CN116143652A - Alfosa intermediate and preparation method and application thereof - Google Patents
Alfosa intermediate and preparation method and application thereof Download PDFInfo
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- CN116143652A CN116143652A CN202310199887.0A CN202310199887A CN116143652A CN 116143652 A CN116143652 A CN 116143652A CN 202310199887 A CN202310199887 A CN 202310199887A CN 116143652 A CN116143652 A CN 116143652A
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- glycine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 55
- 238000006243 chemical reaction Methods 0.000 claims description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- -1 glycine ester Chemical class 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 23
- 239000004471 Glycine Substances 0.000 claims description 23
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 230000009471 action Effects 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- 150000002825 nitriles Chemical class 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 150000003462 sulfoxides Chemical class 0.000 claims description 6
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 150000002443 hydroxylamines Chemical class 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- HTMQZWFSTJVJEQ-UHFFFAOYSA-N benzylsulfinylmethylbenzene Chemical compound C=1C=CC=CC=1CS(=O)CC1=CC=CC=C1 HTMQZWFSTJVJEQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 2
- NEHMKBQYUWJMIP-OUBTZVSYSA-N chloromethane Chemical group Cl[13CH3] NEHMKBQYUWJMIP-OUBTZVSYSA-N 0.000 claims description 2
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000007787 solid Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000007810 chemical reaction solvent Substances 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001819 mass spectrum Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- 230000003321 amplification Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000003199 nucleic acid amplification method Methods 0.000 description 7
- 238000004321 preservation Methods 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- ZTUJDPKOHPKRMO-UHFFFAOYSA-N hydron;2,2,2-trifluoroethanamine;chloride Chemical compound Cl.NCC(F)(F)F ZTUJDPKOHPKRMO-UHFFFAOYSA-N 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 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 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VLQHNAMRWPQWNK-UHFFFAOYSA-N benzyl 2-aminoacetate;hydron;chloride Chemical compound Cl.NCC(=O)OCC1=CC=CC=C1 VLQHNAMRWPQWNK-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000077 insect repellent Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical class CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UBKCIXXGQRZHRO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)OC(=O)CN UBKCIXXGQRZHRO-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 241000238421 Arthropoda Species 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-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
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940058878 nexgard Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly discloses an aforana intermediate and a preparation method thereof, and application of the intermediate in preparation of aforana medicaments, and the invention has the following beneficial effects: the synthesis raw materials are cheap and easy to obtain, the intermediate preparation condition is mild, the operation is safe, the environmental pollution is small, and the method is more suitable for industrialized mass production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an aforana intermediate, a preparation method thereof and application of the intermediate in preparation of aforana medicines.
Background
The new-generation oral in vitro insect repellent Nishi (NexGard) (common name: affrana chewing tablet) for dogs is the first oral insect repellent for dogs for killing two parasites, namely ticks and fleas. The Nishi belongs to the isoxazoline family, and is a revolutionary powerful pesticide by inhibiting GABA chloride ion channels to make arthropod nerves highly excited to death. Wherein the chemical name is 4- [5- [ 3-chloro-5- (trifluoromethyl) phenyl ] -4, 5-dihydro-5- (trifluoromethyl) -3-isoxazolyl ] -nitrogen- [ 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl ] -1-naphthacenecarboxamide, and the structural formula is as follows:
patent WO2009002809A2 discloses a method for preparing aforana, which has a long preparation route, a low yield and difficulty in purification due to the use of an insertion reaction in the presence of a catalyst in the final butt joint step, and fragments 1, 2 and 3 are not produced in a large amount in industry, and all require customization or self synthesis. Therefore, it is necessary to develop a new, more suitable, industrialized, lower cost method for preparing aforana.
Disclosure of Invention
In order to solve the problems of long preparation route, low yield and high cost of the Alfosa reaction in the prior art, the invention provides an Alfosa intermediate and a preparation method thereof.
The invention provides an intermediate, which has a structure shown in a formula (1)
R 1 Selected from H or C 1 -C 6 An alkyl group;
R 1 preferably H or C 1 -C 3 An alkyl group.
In some specific embodiments, the intermediate is selected from the following compounds:
the invention also provides a preparation method of the intermediate, which comprises the following steps:
reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
wherein R is 1 As defined above.
Further, the reaction of the compound of the formula a and the glycine ester derivative also comprises the activation by using a condensing agent, wherein the condensing agent is selected from CDI, DCC or EDCI; the temperature of activation with the condensing agent is 0-85 ℃, preferably 0-45 ℃, most preferably 15-25 ℃.
