this area
Salt, preferably hypobromite or hypochlorite are more preferably sodium hypobromite, in potassium hypobromite, sodium hypochlorite and postassium hypochlorite
One or more, be most preferably sodium hypochlorite.
In described hoffman degradation reaction, described hypohalite and the mol ratio of described compound IV can be this
The conventional mol ratio of such reaction of field, preferably 1.5～3.0, it is more preferably 1.8～2.5.
In described hoffman degradation reaction, it is preferred that the water and part described in described sodium hypochlorite, part is described
Sodium hydroxide reaction system is added in the form of antiformin；The parameter of described antiformin is preferably：Contain per 100ml
There are 5.68g active chlorine, 7.8g sodium hydroxide and 32g sodium carbonate.
In described hoffman degradation reaction, it is preferred that the sodium hydroxide described in the water and part described in part is with hydrogen
The form of aqueous solution of sodium oxide adds reaction system.
In described hoffman degradation reaction, the temperature of described degradation reaction can be that such reaction of this area is conventional
Temperature, preferably 25 DEG C～100 DEG C, be more preferably 80 DEG C～100 DEG C.
In described hoffman degradation reaction, the time of described degradation reaction can be that such reaction of this area is conventional
Time, typically with compound IV no longer reacts or (such as TLC) reaction is complete after testing；Preferably 2h～6h, for example
4h。
The preparation method of described compound V can comprise further steps：In C2～C6Alcohols solvent in, depositing in alkali
Under, compound III is hydrolyzed reaction, obtains described compound IV；
In described hydrolysis, described C2～C6Alcohols solvent can be the conventional C of such reaction of this area2~
C6Alcohols solvent, preferably isopropanol or the tert-butyl alcohol.
It is preferred that not aqueous in described hydrolysis.
In described hydrolysis, described alcohols solvent and the Molar ratio of described compound III can be this
The conventional Molar ratio of such reaction of field, such as preferably 0.5L/mol～1.5L/mol, 1.0L/mol.
In described hydrolysis, described alkali can be the conventional alkali of such reaction of this area, for example organic base and/or
Inorganic base；Described organic base can be the conventional organic base of such reaction of this area, preferably potassium tert-butoxide；Described is inorganic
Alkali can be the conventional inorganic base of such reaction of this area, preferably sodium hydroxide and/or potassium hydroxide, be most preferably hydroxide
Potassium.
In described hydrolysis, described alkali is with the mol ratio of described compound III can such be anti-for this area
Mol ratio that should be conventional, preferably 2.0～5.0, such as 3.0～4.0.
In described hydrolysis, the temperature of described reaction can be the conventional temperature of such reaction of this area；Preferably
Ground is 50 DEG C～120 DEG C, is more preferably 65 DEG C～85 DEG C, such as 80 DEG C.
In described hydrolysis, the time of described reaction can be such reaction of this area conventional time, typically
With compound III no longer reacts or (such as TLC) reaction is complete after testing；At least 1h, such as 2h, 6h.
In the preparation method of described compound V, it is preferred that after the completion of described hydrolysis, compound IV without
Separate (compound IV is not isolated and purified, or, obtain the mixture containing compound IV；The reaction of such as hydrolysis
Liquid is not post-treated, the reactant liquor of hydrolysis carries out simple post processing etc., obtains the mixture containing compound IV；Described
Simple post processing can be removing solvent, concentration, filtration etc.), then carry out described hoffman degradation reaction.
It is described that " after the completion of described hydrolysis, without isolation, then to carry out described Hofmann degradation anti-for compound IV
Should " it is preferably " the C after the completion of described hydrolysis, in the reactant liquor of removing hydrolysis2～C6Alcohols solvent obtain
Residue；Described residue is carried out into described hoffman degradation reaction ", more preferably for " after the completion of described hydrolysis,
Remove the C in the reactant liquor of hydrolysis2～C6Alcohols solvent obtain residue；In water, in the presence of alkali and hypohalite
Under, described residue is carried out into described hoffman degradation reaction ".
