CN105085434A - 硫乙拉嗪或其中间体的制备方法 - Google Patents
硫乙拉嗪或其中间体的制备方法 Download PDFInfo
- Publication number
- CN105085434A CN105085434A CN201410196562.8A CN201410196562A CN105085434A CN 105085434 A CN105085434 A CN 105085434A CN 201410196562 A CN201410196562 A CN 201410196562A CN 105085434 A CN105085434 A CN 105085434A
- Authority
- CN
- China
- Prior art keywords
- sodium
- potassium
- mercaptan
- tert
- reaction
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- XCTYLCDETUVOIP-UHFFFAOYSA-N thiethylperazine Chemical compound C12=CC(SCC)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 XCTYLCDETUVOIP-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229960004869 thiethylperazine Drugs 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical group CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims description 50
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 28
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 28
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 28
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 28
- 239000012295 chemical reaction liquid Substances 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 24
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 24
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims description 24
- WQAQPCDUOCURKW-UHFFFAOYSA-N butanethiol Chemical compound CCCCS WQAQPCDUOCURKW-UHFFFAOYSA-N 0.000 claims description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 22
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 21
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 claims description 21
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 18
- QPUSANCBJDDXSA-UHFFFAOYSA-N ethanethiol;sodium Chemical compound [Na].CCS QPUSANCBJDDXSA-UHFFFAOYSA-N 0.000 claims description 17
- 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
- -1 N-diethylformamide Chemical compound 0.000 claims description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- 235000011181 potassium carbonates Nutrition 0.000 claims description 15
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 15
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 15
- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 claims description 15
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 15
- 235000017550 sodium carbonate Nutrition 0.000 claims description 15
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 14
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 14
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 14
- 235000011056 potassium acetate Nutrition 0.000 claims description 14
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 14
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 14
- 239000011736 potassium bicarbonate Substances 0.000 claims description 14
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 14