Further, the reaction of the compound of the formula a and the glycine ester derivative also comprises methane sulfonic acid, and the molar ratio of the methane sulfonic acid to the compound of the formula a is 2:1; the molar ratio of condensing agent to compound of formula a is (1-2): 1, preferably (1.2-1.6): 1; the molar ratio of the glycine ester derivative to the compound of formula a is (1-2): 1, preferably (1.2-1.6): 1.
Further, the glycine ester derivative is selected from glycine ethyl ester hydrochloride, glycine isopropyl ester hydrochloride or glycine benzyl ester hydrochloride; preferably glycine ethyl ester hydrochloride.
Further, the reaction solvent of the compound of the formula a and the glycine ester derivative is selected from halogenated alkanes, esters, ethers, sulfoxides or nitriles; preferably, the esters are selected from ethyl acetate, isopropyl acetate or butyl acetate; the ethers are selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane; the halogenated alkane is selected from chloromethane or dichloromethane; the sulfoxide is selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide; the nitriles are selected from acetonitrile or propionitrile; more preferably, the reaction solvent of the compound of formula a and glycine ester derivative is selected from dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide or acetonitrile.
Further, the reaction temperature of the compound of formula a and the glycine ester derivative is 0 to 85 ℃, preferably 20 to 80 ℃, more preferably 60 to 80 ℃, and even more preferably 70 to 80 ℃.
Further, the reaction time of the compound of formula a and the glycine ester derivative is 1-48h, preferably 1-24h.
The invention also provides a method for preparing aforana by using the intermediate, which comprises the following steps:
step 1: reacting the intermediate of the formula (1) with triethylamine hydrochloride to obtain an intermediate d;
step 2: intermediate d is reacted with 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one to afford intermediate e;
step 3: intermediate e reacts with hydroxylamine derivatives to obtain aforana.
Further, the condensing agent is selected from CDI, DCC or EDCI in the step 1.
Further, the molar ratio of the triethylamine hydrochloride to the intermediate of the formula (1) in the step 1 is (1-2): 1, preferably (1-1.4): 1.
Further, the reaction temperature in the step 1 is-10 to 20 ℃, preferably-10 to 10 ℃, more preferably-5 to 5 ℃.
Further, the reaction solvent of step 1 is selected from esters, ethers or haloalkanes as defined above, preferably the reaction solvent of step 1 is selected from dichloromethane, isopropyl acetate, acetonitrile or toluene.
Further, the reaction time of the step 1 is 1 to 48 hours, preferably 1 to 20 hours.
Further, the step 2 also comprises a base, wherein the base is selected from K 2 HPO 4 ·3H 2 O、K 3 PO 4 、Na 2 HPO 4 ·12H 2 O、Na 3 PO 4 Or CH (CH) 3 COONa, preferably Na 3 PO 4 The method comprises the steps of carrying out a first treatment on the surface of the The molar ratio of the base to the intermediate d is (0.1-2): 1, preferably (0.1-1.4): 1.
Further, the reaction solvent of step 2 is selected from the group consisting of amides, esters, aromatic hydrocarbons or nitriles, selected from the group consisting of formamide, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, N-dimethyl-2-imidazolidinone or hexamethylphosphoramide, the esters, aromatic hydrocarbons or nitriles being as defined above, preferably, the reaction solvent of step 2 is selected from the group consisting of N, N-dimethylformamide, isopropyl acetate, acetonitrile or toluene.
Further, the molar ratio of 2, 2-trifluoro-1- [ 3-chloro-5- (trifluoromethyl) phenyl ] ethanone to intermediate d in step 2 is (1-2): 1, preferably (1-1.4): 1.
Further, the reaction temperature of the step 2 is 90 ℃ or reflux reaction.
Further, the reaction time of the step 2 is 1 to 48 hours, preferably 3 to 27 hours.
Further, the step 3 also comprises a base, wherein the base is selected from NaOH and C 2 H 5 ONa、DBU、Na 2 CO 3 TEA or KOH, preferably DBU, naOH or KOH; the molar ratio of base to intermediate e is (2-4): 1, preferably (2.5-3.5): 1.
Further, the reaction solvent of step 3 is selected from ethers selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane, preferably tetrahydrofuran or 2-methyltetrahydrofuran.
Further, the hydroxylamine derivative in the step 3 is selected from hydroxylamine hydrochloride or hydroxylamine sulfate, preferably hydroxylamine hydrochloride, and the molar ratio of the hydroxylamine derivative to the intermediate e is (0.1-2): 1, preferably (0.5-1.4): 1.
