CN115124434A - Nucleophilic fluorinating reagent and synthesis process and application thereof - Google Patents
Nucleophilic fluorinating reagent and synthesis process and application thereof Download PDFInfo
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- CN115124434A CN115124434A CN202210807769.9A CN202210807769A CN115124434A CN 115124434 A CN115124434 A CN 115124434A CN 202210807769 A CN202210807769 A CN 202210807769A CN 115124434 A CN115124434 A CN 115124434A
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 62
- 230000000269 nucleophilic effect Effects 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims abstract description 26
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 23
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 claims abstract description 16
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 14
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 aromatic ring halides Chemical class 0.000 claims abstract description 8
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims abstract description 4
- 229910001863 barium hydroxide Inorganic materials 0.000 claims abstract description 4
- 150000008282 halocarbons Chemical class 0.000 claims abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 238000005342 ion exchange Methods 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 61
- 239000002904 solvent Substances 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 5
- 150000003857 carboxamides Chemical class 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 claims description 3
- ANOOTOPTCJRUPK-UHFFFAOYSA-N 1-iodohexane Chemical compound CCCCCCI ANOOTOPTCJRUPK-UHFFFAOYSA-N 0.000 claims description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 claims description 2
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims description 2
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 claims description 2
- MNDIARAMWBIKFW-UHFFFAOYSA-N 1-bromohexane Chemical compound CCCCCCBr MNDIARAMWBIKFW-UHFFFAOYSA-N 0.000 claims description 2
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 claims description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 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 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000006386 neutralization reaction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 54
- 239000007788 liquid Substances 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 31
- 229910052757 nitrogen Inorganic materials 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 238000001816 cooling Methods 0.000 description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- 238000010438 heat treatment Methods 0.000 description 16
- 238000000746 purification Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 11
- 238000000926 separation method Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012025 fluorinating agent Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 description 4
- 150000001491 aromatic compounds Chemical class 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- ONHMWUXYIFULDO-UHFFFAOYSA-N 4-bromo-2-chloropyridine Chemical compound ClC1=CC(Br)=CC=N1 ONHMWUXYIFULDO-UHFFFAOYSA-N 0.000 description 3
- PTPTZLXZHPPVKG-UHFFFAOYSA-N 4-bromo-2-fluoropyridine Chemical compound FC1=CC(Br)=CC=N1 PTPTZLXZHPPVKG-UHFFFAOYSA-N 0.000 description 3
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 3
- 238000005985 Hofmann elimination reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 1
- NLEPLDKPYLYCSY-UHFFFAOYSA-N 2-fluoroquinoline Chemical compound C1=CC=CC2=NC(F)=CC=C21 NLEPLDKPYLYCSY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000005489 Bromoxynil Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method 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
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/62—Quaternary ammonium compounds
- C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/18—Halogen atoms or nitro radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a nucleophilic fluoride reagent and a synthesis process and application thereof, wherein the nucleophilic fluoride reagent is obtained by the following steps: reacting ethyl isobutyrate serving as a starting material with halogenated hydrocarbon to obtain an intermediate II, hydrolyzing to obtain an intermediate III, condensing with dimethylamine to obtain an intermediate IV, reducing to obtain an intermediate V, reacting with dimethyl sulfate to obtain an intermediate VI, performing ion exchange with barium hydroxide to obtain an intermediate VII, and finally performing acid-base neutralization with hydrofluoric acid to obtain a fluorination reagent I. The nucleophilic fluorination reagent has stable structure, the synthesis process is convenient to operate, the reaction condition is mild, the raw materials are cheap and easy to obtain, the production cost is low, and the nucleophilic fluorination reagent can be applied to the fluorination reaction of aromatic ring halides.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a nucleophilic fluoride reagent, and a synthesis process and application thereof.
Background
In recent years, the application of organofluoro compounds in the fields of medicine, pesticide, dye, material, surfactant, etc. has become more widespread, and the research of organofluoro chemistry has been receiving more and more attention from organic chemists. Fluorine is the element with the greatest electronegativity in nature, and its atomic radius is close to that of hydrogen atom. When designing a drug, chemists usually design and modify the drug by using the electronic effect, the simulation effect, the osmosis effect and the like of fluorine atoms and fluorine-containing substituents. Research shows that the introduction of fluorine atoms can improve the liposolubility of the compound, promote the absorption and transmission speed of the compound in organisms, and improve the metabolic stability and selectivity of the medicine, thereby improving the medicine effect.
