CN116924989A - 一种3-(二氟甲基)-1-甲基-1h-吡唑-4-羧酸的合成方法 - Google Patents
一种3-(二氟甲基)-1-甲基-1h-吡唑-4-羧酸的合成方法 Download PDFInfo
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- CN116924989A CN116924989A CN202310900036.4A CN202310900036A CN116924989A CN 116924989 A CN116924989 A CN 116924989A CN 202310900036 A CN202310900036 A CN 202310900036A CN 116924989 A CN116924989 A CN 116924989A
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- China
- Prior art keywords
- methyl
- catalyst
- pyrazole
- acid
- difluoromethyl
- Prior art date
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- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 238000005899 aromatization reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 16
- ZMMOYIXZGHJMNI-UHFFFAOYSA-N 3-oxopropanenitrile Chemical compound O=CCC#N ZMMOYIXZGHJMNI-UHFFFAOYSA-N 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 difluoroacetaldehyde hemiacetal Chemical class 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- DKNMRIXYSHIIGC-UHFFFAOYSA-N 2,2-difluoroacetaldehyde Chemical compound FC(F)C=O DKNMRIXYSHIIGC-UHFFFAOYSA-N 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- 230000007062 hydrolysis Effects 0.000 claims description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003377 acid catalyst Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- 238000007259 addition reaction Methods 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 4
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims description 2
- 239000005456 alcohol based solvent Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000005453 ketone based solvent Substances 0.000 claims description 2
- FRQONEWDWWHIPM-UHFFFAOYSA-N n,n-dicyclohexylcyclohexanamine Chemical compound C1CCCCC1N(C1CCCCC1)C1CCCCC1 FRQONEWDWWHIPM-UHFFFAOYSA-N 0.000 claims description 2
- DIAIBWNEUYXDNL-UHFFFAOYSA-N n,n-dihexylhexan-1-amine Chemical compound CCCCCCN(CCCCCC)CCCCCC DIAIBWNEUYXDNL-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000003682 fluorination reaction Methods 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract 2
- 239000012467 final product Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 18