Further, the reaction temperature of the step 3 is 0 to 80 ℃, preferably 5 to 60 ℃.
Further, the reaction time of the step 3 is 1 to 24 hours, preferably 3 to 21 hours.
In some specific embodiments, the method of preparing aforana further comprises the steps of: reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
when R is 1 When the compound is not H, the compound of the formula a is mixed with glycinateThe derivative reaction also comprises strong alkali, wherein the strong alkali is selected from NaOH, KOH or LiOH; the molar ratio of the strong base to the compound of formula a is (1-2): 1, preferably (1-1.5): 1;
further, the reaction of the compound of the formula a and the glycine ester derivative also comprises the activation by using a condensing agent, wherein the condensing agent is selected from CDI, DCC or EDCI; the temperature of activation with the condensing agent is 0-85 ℃, preferably 0-45 ℃, most preferably 15-25 ℃.
Further, the reaction of the compound of the formula a and the glycine ester derivative also comprises methane sulfonic acid, and the molar ratio of the methane sulfonic acid to the compound of the formula a is 2:1; the molar ratio of condensing agent to compound of formula a is (1-2): 1, preferably (1.2-1.6): 1; the molar ratio of the glycine ester derivative to the compound of formula a is (1-2): 1, preferably (1.2-1.6): 1.
Further, the glycine ester derivative is selected from glycine ethyl ester hydrochloride, glycine isopropyl ester hydrochloride or glycine benzyl ester hydrochloride; preferably glycine ethyl ester hydrochloride.
Further, the reaction solvent of the compound of the formula a and the glycine ester derivative is selected from halogenated alkanes, esters, ethers, sulfoxides or nitriles; preferably, the esters are selected from ethyl acetate, isopropyl acetate or butyl acetate; the ethers are selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane; the haloalkane is selected from dichloromethane; the sulfoxide is selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide; the nitriles are selected from acetonitrile or propionitrile; more preferably, the reaction solvent of the compound of formula a and glycine ester derivative is selected from dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide or acetonitrile.
Further, the reaction temperature of the compound of formula a and the glycine ester derivative is 0 to 85 ℃, preferably 20 to 80 ℃, more preferably 60 to 80 ℃, and even more preferably 70 to 80 ℃.
Further, the reaction time of the compound of formula a and the glycine ester derivative is 1-48h, preferably 1-24h.
In some specific embodiments, the method of preparing aforana comprises the steps of:
step 1: reacting a compound of the formula a with glycine ethyl ester hydrochloride under the action of methane sulfonic acid and CDI to obtain an intermediate b;
step 2: reacting the intermediate b with NaOH to obtain an intermediate c;
step 3: reacting the intermediate c with triethylamine hydrochloride under the action of CDI to obtain an intermediate d;
step 4: intermediate d and 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one in Na 3 PO 4 The reaction is carried out under the action of the catalyst to obtain an intermediate e;
step 5: intermediate e reacts with hydroxylamine hydrochloride under the action of NaOH to obtain the aforana.
The invention has the following beneficial effects:
(1) Compared with the prior art, the invention has the advantages that the reaction cost is obviously reduced, the 2-amino-N- (2, 2-trifluoroethyl) acetamide which is high in price (17250 yuan/kg) and difficult to self-prepare and purify is not required to be used as a material, the glycine ethyl ester hydrochloride (78-86.5 yuan/kg) and the trifluoroethylamine hydrochloride (1000-1500 yuan/kg) are used as materials, the cost is reduced to 10 percent of the prior art, the yield of the obtained aforana is higher than that of the prior art, the production cost is greatly reduced, and the method is more suitable for industrialized mass production.
(2) The experiment that the preparation condition of the intermediate is mild and the reaction batch is increased to the kilogram level proves that the invention overcomes the problem of incomplete raw material reaction caused by equipment amplification (amplification effect) by specifically adding methane sulfonic acid as a reaction reagent, has higher yield and purity of the intermediate, and is more suitable for industrial mass production.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
The structure of the compound is characterized by Mass Spectrum (MS) or nuclear magnetic resonance 1 HNMR).
Nuclear magnetic resonance 1 HNMR) displacement (δ) is given in parts per million (ppm); nuclear magnetic resonance 1 HNMR) was measured using a bruker avance-400 nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO) as the measuring solvent and Tetramethylsilane (TMS) as the internal standard.
The Mass Spectrum (MS) measuring instrument is Agilent LCMS 1200-6110.