- 239000001632 sodium acetate Substances 0.000 claims description 14
- 235000017281 sodium acetate Nutrition 0.000 claims description 14
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 14
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000012312 sodium hydride Substances 0.000 claims description 14
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 14
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 claims description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 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 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 12
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000008096 xylene Substances 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- FUBTVLXYLYGSOO-UHFFFAOYSA-N C(C)(C)S.[Na] Chemical compound C(C)(C)S.[Na] FUBTVLXYLYGSOO-UHFFFAOYSA-N 0.000 claims description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 10
- 239000000460 chlorine Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- IVYQTULNLZIYGB-UHFFFAOYSA-N ethanethiol;potassium Chemical compound [K].CCS IVYQTULNLZIYGB-UHFFFAOYSA-N 0.000 claims description 10
- NCNISYUOWMIOPI-UHFFFAOYSA-N propane-1,1-dithiol Chemical compound CCC(S)S NCNISYUOWMIOPI-UHFFFAOYSA-N 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 claims description 9
- 229940008406 diethyl sulfate Drugs 0.000 claims description 9
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical group CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 9
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 9
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical group [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical group CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 claims description 8
- NNXFZAQAFHFISS-UHFFFAOYSA-N 2-methylpropane-2-thiol;sodium Chemical compound [Na].CC(C)(C)S NNXFZAQAFHFISS-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- FNYDBZNYZMEWJI-UHFFFAOYSA-N [K].SC Chemical compound [K].SC FNYDBZNYZMEWJI-UHFFFAOYSA-N 0.000 claims description 8
- BQYGCEWROWDDKH-UHFFFAOYSA-N butane-1-thiol;sodium Chemical compound [Na].CCCCS BQYGCEWROWDDKH-UHFFFAOYSA-N 0.000 claims description 8
- XHXXWWGGXFUMAJ-UHFFFAOYSA-N methanethiol;sodium Chemical compound [Na].SC XHXXWWGGXFUMAJ-UHFFFAOYSA-N 0.000 claims description 8
- ZOCLAPYLSUCOGI-UHFFFAOYSA-M potassium hydrosulfide Chemical compound [SH-].[K+] ZOCLAPYLSUCOGI-UHFFFAOYSA-M 0.000 claims description 8
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 claims description 8
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims description 8
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 7
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- 230000006203 ethylation Effects 0.000 claims description 7
- 238000006200 ethylation reaction Methods 0.000 claims description 7
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 7
