CN116134021A - 用于生产噁唑类化合物的方法 - Google Patents
用于生产噁唑类化合物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 150000002916 oxazoles Chemical class 0.000 title abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 12
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims description 29
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 13
- 235000019253 formic acid Nutrition 0.000 claims description 13
- -1 methoxy, ethoxy Chemical group 0.000 claims description 13
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 claims description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 8
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- ZZXUZKXVROWEIF-UHFFFAOYSA-N 1,2-butylene carbonate Chemical compound CCC1COC(=O)O1 ZZXUZKXVROWEIF-UHFFFAOYSA-N 0.000 claims description 4
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 229960005070 ascorbic acid Drugs 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 229940005605 valeric acid Drugs 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 2
- 150000005676 cyclic carbonates Chemical class 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000011541 reaction mixture Substances 0.000 description 10
- JZSLPQXOLZCAME-UHFFFAOYSA-N 4-methyl-1,3-oxazole-5-carbonitrile Chemical compound CC=1N=COC=1C#N JZSLPQXOLZCAME-UHFFFAOYSA-N 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- DELJOESCKJGFML-RQOWECAXSA-N (z)-3-aminobut-2-enenitrile Chemical compound C\C(N)=C\C#N DELJOESCKJGFML-RQOWECAXSA-N 0.000 description 1
- HBKBZJZRIWAICY-UHFFFAOYSA-N 4-methyl-1,3-oxazole-5-carboxamide Chemical compound CC=1N=COC=1C(N)=O HBKBZJZRIWAICY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BQOWUDKEXDCGQS-UHFFFAOYSA-N [CH]1CCCC1 Chemical group [CH]1CCCC1 BQOWUDKEXDCGQS-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- VLRKYJUEGKNWJF-UHFFFAOYSA-N acetic acid hydroiodide Chemical compound I.CC(O)=O.CC(O)=O VLRKYJUEGKNWJF-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XNMORZSEENWFLI-UHFFFAOYSA-N ethyl 4-methyl-1,3-oxazole-5-carboxylate Chemical compound CCOC(=O)C=1OC=NC=1C XNMORZSEENWFLI-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