In the case where no specific explanation is given to the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.
The term "room temperature" according to the invention means a temperature between 15℃and 35 ℃.
The term "amplification effect" according to the present invention refers to the results of studies carried out by chemical process experiments using small-sized equipment, which tend to differ greatly from the results obtained by large-sized production units under the same operating conditions, the effect of these differences being referred to as amplification effect.
The abbreviations for the reactants used in the examples of the present invention are explained in the following table:
example 1 preparation of intermediate b
Taking 1000mL of a three-necked flask, sequentially adding 800mL of acetonitrile and 100.0g of a under stirring, controlling the temperature within T to be 20+/-5 ℃, adding 106.0g of N, N' -carbonyldiimidazole in batches, obviously releasing heat, releasing a large amount of gas, carrying out heat preservation reaction for 1h, then controlling the temperature within 20+/-5 ℃ to drop 89.7g of methanesulfonic acid, and carrying out heat preservation stirring for 0.5h after the completion of the drop. 91.3g of glycine ethyl ester hydrochloride are then added in portions, the heat is obviously released, the temperature is raised to 75+/-5 ℃, the temperature is kept and stirred for 1h, and the standard is controlled in the middle: a is less than or equal to 3.0 percent. Cooling to the temperature of less than or equal to 60 ℃ in T, concentrating under reduced pressure until no obvious fraction exists, adding 400mL of dichloromethane and 300mL of water at room temperature, stirring for 0.5h, separating liquid, extracting aqueous phase by 200mL of CM, combining organic phases, washing sequentially by sodium chloride aqueous solution (25 g of sodium chloride+200 mL of water) and sodium bicarbonate aqueous solution (10 g of sodium bicarbonate+200 mL of water), separating liquid, concentrating the organic phase under reduced pressure at 50 ℃ to obtain 158.0g of brown-black oily substance, namely an intermediate b, directly adding the intermediate b into the next reaction step according to the yield of 100%, and carrying out the chromatographic purity of 97.50%. The resulting oil was detected by nuclear magnetic resonance and mass spectrometry.
1 H-NMR(400MHz，DMSO-d6)：δ9.14-9.11ppm(1H)，8.56-8.54ppm(1H)，8.32-8.29ppm(1H)，8.13ppm(1H)，7.69-7.62ppm(3H)，4.20ppm(2H)，4.10-4.07ppm(2H)，2.75ppm(3H)，1.27ppm(3H)。
EIMS m/z 300.2([M+H] + )。
The preparation method in example 1 was subjected to screening for the kind and amount of the solvent, the activation temperature and reaction temperature, the reaction time, and the amount of glycine ethyl ester hydrochloride (labeled a in the following table), and the screening results are shown in table 1:
TABLE 1 screening of reaction conditions for the preparation method of example 1
Note that: the "V" in the table represents the volume to mass ratio (mL/g) of the reaction solvent to compound a, e.g. DCM 8V means 1g of compound a, 8mL of DCM being added; the designation "eq" represents the molar ratio of reactant/material to compound a, e.g. CDI is used in an amount of 1.4eq, and means that the molar ratio of CDI to compound a is 1.4:1.
the reaction batch in example 1 was increased to kilogram level, a remarkable amplification effect was exhibited, the residue of the compound a was remarkably increased, and the addition of N, N' -Carbonyldiimidazole (CDI) and glycine ethyl ester hydrochloride had no remarkable effect, so that the type and amount of the solvent, the reaction temperature and the type of the acid were further screened, and the results are shown in Table 2.
TABLE 2 screening of reaction conditions in example 1 (kilogram scale reaction)
Note that: in the table, where "V" is the volume to mass ratio (mL/g) of the reaction solvent to compound a, for example DCM 4V means 1g of intermediate b, 4mL of DCM is added; the designation "eq" represents the molar ratio of reactant/material to compound a, e.g. CDI is used in an amount of 1.4eq, and means that the molar ratio of CDI to compound a is 1.4:1.
as shown in Table 2, when methanesulfonic acid is added, the purity of the intermediate b is greatly improved, the reaction rate is also obviously improved, and the addition of reagents of formic acid, glacial acetic acid and the like is ineffective, which indicates that methanesulfonic acid can obviously overcome the amplification effect brought by the amplification of reaction equipment, accelerate the reaction, lead the reaction of the raw material compound a to be complete, and obtain unexpected technical effects.