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- 239000011734 sodium Chemical group 0.000 claims description 7
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 7
- 239000001488 sodium phosphate Substances 0.000 claims description 7
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 229960003975 potassium Drugs 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000012021 ethylating agents Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- KHAZIIVSIJPRGF-UHFFFAOYSA-N [Na].CCCS Chemical compound [Na].CCCS KHAZIIVSIJPRGF-UHFFFAOYSA-N 0.000 claims description 4
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 4
- 229960003750 ethyl chloride Drugs 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052744 lithium Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 238000005987 sulfurization reaction Methods 0.000 claims 4
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- KFZGLJSYQXZIGP-UHFFFAOYSA-N 2-chloro-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(Cl)=CC=C3SC2=C1 KFZGLJSYQXZIGP-UHFFFAOYSA-N 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 7
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 abstract description 6
- 229960003111 prochlorperazine Drugs 0.000 abstract description 6
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- 230000002708 enhancing effect Effects 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- 125000005537 sulfoxonium group Chemical group 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 6
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 description 6
- DMHPUUIDINBWBN-UHFFFAOYSA-N 2-ethylsulfanyl-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(SCC)=CC=C3SC2=C1 DMHPUUIDINBWBN-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 3
- 239000005751 Copper oxide Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002111 antiemetic agent Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229910000431 copper oxide Inorganic materials 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YNHGMBTXSRJGLC-UHFFFAOYSA-N 3-ethylsulfanyl-n-phenylaniline Chemical compound CCSC1=CC=CC(NC=2C=CC=CC=2)=C1 YNHGMBTXSRJGLC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- 0 *c1ccc2Sc3ccccc3N(*)c2c1 Chemical compound *c1ccc2Sc3ccccc3N(*)c2c1 0.000 description 1
- AUERUDPETOKUPT-UHFFFAOYSA-N 1-(3-chloropropyl)-4-methylpiperazine Chemical compound CN1CCN(CCCCl)CC1 AUERUDPETOKUPT-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- QWEVQPRVZIXRQJ-UHFFFAOYSA-N 1-ethylsulfanyl-10H-phenothiazine Chemical compound C(C)SC1=CC=CC=2SC3=CC=CC=C3NC12 QWEVQPRVZIXRQJ-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- IDXNHZYYCSONAN-UHFFFAOYSA-N 10h-phenothiazine-1-thiol Chemical compound S1C2=CC=CC=C2NC2=C1C=CC=C2S IDXNHZYYCSONAN-UHFFFAOYSA-N 0.000 description 1
- LIWNFNNKPBGCFM-UHFFFAOYSA-N 2-(3-ethylsulfanylanilino)benzoic acid Chemical compound CCSC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1 LIWNFNNKPBGCFM-UHFFFAOYSA-N 0.000 description 1