The fluorine-containing aromatic compound has the important function in the field of medicine, the most common method for preparing the fluorine-containing aromatic compound is a halogen exchange method, chlorine or bromine-containing aromatic compound and nucleophilic fluoride reagent are used for halogen exchange, the common nucleophilic fluoride reagent comprises inorganic salts such as sodium fluoride, potassium fluoride and cesium fluoride, quaternary ammonium salt fluoride such as tetrabutylammonium fluoride and tetramethylammonium fluoride, the inorganic salt fluoride reagent is very cheap, but the fluorine-containing aromatic compound has poor solubility in organic solvent, obvious amplification effect and poor universality; the cost of tetrabutylammonium fluoride is not high, but the thermal stability is poor, Hofmann elimination is easy to occur under the heating condition, and the application range is limited; in comparison, tetramethylammonium fluoride has good thermal stability, but also has strong hygroscopicity, poor solubility in most organic solvents, difficulty in removing water, and unsuitability for scale-up production.
Disclosure of Invention
The invention aims to provide a nucleophilic fluorination reagent, a synthesis process and application thereof, wherein the fluorination reagent has a stable structure, the synthesis process is convenient to operate, the reaction condition is mild, the production cost is low, and the nucleophilic fluorination reagent is suitable for industrial production.
The technical scheme adopted by the invention for solving the problems is as follows: a nucleophilic fluoride reagent having the structure:
wherein R is alkyl or aryl.
Another object of the present invention is a process for the synthesis of nucleophilic fluoride reagent, the reaction formula is as follows:
the method comprises the following steps:
(1) under the action of alkaline substances, ethyl isobutyrate is used as a starting material and reacts with halogenated hydrocarbon to obtain an intermediate II;
(2) hydrolyzing the intermediate II under the action of an alkaline substance to obtain an intermediate III;
(3) under the action of a condensing agent, condensing the intermediate III and dimethylamine to obtain an intermediate IV;
(4) the intermediate IV is reduced into an intermediate V under the action of a reducing agent;
(5) reacting the intermediate V with dimethyl sulfate to obtain quaternary ammonium salt VI;
(6) performing ion exchange on the quaternary ammonium salt VI and barium hydroxide to generate an intermediate VII;
(7) and neutralizing the intermediate VII and hydrofluoric acid with acid and base to obtain the fluorination reagent I.
Preferably, in the step (1), the basic substance is one of n-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and sodium hydride.
Preferably, the molar ratio of halogenated hydrocarbon to ethyl isobutyrate in step (1) is from 1 to 2: 1, the molar ratio of the alkaline substance to the ethyl isobutyrate is 1-1.5: 1.
preferably, the reaction temperature of step (1) is 0 to 20 o C, the reaction time is 20-30 h.
Preferably, the halide in the step (1) is one of benzyl bromide, benzyl chloride, p-methoxy benzyl bromide, p-methoxy benzyl chloride, 1-iodohexane, 1-bromohexane, 1-bromooctane, 1-bromodecane and 1-bromododecane.
Preferably, in the step (2), the alkaline substance is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, and the molar ratio of the alkaline substance to the intermediate II is 1-3: 1.
preferably, the reaction temperature of step (2) is 60 to 70 o And C, the reaction time is 5-10 h.
Preferably, in the step (3), the condensing agent is one of thionyl chloride, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-propylphosphoric anhydride, and the molar ratio of the condensing agent to the intermediate III is 4-6: 1, the molar ratio of dimethylamine to intermediate III is 2-3: 1.
preferably, the reaction temperature of step (3) is 20 to 30 o And C, the reaction time is 15-20 h.
Preferably, the reducing agent in step (4) is one of lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride and red aluminum, and the molar ratio of the reducing agent to the intermediate IV is 1.5-3: 1,
preferably, the reaction temperature of step (4) is 60 to 70 o And C, the reaction time is 1-2 h.
Preferably, the molar ratio of dimethyl sulfate to intermediate V in step (5) is 1-1.5: 1, reaction temperature of 100- o C, the reaction time is 15-20 h.
Preferably, the molar ratio of the barium hydroxide to the quaternary ammonium salt VI in the step (6) is 1-1.5: 1, the reaction temperature is 40-50 DEG o And C, the reaction time is 20-24 h.
Preferably, the molar ratio of hydrofluoric acid to intermediate VII in step (7) is 0.95-1.05: 1.
preferably, the step (1), the step (2), the step (3), the step (4), the step (5), the step (6) and the step (7) are all performed in a solvent system, the solvent in the step (1) is an organic amide solvent or an organic ether solvent, the solvent in the step (2) is a mixed solvent of water and an organic alcohol solvent, the solvent in the step (3) is dichloromethane, toluene or an organic ether solvent, the solvent in the step (4) is dichloromethane, toluene or an organic ether solvent, the solvent in the step (5) is toluene or an organic ether solvent, the solvent in the step (6) is water or an organic alcohol solvent, and the solvent in the step (7) is water or an organic alcohol solvent.
