WO2022218734A1 - A process for preparation of substituted enamine compounds - Google Patents
A process for preparation of substituted enamine compounds Download PDFInfo
- Publication number
- WO2022218734A1 WO2022218734A1 PCT/EP2022/058839 EP2022058839W WO2022218734A1 WO 2022218734 A1 WO2022218734 A1 WO 2022218734A1 EP 2022058839 W EP2022058839 W EP 2022058839W WO 2022218734 A1 WO2022218734 A1 WO 2022218734A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- methyl
- ethyl
- carbon
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 52
- -1 enamine compounds Chemical class 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 10
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 8
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 7
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- NZMAJUHVSZBJHL-UHFFFAOYSA-N n,n-dibutylformamide Chemical compound CCCCN(C=O)CCCC NZMAJUHVSZBJHL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- QMYGFTJCQFEDST-UHFFFAOYSA-N 3-methoxybutyl acetate Chemical group COC(C)CCOC(C)=O QMYGFTJCQFEDST-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052790 beryllium Inorganic materials 0.000 claims description 2
- ATBAMAFKBVZNFJ-UHFFFAOYSA-N beryllium atom Chemical compound [Be] ATBAMAFKBVZNFJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003049 inorganic solvent Substances 0.000 claims description 2
- 229910001867 inorganic solvent Inorganic materials 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 150000002916 oxazoles Chemical class 0.000 abstract description 11
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000000725 suspension Substances 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 25
- 239000012065 filter cake Substances 0.000 description 18
- 229940126214 compound 3 Drugs 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 125000003944 tolyl group Chemical group 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 4
- QZRHHEURPZONJU-UHFFFAOYSA-N iron(2+) dinitrate nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O QZRHHEURPZONJU-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-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
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FWPDSAJKWKRRJD-UHFFFAOYSA-N 5-ethoxy-4-methyl-1,3-oxazole Chemical compound CCOC=1OC=NC=1C FWPDSAJKWKRRJD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 235000004279 alanine Nutrition 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
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000002585 base Substances 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
- 239000012620 biological material Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000006210 cyclodehydration reaction Methods 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([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
- 230000000694 effects Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000011066 ex-situ storage Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 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
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 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
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 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
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000007978 oxazole derivatives Chemical class 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 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
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 239000003039 volatile agent Substances 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
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/30—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton
Definitions
- the present invention is related to a new process for producing substituted enamine compounds.
- Oxazole compounds represent a vast class of heterocyclic aromatic organic compounds. Oxazole compounds have become increasingly important because of biological activities and their use as intermediates for the preparation of new biological materials.
- the wide range of biological activities of oxazole compounds includes anti-inflammatory, analgesic, antibacterial, antifungal, hypoglycemic, antiproliferative, anti-tuberculosis, muscle relaxant and HIV inhibitor activity.
- oxazole derivatives are important intermediates for preparation of biological compounds such as vitamin B 6 .
- oxazole compounds Various processes for the preparation of oxazole compounds have been developed.
- One preferred process in industry is from alanine and oxalic acid in ethanol carried out by azeotropic distillation with benzene.
- the ring closure reaction to obtain 5-ethoxy-4-methyloxazole can also be carried out using phosgene or triphosgene, which is toxic and not environment friendly (see CN 104725262 B, CN 102898321 A and CN 105985297 A)
- the present invention provides a substituted enamine compound of formula (I), which can be converted to an oxazole compound, wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.
- the present invention also provides a process for producing the compound of formula (I) and a process for producing oxazole compounds from the compound of formula (I).
- the term "lower alkyl” as used refers to Ci-Cio alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms.
- the "lower alkyl” is Ci-C 6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert- butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclon
- aryl refers to aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthalenyl.
- lower alkoxyl refers to the structure represented by (lower alkyl)-0-, wherein the lower alkyl is defined as above.
- halo or halogen refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br.
- substitutedine or substituted refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH 2 , -N0 2 , cyano or isocyano.