- MLOOXLIVMUZBRJ-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carbonitrile Chemical compound CN1C=C(C#N)C(C(F)F)=N1 MLOOXLIVMUZBRJ-UHFFFAOYSA-N 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- AZPWOLJQERBBBM-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetyl chloride Chemical compound FC(F)(Cl)C(Cl)=O AZPWOLJQERBBBM-UHFFFAOYSA-N 0.000 description 2
- XTDZGXBTXBEZDN-UHFFFAOYSA-N 3-(difluoromethyl)-N-(9-isopropyl-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl)-1-methylpyrazole-4-carboxamide Chemical compound CC(C)C1C2CCC1C1=C2C=CC=C1NC(=O)C1=CN(C)N=C1C(F)F XTDZGXBTXBEZDN-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000005737 Benzovindiflupyr Substances 0.000 description 2
- YHOQMAJZIIUYAZ-UHFFFAOYSA-N C1=CC=C(N)C2=C1C1C(C(C)C)C2CC1 Chemical compound C1=CC=C(N)C2=C1C1C(C(C)C)C2CC1 YHOQMAJZIIUYAZ-UHFFFAOYSA-N 0.000 description 2
- 239000005799 Isopyrazam Substances 0.000 description 2
- CCCGEKHKTPTUHJ-UHFFFAOYSA-N N-[9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxamide Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=CC2=C1C1CCC2C1=C(Cl)Cl CCCGEKHKTPTUHJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YFKFPAQFHBCMQP-UHFFFAOYSA-N acetyl 2-chloro-2,2-difluoroacetate Chemical compound CC(=O)OC(=O)C(F)(F)Cl YFKFPAQFHBCMQP-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical group [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- UFNOUKDBUJZYDE-UHFFFAOYSA-N 2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol Chemical compound C1=NC=NN1CC(O)(C=1C=CC(Cl)=CC=1)C(C)C1CC1 UFNOUKDBUJZYDE-UHFFFAOYSA-N 0.000 description 1
- VLBAAZYGJAXMBQ-UHFFFAOYSA-N 9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-amine Chemical group NC1=CC=CC2=C1C1CCC2C1=C(Cl)Cl VLBAAZYGJAXMBQ-UHFFFAOYSA-N 0.000 description 1
- 239000005738 Bixafen Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000005757 Cyproconazole Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- LDLMOOXUCMHBMZ-UHFFFAOYSA-N bixafen Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=C(F)C=C1C1=CC=C(Cl)C(Cl)=C1 LDLMOOXUCMHBMZ-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 description 1
- KDVPGBVZKTVEIS-UHFFFAOYSA-N ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate Chemical compound CCOC=C(C(=O)C(F)F)C(=O)OCC KDVPGBVZKTVEIS-UHFFFAOYSA-N 0.000 description 1