The preparation method of described compound V can comprise further steps：In organic solvent, in the presence of base, will
Compound I and compound II carry out substitution reaction, obtain described compound III；Described organic solvent is that alcohols is molten
Agent and/or polar non-solute；Wherein, LG is leaving group, R1For hydrogen or metal ion；
In described substitution reaction, described leaving group can be that such aromatic nucleophilic substitution reaction of this area is conventional
Leaving group, preferably fluorine, chlorine, bromine, OTf or OTs, are more preferably fluorine or chlorine.Described aromatic nucleophilic substitution reaction is virtue
The reaction that a group on ring is replaced by a nucleopilic reagent.
In described substitution reaction, described metal ion can be the conventional metal ion of such reaction of this area, compared with
It is alkali metal ion goodly, is more preferably sodium ion or potassium ion.
In described substitution reaction, described alcohols solvent can be the conventional alcohols solvent of such reaction of this area, compared with
It is C goodly1～C6Alcohols solvent；Described polar non-solute can be the conventional aprotic, polar of such reaction of this area
Solvent, preferably dimethyl sulfoxide and/or DMF, are more preferably DMF.
In described substitution reaction, described organic solvent and the Molar ratio of described compound I can be ability
The conventional Molar ratio of such reaction of domain, such as preferably 0.5L/mol～1.5L/mol, 1.0L/mol.
In described substitution reaction, the mol ratio of described compound II and described compound I can be somebody's turn to do for this area
The conventional mol ratio of class reaction, preferably 1.0～1.2, such as 1.05.
In described substitution reaction, described alkali can be the conventional alkali of such reaction of this area, preferably organic base
And/or inorganic base；Described inorganic base can be the conventional inorganic base of such reaction of this area, preferably potassium carbonate and/or carbon
Sour sodium, is more preferably potassium carbonate.
In described substitution reaction, described alkali and the mol ratio of described compound I can be such reaction of this area
Conventional mol ratio, preferably 1.0～1.5, such as 1.2.
In described substitution reaction, the temperature of described reaction can be the conventional temperature of such reaction of this area；Preferably
Ground is 0 DEG C～120 DEG C, is more preferably 100 DEG C～120 DEG C.
In described substitution reaction, the time of described reaction can be such reaction of this area conventional time, typically
With compound I no longer reacts or (such as TLC) reaction is complete after testing；Preferably 2h～6h, such as 4h.
In the present invention, the preparation method of described compound V can be shown below：
Present invention also offers a kind of preparation method of compound IV, which comprises the steps：In C2～C6Alcohols solvent
In, in the presence of base, compound III is hydrolyzed reaction, obtains described compound IV；
The parameter of described hydrolysis is all as described above.
The preparation method of described compound IV can comprise further steps：In organic solvent, in the presence of base, will
Compound I and compound II carry out substitution reaction, obtain described compound III；Described organic solvent is that alcohols is molten
Agent and/or polar non-solute；Wherein, LG is leaving group, R1For hydrogen or metal ion；
The parameter of described substitution reaction is all as described above.
In the present invention, the preparation method of described compound IV can be shown below：
Present invention also offers a kind of preparation method of compound III, which comprises the steps：In organic solvent, exist
In the presence of alkali, compound I and compound II are carried out into substitution reaction, obtain described compound III；Described is organic
Solvent is alcohols solvent and/or polar non-solute；Wherein, LG is leaving group, R1For hydrogen or metal ion；
The parameter of described substitution reaction is all as described above.
Present invention also offers a kind of fertile preparation method for Xi Ting, which comprises the steps,
(1) according to the preparation method of above-mentioned compound V, compound V is obtained；
(2) in high boiling solvent, by described compound V, ring-closure reaction is carried out with Dichloroethyl amine or its salt, be obtained
It is fertile to replace western spit of fland；Described high boiling solvent is solvent of the boiling point more than 120 DEG C under normal pressure；
In described ring-closure reaction, described high boiling solvent is preferably diethylene glycol monomethyl ether and/or equal front three
Benzene.
In described ring-closure reaction, described high boiling solvent and the Molar ratio of described compound V can be this
The conventional Molar ratio of such reaction of field, such as preferably 0.5L/mol～1.5L/mol, 1.0L/mol.
