CN117304112A - Synthesis method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid - Google Patents
Synthesis method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid Download PDFInfo
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- CN117304112A CN117304112A CN202311274247.8A CN202311274247A CN117304112A CN 117304112 A CN117304112 A CN 117304112A CN 202311274247 A CN202311274247 A CN 202311274247A CN 117304112 A CN117304112 A CN 117304112A
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- reaction
- methyl
- difluoromethyl
- pyrazole
- carboxylic acid
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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 33
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 22
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 claims abstract description 9
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- 230000002140 halogenating effect Effects 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000005658 halogenation reaction Methods 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 8
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 6
- 239000004280 Sodium formate Substances 0.000 claims description 5
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 5
- 235000019254 sodium formate Nutrition 0.000 claims description 5
- 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 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-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
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 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
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 3
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 claims description 3
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 2
- ZKLFRQSZDUSMQE-UHFFFAOYSA-N 5,5-dichloroimidazolidine-2,4-dione Chemical compound ClC1(Cl)NC(=O)NC1=O ZKLFRQSZDUSMQE-UHFFFAOYSA-N 0.000 claims description 2
- GZNKMGKTCMHRHA-UHFFFAOYSA-N CC.C(C)(C)PC(C)C Chemical compound CC.C(C)(C)PC(C)C GZNKMGKTCMHRHA-UHFFFAOYSA-N 0.000 claims description 2
- QSOKECQNOMLOPU-UHFFFAOYSA-N CC.CPC Chemical compound CC.CPC QSOKECQNOMLOPU-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000002940 palladium Chemical class 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 5
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- RZSJYVBYLBNFGQ-UHFFFAOYSA-N difluoromethane hydrochloride Chemical compound FCF.Cl RZSJYVBYLBNFGQ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- GOFJDXZZHFNFLV-UHFFFAOYSA-N 5-fluoro-1,3-dimethyl-N-[2-(4-methylpentan-2-yl)phenyl]pyrazole-4-carboxamide Chemical compound CC(C)CC(C)C1=CC=CC=C1NC(=O)C1=C(F)N(C)N=C1C GOFJDXZZHFNFLV-UHFFFAOYSA-N 0.000 description 4
- 239000005815 Penflufen Substances 0.000 description 4
- 230000026030 halogenation Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000003756 stirring Methods 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
- 239000005737 Benzovindiflupyr Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000005788 Fluxapyroxad Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 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
- 239000003899 bactericide agent Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 2
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 description 2
- SXSGXWCSHSVPGB-UHFFFAOYSA-N fluxapyroxad Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=CC=C1C1=CC(F)=C(F)C(F)=C1 SXSGXWCSHSVPGB-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical group [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- KURKJXZWCPWPFX-UHFFFAOYSA-N 2,2-difluoroacetyl chloride Chemical compound FC(F)C(Cl)=O KURKJXZWCPWPFX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QRPNDOFSVHOGCK-UHFFFAOYSA-N 3-di(propan-2-yl)phosphanylpropyl-di(propan-2-yl)phosphane Chemical compound CC(C)P(C(C)C)CCCP(C(C)C)C(C)C QRPNDOFSVHOGCK-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 239000005799 Isopyrazam Substances 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-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
- GUZQPNDMHDZWCJ-UHFFFAOYSA-N ethyl-di(propan-2-yl)phosphane Chemical compound CCP(C(C)C)C(C)C GUZQPNDMHDZWCJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000007149 pericyclic reaction Methods 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
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000002351 wastewater Substances 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
The invention belongs to the field of organic synthesis of compounds, and particularly relates to a synthesis method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The invention provides a novel method for synthesizing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which adopts low-cost propiolic acid as a reaction material in the reaction process and has simple synthesis method. The invention synthesizes 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid by using difluoromethane and carbon monoxide with lower price for the first time, has low price, high reaction selectivity and less three wastes, has higher economic value and environmental protection value, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis of compounds, and particularly relates to a synthesis method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid.
Background
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is an important intermediate of medicines and pesticides, and is commonly used for synthesizing SDHI (succinate dehydrogenase inhibitor) bactericides, in recent years, the SDHI bactericides grow rapidly, and are mainly driven by the strong market of new products, especially after 2000 years, a plurality of multi-pound products and heavy-pound potential products are emerging. Such as fluxapyroxad, benzovindiflupyr, have been sold in the year for more than 3.00 million dollars with their broad-spectrum bactericidal activity; the fluxapyroxad hydroxylamine can prevent and treat wheat scab in a breakthrough manner, and can obviously reduce the DON toxin content; the penflufen and the penflufen have important roles in the field of seed treatment agents, such as products of isopyrazam, penflufen, benzovindiflupyr, penflufen and the like.