Example 2 preparation of intermediate c
Taking 1000ml single-mouth bottle, sequentially adding crude product of intermediate b and 400ml tetrahydrofuran, heating to T Inner part =50±5 ℃, and stirred until the solid is dissolved. The system is cooled to 15-35 ℃, sodium hydroxide aqueous solution (24.3 g sodium hydroxide and 100ml water) prepared in advance is added dropwise, the temperature is obviously raised, the reaction is carried out for 1h at room temperature after the dripping is finished, the HPLC monitoring and the center control standard are adopted: b is less than or equal to 1.0 percent.
130ml of diluted hydrochloric acid (6M/L) was added to the reaction mixture, the pH of the system was adjusted to 2 to 3, and the mixture was concentrated under reduced pressure at 50℃to remove most of tetrahydrofuran, whereby a large amount of solids was precipitated.
300ml of acetonitrile was added to the concentrate, and the temperature was raised to T Inner part =75±5 ℃, stirring at a constant temperature for 30min until the system is dissolved, and dripping 100mL of water. Heating is closed after heat preservation and stirring for 30min, naturally cooling to room temperature, and then ice bath is carried outCooling to T Inner part =5±5 ℃, stirring for 1h with heat preservation, filtering, leaching the filter cake with 100mL, drying under reduced pressure at 60 ℃ for 30h, and collecting 102.0g of light brown solid, the yield is 80.3%, and the chromatographic purity is 99.48%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)δ12.75ppm(1H)，9.03ppm(1H)，8.57-8.54ppm(1H)，8.34-8.32ppm(1H)，8.13ppm(1H)，7.69-7.61ppm(3H)，4.03ppm(2H)，2.75ppm(3H)。
EIMS m/z 272.4([M+H] + )。
The amount of sodium hydroxide, the reaction temperature and the reaction time were selected in example 2, and the results are shown in Table 3.
TABLE 3 screening of reaction conditions in example 2
Note that: the designation "eq" represents the molar ratio of reactant/material to compound a, for example 1.3eq for sodium hydroxide, and means a molar ratio of sodium hydroxide to compound a of 1.4:1.
as shown in Table 3, the purity of the intermediate c was higher (higher than 90%) under different conditions of sodium hydroxide usage, reaction temperature and reaction time, indicating that the above-mentioned changes in reaction conditions had no significant effect on the preparation of intermediate c.
Example 3 preparation of intermediate d
Taking 1000mL three-necked flask, sequentially adding 190mL N, N-dimethylformamide and 95.0g of intermediate c under stirring, and cooling to T in an ice bath Inner part =5±5 ℃. 79.5g of N, N' -carbonyldiimidazole are added in portions, and the temperature T is controlled Inner part No significant exotherm was observed, but significant gas evolution was observed, =5±5℃. After the addition is finished, keep T Inner part =5±5 ℃ for 3h. Then 57.0g of trifluoroethylamine hydrochloride is added in batches, the temperature is obviously raised, and the temperature T is controlled Inner part =5±5 ℃. After the addition is finished, keep T Inner part =5±5 ℃ for 3h, center control standard: c is less than or equal to 4.0 percent.
Naturally heating the reaction system to T Inner part Adding aqueous potassium carbonate solution (9.5 g of potassium carbonate+380 mL of water) into the reaction solution, precipitating a large amount of yellow solid, stirring for 1h at a temperature of 20 ℃ C., cooling to T in an ice bath Inner part Keep temperature and stir for 1h =5±5℃. Filtration (difficult filtration) and the filter cake was rinsed with 50mL of water to give M3 wet product.
190mL of acetonitrile is added into the crude product, and the temperature is raised to T Inner part The reaction system was stirred at 75±5 ℃ for 1 hour with heat preservation, and the solid was not dissolved in the reaction system. An aqueous potassium carbonate solution (4.75 g of potassium carbonate+190 mL of water) was added dropwise to the reaction system at a constant temperature, and the solid in the system remained undissolved after the addition. Closing heating, naturally cooling to room temperature, and cooling to T in ice bath Inner part =5±5 ℃, and stirred for 1h with heat preservation. Filtering, leaching the filter cake with 95mL of water, and vacuum drying at 60 ℃ for 48h, and obtaining 109.0g of the obtained product with the yield of 88.6% and the chromatographic purity of 99.35%, namely the intermediate d. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)：δ8.95(1H)，8.72ppm(1H)，8.56-8.53ppm(1H)，8.37-8.34ppm(1H)，8.12ppm(1H)，7.70-7.61ppm(3H)，4.05-3.99ppm(4H)，2.75ppm(3H)。
EIMS m/z 353.3([M+H] + )。
The amount of sodium hydroxide, the reaction temperature, the reaction time and the amount of trifluoroethylamine hydrochloride (labeled B in the following table) used in example 3 were selected, and the results of the selection are shown in Table 4.