In described ring-closure reaction, described salt can be the conventional salt in this area, preferably hydrochlorate and/or sulphuric acid
Salt.
In described ring-closure reaction, described Dichloroethyl amine or its salt, the mol ratio with described compound V can be
The conventional mol ratio of such reaction of this area, preferably 1.0～1.5.
In described ring-closure reaction, the temperature of described ring-closure reaction can be the conventional temperature of such reaction of this area；
When described solvent is diethylene glycol monomethyl ether, preferably 120 DEG C～140 DEG C, such as 130 DEG C of described temperature；Work as institute
When the solvent stated is sym-trimethylbenzene., preferably 160 DEG C～165 DEG C of described temperature.
In described ring-closure reaction, the time of described ring-closure reaction can be such reaction of this area conventional time,
Typically with compound V no longer reacts or (such as TLC) reaction is complete after testing.
In the present invention, the described fertile preparation method for Xi Ting can be shown below：
Present invention also offers a kind of compound III or its salt (can be the conventional salt in this area, such as hydrochlorate, sulphuric acid
Salt etc.), its structure is as follows：
Present invention also offers a kind of compound IV or its salt (can be the conventional salt in this area, such as hydrochlorate, sulfate
Deng), its structure is as follows：
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：The preparation method low cost of the present invention, reaction condition are gentle, operation letter
List, safety and environmental protection, high income, suitable for industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description is selected.
Antiformin used in the present invention is purchased from traditional Chinese medicines reagent, and design parameter is：Per 100ml contain 5.68g active chlorine,
7.8g sodium hydroxide and 32g sodium carbonate, oxidizing and corrosivity.
Embodiment 1 prepares intermediate 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (III) by 2- fluorobenzonitriles (Ia)
2- fluorobenzonitriles (compound as shown in Formulas I a) (12.1g, 100mmol), potassium carbonate are added in 250ml reaction bulbs
(16.6g, 120mmol), DMF (100ml), add 2,4- thiophenol dimethyl benzenes (compound as shown in Formula II) (14.5g,
105mmol), 100 DEG C of reaction 4h are warming up to, the detection reaction of TLC points plate is completed.Reaction system is down to room temperature, adds frozen water
(200ml), it is stirred at room temperature one hour, slowly separates out white solid, filters, 20ml frozen water washing filter cake, 50 DEG C are vacuum dried
2- (2,4- thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III) crude product 24g, yield 100%.
Mp=58.9-60.2 DEG C；MS(m/z):240[M+H]+；1H NMR(400MHz,CDCl3,TMS)δ：7.70(dd,J
=8.2,1.2Hz, 1H), 7.48 (d, J=7.8Hz, 1H), 7.36-7.40 (m, 1H), 7.20-7.25 (m, 2H), 7.15 (d, J
=7.8Hz, 1H), 6.80 (dd, J=8.2,1.2Hz, 1H), 2.42 (s, 3H), 2.35 (s, 3H).
Embodiment 2 prepares intermediate 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (III) by 2- 6-chlorophenyl nitriles (Ib)
2- 6-chlorophenyl nitriles (compound as shown in Formulas I b) (13.7g, 100mmol), potassium carbonate are added in 250ml reaction bulbs
(16.6g, 120mmol), DMF (100ml), add 2,4- thiophenol dimethyl benzenes (compound as shown in Formula II) (14.5g,
105mmol), 100 DEG C of reaction 4h are warming up to, the detection reaction of TLC points plate is completed.Reaction system is down to room temperature, adds frozen water
(200ml), it is stirred at room temperature one hour, slowly separates out white solid, filters, 20ml frozen water washing filter cake, 50 DEG C are vacuum dried
(23.5g, yield is 98%) for 2- (2,4- thiophenol dimethyl benzene) cyanophenyl (compound as shown in formula III).