- DBQWEIGOXKOQAG-UHFFFAOYSA-N 3-ethylsulfanylaniline Chemical compound CCSC1=CC=CC(N)=C1 DBQWEIGOXKOQAG-UHFFFAOYSA-N 0.000 description 1
- RJWLLQWLBMJCFD-UHFFFAOYSA-O CN(CC1)CCN1[NH3+] Chemical compound CN(CC1)CCN1[NH3+] RJWLLQWLBMJCFD-UHFFFAOYSA-O 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005941 Thiamethoxam Substances 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 159000000006 cesium salts Chemical class 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- RNRNDNRVCAYZOP-UHFFFAOYSA-M potassium;2-chlorobenzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1Cl RNRNDNRVCAYZOP-UHFFFAOYSA-M 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- NWWZPOKUUAIXIW-FLIBITNWSA-N thiamethoxam Chemical compound [O-][N+](=O)\N=C/1N(C)COCN\1CC1=CN=C(Cl)S1 NWWZPOKUUAIXIW-FLIBITNWSA-N 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
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- General Health & Medical Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及硫乙拉嗪(Thiethylperazine)或其中间体的制备方法。本发明所述制备方法的原料如丙氯拉嗪和2-氯吩噻嗪等均价廉易得;且通过价廉易得的丙氯拉嗪和2-氯吩噻嗪等原料经一步或两步反应就可得到硫乙拉嗪和其中间体2-乙硫基吩噻嗪,简化了工艺,大大提高了反应收率。
Description
技术领域
本发明涉及一种止吐药物硫乙拉嗪(Thiethylperazine)或其中间体的制备方法。
背景技术
硫乙拉嗪是一种吩噻嗪类的止吐剂,通过抑制催吐化学敏感区而产生镇吐作用,临床用于治疗全身麻醉或眩晕所致的恶心和呕吐,对化疗或放疗所致的呕吐亦有效,其化学名为2-乙硫基-10-[3-(4-甲基-1-哌嗪基)丙基]-吩噻嗪,结构如下:
已有的合成路线包括两种:(1)2-乙硫基吩噻嗪先与1-溴-3-氯丙烷反应生成中间体2-乙硫基-10-(3-氯丙基)-吩噻嗪,再与N-甲基哌嗪反应,如反应式1-A表示;(2)2-乙硫基吩噻嗪直接与1-甲基-4-(3-氯丙基)哌嗪反应,如反应式1-B表示。其中,2-乙硫基吩噻嗪由3-乙硫基苯胺与邻氯苯甲酸钾盐反应生成N-(3-乙硫基苯基)邻氨基苯甲酸,经加热脱羧得到N-(3-乙硫基苯基)苯胺,N-(3-乙硫基苯基)苯胺与硫在碘催化下约160℃反应生成,如反应式1-C表示:
上述路线中,原料3-乙硫基苯胺基本没有商业化产品,价格昂贵,且反应路线较长。
为了解决已有生产方法中存在的工艺路线长、成本高等缺陷,急需提供一条原料价廉易得、路线简短、操作简便的硫乙拉嗪或其中间体的合成路线。
发明内容
本发明的目的是提供一种硫乙拉嗪或其中间体的制备方法,所述方法由化合物II与硫化试剂经取代反应一步生成化合物I,如反应式2所示;
其中,R为H、-(CH2)3NH2或R优选H或X为氟、氯、溴或碘,X优选氯;
所述硫化试剂为乙硫醇、乙硫醇钾或乙硫醇钠;优选乙硫醇或乙硫醇钠;当硫化试剂为乙硫醇时,反应需要在碱存在下进行,所述碱选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、氢化钾、甲醇钠、乙醇钠、氨基钠、氨基钾、二异丙基乙胺、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾、吡啶、三乙胺、乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和二(三甲基硅基)氨基钠中的一种或多种;优选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、甲醇钠、乙醇钠、二异丙基乙胺、吡啶、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯和二(三甲基硅基)氨基钠中的一种或多种;所述乙硫醇与碱的投料量的摩尔比为1:1~1:5,优选1:1~1:3;
化合物II与硫化试剂投料量的摩尔比为1:1~1:15,优选1:1~1:10,最优选1:1~1:5;
所述取代反应可以在有或无催化剂存在下进行,所述催化剂选自四(三苯基膦)钯、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、四丁基溴化膦、碘化亚酮、溴化亚酮、氯化亚酮、三(二亚苄基丙酮)二钯、醋酸钯和氧化铜中的一种或多种;优选自四(三苯基膦)钯、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、四丁基溴化膦、碘化亚酮和溴化亚酮中的一种或多种。
所述取代反应可在合适的溶剂中进行,所述溶剂选自苯、甲苯、氯苯、二甲苯、乙腈、2-丁酮、丙酮、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺(HMPA)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N,N-二乙基甲酰胺、N-甲基吡咯烷酮(NMP)、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙二醇、乙硫醇、聚乙二醇、二氧六环、四乙二醇二甲醚、甲基叔丁基醚、异丙醚、四氢呋喃、水、正己烷、环己烷、二氯甲烷、二氯乙烷、氯仿和喹啉中的一种或多种;优选自苯、甲苯、氯苯、二甲苯、乙腈、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺(HMPA)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N,N-二乙基甲酰胺、N-甲基吡咯烷酮(NMP)、甲醇、乙醇、异丙醇、二氧六环、四氢呋喃和水中的一种或多种;