TABLE 4 screening of reaction conditions in example 3
Note that: in the table, the "V" is the volume to mass ratio (mL/g) of the reaction solvent to intermediate c, for example DMF 5V, representing 1g of intermediate c, 5mL of DMF being added; the designation "eq" represents the molar ratio of reactant/material to intermediate c, e.g. CDI is used in an amount of 1.4eq, and means that the molar ratio of CDI to intermediate c is 1.4:1.
as shown in Table 4, the purity of the intermediate d was higher under the conditions of different amounts of sodium hydroxide, reaction temperature, reaction time and amount of triethylamine hydrochloride, which indicated that the above-mentioned changes in reaction conditions had no significant effect on the preparation of the intermediate c.
Example 4 preparation of intermediate e
1000mL of a three-necked flask was taken, and a thermometer, a water separator and a nitrogen gas protector were added thereto, followed by sequentially adding 400mL of acetonitrile, 100g of d, 94.2g of 2, 2-trifluoro-1- [ 3-chloro-5- (trifluoromethyl) phenyl group]After three times of substitution of ethyl ketone and 28g of sodium phosphate and nitrogen, the temperature is raised to T Inner part Reflux reaction for 21h at 80-83 ℃, system cooling to 50 ℃, concentrating and removing most acetonitrile.
600ml of methyl tert-butyl ether and 200ml of water were added to the concentrate for extraction, the mixture was allowed to stand for demixing, the aqueous phase was extracted with 100ml of methyl tert-butyl ether, the organic phases were combined and washed with 100ml of water. The organic phase was concentrated under reduced pressure at 50 ℃ to give a tan solid. 200ml of acetonitrile was added to the concentrate, and the temperature was raised to T Inner part Dissolving at 75+/-5 ℃, dropwise adding 100ml of water at the temperature, and stirring for 0.5h after the dripping is finished. Closing heating, naturally cooling to room temperature, and cooling to T in ice bath Inner part =5±5 ℃, and stirred for 1h with heat preservation. The filter cake was filtered and rinsed with 50ml of x 3 water. Vacuum drying at 60deg.C for 19h, collecting 143.0g pale yellow solid, namely intermediate e, with a yield of 82.7% and a chromatographic purity of 94.12%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)：δ8.90ppm(1H)，8.73ppm(1H)，8.40-8.37ppm(1H)，8.35-8.31ppm(1H)，8.18ppm(1H)，7.915、7.912ppm(1H)，7.82ppm(1H)，7.72ppm(1H)，7.68-7.60ppm(4H)，4.05-3.96ppm(4H)。
EIMS m/z 610.9([M+H] + )。
The type and equivalent of the base, the reaction solvent, the amount of 2, 2-trifluoro-1- [ 3-chloro-5- (trifluoromethyl) phenyl ] ethanone (labeled C in the table) and the reaction time in example 4 were selected, and the results are shown in Table 5.
TABLE 5 screening of reaction conditions in example 4
Note that: in the table, the "V" is the volume to mass ratio (mL/g) of the reaction solvent to intermediate d, for example, DMF 4V indicates that 1g of intermediate d is to be added with 4mL of DMF; the designation "eq" represents the molar ratio of reactant/material to intermediate d, for example 1.4eq for the amount of base, and means a molar ratio of base to intermediate d of 1.4:1.
as shown in Table 5, the choice of solvent and base in this step has a certain effect on the purity of intermediate e, where Na 3 PO 4 When acetonitrile is used as a solvent, the purity of the intermediate e is the highest, and the intermediate e is the most preferable.
EXAMPLE 5 preparation of Alfosan
A2000 ml three-necked flask was taken, 390ml of tetrahydrofuran and 130.0g of intermediate e were sequentially added thereto, and the mixture was dissolved by stirring at room temperature. Cooling in ice bath to T Inner part Slowly adding hydroxylamine hydrochloride aqueous solution (20.7 g hydroxylamine hydrochloride+260 ml water) at a temperature of =5+ -5deg.C, heating to a temperature of significantly controlled temperature T Inner part =5±5 ℃. Slowly dropwise adding sodium hydroxide aqueous solution (23.8 g sodium hydroxide+130 ml water) after the addition, obviously heating, and controlling the temperature T Inner part =5±5 ℃. After the addition was completed, the reaction was stirred for 3 hours and monitored by HPLC.