The synthesis method reported at present mainly comprises the following steps:
(1) Patent EP1997808A discloses that ethyl difluoroacetate is used as a raw material, and reacts with methyl orthoformate and acetic anhydride to generate an intermediate ethyl 4, 4-difluoro-2- (ethoxymethylene) -3-oxobutyrate, and then the intermediate is subjected to cyclization with methyl hydrazine, and 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is generated by hydrolysis under alkaline conditions.
(2) The patent CN101687806A and the patent CN101679282A are disclosed to take dichloroacetyl chloride and vinyl ether as raw materials, and react with methyl hydrazine ring closure, bromination, potassium fluoride substitution, carbonyl insertion and other five steps to synthesize the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, wherein the temperature span is large in the process, the carbonyl insertion process also needs catalytic pressurization, the condition is harsh, the operation is difficult, the cost is high, and the method is not suitable for industrial production.
(3) According to the method disclosed in the patent W02012025469, difluoro-chloracetyl chloride is used as a raw material, the difluoro-chloracetyl chloride is reacted with ketene to obtain difluoro-chloracetyl acetate, the difluoro-chloracetyl acetate is subjected to ring closure with methyl hydrazine to obtain 3- (difluoromethyl) -1-methyl-IH-pyrazole-4-carboxylic acid ethyl ester, and the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is obtained through hydrolysis under alkaline conditions.
Disclosure of Invention
Aiming at the problems that in the prior art, most of the processes for synthesizing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid are used for constructing difluoromethyl, the main source is provided by the reaction of difluoroacetic acid, the waste water is excessively large in the process of preparing difluoroacetic acid chloride and ethyl difluoroacetate by using difluoroacetic acid, equipment corrosion is serious, the reaction steps of the existing process are complex, and three wastes are generated, and the like, the invention provides a novel method for synthesizing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which uses inexpensive and large amount of difluorochloromethane as an initial raw material, and uses difluorochloromethane with cheaper price through the reaction of carbonyl insertion, halogenation and cyclic reaction.
The structural formula of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid synthesized by the invention is shown as the formula (VII):
。
the technical scheme adopted by the invention for achieving the purpose is as follows:
the invention provides a synthesis method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which comprises the following steps:
(A) The carbointercalation reaction: the intermediate formula (I) is obtained by the carbointercalation of difluoro-chloromethane, carbon monoxide and methyl hydrazine under the action of a catalyst and sodium formate;
(B) Halogenation reaction: halogenating the reaction solution of the intermediate shown in the formula (I) by using a halogenating reagent to obtain an intermediate shown in the formula (II);
(C) And (3) performing a cyclic reaction: the intermediate shown in the formula (II), alkali and propiolic acid react to generate a cyclic reaction to 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid shown in the formula (V);
。
further, in the step (A), the catalyst is one or two of palladium salt and phosphine ligand; the palladium-containing salt is Pd (CH) 3 CN)Cl 2 、Pd(dppf)Cl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 2 Cl 2 、Pd(acac) 2 Or PdCl 2 The method comprises the steps of carrying out a first treatment on the surface of the The phosphine ligand is 1, 2-bis (diisopropylphosphine) ethane, BINAP, xantphos, 1, 3-bis (diphenylphosphine) propane or 1, 2-bis (dimethylphosphine) ethane.
Further, in the step (a), the molar ratio of the difluoromethane, the catalyst and the ligand is 1:0.02% -1%: 0.02% -1%; the molar ratio of the difluoro chloromethane to the sodium formate is 1:1.03 to 4; the molar ratio of the difluoro-chloromethane to the methyl hydrazine is 1:1.05; the carbon monoxide was introduced in an amount to maintain the pressure of the reaction system at 50psi.
In the step (A) provided by the invention, the carbonyl inserting reaction is carried out in a solvent; the solvent is water, alcohol solvent, ether solvent or amide solvent.
The solvent is methanol, N-dimethylformamide, ethanol, isopropanol, tetrahydrofuran, isopropyl ether or methyltetrahydrofuran
Further, in the step (A), the carbointercalation reaction is carried out at the temperature of-5-30 ℃ for 3-6 hours.