The invention also aims to provide the application of the nucleophilic fluorinating reagent, wherein the nucleophilic substitution reaction of the aromatic ring compound is carried out under the action of the nucleophilic fluorinating reagent to obtain a fluorinated product, and the reaction formula is as follows:
wherein, the A ring is a five-membered aromatic ring or a six-membered aromatic ring
X is Cl or Br.
Preferably, the molar ratio of the nucleophilic fluoride reagent to the aromatic ring compound is 1-3: the nucleophilic substitution reaction is carried out in a solvent system, and the solvent is one of an organic amide solvent and an organic ether solvent.
Preferably, the nucleophilic substitution reaction time is 5-10 hours, and the reaction temperature range is 20-50 DEG o C。
More preferably, the organic amide solvent is one of N, N-dimethylacetamide, N-dimethylformamide and N-methylpyrrolidone.
Compared with the prior art, the invention has the advantages that:
(1) the nucleophilic fluoride reagent of the invention has convenient preparation and low production cost.
(2) The nucleophilic fluoride reagent synthesized by the invention has good solubility in an organic solvent, and cannot generate Hofmann elimination under heating, so that the heating stability is good, and the water in the fluoride reagent can be efficiently removed by using a reflux water diversion method.
(3) The nucleophilic fluorinating reagent synthesized by the invention has wide application range, and most of aromatic ring halides can be fluorinated.
Drawings
FIG. 1 shows a fluorinating agent I in example 1 of the present invention 1 HNMR map of (a).
FIG. 2 shows a fluorinating agent I in example 1 of the present invention 1 FNMR map of (a).
FIG. 3 shows a fluorinating agent I in example 2 of the present invention 2 HNMR map of (a).
FIG. 4 shows a fluorinating agent I in example 2 of the present invention 2 FNMR map of (a).
FIG. 5 shows a fluorinating agent I in example 3 of the present invention 3 HNMR map of (a).
FIG. 6 shows a fluorinating agent I in example 3 of the present invention 3 FNMR map of (a).
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
Example 1
A synthesis process of nucleophilic fluoride reagent comprises the following steps:
(1) preparation of intermediate II 1
A5L three-necked flask equipped with a stirrer was charged with 180g (1.5 mol) of ethyl isobutyrate and 800mL of tetrahydrofuran, the nitrogen gas was replaced three times, and the temperature was reduced to 5 o C, slowly adding lithium diisopropylamide LDA (2.0M in THF, 850mL) dropwise, after adding, 5 o C stirring for 1 hour, then dropwise adding 1-iodohexane (318 g), and after the addition is finished, heating to 15 DEG o C, reacting for 12 hours; the reaction was concentrated to remove tetrahydrofuran, water and ethyl acetate were sequentially added, liquid separation was performed, the organic phase was concentrated, and then distillation under reduced pressure was performed to obtain 265g of a pale yellow oily liquid with a yield of 91%.
(2) Preparation of intermediate III 1
265g (1.35 mol) of intermediate II are introduced into a 3L three-necked flask with stirring 1 900mL of methanol, 550mL of water and 108g (2.7 mol) of sodium hydroxide, replacing nitrogen, and raising the temperature to 65 o C, stirring for 6 hours; cooling to 40 deg.C after reaction, concentrating to remove methanol, adding water and methyl tert-butyl ether, and separatingAnd adjusting the pH of a water phase to 3 by hydrochloric acid, extracting by using ethyl acetate, and concentrating an organic phase to obtain 213g of light yellow oily liquid, wherein the yield is 92%, and a crude product is directly put into the next reaction without purification.
(3) Preparation of intermediate IV 1
213g (1.24 mol) of intermediate III are introduced into a 2L three-necked flask with magnetic means 1 737g (5.0 eq) of thionyl chloride, nitrogen was replaced, and the temperature was raised to 80 o C, stirring for 1 hour; cooling to 40 deg.C, concentrating to remove thionyl chloride, adding 2100mL of dichloromethane, transferring to 5L three-necked flask, replacing nitrogen, cooling to 5 deg.C o C, 320g (2.0 eq) of diisopropylethylamine was added slowly, then dimethylamine (2.0M in THF, 1240 mL) was added dropwise, and after addition, the temperature was raised to 20 deg.C o C, stirring for 15 hours; after the reaction, concentrating to remove the organic solvent, adding 1500mL of dichloromethane, adjusting the pH to 1 with 1N hydrochloric acid, separating, and concentrating the organic phase to obtain 241g of brown oily liquid, wherein the yield is 98%, and the crude product is directly put into the next reaction without purification.