Mp=58.9-60.2 DEG C；MS(m/z):240[M+H]+；1H NMR(400MHz,CDCl3,TMS)δ：7.70(dd,J
=8.2,1.2Hz, 1H), 7.48 (d, J=7.8Hz, 1H), 7.36-7.40 (m, 1H), 7.20-7.25 (m, 2H), 7.15 (d, J
=7.8Hz, 1H), 6.80 (dd, J=8.2,1.2Hz, 1H), 2.42 (s, 3H), 2.35 (s, 3H).
The preparation of embodiment 3a intermediate 2- (2,4- thiophenol dimethyl benzenes) Benzoylamide (IV)
In 250ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (12.0g,
50mmol), potassium hydroxide (11.2g, 200mmol), isopropanol (50ml) are warming up to 80 DEG C of reaction 2h, and reaction is completed.Reactant
System is down to room temperature, and concentrating under reduced pressure removes solvent, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtains white
Solid, 50 DEG C are vacuum dried to obtain 12g products (compound as shown in formula IV), yield 93%.
Mp=148.5-150.0 DEG C；MS(m/z):258[M+H]+；1H NMR(400MHz,CDCl3,TMS)δ：7.75(dd,
J=8.2,1.2Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.18-7.25 (m, 3H), 7.12 (d, J=7.8Hz, 1H), 6.82
(dd, J=8.5,1.2Hz, 1H), 6.30 (br s, 2H), 2.42 (s, 3H), 2.35 (s, 3H).
The preparation of embodiment 3b intermediate 2- (2,4- thiophenol dimethyl benzenes) Benzoylamide (IV)
In 250ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (12.0g,
50mmol), potassium hydroxide (11.2g, 200mmol), the tert-butyl alcohol (50ml), 80 DEG C of reactions, TLC are monitored to reaction and are completed.Reaction
System is down to room temperature, and concentrating under reduced pressure removes solvent, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtained in vain
Color solid, 50 DEG C are vacuum dried to obtain 11.6g products (compound as shown in formula IV), yield 90%.
The preparation of embodiment 3c intermediate 2- (2,4- thiophenol dimethyl benzenes) Benzoylamide (IV)
In 250ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (12.0g,
50mmol), potassium tert-butoxide (22.4g, 200mmol), isopropanol (50ml) are warming up to 80 DEG C of reaction 2h, and reaction is completed.Reactant
System is down to room temperature, and concentrating under reduced pressure removes solvent, obtains white paste, and silica gel column chromatography is crossed post separation (PE/EA=2/1) and obtained in vain
Color solid, 50 DEG C are vacuum dried to obtain 9.7g products (compound as shown in formula IV), yield 75%.
The preparation of 4 intermediate 2- of embodiment (2,4- thiophenol dimethyl benzenes) aniline (V)
2- (2,4- thiophenol dimethyl benzenes) Benzoylamide (compound as shown in formula IV) is added in 250ml reaction bulbs
(3.8g, 15mmol), antiformin (50ml, the active chlorine containing 38mmol), adds the sodium hydroxide that mass fraction is 50%
Solution (3.2g sodium hydroxide is dissolved in 3.2ml water), is warming up to 80 DEG C of reaction 6h, and reaction is completed.Reaction system is down to room temperature, second
Acetoacetic ester is extracted, and washing, anhydrous sodium sulfate drying, concentrating under reduced pressure remove solvent and obtain brown oil 3g, structure determination its be 2-
(2,4- thiophenol dimethyl benzene) aniline (compound shown as a formula V), yield 87%.
MS(m/z):230[M+H]+；1H NMR(400MHz,CDCl3,TMS)δ：7.35 (dd, J=7.2,1.3Hz, 1H),
7.23 (m, 1H), 7.01 (m, 1H), 6.76-6.83 (m, 3H), 6.72 (d, J=8.5Hz, 1H), 4.30 (br s, 2H), 2.40
(s, 3H), 2.28 (s, 3H).
Embodiment 5 prepares intermediate 2- (2,4- thiophenol dimethyl benzenes) by 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (III)
Aniline (V)
In 250ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (12.0g,
50mmol), potassium hydroxide (11.2g, 200mmol), isopropanol (50ml) are warming up to 80 DEG C of reaction 2h, and reaction is completed.Reactant
System is down to room temperature, and concentrating under reduced pressure removes solvent, obtains white paste.