Further, in the step (B), the molar ratio of the intermediate represented by the formula (I) to the halogenating agent is 1:1.03 to 1.5; the halogenation reaction is carried out for 3 hours at the temperature of-5 to 25 ℃.
Further, the halogenating agent is Cl 2 、Br 2 NBS, NCS, TCCA, dibromohydantoin or dichlorohydantoin.
Further, in the step (C), the molar ratio of the intermediate represented by the formula (II) to the propiolic acid is 1:1.03 to 2; the molar ratio of the propiolic acid to the alkali is 1:1.8-2.0; the reaction temperature is-5-25 ℃ and the reaction time is 2-4 h.
Further, in step (C), the base includes, but is not limited to, at least one of triethylamine, potassium bicarbonate, DBU, sodium bicarbonate, sodium hydroxide, sodium carbonate, potassium carbonate, and potassium hydroxide.
Compared with the prior art, the invention has the following advantages:
1. the invention provides a novel method for synthesizing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which adopts low-cost propiolic acid as a reaction material in the reaction process and has simple synthesis method.
2. The invention synthesizes 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid by using difluoromethane and carbon monoxide with lower price for the first time, has low price, high reaction selectivity and less three wastes, has higher economic value and environmental protection value, and is more suitable for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid;
FIG. 2 is a carbon spectrum of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid.
Detailed Description
The invention is further illustrated below with reference to specific examples. The following description is merely exemplary in nature and is in no way intended to limit the scope of the present disclosure. Other embodiments, which are not creatively obtained by the person skilled in the art without departing from the inventive concept, are also within the protection scope.
In the examples described below, all materials were commercially available unless otherwise specified.
In the following examples, the concentrations are mass percent concentrations unless otherwise specified.
In the examples below, yield = actual mass of product x purity/theoretical mass of product.
Example 1
The carbointercalation reaction: after adding 50mL of N, N-dimethylformamide, 43.23g (0.500 mol) of difluoromethane chloride, 37.4g (0.550 mol) of sodium formate and Pd (OAc) as a catalyst were added to the autoclave at room temperature 2 0.22g (0.001 mol), ligand dippp, 2-bis (di-isopropylphosphino) ethane 0.26g (0.001 mol), methyl hydrazine aqueous solution 60.47g (0.525 mol) CO was introduced into the autoclave at room temperature, and a pressure of 50psi was maintained. After 4h of reaction, the reaction was stopped to obtain an N, N-dimethylformamide solution of intermediate I.
Halogenation reaction: adding the N, N-dimethylformamide solution of the intermediate I into a four-mouth bottle, putting the four-mouth bottle at the temperature of-5-0 ℃, slowly dropwise adding 82.96g (0.519 mol) of bromine, after 2h of dropwise adding, keeping the temperature at the temperature of-5-0 ℃ and stirring for 2h, heating to room temperature and stirring for 1h to obtain a bromination reaction liquid.
And (3) performing a cyclic reaction: to the above bromination reaction solution was added propiolic acid 34.83 (0.497 mol), 30% of liquid base 128.74g (0.965 mol) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 2 hours, the HPLC was conducted, no raw material remained, 15% of hydrochloric acid was added dropwise to adjust pH=6, stirring was cooled to-5 ℃ for crystallization, filtration was carried out, and the solid was collected and dried to obtain a white solid, 76.83g (0.431 mol) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, the purity was 98.8%, and the yield was 86.2% in terms of difluoromethane.
The hydrogen spectrum of the synthesized final product 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is shown in figure 1; the carbon spectrum is shown in fig. 2:
1 H 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).
13 C 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.
example 2
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of example 1, except: selective solvent in the Carbonisation step 50mL tetrahydrofuran was added with 0.26g Pd (CH) 3 CN) 2 Cl 2 The rest steps are unchanged as the catalyst. 74.66g of a white solid was obtained as 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The purity was found to be 98.5% and the yield was found to be 83.51% based on difluoromethane chloride.
Example 3
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of example 1, except: in the halogenation step, 70g of chlorine is used as the halogenating reagent, and the rest steps are unchanged. 77.56g of a white solid was obtained as 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The purity was found to be 98.9% and the yield was found to be 87.1% based on difluoromethane chloride.