(4) Preparation of intermediate V 1
241g (1.21 mol) of intermediate IV was added to a 3L three-necked flask with a stirrer 1 And 1250mL of toluene, replacing nitrogen, cooling to 5 ℃, slowly adding red aluminum (70% toluene solution, 699g, 2.0 eq) dropwise, heating to 60 ℃ after the addition is finished o C, stirring for 2 hours; after the reaction is finished, cooling to 5 ℃, dropwise adding a sodium hydroxide aqueous solution to quench the reaction, stirring and separating liquid, and concentrating an organic phase to obtain 215g of brown oily liquid; the crude product was dissolved in 5L of ethyl acetate, 226g of oxalic acid dihydrate, 20g o C stirring for 2h, filtering, transferring the filter cake to a 5L three-necked bottle, adding 1L water, and cooling to 5L o And C, adjusting the pH value to 9 by using an aqueous sodium hydroxide solution, extracting by using 1.5L of ethyl acetate, and concentrating an organic phase to obtain 204g of light yellow oily liquid, wherein the yield is 92%, and the crude product is directly put into the next reaction without purification.
(5) Preparation of intermediate VI 1
204g (1.1 mol) of intermediate V are introduced into a 3L three-necked flask with stirring 1 And 1200mL of toluene, the nitrogen gas was replaced, and 152g (1.1 eq) of sulfuric acid bis (ether)Methyl ester, heating to 110 deg.C o C, stirring for 20 hours; after the reaction is finished, the temperature is reduced to 80 DEG o And C, adding 21.8g (1.1 eq) of water to quench the reaction, keeping the temperature, stirring for 6 hours, concentrating to obtain 330g of oily liquid, wherein the yield is 100 percent, and the crude product is directly put into the next reaction without purification.
(6) Preparation of intermediate VII 1
To a 5L three-necked flask with stirring apparatus was added 330g (1.1 mol) of intermediate VI 1 And 660mL of water, replacing nitrogen, and raising the temperature to 40 o C, dissolving barium hydroxide octahydrate (381 g, 1.1 eq) in 4100mL of water, slowly dripping into the three-mouth bottle with 5L, stirring for 24 hours after adding, and then cooling to 10 DEG o And C, filtering, and directly putting the filtrate into the next reaction.
(7) Preparation of fluorination reagent I 1
Intermediate VII mentioned above 1 The filtrate was transferred to a 5L three-necked flask equipped with a stirrer, the pH was adjusted to 6.5 with hydrofluoric acid (40% aqueous solution), and the filtrate was concentrated and removed of water to obtain 214g of an off-white solid, and the yield in the two steps of step (6) and step (7) was 89%.
Step (7) fluorination reagent I 1 The nuclear magnetic structure identification results are as follows:
1HNMR(DMSO-d6，400MHz) δ ppm 3.27 (s, 2H), 3.13 (s, 9H), 1.35-1.16 (m, 10H), 1.08 (s, 6H), 0.84 (t, J=20Hz, 3H)。
example 2
A process for synthesizing nucleophilic fluoride reagent includes the following steps:
(1) preparation of intermediate II 2
A5L three-necked flask equipped with a stirrer was charged with 180g (1.5 mol) of ethyl isobutyrate and 800mL of tetrahydrofuran, the nitrogen gas was replaced three times, and the temperature was reduced to 5 o C, LDA (2.0M in THF, 850mL) was slowly added dropwise, 5 o C stirring for 1 hour, then dropwise adding bromododecane (374 g), heating to 20 ℃ after the addition is finished o C, reacting for 13 hours; the reaction was concentrated to remove tetrahydrofuran, water and ethyl acetate were sequentially added, liquid separation was performed, the organic phase was concentrated, and distillation under reduced pressure was performed to obtain 372g of a pale yellow oily liquid with a yield of 87%.
(2) Preparation of intermediate III 2
To a 3L three-necked flask with stirring was added 372g (1.3 mol) of intermediate II 2 1800mL of methanol, 370mL of water and 104g (2.6 mol) of sodium hydroxide, replacing nitrogen, and increasing the temperature to 60 o C, stirring for 6 hours; after the reaction is finished, the temperature is reduced to 40 ℃, methanol is removed by concentration, water and methyl tert-butyl ether are added, liquid separation is carried out, the pH of an aqueous phase is adjusted to 3 by hydrochloric acid, ethyl acetate is used for extraction, an organic phase is concentrated to obtain 294g of light yellow oily liquid, the yield is 88%, and a crude product is directly put into the next reaction without purification.