Description
技术领域
本发明涉及一种用于生产噁唑类化合物的新方法。
背景技术
噁唑类化合物代表一大类杂环芳族有机化合物。噁唑类化合物已经由于生物活性及其作为用于制备新生物材料的中间体的用途而变得越来越重要。噁唑类化合物的广泛生物活性包括抗炎、镇痛、抗细菌、抗真菌、降血糖、抗增殖、抗结核、肌肉松弛和HIV抑制剂活性。
4-甲基-5-氰基噁唑是用于生产维生素B6的重要中间体。在工业上其主要通过包括以下步骤的方法生产:a)将乙酰乙酸乙酯氯化成乙酰乙酸氯乙酯,b)使乙酰乙酸氯乙酯与甲酰胺反应以得到4-甲基-5-噁唑甲酸乙酯,以及c)将所获得的酯经由4-甲基-5-噁唑甲酰胺脱水成4-甲基-5-氰基噁唑(参见H.Pauling,B.Weimann,Ullmann,VCH,(2012)248;Werner Bonrath;Kun Peng,Qiong-Mei Zhang,Horst Pauling,Bernd-Jurgen Weimann,Ullmann's Encyclopedia of Industrial Chemistry(第7版)(2020))。
上述方法有几个缺点。例如,氯化步骤使用氯气,并且脱水反应使用有毒或腐蚀性的五氧化二磷。此外,该方法会产生许多导致环境问题的盐。
因此,仍需要用于生产噁唑类化合物的新方法。
发明内容
本发明提供了一种用于生产式(I)的噁唑类化合物的新方法,该方法可避免有毒试剂并高效减少盐类副产物,
其中R1是H,或任选地被一个或多个取代基取代的低级烷基或芳基;并且E是C≡N或C(=O)R',其中R'是H、低级烷基、芳基或低级烷氧基。
具体实施方式
具体地,本发明提供了一种用于生产式(I)的化合物的方法,所述方法包括用第一酸处理式(II)的化合物,之后在溶剂存在下用第二酸和酸酐处理以获得所述式(I)的化合物,
其中R1是H,或任选地被一个或多个取代基取代的低级烷基或芳基;R2是一个或多个选自由以下组成的组的取代基:H、NO2、羟基、低级烷基、低级烷氧基和卤基;并且E是C≡N或C(=O)R',其中R'可为H、低级烷基、芳基或低级烷氧基。
在本发明中,如所使用的术语“低级烷基”是指C1-C10烷基,即含有1至10个碳原子的支链或非支链、环状或非环状饱和烃。优选地,“低级烷基”是C1-C6烷基,包括但不限于甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、叔丁基、环丁基、戊基、异戊基、叔戊基、环戊基、己基、异己基、叔己基、环己基、辛基、异辛基、叔辛基、环辛基、壬基、异壬基、叔壬基、环壬基、癸基、异癸基、叔癸基、环癸基。更优选地,“低级烷基”是甲基或乙基。
在本发明中,如所使用的术语“芳基”是指芳族烃,例如苯基、苄基、二甲苯基和萘基。
在本发明中,如所使用的术语“低级烷氧基”是指由(低级烷基)-O-表示的结构,其中“低级烷基”如上所定义。
在本发明中,如所使用的术语“取代基”是指低级烷基、低级烷氧基、羟基、卤基、-NH2、-NO2、氰基和/或异氰基。
在本发明中,如所使用的术语“卤基”或“卤素”是指一组元素,包括氟(F)、氯(Cl)、溴(Br)和碘(I),优选是指Cl或Br。
在本发明中,R1优选地为H,或任选地被一个或多个取代基取代的低级烷基或苯基。更优选地,R1是H或任选地被一个或多个取代基取代的C1-C6烷基或苯基。更优选地,R1是H,任选地被一个或多个取代基取代的甲基、乙基或苯基。最优选地,R1是H、CH3或苯基。
在本发明中,R2优选地为选自由以下组成的组的一个或多个取代基:H、NO2、羟基、C1-C6烷基、C1-C6烷氧基或卤基。更优选地,R2是H、卤基、甲基、乙基、甲氧基、乙氧基和/或-NO2。
在本发明中,E优选地为C≡N,或C(=O)R',其中R'是低级烷氧基,例如甲氧基和乙氧基。
在本发明的一个实施方式中,R1是H或甲基;R2是H或NO2;并且E是C≡N。
在本发明的另一实施方式中,R1是H或甲基;R2是H或NO2;并且E是C(=O)R',其中R'是低级烷氧基,例如甲氧基和乙氧基。
在本发明的方法中,第一酸和第二酸可为相同或不同的,独立地选自任何有机酸或无机酸。有机酸的示例包括但不限于甲酸、乙酸、乙醇酸、丙酸、3-羟基丙酸、丁酸、琥珀酸、戊酸、三甲基乙酸、甲磺酸、三氟乙酸、对甲苯磺酸、抗坏血酸和柠檬酸。无机酸的示例包括但不限于盐酸、硫酸和硝酸。优选地,第一酸和第二酸是相同的且选自甲酸、乙酸、乙醇酸、丙酸、3-羟基丙酸、丁酸、琥珀酸、戊酸、三甲基乙酸、抗坏血酸和柠檬酸。最优选地,第一酸和第二酸是甲酸。