6N diluted hydrochloric acid (90 ml) was slowly added to the reaction mixture, the pH was 1-3 after the addition, and then 520ml MTBE was added for extraction, and the mixture was allowed to stand for delamination. The aqueous phase was extracted with 260ml of MTBE and the organic phases were combined and washed with 260ml of water (significant emulsification) with the addition of partially saturated sodium chlorideAnd sodium chloride solids, there was still slight emulsification after stirring for 10 min. The separated organic phase was concentrated under reduced pressure to remove most of the solvent, 260ml of methanol was added to the concentrate, and concentrated again under reduced pressure to remove most of the solvent. 585ml of methanol is added into the concentrated solution, and the temperature is raised to T Inner part The concentrate was dissolved in the system at 45-50 ℃, and 195ml of water was added dropwise at constant temperature. After the dripping is finished, the system is slightly turbid, but no obvious solid is separated out, and the temperature is kept for stirring for 1h. Closing heating, changing mechanical stirring, naturally cooling to T Inner part Keep warm and stir overnight =20-25 ℃. Then continue to cool down to T Inner part The mixture was stirred at 5.+ -. 5 ℃ for 1h, filtered and the filter cake rinsed with 260ml water. The filter cake was dried in vacuo at 60℃for 16h to yield 119g of off-white solid. The dried sample is dissolved in 585ml of methanol again and heated to T Inner part The concentrate was dissolved in the system at 45-50 ℃, and 195ml of water was added dropwise at constant temperature. After the dripping is finished, the system is slightly turbid, but no obvious solid is separated out, and the temperature is kept for stirring for 1h. Closing heating, changing mechanical stirring, naturally cooling to T Inner part Keep warm and stir overnight =20-25 ℃. Then continue to cool down to T Inner part The mixture was stirred at 5.+ -. 5 ℃ for 1h, filtered and the filter cake rinsed with 260ml water. The filter cake was dried in vacuo at 60℃for 16h, yielding 110g of off-white solid in 82.6% yield. Taking 1000ml single-mouth bottle, sequentially adding 110g crude product (P0-20210701 batch) and 660ml acetonitrile, heating to T Inner part Keep temperature and stir until system is clear, =45±5℃. And (3) dropwise adding 220ml of water at the temperature, closing heating after the dropwise adding, changing the stirring mode from magnetic stirring to mechanical stirring, and slowly cooling for 19h. Continuing ice bath cooling to T Inner part The mixture was stirred at 5.+ -. 5 ℃ for 1h, filtered and the filter cake rinsed with 220ml water. The filter cake is dried under reduced pressure at 45 ℃ and is recovered to obtain 103.2g of off-white solid, namely the Affordna A crystal form, the yield is 93.8%, and the chromatographic purity is 99.97%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)：δ8.97-8.95ppm(1H)，8.77-8.72ppm(2H)，8.41-8.40ppm(1H)，8.10-8.06ppm(2H)，7.96-7.84ppm(2H)，7.76-7.73ppm(3H)，4.65-4.60ppm(2H)，4.05-3.99ppm(4H)。
EIMS m/z 625.18([M+H] + )。
The conditions of hydroxylamine type, amount, reaction temperature, alkali type, solvent type, reaction time and the like in example 5 were selected, and the results are shown in Table 6.
TABLE 6 screening of reaction conditions for example 5
Note that: in the table, the "V" is the volume to mass ratio (mL/g) of the reaction solvent to intermediate e, for example THF 3V, 1g intermediate e, 3mL THF being added; the designation "eq" represents the molar ratio of reactant/material to intermediate e, for example 1.4eq for the amount of base, and means a molar ratio of base to intermediate e of 1.4:1.
as shown in Table 6, the selection of hydroxylamine type and base in this step has a certain influence on the purity of aforana, and among them, when hydroxylamine hydrochloride is selected as the hydroxylamine type, the highest purity of aforana is the most preferable, with alkali such as NaOH, KOH or DBU as the base.
Although the invention has been described herein with reference to illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the scope and spirit of the principles of this disclosure. More specifically, various variations and modifications may be made to the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure. In addition to variations and modifications in the component parts and/or arrangements, other uses will be apparent to those skilled in the art.
Claims (10)
1. An intermediate having a structure represented by formula (1):
wherein R is 1 Selected from H or C 1 -C 6 An alkyl group;
R 1 preferablyH or C 1 -C 3 An alkyl group.