(3) Preparation of intermediate IV 2
294g (1.15 mol) of intermediate III are added to a 2L three-necked flask with magnetic means 2 684g (5.0 eq) of thionyl chloride, nitrogen is replaced, the temperature is raised to 80 o C, stirring for 1 hour; cooling to 40 deg.C, concentrating to remove thionyl chloride, adding 1800mL of dichloromethane, transferring to 5L three-necked flask, replacing nitrogen, cooling to 5 deg.C o C, 296g (2.0 eq) of diisopropylethylamine was slowly added, then dimethylamine (2.0M in THF, 1150 mL) was added dropwise, and after the addition was complete, the temperature was raised to 20 deg.C o C, stirring for 16 hours; after the reaction, the mixture is concentrated to remove the organic solvent, 1600mL of dichloromethane is added, the pH value is adjusted to 1 by 1N hydrochloric acid, liquid separation is carried out, the organic phase is concentrated to obtain 311g of brown oily liquid, the yield is 95%, and the crude product is directly put into the next reaction without purification.
(4) Preparation of intermediate V 2
311g (1.1 mol) of intermediate IV was added to a 3L three-necked flask with stirring 2 And 1500mL of toluene, replacing nitrogen, cooling to 5 ℃, slowly adding red aluminum (70% toluene solution, 635g, 2.0 eq) dropwise, and after the addition is finished, heating to 60 DEG o C, stirring for 2 hours; after the reaction is finished, cooling to 5 ℃, dropwise adding a sodium hydroxide aqueous solution to quench the reaction, stirring and separating the solution, and concentrating the organic phase to obtain 290g of brown oily liquid; dissolving the crude product with 5L ethyl acetate, adding 139g oxalic acid dihydrate, 20-30 o C stirring for 2h, filtering, transferring the filter cake to a 5L three-necked bottle, adding 1.2L water, and cooling to 5% o C, adjusting the pH to 9 with aqueous sodium hydroxide solution, and extracting with 1.5L ethyl acetateThe organic phase was concentrated to give 257g of a pale yellow oily liquid, yield: 87 percent, the crude product is directly put into the next reaction without purification.
(5) Preparation of intermediate VI 2
257g (0.95 mol) of intermediate V are introduced into a 3L three-necked flask with stirring 2 And 1100mL of toluene, the nitrogen gas was replaced, 132g (1.1 eq) of dimethyl sulfate was added, and the temperature was raised to 110 o C, stirring for 18 hours; after the reaction is finished, the temperature is reduced to 80 DEG o And C, adding 18.8g (1.1 eq) of water to quench and react, keeping the temperature, stirring for 6 hours, concentrating to obtain 375g of oily liquid, obtaining the yield of 100 percent, and directly putting the crude product into the next reaction without purification.
(6) Preparation of intermediate VII 2
To a 5L three-necked flask with stirring apparatus was added 375g (0.95 mol) of intermediate VI 2 And 660mL of water, replacing nitrogen, and raising the temperature to 40 DEG o C, dissolving barium hydroxide octahydrate (329 g, 1.1 eq) in 3700mL of water, slowly dripping into the 5L three-necked bottle, stirring for 21 hours after the addition is finished, and then cooling to 10 DEG o And C, filtering, and directly putting the filtrate into the next reaction.
(7) Preparation of fluorination reagent I 2
Intermediate VII mentioned above 2 The filtrate was transferred to a 5L three-necked flask equipped with a stirrer, the pH was adjusted to 6.5 with hydrofluoric acid (40% aqueous solution), and concentration and water removal were carried out to obtain 249g of an off-white solid, and the yield in the two steps of step (6) and step (7) was 87%.
Step (7) fluorination reagent I 2 The nuclear magnetic structure identification result of (1) is as follows:
1HNMR(DMSO-d6，400MHz) δ ppm 3.25 (s, 2H), 3.12 (s, 9H), 1.35-1.15 (m, 22H), 1.06 (s, 6H), 0.82 (t, J=20Hz, 3H)。
example 3
A synthesis process of nucleophilic fluoride reagent comprises the following steps:
(1) preparation of intermediate II 3
Adding 180g (1.5 mol) ethyl isobutyrate and 800mL tetrahydrofuran into a 5L three-necked flask with a stirring device, replacing nitrogen for three times, and cooling to room temperature5 o C, LDA (2.0M in THF, 850mL) was slowly added dropwise, 5 o C stirring for 1 hour, then dropwise adding benzyl bromide (265 g), and after the addition is finished, heating to 10 DEG o C, reacting for 12 hours; the reaction was concentrated to remove tetrahydrofuran, water and ethyl acetate were added in sequence, the liquid was separated, the organic phase was concentrated to give 319g of a pale yellow oily liquid with a yield of 83%, the crude product was directly subjected to the next reaction without purification.