- MRQQMVMIANXDKC-UHFFFAOYSA-N ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate Chemical compound CCOC(=O)C1=CN(C)N=C1C(F)F MRQQMVMIANXDKC-UHFFFAOYSA-N 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- WVQLSCLGUOMMKV-UHFFFAOYSA-N formyl chloride 1H-pyrazole Chemical compound N1N=CC=C1.C(=O)Cl WVQLSCLGUOMMKV-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于化合物合成领域,具体涉及一种3‑(二氟甲基)‑1‑甲基‑1H‑吡唑‑4‑羧酸的合成方法。本发明通过二氟乙醛缩半乙醇与氰基乙醛在催化剂作用下进行缩合反应;然后得到的中间体经水洗后直接与水合肼反应得到中间产物,最后同甲醛,在催化剂作用下反应发生环化芳构化后水解成终产物。本发明提供了一种新的合成3‑(二氟甲基)‑1‑甲基‑1H‑吡唑‑4‑羧酸的方法,反应过程中二氟乙醛缩半乙醇作为氟化试剂,合成方法简单。本发明首次采用价格更低廉的水合肼代替甲基肼来合成3‑(二氟甲基)‑1‑甲基‑1H‑吡唑‑4‑羧酸,价格低廉,操作简单,三废产生较少,具有较高的经济价值与环保价值,更适于工业化生产。
Description
技术领域
本发明属于化合物合成领域,具体涉及一种3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的合成方法。
背景技术
含氟吡唑类化合物时常见的医药和农药的中间体,其中,3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸作为一个重要的中间体,常用于杀菌剂如吡唑萘菌胺、氟唑环菌胺、苯并烯氟菌唑,联苯吡菌胺以及氟唑菌酰胺等产品的合成。
目前报道的合成方法主要包括:
(1)专利EP1997808A公开的以二氟乙酸乙酯为原料,与原甲酸甲酯、乙酸酐反应生成中间体4,4_二氟-2-(乙氧亚甲基)-3-氧代丁酸乙酯,然后该中间体与甲基肼关环,碱性条件下水解生成3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,该方法步骤简单,三废较少,但是所需的原料昂贵,不易获得,而且产物的选择性差。
(2)专利CN101687806A与专利CN101679282A公开的以二氯乙酰氯、乙烯基醚为原料,与甲基肼关环、溴代、氟化钾取代、插羰等五步反应合成3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,过程中温度跨度较大,插羰过程还需要催化加压,条件苛刻,不易操作,成本较高,不适用于工业化生产。
(3)专利W02012025469公开的以二氟氯乙酰氯为原料,与乙烯酮反应得到二氟氟氯乙酰乙酸乙酯,与甲基肼关环后通过氢化脱氯得到到3-(二氟甲基)-1-甲基-IH-吡唑-4-羧酸乙酯,碱性条件下水解得到3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,该方法路线较长,原材料不易获得,氢化脱氯步骤操作复杂,成本较高,产生的三废较多。
发明内容
针对现有技术中,绝大多数合成3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的过程中用到了甲基肼,再加上现有工艺中原材料贵,反应步骤复杂,产生三废多的不足,本发明提供了一种新的合成3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的方法,该方法使用价格更加便宜的水合肼来代替甲基肼,且该方法步骤较少,方法简单,可操作性强,具有很好的工业实用价值。
本发明合成的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸结构式为:
。
本发明为了实现上述目的所采用的技术方案为:
本发明提供了一种3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的合成方法,包括以下步骤:
(A)缩合反应:由式(II)所示的二氟乙醛缩半乙醇与式(I)所示氰基乙醛在催化剂作用下发生脑文格缩合得到中间体式(III);
(B)加成反应:由式(III)所示的中间体的反应液经水洗后直接与水合肼反应得到中间体式(IV);
(C)环化芳构化反应:由式(IV)所示的中间体与甲醛,在催化剂作用下反应发生环化芳构化后水解成式(V)所示3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸;
。
进一步的,步骤(A)中,所述催化剂为含氮类催化剂和酸类催化剂的混合催化剂;所述氰基乙醛、含氮催化剂和酸类催化剂的摩尔比为1:0.5~1:0.5~1;所述氰基乙醛与二氟乙醛缩半乙醇的摩尔比为1:1.03~1.5。