Antiformin (120ml, the active chlorine containing 91mmol) is added in white paste obtained above, is warming up to
80 DEG C of reaction 6h, reaction are completed.Reaction system is down to room temperature, ethyl acetate extraction, saturated common salt washing, washing, anhydrous slufuric acid
Sodium is dried, and concentrating under reduced pressure removes solvent and obtains brown oil 9g, two step yields 78%.
MS(m/z):230[M+H]+；1H NMR(400MHz,CDCl3,TMS)δ：7.35 (dd, J=7.2,1.3Hz, 1H),
7.23 (m, 1H), 7.01 (m, 1H), 6.76-6.83 (m, 3H), 6.72 (d, J=8.5Hz, 1H), 4.30 (br s, 2H), 2.40
(s, 3H), 2.28 (s, 3H).
The preparation of 6 1- of embodiment [2- (2,4- methylphenyl-sulfanyl) phenyl] piperazine (VI is irrigated for Xi Ting)
In 250ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) aniline (compound shown as a formula V) (9.2g,
40mmol), two (2- chloroethyls) amine hydrochlorate (7.1g, 40mmol), diethylene glycol monomethyl ether (40ml), are warming up to 130 DEG C instead
Should, it is complete to the detection reaction of TLC points plate.Room temperature is cooled to, adds frozen water (80ml), ice bath to stir one hour, filtering precipitate,
20ml frozen water washs filter cake.The precipitate collected is dissolved in into methyltetrahydrofuran (40ml), 1M sodium hydroxide during room temperature, is added
(40ml) organic faciess, are collected, water is mutually extracted with methyltetrahydrofuran (20ml) again, merges organic faciess, and anhydrous sodium sulfate drying subtracts
Pressure concentration removes solvent, obtains colorless solid 5.8g, and yield is 48.6%.
Mp=224-226 DEG C；MS(m/z):299[M+H]+；1H NMR(400MHz,CDCl3,TMS)δ：7.35 (d, J=
7.2Hz,1H),7.21(m,1H),7.06-7.12(m,3H),6.86(m,1H),6.43(m,1H),3.12-3.18(m,8H),
2.38 (s, 3H), 2.25 (s, 3H), 1.65 (br s, 1H).
The preparation of 7 1- of embodiment [2- (2,4- methylphenyl-sulfanyl) phenyl] piperazine (VI is irrigated for Xi Ting)
In 250ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) aniline (compound shown as a formula V) (9.2g,
40mmol), two (2- chloroethyls) amine hydrochlorate (7.1g, 40mmol), sym-trimethylbenzene. (40ml), are warming up to 165 DEG C of reactions, extremely
The detection reaction of TLC points plate is complete.Room temperature is cooled to, is added frozen water (80ml), ice bath to stir one hour, precipitate is collected by filtration.
HCl gas are passed through toward filtrate, are had precipitate to separate out, is collected by filtration.Merge precipitate, add methyltetrahydrofuran (40ml),
1M sodium hydroxide (40ml) is added during room temperature, organic faciess are collected, water is mutually extracted with methyltetrahydrofuran (20ml) again, is merged organic
Phase, anhydrous sodium sulfate drying, concentrating under reduced pressure remove solvent, obtain colorless solid 6.2g, and yield is 52%.
Mp=224-226 DEG C；MS(m/z):299[M+H]+；1H NMR(400MHz,CDCl3,TMS)δ：7.35 (d, J=
7.2Hz,1H),7.21(m,1H),7.06-7.12(m,3H),6.86(m,1H),6.43(m,1H),3.12-3.18(m,8H),
2.38 (s, 3H), 2.25 (s, 3H), 1.65 (br s, 1H).
Comparative example 1
In 25ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (1.2g,
5mmol), concentrated hydrochloric acid (10ml), 80 DEG C of stirring reactions 2h, TLC monitoring are generated without product, and the time that extends also is given birth to without product to 24h
Into.