所述取代反应的温度选自20~139℃,反应时间为0.5~36小时;优选的反应温度为70~139℃,反应时间为0.5~10小时;
本发明还提供了一种硫乙拉嗪或其中间体的制备方法,其包括以下步骤:(1)化合物II与硫化试剂反应生成化合物III或其盐;(2)化合物III或其盐再与乙基化试剂经取代反应得到化合物I,如反应式3所示:
其中,R和X的定义同上;步骤(1)反应结束后,在后处理过程中加入酸,如盐酸或硫酸等,调pH值至酸性,则得到的产物为化合物III;在后处理过程中不加入酸,则得到的产物为化合物III的盐;化合物III的盐形式可选自钠盐、钾盐、锂盐或铯盐等,优选为钠盐、钾盐或锂盐。视情况需要,化合物III或其盐可以分离也可不经分离直接用于下步反应;
所述硫化试剂选自硫化钠、硫化钾、硫氢化钠、硫氢化钾、乙二硫醇、丙二硫醇、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠;优选自硫化钠、硫化钾、硫氢化钠、硫氢化钾、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠;
当硫化试剂为乙二硫醇、丙二硫醇、甲硫醇、乙硫醇、正丙硫醇、异丙硫醇、正丁硫醇或叔丁硫醇时,反应需要在碱存在下进行,所述碱选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、氢化钾、甲醇钠、乙醇钠、氨基钠、氨基钾、二异丙基乙胺、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾、吡啶、三乙胺、乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和二(三甲基硅基)氨基钠中的一种或多种;优选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、甲醇钠、乙醇钠、二异丙基乙胺、吡啶、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯和二(三甲基硅基)氨基钠中的一种或多种。
所述乙二硫醇、丙二硫醇、甲硫醇、乙硫醇、正丙硫醇、异丙硫醇、正丁硫醇或叔丁硫醇与碱的投料量的摩尔比为1:1~1:5,优选1:1~1:3;
所述步骤(1)和步骤(2)的反应可以在有或无催化剂存在下进行,所述催化剂选自四(三苯基膦)钯、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、四丁基溴化膦、碘化亚酮、溴化亚酮、氯化亚酮、三(二亚苄基丙酮)二钯、醋酸钯和氧化铜中的一种或多种;优选自四(三苯基膦)钯、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、四丁基溴化膦、碘化亚酮和溴化亚酮的一种或多种。
所述步骤(1)和步骤(2)的反应可在合适的溶剂中进行,所述溶剂选自苯、甲苯、氯苯、二甲苯、乙腈、2-丁酮、丙酮、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺(HMPA)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N,N-二乙基甲酰胺、N-甲基吡咯烷酮(NMP)、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙二醇、乙硫醇、聚乙二醇、二氧六环、四乙二醇二甲醚、甲基叔丁基醚、异丙醚、四氢呋喃、水、正己烷、环己烷、二氯甲烷、二氯乙烷、氯仿和喹啉中的一种或多种;优选自苯、甲苯、氯苯、二甲苯、乙腈、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺(HMPA)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N,N-二乙基甲酰胺、N-甲基吡咯烷酮(NMP)、甲醇、乙醇、异丙醇、二氧六环、四氢呋喃和水中的一种或多种;
化合物II与硫化试剂投料量的摩尔比为1:1~1:15,优选1:2~1:10,最优选1:2~1:5;
所述步骤(1)的反应温度为140℃~210℃,优选150℃~210℃;所述步骤(1)的反应时间为0.5~36小时,优选0.5~10小时;
所述乙基化试剂为碘乙烷、溴乙烷、氯乙烷、碳酸二乙酯或硫酸二乙酯,优选碘乙烷、溴乙烷或硫酸二乙酯。
化合物III或其盐与乙基化试剂投料量的摩尔比为1:1~1:5,优选1:1~1:3。
当步骤(2)的反应原料为化合物III时,所述反应需要在碱存在下进行,所述碱选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、氢化钾、甲醇钠、乙醇钠、氨基钠、氨基钾、二异丙基乙胺、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾、吡啶、三乙胺、乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和二(三甲基硅基)氨基钠中的一种或多种;优选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、甲醇钠、乙醇钠、二异丙基乙胺、吡啶、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯和二(三甲基硅基)氨基钠中的一种或多种。
化合物III与碱投料量的摩尔比为1:1~1:5,优选1:1~1:3。
所述步骤(2)的反应温度为0℃~120℃,优选20℃~100℃;所述反应时间为0.5~36小时,优选0.5~18小时;
本发明提供了通过“一锅法”制备硫乙拉嗪或其中间体,所述“一锅法”为化合物II与硫化试剂反应生成化合物III的盐,直接在反应液中加入乙基化试剂反应生成化合物I,如反应式4所示:
其中,R为H、-(CH2)3NH2或R优选H或X为氟、氯、溴或碘,X优选氯;M为钾(K)、钠(Na)或锂(Li),,优选为钾或钠;