(2) Preparation of intermediate III 3
319g (1.5 mol) of intermediate II are added to a 5L three-necked flask with stirring 3 2200mL of methanol, 45mL of water and 180g (4.5 mol) of sodium hydroxide, replacing nitrogen, and raising the temperature to 60 o C, stirring for 14 hours; after the reaction is finished, the temperature is reduced to 40 ℃, methanol is removed by concentration, water and methyl tert-butyl ether are added, liquid separation is carried out, the pH value of a water phase is adjusted to 3 by hydrochloric acid, ethyl acetate is used for extraction, an organic phase is concentrated to obtain 222g of light yellow oily liquid, the yield is 83%, and a crude product is directly put into the next reaction without purification.
(3) Preparation of intermediate IV 3
222g (1.2 mol) of intermediate III are introduced into a 2L three-necked flask with magnetic means 3 And 713g (5.0 eq) of thionyl chloride, displacing the nitrogen, heating to 80 o C, stirring for 1 hour; cooling to 40 deg.C, concentrating to remove thionyl chloride, adding 2200mL of dichloromethane, transferring to 5L three-necked flask, replacing nitrogen, cooling to 0-10 o C, slowly adding 310g (2.0 eq) of diisopropylethylamine, then dropwise adding dimethylamine (2.0M in THF, 1200 mL), heating to 20 o C, stirring for 19 hours; after the reaction, the mixture was concentrated to remove the organic solvent, then 1500mL of dichloromethane was added, the pH was adjusted to 1 with 1N hydrochloric acid, the mixture was separated, and the organic phase was concentrated to obtain 246g of a brownish red oily liquid with a yield of 100%, and the crude product was directly used in the next reaction without purification.
(4) Preparation of intermediate V 3
To a 3L three-necked flask with stirring was added 246g (1.2 mol) of intermediate IV 3 And 1250mL of toluene (nitrogen was replaced, the temperature was reduced to 0-10 ℃ C., and red aluminum (70% toluene solution, 693g, 2.0 eq) was slowly added dropwise thereto, and then the volume was increasedThe temperature is up to 60 DEG o C, stirring for 1 hour; after the reaction is finished, cooling to 5 ℃, dropwise adding a sodium hydroxide aqueous solution to quench the reaction, stirring and separating the solution, and concentrating the organic phase to obtain 270g of brownish red oily liquid; the crude product was dissolved in 5L of ethyl acetate, 226g of oxalic acid dihydrate, 20g o C stirring for 2 hours, filtering, transferring a filter cake to a 5L three-necked bottle, adding 1L of water, and cooling to 5L o C, pH adjusted to 9 with aqueous sodium hydroxide solution, extracted with 1.5L ethyl acetate and the organic phase concentrated to give 207g of a pale yellow oily liquid, yield: 90 percent, the crude product is directly put into the next reaction without purification.
(5) Preparation of intermediate VI 3
Into a 3L three-necked flask equipped with a stirring device was charged 207g (1.08 mol) of intermediate V 3 And 1400mL of toluene, replacing nitrogen, adding 150g (1.1 eq) of dimethyl sulfate, and heating to 110% o C, stirring for 20 hours; after the reaction is finished, the temperature is reduced to 80 DEG o And C, adding 21.3g (1.1 eq) of water to quench and react, keeping the temperature, stirring for 7 hours, concentrating to obtain 370g of oily liquid, wherein the yield is 100%, and the crude product is directly put into the next reaction without purification.
(6) Preparation of intermediate VII 3
370g (1.08 mol) of intermediate VI are introduced into a 5L three-necked flask with stirring 3 And 700mL of water, replacing nitrogen, and raising the temperature to 40 o C, dissolving barium hydroxide octahydrate (374 g, 1.1 eq) in 4000mL of water, slowly dripping into the 5L three-neck bottle, stirring for 24 hours after the addition is finished, and then cooling to 10 DEG o And C, filtering, and directly putting the filtrate into the next reaction.
(7) Preparation of fluorination reagent I 3
Intermediate VII mentioned above 3 The filtrate was transferred to a 5L three-necked flask equipped with a stirrer, the pH was adjusted to 6 to 7 with hydrofluoric acid (40% aqueous solution), and the mixture was concentrated and removed of water to obtain 219g of an off-white solid, and the yield in the two steps of step (6) and step (7) was 90%.