Example 4
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of example 1, except: the solvent selected in the step of inserting the carbonyl is 50mL of methanol, and the catalyst is 0.732g Pd (dppf) Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The halogenating reagent in the halogenating step is 70g chlorine gas; the pericyclic reaction was chosen from 81.1g of sodium bicarbonate, the remaining steps being unchanged. 76.42g of white solid was obtained as 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The purity was found to be 98.3% and the yield was found to be 85.3% based on difluoromethane chloride.
Example 5
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of example 1, except: in the step of inserting carbonyl, the solvent is selected to be 50mL of ethanol, and the catalyst is 0.177g of PdCl 2 Ligand 0.623g binap; the halogenating reagent in the halogenation step was 92.3gNBS, the remaining steps being unchanged. 74.96g of a white solid was obtained as 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The purity was found to be 98.1% and the yield was found to be 83.5% based on difluoromethane chloride.
Example 6
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of example 1, except: the solvent selected in the carbonyl inserting step is 50mL of ethanol, and the ligand is 0.578g Xantphos; the halogenating reagent in the halogenation step was 40.2g TCCA, the remainder of the steps being unchanged. 74.83g of a white solid was obtained as 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The purity was found to be 98.2% and the yield was found to be 83.4% based on difluoromethane chloride.
Claims (10)
1. A method for synthesizing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which is characterized by comprising the following steps:
(A) The carbointercalation reaction: the intermediate formula (I) is obtained by the carbointercalation of difluoro-chloromethane, carbon monoxide and methyl hydrazine under the action of a catalyst and sodium formate;
；
(B) Halogenation reaction: halogenating the reaction solution of the intermediate shown in the formula (I) by using a halogenating reagent to obtain an intermediate shown in the formula (II);
；
(C) And (3) performing a cyclic reaction: the intermediate shown in the formula (II), alkali and propiolic acid react to generate a cyclic reaction to 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid shown in the formula (V);
。
2. the synthetic method of claim 1 wherein in step (a), the catalyst is one or both of a palladium salt and a phosphine ligand; the palladium-containing salt is Pd (CH) 3 CN)Cl 2 、Pd(dppf)Cl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 2 Cl 2 、Pd(acac) 2 Or PdCl 2 The method comprises the steps of carrying out a first treatment on the surface of the The phosphine ligand is 1, 2-bis (diisopropylphosphine) ethane, BINAP, xantphos, 1, 3-bis (diphenylphosphine) propane or 1, 2-bis (dimethylphosphine) ethane.
3. The synthetic method of claim 2 wherein in step (a), the molar ratio of difluoromethane, catalyst and ligand is 1:0.02% -1%: 0.02% -1%; the molar ratio of the difluoro chloromethane to the sodium formate is 1:1.03 to 4; the molar ratio of the difluoro-chloromethane to the methyl hydrazine is 1:1.05; the carbon monoxide was introduced in an amount to maintain the pressure of the reaction system at 50psi.
4. A synthetic process according to any one of claims 1 to 3 wherein in step (a) the carbointercalation is carried out in a solvent; the solvent is water, alcohol solvent, ether solvent or amide solvent.
5. The method according to claim 4, wherein in the step (A), the solvent is methanol, N-dimethylformamide, ethanol, isopropanol, tetrahydrofuran, isopropyl ether or methyltetrahydrofuran.
6. The method according to any one of claims 1 to 5, wherein in step (a), the carbointercalation is carried out at a temperature of-5 to 30 ℃ for 3 to 6 hours.
7. The synthetic method of claim 1 wherein in step (B), the molar ratio of the intermediate of formula (I) to the halogenating agent is 1:1.03 to 1.5; the halogenation reaction is carried out for 3 hours at the temperature of-5 to 25 ℃.
8. The synthesis according to claim 1 or 7, wherein the halogenating reagent is Cl 2 、Br 2 NBS, NCS, TCCA, dibromohydantoin or dichlorohydantoin.
9. The synthetic method of claim 1 wherein in step (C), the molar ratio of the intermediate of formula (II) to propiolic acid is 1:1.03 to 2; the molar ratio of the propiolic acid to the alkali is 1:1.8-2.0; the reaction temperature is-5-25 ℃ and the reaction time is 2-4 h.
10. The synthetic method of claim 1 or 9, wherein in step (C), the base includes, but is not limited to, at least one of triethylamine, potassium bicarbonate, DBU, sodium bicarbonate, sodium hydroxide, sodium carbonate, potassium carbonate, and potassium hydroxide.
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