优选的,所述含氮类催化剂包括但不限于:三乙胺、三甲胺、二异丙基乙基胺、三正丙基胺、三正丁基胺、三正己基胺、三环己基胺、N-甲基环己基胺、N-甲基吡咯烷、哌啶、N-甲基哌啶、N-乙基哌啶、N,N-二甲基苯胺、N-甲基吗啉、吡啶、2-甲基吡啶、3-甲基吡啶、4-甲基吡啶、2-甲基-5-乙基吡啶、2,6_二甲基吡啶、2,4,6_三甲基吡啶、4-二甲基氨基吡啶中的至少一种;所述酸类催化剂包括但不限于:乙酸、甲酸中的至少一种。
本发明提供的合成方法,步骤(A)中,所述缩合反应在溶剂中进行;所述溶剂包括但不限于:苯类溶剂、酰胺类溶剂、醇类溶剂、腈类溶剂、酸类溶剂或酮类溶剂;优选的,所述溶剂为甲苯、N,N-二甲基甲酰胺、乙醇、乙腈、乙酸、丙酮、二氯甲烷;所述缩合反应可加入包括但不限于甲苯、苯、二甲苯、环己烷、石油醚、氯仿、四氯化碳有机溶剂共沸带水。
进一步的,步骤(B)中,式(III)所示的中间体与水合肼的摩尔比为1:1.03~1.5;所述加成反应为首先在-5-0℃下保温搅拌1h,然后升温至室温搅拌1h。
进一步的,步骤(C)中,式(IV)所示的中间体与甲醛的摩尔比为1:1.03~1.5;所述催化剂为酸类催化剂;式(IV)所示的中间体与酸类催化剂的摩尔比为1:1.03~1.5;所述酸类催化剂包括但不限于乙酸、甲酸或磷酸。
优选的,步骤(C)中,所述水解为将环化芳构化反应生成的3-氟代氰基吡唑和无机碱溶液发生水解;所述3-氟代氰基吡唑和无机碱的摩尔比为1:1.03~1.5;所述无机碱选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙、碳酸钠或碳酸钾中的至少一种。
上述水解在水相或水油两相中进行;所述油相包括但不限于:烷基类,苯类、酯类、醚类溶剂中的至少一种;优选的,所述油相为二氯甲烷、甲苯、二甲苯、乙酸乙酯、乙酸异丙酯、乙醚、甲基叔丁基醚中的至少一种。
与现有技术相比,本发明具有以下优势:
1.本发明提供了一种新的合成3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的方法,反应过程中二氟乙醛缩半乙醇作为氟化试剂,合成方法简单。
2.本发明首次采用价格更低廉的水合肼代替甲基肼来合成3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,价格低廉,操作简单,三废产生较少,具有较高的经济价值与环保价值,更适于工业化生产。
3.甲基肼是剧毒品,对环境和工人会造成巨大危害,本发明采用水合肼代替甲基肼,具有较高的环保价值,是绿色化学的体现。
附图说明
图1为合成的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的氢谱图。
图2为合成的3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的碳谱图。
具体实施方式
以下结合具体实施例对本发明做进一步说明。下述说明仅是示例性的,并不对保护范围进行限制。在不脱离本发明发明构思的基础上,本领域技术人员不经创造性劳动所得的其他实施方案,也在保护范围之内。
下述实施例中,如无特别说明,所用原料均为市购产品。
下述实施例中,如无特别说明,所述浓度均为质量百分浓度。
下述实施例中,收率=产品的实际质量×纯度/产品的理论质量。
实施例1
缩合反应:室温下,在四口瓶中加入氰基乙醛34.53g(0.500mol),甲苯103.59g,乙酸15.01g(0.250mol),哌啶19.78g(0.250mol),室温下滴加二氟乙醛缩半乙醇126.10g(0.525mol),搅拌12h,加入50g水,分液得到缩合反应液。
加成反应:在四口瓶中加入80%的水合肼21.03g(0.525mol)、甲苯34.53g,置于-5-0℃下,缓慢滴加缩合反应液,滴加完毕后,在-5-0℃下保温搅拌1h,升温至室温搅拌1h。静置分液,得到加成反应液。
环化芳构化反应:在四口瓶中加入40%的甲醛溶液39.41g(0.525mol)、乙酸31.53(0.525mol)、甲苯34.53g,置于-5-0℃下,滴加加成反应液,滴加完毕后,在-5-0℃下保温搅拌1h,升温至室温搅拌1h。加入50g水洗,分液后有机相减压蒸除甲苯,得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈的粗品80.95,纯度87.5%,加入80g正己烷加热全溶,回流1h,搅拌冷却至室温析晶,过滤得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈64.57g,纯度为98.8%。
环化芳构化水解:在四口瓶中加入3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈67.77g(0.427mol),加入210g甲苯,滴加10%的NaOH溶液170g(0.448mol),升温至60℃下搅拌3h,冷却至室温,分液,水相中滴加盐酸,调节至pH2-3,此时有大量白色固体析出,过滤,加入30g水洗涤滤饼,烘干得到白色固体71.93g,即为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。经检测纯度为98.6%,收率以氰基乙醛计为80.58%。