所述硫化试剂为硫化钠、硫化钾、硫氢化钠、硫氢化钾、乙二硫醇、丙二硫醇、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠;优选自硫化钠、硫化钾、硫氢化钠、硫氢化钾、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠;
当硫化试剂为乙二硫醇、丙二硫醇、甲硫醇、乙硫醇、正丙硫醇、异丙硫醇、正丁硫醇或叔丁硫醇时,反应需要在碱存在下进行,所述碱选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、氢化钾、甲醇钠、乙醇钠、氨基钠、氨基钾、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾和二(三甲基硅基)氨基钠中的一种或多种;优选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、甲醇钠、乙醇钠和二(三甲基硅基)氨基钠中的一种或多种。
所述乙二硫醇、丙二硫醇、甲硫醇、乙硫醇、正丙硫醇、异丙硫醇、正丁硫醇或叔丁硫醇与碱的投料量的摩尔比为1:1~1:5,优选1:1~1:3;
所述乙基化试剂为碘乙烷、溴乙烷、氯乙烷、碳酸二乙酯或硫酸二乙酯,优选碘乙烷、溴乙烷或硫酸二乙酯。
所述反应可以在有或无催化剂存在下进行,所述催化剂选自四(三苯基膦)钯、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、四丁基溴化膦、碘化亚酮、溴化亚酮、氯化亚酮、三(二亚苄基丙酮)二钯、醋酸钯和氧化铜中的一种或多种;优选自四(三苯基膦)钯、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、四丁基溴化膦、碘化亚酮和溴化亚酮的一种或多种。
所述反应可在合适的溶剂中进行,所述溶剂选自苯、甲苯、氯苯、二甲苯、乙腈、2-丁酮、丙酮、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺(HMPA)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N,N-二乙基甲酰胺、N-甲基吡咯烷酮(NMP)、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙二醇、乙硫醇、聚乙二醇、二氧六环、四乙二醇二甲醚、甲基叔丁基醚、异丙醚、四氢呋喃、水、正己烷、环己烷、二氯甲烷、二氯乙烷、氯仿和喹啉中的一种或多种;优选自苯、甲苯、氯苯、二甲苯、乙腈、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺(HMPA)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N,N-二乙基甲酰胺、N-甲基吡咯烷酮(NMP)、甲醇、乙醇、异丙醇、二氧六环、四氢呋喃和水中的一种或多种;
化合物II与硫化试剂投料量的摩尔比为1:1~1:15,优选1:2~1:10,最优选1:2~1:5;
化合物II与乙基化试剂投料量的摩尔比为1:1~1:15,优选1:1~1:10,最优选1:1~1:5。
所述化合物II与硫化试剂的反应温度为140℃~210℃,优选150℃~210℃;反应时间为0.5~36小时,优选0.5~10小时;所述化合物III的盐与乙基化试剂的反应温度为0℃~120℃,优选20℃~100℃;所述反应时间为0.5~36小时,优选0.5~18小时。
有益效果
(1)本发明方法的原料如丙氯拉嗪和2-氯吩噻嗪等价廉易得;
(2)通过价廉易得的丙氯拉嗪和2-氯吩噻嗪等原料经一步或两步反应就可得到硫乙拉嗪和其中间体2-乙硫基吩噻嗪,简化了工艺,大大提高了反应收率。
总之,本发明的方法具有操作简单易行、工艺稳定、易于控制、反应后处理方便、安全、不对人体健康与环境产生危害、生产成本低、产物收率高、纯度好等优点,可以经济、方便地用于工业化生产。
具体实施方式
下面结合实施例对本发明加以进一步说明,以下实施方式只以举例的方式描述本发明。但这些实施例并不意味着对本发明加以任何限制。很明显,本领域普通技术人员可在本发明的范围和实质内,对本发明进行各种变通和修改。需要了解的是,本发明意欲涵盖在所附权利要求书中包括的变通和修改。
实施例12-乙硫基吩噻嗪的制备
将2-氯吩噻嗪(50g,0.21mol)和乙硫醇钠(60g,0.71mol)加入到N-甲基吡咯烷酮(250ml)中,氮气保护下升温到130℃反应3小时,将反应液冷却到室温,倒入冷水中,用甲基叔丁基醚(400ml×2)萃取,合并有机相,用无水硫酸钠干燥后浓缩干得到淡黄色固体,50℃真空干燥后,用乙醇(100ml)和水(100ml)的混合溶剂重结晶,得到类白色产品35g,收率63%。
1HNMR(400MHz,DMSO-d6):δ8.63(s,1H),6.99(t,1H,J=7.6Hz),6.92(d,1H,J=7.6Hz),6.86(d,1H,J=7.6Hz),6.75(t,1H,J=7.6Hz),6.70(dd,1H,J1=7.6Hz,J2=2Hz),6.65(d,1H,J=2Hz),2.90(q,2H,J=7.2Hz),1.23(t,3H,J=7.2Hz).MS:[M+H]+=259.0。
实施例22-乙硫基吩噻嗪的制备
将2-氯吩噻嗪(10g,0.04mol)和乙硫醇钠(12g,0.14mol)加入到二甲亚砜(50ml)中,氮气保护下升温到180℃反应2小时,将反应液冷却到0~10℃,将溴乙烷(14g,0.13mol)缓慢滴入到反应液中,滴加完毕后维持在0~10℃搅拌反应18小时,将反应液倒入冷水中,析出淡黄色固体,抽滤,固体在50℃真空干燥后,用乙醇(30ml)和水(30ml)的混合溶剂重结晶,得到类白色产品8g,收率72%。
氢谱数据同实施例1。
实施例32-乙硫基吩噻嗪的制备
将2-氯吩噻嗪(10g,0.04mol)和甲硫醇钠(5.6g,0.08mol)加入到N,N-二甲基甲酰胺(50ml)中,氮气保护下升温到140℃反应36小时,将反应液冷却到0~10℃,将碘乙烷(6.25g,0.04mol)缓慢滴入到反应液中,滴加完毕后升温至70℃反应5小时。将反应液倒入冷水中,析出淡黄色固体,抽滤,将固体在50℃真空干燥后,用乙醇(30ml)重结晶,得到类白色产品5g,收率45%。氢谱数据同实施例1。
实施例42-乙硫基吩噻嗪的制备
将2-氯吩噻嗪(10g,0.04mol)、碳酸钾(11.2g,0.08mol)、乙硫醇(3.4g,0.04mol)和碘化亚铜(2.5g)加入到二氧六环(50ml)中,氮气保护下升温到70℃反应24小时,将反应液冷却到冷却到室温,倒入冷水中,用甲基叔丁基醚(200ml×2)萃取,合并有机相,用无水硫酸钠干燥后浓缩干得到淡黄色固体,50℃真空干燥后,用甲苯重结晶,得到类白色产品3.5g,收率31%。