Comparative example 2
In 25ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (1.2g,
5mmol), the sulphuric acid (10ml) of 5mol/L, 80 DEG C of stirring reactions 2h, TLC monitoring without product generate, extend the time to 24h also without
Product is generated.
Comparative example 3
In 50ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (2.4g,
10mmol), potassium hydroxide (2.2g, 40mmol), hydrogen peroxide (2ml), isopropanol (10ml) are warming up to 80 DEG C of reaction 2h, TLC inspections
Survey reaction to complete, in addition to generating target product (compound as shown in formula IV), have miscellaneous point to produce and (thioether bond is speculated as by oxygen
The corresponding sulfoxide of product and sulfone have been melted into it).Reaction system is down to room temperature, and concentrating under reduced pressure removes solvent, obtains white paste, silica gel
Column chromatography is crossed post separation (PE/EA=2/1) and obtains white solid, and 50 DEG C are vacuum dried to obtain the 1.3g products (chemical combination as shown in formula IV
Thing), yield 50%.
Comparative example 4
In 50ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (2.4g,
10mmol), potassium hydroxide (2.2g, 40mmol), water (2ml), isopropanol (10ml) are warming up to 80 DEG C of reaction 2h, and TLC detections are anti-
Should complete, in addition to generating target product (compound as shown in formula IV), have miscellaneous point to produce and (compare through TLC, thus it is speculated that for phase
The carboxylic acid product answered).Reaction system is down to room temperature, and concentrating under reduced pressure removes solvent, obtains white paste, and silica gel column chromatography crosses post
Separate (PE/EA=2/1) and obtain white solid, 50 DEG C are vacuum dried to obtain 0.7g products (compound as shown in formula IV), yield
28%.
Comparative example 5
In 50ml reaction bulbs add 2- (2,4- thiophenol dimethyl benzenes) cyanophenyl (compound as shown in formula III) (2.4g,
10mmol), potassium hydroxide (2.2g, 40mmol), methanol (10ml) are warming up to 60 DEG C of reaction 2h, and TLC detections are generated without product,
Extend the response time to 24h still without target product generation.
Claims (13)
1. a kind of preparation method of compound V, which comprises the steps：In C2～C6Alcohols solvent in, in the presence of base,
Compound III is hydrolyzed reaction, described compound IV is obtained；In water, in the presence of alkali and hypohalite, will change
Compound IV carries out hoffman degradation reaction, and compound V is obtained；It is not aqueous in described hydrolysis；Described C2～C6's
Alcohols solvent is isopropanol or the tert-butyl alcohol；
2. preparation method as claimed in claim 1, it is characterised in that in described hoffman degradation reaction, described water
Molar ratio with described compound IV is 3L/mol～4L/mol；
And/or, in described hoffman degradation reaction, described alkali is potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate
In one or more；
And/or, in described hoffman degradation reaction, described alkali and the mol ratio of described compound IV are 15～25；
And/or, in described hoffman degradation reaction, described hypohalite is sodium hypobromite, potassium hypobromite, sodium hypochlorite
With one or more in postassium hypochlorite；
And/or, in described hoffman degradation reaction, described hypohalite with the mol ratio of described compound IV is
1.5～3.0；
And/or, in described hoffman degradation reaction, the temperature of described degradation reaction is 25 DEG C～100 DEG C；
And/or, in described hoffman degradation reaction, the time of described degradation reaction is 2h～6h.
3. preparation method as claimed in claim 1, it is characterised in that in described hydrolysis,
And/or, in described hydrolysis, described alcohols solvent with the Molar ratio of described compound III is
0.5L/mol～1.5L/mol；
And/or, in described hydrolysis, described alkali be the one kind in potassium tert-butoxide, sodium hydroxide and potassium hydroxide or
It is various；
And/or, in described hydrolysis, described alkali and the mol ratio of described compound III are 2.0～5.0；
And/or, in described hydrolysis, the temperature of described reaction is 50 DEG C～120 DEG C；
And/or, in described hydrolysis, the time of described reaction is at least 1h.
4. preparation method as claimed in claim 1, it is characterised in that after the completion of described hydrolysis, compound IV without
Separate, then carry out described hoffman degradation reaction.