2. A process for the preparation of an intermediate as claimed in claim 1, comprising the steps of: reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
wherein R is 1 As defined in claim 1.
3. The preparation method of the aforana is characterized by comprising the following steps of:
step 1: reacting the intermediate of the formula (1) with triethylamine hydrochloride to obtain an intermediate d;
step 2: intermediate d is reacted with 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one to afford intermediate e;
step 3: reacting the intermediate e with hydroxylamine derivatives to obtain aforana;
wherein R is 1 As defined in claim 1.
4. A method of preparing as claimed in claim 3, further comprising the steps of: reacting the compound of the formula a with glycine ester derivatives to prepare an intermediate of the formula (1);
when R is 1 When the alkali is not H, the reaction of the compound of the formula a and the glycine ester derivative also comprises strong alkali, wherein the strong alkali is selected from NaOH, KOH or LiOH;
wherein R is 1 As defined in claim 1.
5. The method of claim 3, wherein step 1 further comprises a condensing agent selected from CDI, DCC, and EDCI; the hydroxylamine derivative in the step 3 is selected from hydroxylamine hydrochloride or hydroxylamine sulfate.
6. The process according to claim 3, wherein the step 2 further comprises a base selected from the group consisting of K 2 HPO 4 ·3H 2 O、K 3 PO 4 、Na 2 HPO 4 ·12H 2 O、Na 3 PO 4 Or CH (CH) 3 COONa。
7. The process according to claim 2 or 4, wherein the reaction of the compound of formula a with glycine ester derivative further comprises methanesulfonic acid.
8. The process according to claim 2 or 4, wherein the solvent for the reaction of the compound of formula a with glycine ester derivatives is selected from esters, ethers, haloalkanes, aromatic hydrocarbons, sulfoxides or nitriles.
9. The method of claim 8, wherein the esters are selected from ethyl acetate, isopropyl acetate, or butyl acetate; the ethers are selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4 dioxane; the halogenated alkane is selected from chloromethane or dichloromethane; the aromatic hydrocarbon is selected from benzene, toluene, xylene or chlorobenzene; the sulfoxide is selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide; the nitriles are selected from acetonitrile or propionitrile.
10. The method of manufacturing as claimed in claim 4, comprising the steps of:
step 1: reacting a compound of the formula a with glycine ethyl ester hydrochloride under the action of methane sulfonic acid and CDI to obtain an intermediate b;
step 2: reacting the intermediate b with NaOH to obtain an intermediate c;
step 3: reacting the intermediate c with triethylamine hydrochloride under the action of CDI to obtain an intermediate d;
step 4: intermediate d and 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethan-1-one in Na 3 PO 4 The reaction is carried out under the action of the catalyst to obtain an intermediate e;
step 5: reacting the intermediate e with hydroxylamine hydrochloride under the action of NaOH to obtain aforana;
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| EP3150575A1 (en) * | 2010-09-27 | 2017-04-05 | E. I. du Pont de Nemours and Company | Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide |
| CN109195955A (en) * | 2016-04-06 | 2019-01-11 | 梅里亚股份有限公司 | The method of the crystallization toluene solvate for isoxazoline compound-(the S)-afoxolaner being enriched with being used to prepare enantiomerism |
| JP2020023442A (en) * | 2016-12-19 | 2020-02-13 | 住友化学株式会社 | Oxadiazole compound and plant disease control method |
| CN115433140A (en) * | 2022-11-08 | 2022-12-06 | 世华合创生物技术开发(山东)有限公司 | Synthetic method of Aforana |
| CN116253658A (en) * | 2022-11-25 | 2023-06-13 | 济南久隆医药科技有限公司 | Synthesis method of aforana intermediate |
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| EP3150575A1 (en) * | 2010-09-27 | 2017-04-05 | E. I. du Pont de Nemours and Company | Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide |
| CN109195955A (en) * | 2016-04-06 | 2019-01-11 | 梅里亚股份有限公司 | The method of the crystallization toluene solvate for isoxazoline compound-(the S)-afoxolaner being enriched with being used to prepare enantiomerism |
| JP2020023442A (en) * | 2016-12-19 | 2020-02-13 | 住友化学株式会社 | Oxadiazole compound and plant disease control method |
| CN115433140A (en) * | 2022-11-08 | 2022-12-06 | 世华合创生物技术开发(山东)有限公司 | Synthetic method of Aforana |
| CN116253658A (en) * | 2022-11-25 | 2023-06-13 | 济南久隆医药科技有限公司 | Synthesis method of aforana intermediate |
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