合成的产物3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的结构式为:
1H NMR (400 MHz, DMSO-d 6) δ 12.82 (s, 1H), 8.33 (s, 1H), 7.20 (t,J=53.8 Hz, 1H), 3.91 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 163.0, 145.1 (t,J= 23.8 Hz), 136.2, 113.0(t,J= 3.3 Hz), 109.6 (t,J= 234.7 Hz). 39.3。
实施例2
按照实施例1的方法制备3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,不同的是:缩合步骤中加入30g甲苯作为带水剂,加热至回流,分出9g左右的水,停止加热,冷却至室温,加50g水,分液得到缩合反应液。
环化芳构化反应:得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈的粗品81.37,纯度90.7%,加入80g正己烷加热全溶,回流1h,搅拌冷却至室温析晶,过滤得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈68.03g纯度为99.1%。
环化芳构化水解:滴加10%的NaOH溶液170g(0.451mol),得到白色固体75.93g,即为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。经检测纯度为98.9%,收率以氰基乙醛计为85.32%。
实施例3
按照实施例1的方法制备3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,不同的是:环化芳构化水解步骤不加有机溶剂甲苯,滴加10%的NaOH溶液170g(0.427mol),升温至60℃下搅拌3h,冷却至室温,分液,水相中滴加盐酸,调节至pH2-3,此时有大量白色固体析出,过滤,加入30g水洗涤滤饼,烘干得到白色固体71.53g,即为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。经检测纯度为98.0%,收率以氰基乙醛计为79.64%。
实施例4
按照实施例1的方法制备3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,不同的是:缩合步骤中碱性催化剂将哌啶改为加入三乙胺25.30g(0.250mol)。
环化芳构化反应:得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈的粗品81.79,纯度86.91%,加入80g正己烷加热全溶,回流1h,搅拌冷却至室温析晶,过滤得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈65.57g纯度为98.4%。
环化芳构化水解:滴加10%的NaOH溶液173g(0.431mol),得到白色固体70.97g,即为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。经检测纯度为98.4%,收率以氰基乙醛计为79.34%。
实施例5
按照实施例1的方法制备3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,不同的是:缩合步骤中碱性催化剂由哌啶改为加入吡啶19.78g(0.250mol)。
环化芳构化反应:得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈的粗品79.87,纯度88.11%,加入80g正己烷加热全溶,回流1h,搅拌冷却至室温析晶,过滤得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈63.39g纯度为99.3%。
环化芳构化水解:滴加10%的NaOH溶液168g(0.421mol),得到白色固体70.53g,即为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。经检测纯度为99.2%,收率以氰基乙醛计为78.87%。
实施例6
按照实施例1的方法制备3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,不同的是:缩合步骤中酸性催化剂由乙酸改为加入甲酸11.51g(0.250mol)。
环化芳构化反应:得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈的粗品79.87,纯度88.11%,加入80g正己烷加热全溶,回流1h,搅拌冷却至室温析晶,过滤得到3-(二氟甲基)-1-甲基-1H-吡唑-4-甲腈63.39g纯度为99.3%。
环化芳构化水解:滴加10%的NaOH溶液166g(0.415mol),得到白色固体70.53g,即为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸。经检测纯度为99.2%,收率以氰基乙醛计为78.87%。