在本发明的方法中,第一酸可以每1摩尔式(II)化合物0.01摩尔至10摩尔,优选地0.05摩尔至5摩尔,更优选地0.1摩尔至1摩尔,例如0.1摩尔、0.2摩尔、0.3摩尔、0.4摩尔、0.5摩尔、0.6摩尔、0.7摩尔、0.8摩尔、0.9摩尔和1.0摩尔的量使用。
在本发明的方法中,第二酸可以每1摩尔式(II)化合物0.01摩尔至30摩尔,更优选地0.05摩尔至25摩尔,进一步优选地0.08摩尔至20摩尔,最优选地0.1摩尔至18摩尔,例如0.1摩尔、0.2摩尔、0.3摩尔、0.4摩尔、0.5摩尔、0.6摩尔、0.7摩尔、0.8摩尔、0.9摩尔、1.0摩尔、2.0摩尔、3.0摩尔、4.0摩尔、5.0摩尔、6.0摩尔、7.0摩尔、8.0摩尔、9.0摩尔、10.0摩尔、11.0摩尔、12.0摩尔、13.0摩尔、14.0摩尔、15.0摩尔、16.0摩尔、17.0摩尔和18.0摩尔的量使用。
在本发明的方法中,溶剂可以是任何非质子溶剂或其混合物。非质子溶剂的示例包括但不限于四氢呋喃(tetrahydrofuran,THF)、乙酸乙酯、丙酮、二甲基甲酰胺(dimethylformamide,DMF)、乙腈、二甲基亚砜(dimethyl sulfoxide,DMSO)、二氯甲烷(dichloromethane,DCM)、碳酸二甲酯、乙酸丁酯、甲基叔丁基醚(methyl tert-butylether,MTBE)、硝基甲烷和硝基乙烷;以及环状碳酸酯,例如碳酸亚乙酯(ethylenecarbonate,EC)、碳酸亚丙酯(propylene carbonate,PC)、和碳酸亚丁酯(butylenecarbonate,BC),以及它们的混合物。优选地,溶剂是DCM或PC。溶剂可以每1摩尔的式(II)化合物20L至80L,优选地30L至60L,更优选地45L至55L的量添加。
在本发明中,酸酐可以是乙酸酐、丙酸酐或邻苯二甲酸酐。所述酸酐可以以每1摩尔的式(II)化合物0.01摩尔至10摩尔,优选地0.05摩尔至5摩尔,更优选地0.1摩尔至1摩尔,例如0.1摩尔、0.2摩尔、0.3摩尔、0.4摩尔、0.5摩尔、0.6摩尔、0.7摩尔、0.8摩尔、0.9摩尔或1摩尔的量添加到反应中。
根据本发明用第一酸进行处理可以在室温下进行。根据本发明用第二酸进行处理可在20℃至120℃,优选地50℃至100℃,更优选地80℃至90℃的温度下进行。
用第一酸和第二酸进行处理可以在一个锅中进行,或在分开的锅中进行。优选地,用第一酸和第二酸进行处理在一个锅中进行。
所获得的式(I)化合物可以通过任何已知的方法(例如蒸馏、精馏和柱色谱法)容易地分离和纯化。
从式(II)化合物开始,根据本发明的用于生产噁唑类化合物的方法易于在温和的温度下操作。此外,该方法避免产生任何对环境不利的盐并提供噁唑类化合物的高产率。
本发明及其优点将通过以下实施例进一步说明。
实施例
实施例1
在20mL圆底烧瓶中,将二乙酸碘(III)苯(phenyliodine(III)diacetate)(332mg,1.030mmol)添加到TFE(5ml)中,以得到无色溶液。添加甲酸(120mg,2.5mmol)。将混合物在室温下搅拌10min。添加3-氨基丁-2-烯腈(90mg,1.030mmol)。将所得黄色混合物在室温下搅拌1h,以获得化合物1(产率90%)
1H NMR(400MHz,氧化氘)δ8.38(s,1H),8.02-7.92(m,2H),7.67(t,J=7.4Hz,1H),7.51(t,J=7.9Hz,2H),2.31(s,2H).MS:285.0
实施例2
在100mL圆底烧瓶中,将根据实施例1获得的化合物1(10g)于60℃一次性添加到甲酸(400ul)在碳酸亚丙酯(50ml)中的溶液中。在60℃搅拌15min后,将反应混合物冷却至室温。将所得溶液于90℃滴加到甲酸(20ml)和乙酸酐(3.8ml)的溶液中。将反应混合物在相同温度下再搅拌2小时,以得到5-氰基-4-甲基噁唑(2),产率为80%。
实施例3
在10mL圆底烧瓶中,将根据实施例1获得的化合物1(1g)于60℃一次性添加到甲酸(40ul)在碳酸亚丙酯(5ml)中的溶液中。在60℃搅拌15min后,将反应混合物冷却至室温。在90℃将所得溶液滴加到甲磺酸(methanesulfonic acid,MSA)(100ul)和乙酸酐(200ul)在碳酸亚丙酯(5ml)中的溶液中。将反应混合物在相同温度下再搅拌2小时,以得到5-氰基-4-甲基噁唑(2),产率为60%。
实施例4