Step (7) fluorination reagent I 3 The nuclear magnetic structure identification results are as follows:
1HNMR(DMSO-d6，400MHz) δ ppm 7.33-7.15 (m, 5H), 3.40 (s, 2H), 3.21 (s, 9H), 2.69 (s, 2H), 1.07 (s, 6H)。
example 4
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 21.9g (0.1 mol) of the above-mentioned fluorination reagent I 1 And 220mL of toluene, refluxing for 20-24h until the water content is less than 0.05%, concentrating, removing toluene, adding 50mL of DMF and 6.8g (0.05 mol) of 4-chlorobenzonitrile, replacing nitrogen, and replacing by 20 o C is stirred for 5 hours, after the reaction is finished, water and methyl tert-butyl ether are added, liquid separation is carried out by stirring, an organic phase is washed by water, and the organic phase is concentrated to obtain 5.2g of yellowish liquid 4-fluorobenzonitrile with the yield of 86%.
Example 5
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 21.9g (0.1 mol) of the above-mentioned fluorination reagent I 1 And 220mL of toluene, refluxing for water separation for 20-24h until the water content is less than 0.05%, concentrating, removing toluene, adding 50mL of DMF and 9.1g (0.05 mol) of 4-bromoxynil, replacing nitrogen, and replacing 20g of nitrogen o C is stirred for 5 hours, after the reaction is finished, water and methyl tert-butyl ether are added, liquid separation is carried out by stirring, an organic phase is washed by water, and the organic phase is concentrated to obtain 5.4g of yellowish liquid 4-fluorobenzonitrile, wherein the yield is as follows: and 90 percent.
Example 6
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 21.9g (0.1 mol) of the above-mentioned fluorination reagent I 1 And 220mL of toluene, refluxing, water-separating for 20-24h until the water content is less than 0.05%, concentrating, removing toluene, adding 50mL of DMF and 9.6g (0.05 mol) of 4-bromo-2-chloropyridine, replacing nitrogen, and heating to 40 deg.C o C, stirring for 6 hours, finishing the reaction, and cooling to 20 DEG o And C, adding water and methyl tert-butyl ether, stirring, separating liquid, washing an organic phase with water, and concentrating the organic phase to obtain 8.0g of light yellow liquid 4-bromo-2-fluoropyridine, wherein the yield is as follows: 92 percent.
Example 7
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 30.3g (0.1 mol) of the fluorination reagent I 2 And 240mL of toluene, refluxDividing water for 20-24h until the water content is less than 0.05%, concentrating, removing toluene, adding 80mL DMF and 6.8g (0.05 mol) 4-chlorobenzonitrile, replacing nitrogen, 20 o C, stirring for 5 hours, finishing the reaction, adding water and methyl tert-butyl ether, stirring, separating liquid, washing an organic phase with water, and concentrating the organic phase to obtain 5.0g of yellowish liquid 4-fluorobenzonitrile, wherein the yield is as follows: 83 percent.
Example 8
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 30.3g (0.1 mol) of the above-mentioned fluorination reagent I 2 And 240mL of toluene, refluxing for water separation for 20-24h until the water content is less than 0.05%, concentrating, removing the toluene, adding 80mL of DMF and 9.6g (0.05 mol) of 4-bromo-2-chloropyridine, replacing nitrogen, and heating to 40 deg.C o C, stirring for 6 hours, finishing the reaction, and cooling to 20 DEG o And C, adding water and methyl tert-butyl ether, stirring, separating liquid, washing an organic phase with water, and concentrating the organic phase to obtain 7.6g of light yellow liquid 4-bromo-2-fluoropyridine, wherein the yield is as follows: 87 percent.
Example 9
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 22.5g (0.1 mol) of the above-mentioned fluorination reagent I 3 And 225mL of toluene, refluxing for 20-24h until the water content is less than 0.05%, concentrating, removing toluene, adding 56mL of DMF and 6.8g (0.05 mol) of 4-chlorobenzonitrile, replacing nitrogen, 20 o C is stirred for 5 hours, after the reaction is finished, water and methyl tert-butyl ether are added, liquid separation is carried out by stirring, an organic phase is washed by water, and the organic phase is concentrated to obtain 5.3g of yellowish liquid 4-fluorobenzonitrile, wherein the yield is as follows: 88 percent.
Example 10
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 22.5g (0.1 mol) of the fluorination reagent I described above 3 And 225mL of toluene, refluxing for 20-24h until the water content is less than 0.05%, concentrating, removing toluene, adding 56mL of DMF and 9.6g (0.05 mol) of 4-bromo-2-chloropyridine, replacing nitrogen, and heating to 40 deg.C o C, stirring for 6 hours, finishing the reaction, and cooling to 20 DEG o C, adding water and methyl tert-butyl ether, stirring, separating, and washing organic phase with waterThe organic phase was concentrated to give 7.9g of 4-bromo-2-fluoropyridine as a pale yellow liquid, in yield: 91 percent.