应用例1
3-单氟甲基-1-甲基-N-(9-异丙基-1,2,3,4-四氢-l,4-甲桥萘-5-基)-1H-吡唑-4-甲酸酰胺(吡唑萘菌胺)的合成:
根据CN 109970652 A专利的合成方法:将3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸(96mg,0.55mmol)和五氯化磷(125mg,0.6mmol)悬浮在2L乙醚 溶剂中,在氮气保护下室温搅拌至均相透明。减压脱除溶剂和微量五氯化磷后,将吡唑甲酰 氯中间体溶解于2mL四氢呋喃中,加入吡啶(87mg,1.1mmol)和9-异丙基-1,2,3,4-四氢-1,4-甲桥萘-5-胺(110.7mg,0.55mmol)。混合物在室温搅拌反应2小时。向反应混合物中加入5mL水和15mL乙酸乙酯,并转移至分液漏斗中,分离得到有机相,用4% HC1(1OmL)、5% NaHCO3(10mL)及饱和食盐水(1OmL)洗涤后,加入无水硫酸镁干燥,脱除溶剂,经快速硅胶柱分离(乙酸乙酯为洗脱剂),得到化合物3-单氟甲基-1-甲基-N-(9-异丙基-1,2,3,4-四氢-l,4-甲桥萘-5-基)-1H-吡唑-4-甲酸酰胺(吡唑萘菌胺) (113mg,收率60%)
应用例2
3-单氟甲基-1-甲基-N-(9-二氯甲叉烯基-l,2,3,4-四氢-l,4-甲桥萘-5-基) -IH-吡唑-4-甲酸酰胺(苯并烯氟菌唑)的合成
根据专利CN 109970652 A专利的合成方法,与引用例1类似,不同的是将9-异丙基-1,2,3,4-四氢-1,4-甲桥萘-5-胺替换为9-二氯甲叉烯基-1,2,3,4-四氢-1,4-甲桥萘-5-胺,得到化合物3-单氟甲基-1-甲基-N-(9-二氯甲叉烯基-l,2,3,4-四氢-l,4-甲桥萘-5-基) -IH-吡唑-4-甲酸酰胺(115mg,收率55 %)。
Claims (9)
1.一种3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸的合成方法,其特征在于,包括以下步骤:
(A)缩合反应:由式(II)所示的二氟乙醛缩半乙醇与式(I)所示氰基乙醛在催化剂作用下发生脑文格缩合得到中间体式(III);
(B)加成反应:由式(III)所示的中间体的反应液经水洗后直接与水合肼反应得到中间体式(IV);
(C)环化芳构化反应:由式(IV)所示的中间体与甲醛,在催化剂作用下反应发生环化芳构化后水解成式(V)所示3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸;
。
2.根据权利要求1所述的合成方法,其特征在于,步骤(A)中,所述催化剂为含氮类催化剂和酸类催化剂的混合催化剂;所述氰基乙醛、含氮催化剂和酸类催化剂的摩尔比为1:0.5~1:0.5~1;所述氰基乙醛与二氟乙醛缩半乙醇的摩尔比为1:1.03~1.5。
3.根据权利要求2所述的合成方法,其特征在于,所述含氮类催化剂包括但不限于:三乙胺、三甲胺、二异丙基乙基胺、三正丙基胺、三正丁基胺、三正己基胺、三环己基胺、N-甲基环己基胺、N-甲基吡咯烷、哌啶、N-甲基哌啶、N-乙基哌啶、N,N-二甲基苯胺、N-甲基吗啉、吡啶、2-甲基吡啶、3-甲基吡啶、4-甲基吡啶、2-甲基-5-乙基吡啶、2,6_二甲基吡啶、2,4,6_三甲基吡啶、4-二甲基氨基吡啶中的至少一种;所述酸类催化剂包括但不限于:乙酸、甲酸中的至少一种。
4.根据权利要求1-3任一项所述的合成方法,其特征在于,步骤(A)中,所述缩合反应在溶剂中进行;所述溶剂包括但不限于:苯类溶剂、酰胺类溶剂、醇类溶剂、腈类溶剂、酸类溶剂或酮类溶剂;优选的,所述溶剂为甲苯、N,N-二甲基甲酰胺、乙醇、乙腈、乙酸、丙酮、二氯甲烷;所述缩合反应可加入包括但不限于甲苯、苯、二甲苯、环己烷、石油醚、氯仿、四氯化碳有机溶剂共沸带水。
5.根据权利要求1所述的合成方法,其特征在于,步骤(B)中,式(III)所示的中间体与水合肼的摩尔比为1:1.03~1.5;所述加成反应为首先在-5-0℃下保温搅拌1h,然后升温至室温搅拌1h。
6.根据权利要求1所述的合成方法,其特征在于,步骤(C)中,式(IV)所示的中间体与甲醛的摩尔比为1:1.03~1.5;所述催化剂为酸类催化剂;式(IV)所示的中间体与酸类催化剂的摩尔比为1:1.03~1.5;所述酸类催化剂包括但不限于乙酸、甲酸或磷酸。
7.根据权利要求1或6所述的合成方法,其特征在于,步骤(C)中,所述水解为将环化芳构化反应生成的3-氟代氰基吡唑和无机碱溶液发生水解;所述3-氟代氰基吡唑和无机碱的摩尔比为1:1.03~1.5;所述无机碱选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙、碳酸钠或碳酸钾中的至少一种。
8.根据权利要求7所述的合成方法,其特征在于,所述水解在水相或水油两相中进行;所述油相包括但不限于:烷基类,苯类、酯类、醚类溶剂中的至少一种。
9.根据权利要求8所述的合成方法,其特征在于,所述油相为二氯甲烷、甲苯、二甲苯、乙酸乙酯、乙酸异丙酯、乙醚、甲基叔丁基醚中的至少一种。
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