氢谱数据同实施例1。
实施例52-乙硫基吩噻嗪的制备
将2-氯吩噻嗪(50g,0.21mol)和硫化钠(82g,1.05mol)加入到1,3-二甲基-2-咪唑啉酮(250ml)中,氮气保护下升温到210℃反应1小时,将反应液冷却到0~10℃,将溴乙烷(114g,1.05mol)缓慢滴入到反应液中,滴加完毕后在室温反应10小时,将反应液倒入冷水中,析出淡黄色固体,抽滤,固体在50℃真空干燥后,用乙醇(150ml)和水(150ml)的混合溶剂重结晶,得到类白色产品48g,收率87%。
氢谱数据同实施例1。
实施例62-乙硫基吩噻嗪的制备
将氢氧化钾(33.6g,0.6mol)加入到N,N-二乙基甲酰胺(50ml)中,滴加正丙硫醇(15.2g,0.2mol),滴加完毕后室温搅拌1小时。再加入2-氯吩噻嗪(5g,0.02mol),氮气保护下升温到170~180℃反应10小时,将反应液冷却到0~10℃,将硫酸二乙酯(30.8g,0.2mol)缓慢滴入到反应液中,滴加完毕后升温至110~120℃搅拌反应1小时,将反应液倒入冷水中,析出淡黄色固体,抽滤,固体在50℃真空干燥后,得到类白色产品4.4g,收率79%。
实施例72-乙硫基吩噻嗪的制备
将叔丁醇钾(11.2g,0.1mol)加入到六甲基磷酰胺(50ml)中,滴加乙硫醇(6.2g,0.1mol),滴加完毕后室温搅拌1小时。再加入2-氯吩噻嗪(5g,0.02mol),氮气保护下升温到190~200℃反应5小时,将反应液冷却到0~10℃,将溴乙烷(10g,0.1mol)缓慢滴入到反应液中,滴加完毕后升温至80~90℃搅拌反应2小时,将反应液倒入冷水中,析出淡黄色固体,抽滤,固体在50℃真空干燥后,得到类白色产品4.6g,收率83%。
实施例82-乙硫基吩噻嗪的制备
将2-氯吩噻嗪(10g,0.04mol)和乙硫醇钠(24g,0.28mol)加入到N-甲基吡咯烷酮(50ml)中,氮气保护下在150~160℃℃反应24小时,将反应液冷却到0~10℃,将溴乙烷(28g,0.26mol)缓慢滴入到反应液中,滴加完毕后升温至50℃搅拌反应6小时。将反应液倒入冷水中,析出淡黄色固体,抽滤,将固体在50℃真空干燥后,用乙醇(30ml)重结晶,得到类白色产品8g,收率72%。氢谱数据同实施例1。
实施例9硫乙拉嗪的制备
将丙氯拉嗪(5g,0.013mol)、乙硫醇钠(6g,0.07mol)加入到N,N-二甲基甲酰胺(25ml)中,氮气保护下升温到120℃反应10小时,将反应液冷却到室温,倒入冷水中,用甲苯(50ml×2)萃取,合并有机相,用无水硫酸钠干燥后浓缩干得到淡黄色固体,用丙酮重结晶,得到类白色产品3g,收率56%。
1HNMR(300MHz,CDCl3):δ7.12(m,2H),7.03(d,1H,J=8.1Hz),6.95-6.82(m,4H),3.90(t,2H,J=6.6Hz),2.90(q,2H,J=7.2Hz),2.60-2.30(br,10H),2.26(s,3H),1.94(m,2H),1.29(t,3H,J=7.2Hz).MS:[M+H]+=400。
实施例10硫乙拉嗪的制备
将丙氯拉嗪(5g,0.013mol)、乙硫醇钠(12g,0.14mol)加入到N-甲基吡咯烷酮(25ml)中,氮气保护下升温到200~210℃反应10小时,将反应液冷却到室温,将溴乙烷(15g,0.14mol)缓慢滴入到反应液中,滴加完毕后继续搅拌0.5小时,倒入冷水中,析出固体,抽滤,固体在50℃真空干燥,得到类白色产品4.3g,收率80%。氢谱数据同实施例9。
实施例112-巯基吩噻嗪的制备
将氢氧化钠(4g,0.1mol)溶于水(10ml)中,与二甲亚砜(50ml)混合,滴加乙硫醇(6.2g,0.1mol),滴加完毕后室温搅拌1小时。再加入2-氯吩噻嗪(5g,0.02mol)和四丁基溴化铵(0.3g),氮气保护下升温到180℃反应6小时,将反应液冷至室温,加入水(100ml),用10%盐酸调pH值至2~3,用乙酸乙酯(30ml×3)萃取,合并有机相,用饱和盐水洗涤,无水硫酸钠干燥,浓缩得固体4g,收率82%。
实施例122-乙硫基吩噻嗪的制备
将2-乙巯基吩噻嗪(4g,0.017mol),溴乙烷(2.2g,0.02mol),碳酸钠(5g,0.047mol)和乙腈(30ml)混合,80~85℃回流反应3小时,反应液倒入冰水中,析出固体,抽滤,用水洗涤,固体在50℃真空干燥后,得到类白色产品4.2g,收率92%。氢谱数据同实施例1。
Claims (10)
1.一种硫乙拉嗪或其中间体的制备方法,其特征在于,所述方法由化合物II与硫化试剂经取代反应一步生成化合物I,如反应式2所示;
其中,
R为H、-(CH2)3NH2或优选为H或
X为氟、氯、溴或碘,优选为氯;
所述硫化试剂为乙硫醇、乙硫醇钾或乙硫醇钠,优选为乙硫醇或乙硫醇钠;所述硫化试剂为乙硫醇时,反应在碱存在下进行。
2.如权利要求1所述的制备方法,其特征在于:所述碱选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、氢化钾、甲醇钠、乙醇钠、氨基钠、氨基钾、二异丙基乙胺、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾、吡啶、三乙胺、乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和二(三甲基硅基)氨基钠中的一种或多种;所述碱优选为叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、甲醇钠、乙醇钠、二异丙基乙胺、吡啶、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯和二(三甲基硅基)氨基钠中的一种或多种。
3.如权利要求1所述的制备方法,其特征在于:所述取代反应在溶剂中进行,所述溶剂为苯、甲苯、氯苯、二甲苯、乙腈、2-丁酮、丙酮、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙二醇、乙硫醇、聚乙二醇、二氧六环、四乙二醇二甲醚、甲基叔丁基醚、异丙醚、四氢呋喃、水、正己烷、环己烷、二氯甲烷、二氯乙烷、氯仿、喹啉中的一种或多种;优选为:苯、甲苯、氯苯、二甲苯、乙腈、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、异丙醇、二氧六环、四氢呋喃和水中的一种或多种。
4.如权利要求1所述的制备方法,其特征在于:所述取代反应的反应温度为20℃~139℃,优选为70℃~139℃。