Example 11
The application of the nucleophilic fluorinating reagent comprises the following steps:
a500 mL three-necked flask was charged with 22.5g (0.1 mol) of the above-mentioned fluorination reagent I 3 And 225mL of toluene, refluxing for 20-24h until the water content is less than 0.05%, concentrating, removing toluene, adding 56mL of DMF and 16.3g (0.05 mol) of 2-chloroquinoline, displacing nitrogen, and heating to 45% o C, stirring for 6 hours, finishing the reaction, and cooling to 20 DEG o And C, adding water and methyl tert-butyl ether, stirring, separating liquid, washing an organic phase with water, concentrating the organic phase, and recrystallizing and purifying a crude product by using ethyl acetate and n-heptane to obtain 11.7g of white solid 2-fluoroquinoline, wherein the yield is as follows: 80 percent.
In addition to the above embodiments, the present invention also includes other embodiments, and any technical solutions formed by equivalent transformation or equivalent replacement should fall within the scope of the claims of the present invention.
Claims (10)
1. A nucleophilic fluoride reagent, characterized by: the structure is as follows:
wherein R is alkyl or aryl.
2. A process for the synthesis of nucleophilic fluoride reagent according to claim 1, wherein: the reaction formula is as follows:
the method comprises the following steps:
(1) under the action of alkaline substances, ethyl isobutyrate is used as a starting material and reacts with halogenated hydrocarbon to obtain an intermediate II;
(2) hydrolyzing the intermediate II under the action of an alkaline substance to obtain an intermediate III;
(3) under the action of a condensing agent, condensing the intermediate III and dimethylamine to obtain an intermediate IV;
(4) the intermediate IV is reduced into an intermediate V under the action of a reducing agent;
(5) reacting the intermediate V with dimethyl sulfate to obtain quaternary ammonium salt VI;
(6) performing ion exchange on the quaternary ammonium salt VI and barium hydroxide to generate an intermediate VII;
(7) and neutralizing the intermediate VII and hydrofluoric acid with acid and base to obtain the fluorination reagent I.
3. The process for the synthesis of nucleophilic fluoride reagent according to claim 2, wherein: in the step (1), the alkaline substance is one of n-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and sodium hydride.
4. The process for the synthesis of nucleophilic fluoride reagents of claim 2, wherein: in the step (1), the halide is one of benzyl bromide, benzyl chloride, p-methoxy benzyl bromide, p-methoxy benzyl chloride, 1-iodohexane, 1-bromohexane, 1-bromooctane, 1-bromodecane and 1-bromododecane.
5. The process for the synthesis of nucleophilic fluoride reagents of claim 2, wherein: in the step (2), the alkaline substance is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.
6. The process for the synthesis of nucleophilic fluoride reagents of claim 2, wherein: in the step (3), the condensing agent is one of thionyl chloride, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-propylphosphoric anhydride.
7. The process for the synthesis of nucleophilic fluoride reagents of claim 2, wherein: in the step (4), the reducing agent is one of lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride and red aluminum.
8. The process for the synthesis of nucleophilic fluoride reagents of claim 2, wherein: the step (1), the step (2), the step (3), the step (4), the step (5), the step (6) and the step (7) are all carried out in a solvent system, the solvent in the step (1) is an organic amide solvent or an organic ether solvent, the solvent in the step (2) is a mixed solvent of water and an organic alcohol solvent, the solvent in the step (3) is dichloromethane, toluene or an organic ether solvent, the solvent in the step (4) is dichloromethane, toluene or an organic ether solvent, the solvent in the step (5) is toluene or an organic ether solvent, the solvent in the step (6) is water or an organic alcohol solvent, and the solvent in the step (7) is water or an organic alcohol solvent.
9. Use of the nucleophilic fluoride reagent of claim 1, wherein: the aromatic ring compound is subjected to nucleophilic substitution reaction under the action of a nucleophilic fluorinating reagent to obtain a fluorinated product, wherein the reaction formula is as follows:
wherein, the A ring is a five-membered aromatic ring or a six-membered aromatic ring
And X is Cl or Br.
10. Use of nucleophilic fluoride reagent according to claim 9, characterized in that: the molar ratio of the nucleophilic fluoride reagent to the aromatic ring compound is 1-3: the nucleophilic substitution reaction is carried out in a solvent system, and the solvent is one of organic amide solvents and organic ether solvents.
Priority Applications (1)
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| CN117486728A (en) * | 2023-12-28 | 2024-02-02 | 山东国邦药业有限公司 | Efficient circulating fluorination reagent and preparation method and application thereof |
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