在10mL圆底烧瓶中,将根据实施例1获得的化合物1(1g)于60℃一次性添加到甲酸(40ul)在碳酸亚丙酯(5ml)中的溶液中。在60℃搅拌15min后,将反应混合物冷却至室温。在90℃将所得溶液滴加到三氟乙酸(trifloroacetic acid,TFA)(2ml)和乙酸酐(200ul)在碳酸亚丙酯(5ml)中的溶液中。将反应混合物在相同温度下再搅拌2小时,以得到5-氰基-4-甲基噁唑(2),产率为30%。
实施例5
在10mL圆底烧瓶中,将根据实施例1获得的化合物1(1g)于60℃一次性添加到甲酸(40ul)在碳酸亚丙酯(5ml)中的溶液中。在60℃搅拌15min后,将反应混合物冷却至室温。在90℃将所得溶液滴加到对甲苯磺酸一水合物(p-TSA)(50mg)和乙酸酐(400ul)在碳酸亚丙酯(5ml)中的溶液中。将反应混合物在相同温度下再搅拌2小时,以得到5-氰基-4-甲基噁唑(2),产率为35%。
实施例6
在10mL圆底烧瓶中,将根据实施例1获得的化合物1(1g)于60℃一次性添加到甲酸(40ul)在碳酸亚丙酯(5ml)中的溶液中。在60℃搅拌15min后,将反应混合物冷却至室温。在90℃将所得溶液滴加到硫酸(50ul)和乙酸酐(100ul)在碳酸亚丙酯(5ml)中的溶液中。将反应混合物在相同温度下再搅拌2小时,以得到5-氰基-4-甲基噁唑(2),产率为30%。
Claims (15)
2.根据权利要求1所述的方法,其中R1是H,或任选地被一个或多个取代基取代的低级烷基或苯基;优选地,R1是H或任选地被一个或多个取代基取代的C1-C6烷基或苯基;更优选地,R1是H,任选地被一个或多个取代基取代的甲基、乙基或苯基;并且最优选地,R1是H、CH3或苯基。
3.根据权利要求1所述的方法,其中R2是一个或多个选自由以下组成的组的取代基:H、NO2、羟基、C1-C6烷基、C1-C6烷氧基或卤基;优选地,R2是H、卤基、甲基、乙基、甲氧基、乙氧基和/或-NO2。
4.根据权利要求1所述的方法,其中E优选地是C≡N、或C(=O)R',其中R'是低级烷氧基,例如甲氧基和乙氧基。
5.根据权利要求1所述的方法,其中R1是H或甲基,R2是H或NO2,并且E是C≡N;或者R1是H或甲基,R2是H或NO2,并且E为C(=O)R',其中R'是低级烷氧基,例如甲氧基和乙氧基。
6.根据权利要求1-5中任一项所述的方法,其中所述第一酸和所述第二酸是相同或不同的,独立地选自任何有机酸或无机酸。
7.根据权利要求6所述的方法,其中所述有机酸选自由以下组成的组:甲酸、乙酸、乙醇酸、丙酸、3-羟基丙酸、丁酸、琥珀酸、戊酸、三甲基乙酸、甲磺酸、三氟乙酸、对甲苯磺酸、抗坏血酸和柠檬酸。
8.根据权利要求6所述的方法,其中所述无机酸选自由以下组成的组:盐酸、硫酸和硝酸。
9.根据权利要求1-5中任一项所述的方法,其中所述第一酸和所述第二酸是相同的且选自甲酸、乙酸、乙醇酸、丙酸、3-羟基丙酸、丁酸、琥珀酸、戊酸、三甲基乙酸、抗坏血酸和柠檬酸,并且优选地所述第一酸和所述第二酸是甲酸。
10.根据权利要求1-9中任一项所述的方法,其中所述第一酸以每1摩尔式(II)化合物0.01摩尔至10摩尔,优选地0.05摩尔至5摩尔,更优选地0.1摩尔至1摩尔,例如0.1摩尔、0.2摩尔、0.3摩尔、0.4摩尔、0.5摩尔、0.6摩尔、0.7摩尔、0.8摩尔、0.9摩尔和1.0摩尔的量使用。
11.根据权利要求1-9中任一项所述的方法,其中所述第二酸以每1摩尔式(II)化合物0.01摩尔至30摩尔,更优选地0.05摩尔至25摩尔,进一步优选地0.08摩尔至20摩尔,最优选地0.1摩尔至18摩尔,例如0.1摩尔、0.2摩尔、0.3摩尔、0.4摩尔、0.5摩尔、0.6摩尔、0.7摩尔、0.8摩尔、0.9摩尔、1.0摩尔、2.0摩尔、3.0摩尔、4.0摩尔、5.0摩尔、6.0摩尔、7.0摩尔、8.0摩尔、9.0摩尔、10.0摩尔、11.0摩尔、12.0摩尔、13.0摩尔、14.0摩尔、15.0摩尔、16.0摩尔、17.0摩尔和18.0摩尔的量使用。
12.根据权利要求1-11中任一项所述的方法,其中所述溶剂是非质子溶剂或其混合物。
13.根据权利要求12所述的方法,其中所述非质子溶剂选自由以下组成的组:四氢呋喃(THF)、乙酸乙酯、丙酮、二甲基甲酰胺(DMF)、乙腈、二甲基亚砜(DMSO)、二氯甲烷(DCM)、碳酸二甲酯、乙酸丁酯、甲基叔丁基醚(MTBE)、硝基甲烷和硝基乙烷;以及环状碳酸酯,例如碳酸亚乙酯(EC)、碳酸亚丙酯(PC)、和碳酸亚丁酯(BC),以及它们的混合物。
14.根据权利要求1-13中任一项所述的方法,其中所述酸酐是乙酸酐、丙酸酐或邻苯二甲酸酐。
15.根据权利要求1-14中任一项所述的方法,其中用所述第一酸和所述第二酸进行的所述处理可以在一个锅中进行。
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