5.一种硫乙拉嗪或其中间体的制备方法,其特征在于,其包括以下步骤:(1)化合物II与硫化试剂反应生成化合物III或其盐;(2)化合物III或其盐再与乙基化试剂经取代反应得到化合物I,如反应式3所示:
其中,
R为H、-(CH2)3NH2或优选为H或
X为氟、氯、溴或碘,优选为氯;
所述硫化试剂为硫化钠、硫化钾、硫氢化钠、硫氢化钾、乙二硫醇、丙二硫醇、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠,优选为硫化钠、硫化钾、硫氢化钠、硫氢化钾、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠;
所述硫化试剂为乙二硫醇、丙二硫醇、甲硫醇、乙硫醇、正丙硫醇、异丙硫醇、正丁硫醇或叔丁硫醇时,反应在碱存在下进行;
步骤(2)的反应物为化合物III时,反应在碱存在下进行;
所述乙基化试剂为碘乙烷、溴乙烷、氯乙烷、碳酸二乙酯或硫酸二乙酯,优选为碘乙烷、溴乙烷或硫酸二乙酯。
6.如权利要求5所述的制备方法,其特征在于:所述碱独立的选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、氢化钾、甲醇钠、乙醇钠、氨基钠、氨基钾、二异丙基乙胺、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾、吡啶、三乙胺、乙二胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和二(三甲基硅基)氨基钠中的一种或多种;所述碱优选为叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸铯、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、甲醇钠、乙醇钠、二异丙基乙胺、吡啶、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯和二(三甲基硅基)氨基钠中的一种或多种。
7.如权利要求5所述的制备方法,其特征在于:步骤(1)和步骤(2)的反应在溶剂中进行,所述溶剂为苯、甲苯、氯苯、二甲苯、乙腈、2-丁酮、丙酮、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙二醇、乙硫醇、聚乙二醇、二氧六环、四乙二醇二甲醚、甲基叔丁基醚、异丙醚、四氢呋喃、水、正己烷、环己烷、二氯甲烷、二氯乙烷、氯仿、喹啉中的一种或多种;优选为:苯、甲苯、氯苯、二甲苯、乙腈、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、异丙醇、二氧六环、四氢呋喃和水中的一种或多种。
8.如权利要求5所述的制备方法,其特征在于:步骤(1)的反应温度为140℃~210℃,优选为150℃~210℃;步骤(2)的反应温度为0℃~120℃,优选为20℃~100℃。
9.“一锅法”制备硫乙拉嗪或其中间体的方法,其特征在于:化合物II与硫化试剂反应生成化合物III的盐,直接在反应液中加入乙基化试剂反应生成化合物I,如反应式4所示:
其中,
R为H、-(CH2)3NH2或优选为H或
X为氟、氯、溴或碘,优选为氯;
M为钾、钠或锂,优选为钾或钠;
硫化试剂为硫化钠、硫化钾、硫氢化钠、硫氢化钾、乙二硫醇、丙二硫醇、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠,优选为硫化钠、硫化钾、硫氢化钠、硫氢化钾、甲硫醇、甲硫醇钾、甲硫醇钠、乙硫醇、乙硫醇钾、乙硫醇钠、正丙硫醇、正丙硫醇钠、异丙硫醇、正丁硫醇、叔丁硫醇、异丙硫醇钠、正丁硫醇钠或叔丁硫醇钠;当硫化试剂为乙二硫醇、丙二硫醇、甲硫醇、乙硫醇、正丙硫醇、异丙硫醇、正丁硫醇或叔丁硫醇时,生成化合物III的盐的反应需要在碱存在下进行,所述碱选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、氢化钾、甲醇钠、乙醇钠、氨基钠、氨基钾、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾和二(三甲基硅基)氨基钠中的一种或多种;所述碱优选自叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、醋酸钠、醋酸钾、氢氧化钠、氢氧化钾、氢氧化锂、氢化钠、甲醇钠、乙醇钠和二(三甲基硅基)氨基钠中的一种或多种;
乙基化试剂为碘乙烷、溴乙烷、氯乙烷、碳酸二乙酯或硫酸二乙酯,优选为碘乙烷、溴乙烷或硫酸二乙酯。
10.如权利要求9所述的方法,其特征在于:反应溶剂选自苯、甲苯、氯苯、二甲苯、乙腈、2-丁酮、丙酮、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙二醇、乙硫醇、聚乙二醇、二氧六环、四乙二醇二甲醚、甲基叔丁基醚、异丙醚、四氢呋喃、水、正己烷、环己烷、二氯甲烷、二氯乙烷、氯仿和喹啉中的一种或多种;优选自苯、甲苯、氯苯、二甲苯、乙腈、1,3-二甲基-2-咪唑啉酮、二甲亚砜、二甲基砜、环丁砜、六甲基磷酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、异丙醇、二氧六环、四氢呋喃和水中的一种或多种;
化合物II与硫化试剂的反应温度为140℃~210℃,优选为150℃~210℃;
化合物III的盐与乙基化试剂的反应温度为0℃~120℃,优选为20℃~100℃。
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刘刚等: "4-硫醚基喹唑啉类化合物的合成及抑菌活性研究", 《有机化学》 * |
史少辉等: "硫醚合成研究进展", 《广州化工》 * |
Cited By (2)
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CN107663150A (zh) * | 2016-07-27 | 2018-02-06 | 西南民族大学 | 一种姜烯酚类化合物的快速合成方法 |
CN111269159A (zh) * | 2018-12-05 | 2020-06-12 | 上海交通大学 | 一种化工中间体2,2′-二硫代二苯酰胺类化合物的制备方法 |
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WO2015169241A1 (zh) | 2015-11-12 |
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