5. preparation method as claimed in claim 4, it is characterised in that " after the completion of described hydrolysis, compound IV without
Separate, then carry out described hoffman degradation reaction " " after the completion of described hydrolysis, to remove the reactant liquor of hydrolysis
In C2～C6Alcohols solvent obtain residue；Described residue is carried out into described hoffman degradation reaction ".
6. preparation method as claimed in claim 5, it is characterised in that " after the completion of described hydrolysis, remove hydrolysis
Reactant liquor in C2～C6Alcohols solvent obtain residue；Described residue is carried out into described hoffman degradation reaction "
" after the completion of described hydrolysis, to remove the C in the reactant liquor of hydrolysis2～C6Alcohols solvent obtain residue；
In water, in the presence of alkali and hypohalite, described residue is carried out into described hoffman degradation reaction ".
7. preparation method as claimed in claim 1, it is characterised in that also comprise the steps：In organic solvent, in alkali
In the presence of, compound I and compound II are carried out into substitution reaction, described compound III is obtained；Described organic solvent
For alcohols solvent and/or polar non-solute；
Wherein, leaving groups of the LG for aromatic nucleophilic substitution reaction, R1For hydrogen or metal ion.
8. preparation method as claimed in claim 7, it is characterised in that in described substitution reaction, described leaving group
For fluorine, chlorine, bromine, OTf or OTs；
And/or, in described substitution reaction, described metal ion is sodium ion or potassium ion；
And/or, in described substitution reaction, described alcohols solvent is C1～C6Alcohols solvent；
And/or, in described substitution reaction, described polar non-solute is dimethyl sulfoxide and/or N, N- dimethyl methyl
Amide；
And/or, in described substitution reaction, described organic solvent and the Molar ratio of described compound I are 0.5L/
Mol～1.5L/mol；
And/or, in described substitution reaction, the mol ratio of described compound II and described compound I is 1.0～1.2；
And/or, in described substitution reaction, described alkali is potassium carbonate and/or sodium carbonate；
And/or, in described substitution reaction, described alkali and the mol ratio of described compound I are 1.0～1.5；
And/or, in described substitution reaction, the temperature of described reaction is 0 DEG C～120 DEG C；
And/or, in described substitution reaction, the time of described reaction is 2h～6h.
9. a kind of preparation method of compound IV, which comprises the steps：In C2～C6Alcohols solvent in, in the presence of base,
Compound III is hydrolyzed reaction, described compound IV is obtained；It is not aqueous in described hydrolysis；Described
C2～C6Alcohols solvent be isopropanol or the tert-butyl alcohol；
The condition of described hydrolysis is as described in claim 1 or 3.
10. preparation method as claimed in claim 9, it is characterised in that also comprise the steps：In organic solvent, in alkali
In the presence of, compound I and compound II are carried out into substitution reaction, described compound III is obtained；Described is organic molten
Agent is alcohols solvent and/or polar non-solute；
Wherein, leaving groups of the LG for aromatic nucleophilic substitution reaction, R1For hydrogen or metal ion；The condition of described substitution reaction
As described in claim 7 or 8.
A kind of 11. fertile preparation methoies for Xi Ting, which comprises the steps：
(1) according to the preparation method of the compound V any one of claim 1～8, compound V is obtained；
(2) in high boiling solvent, by described compound V, ring-closure reaction is carried out with Dichloroethyl amine or its salt, fertile replacing is obtained
Western spit of fland；Described high boiling solvent is solvent of the boiling point more than 120 DEG C under normal pressure；
A kind of 12. compound III or its salt, its structure are as follows：
A kind of 13. compound IV or its salt, its structure are as follows：
Priority Applications (1)
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| Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder;Benny Bang-Andersen;《J. Med. Chem.》;20110412;第54卷(第9期);第3206-3221页 * |
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Denomination of invention: A preparation method and intermediate of voxetine Granted publication date: 20170329 Pledgee: China Minsheng Banking Corp Shanghai branch Pledgor: Shanghai gufangmeng Pharmaceutical Technology Co.,Ltd. Registration number: Y2024310001038 |