- a compound represented by a formula or a name also cover stereoisomers thereof, including diastereomers and enantiomers, such as cis/trans-isomers or E/Z-isomers.
- the present invention provides a process for producing a compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III) to produce the compound of formula (I), wherein
- R is H, lower alkyl or aryl, optionally substituted by one or more substituents
- R' is H; and any two of Ri, R 2 and R 3 , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, lower alkyl, lower alkoxyl, aryl, or NR 4 R 4 ' (wherein R and R ' are dependently H or lower alkyl), optionally substituted by one or more substituents; or R', Ri, R 2 and R 3 , together with the carbon they connect, form carbon monoxide (Co0).
- R is H or Ci-C 6 alkyl, optionally substituted by one or more substituents. More preferably, R is H, methyl, ethyl, propyl or butyl, optionally substituted by one or more substituents. The most preferably, R is H or methyl.
- the rest one is hydroxyl, methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, or NR 4 R 4 ' (wherein R and R ' are dependently H, methyl, ethyl, propyl or butyl), optionally substituted by one or more substituents.
- R is H, methyl, ethyl or phenyl; and any two of Ri, R 2 and R 3 , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, or NR R ' (wherein R and R ' are dependently H, methyl or ethyl).
- R is H, methyl, ethyl or phenyl
- the compound of formula (III) is carbon monoxide.
- R is H or methyl; and any two of Ri, R 2 and R 3 , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, -NH 2 or -NHCH 3 .
- the compound of formula (I) and (II) may be in a form of any salt of formula (G) and (IG) respectively: wherein R is defined as above, and X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), potassium (K), and cesium (Cs)), or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), and barium (Ba)), or Iron (ll/lll); or ammonium (NH ) or substituted ammonium.
- X and Y are dependently Na or K.
- the compound of formula (III) may be added in an amount of from 0.01 mols to 20 moles, preferably from 0.05 moles to 15 moles, more preferably from 0.1 mole to 10 moles such as 0.2, 0.5, 0.8, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10 moles, per 1 mole of the compound of formula (II).
- the process of the present invention may be carried out in the presence of a solvent.
- the solvent may be an inorganic solvent such as liquid ammonia, or an organic solvent including but not limited to alkane such as pentane, hexane, heptane, cyclopentane and cyclohexane, aromatic hydrocarbon such as benzene and toluene, ester such as methyl formate and ethyl formate, alcohol such as ethanol, ether such as methyl tert-butyl ether (TBME) and cyclopentyl methyl ether, tertiary amine such as N,N-diethylaniline, triethylamine and tributylamine, amide such as dimethylformamide (DMF), diethylformamide (DEF) and dibutylformamide (DBF), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), or
- the solvent is liquid ammonia, toluene, THF, heptane, acetonitrile, methyl formate, N,N- diethylaniline, triethylamine, TBME, cyclopentyl methyl ether, toluene, ethanol, or mixture thereof.
- the solvent is liquid ammonia, toluene, heptane, acetonitrile, methyl formate, TBME, or mixture thereof.
- the compound of formula (III) is methyl formate
- the solvent is selected from the group consisting of liquid ammonia, heptane, acetonitrile, methyl formate, N,N-diethylaniline, triethylamine, TBME, cyclopentyl methyl ether and toluene, and mixture thereof.
- the compound of formula (III) is ethyl formate
- the solvent is selected from the group consisting of liquid ammonia, toluene, THF and heptane, and mixture thereof.
- the solvent may be added in an amount of from 0.05 mL to 10 mL, preferably from 0.1 mL to 9 mL, more preferably from 0.15 mL to 5 mL such as 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 2, 3, 4 and 5 mL, per 1 mmol of the compound of formula (II).
- the reaction of the present invention may be carried out at the temperature from -50°C to 110°C, preferably from -40°C to 100°C, more preferably from -10°C to 50°C such as -10, -5, 0, 10, 15, 20, 25, 30, 35, 40, 45 and 50°C, under a pressure at 1-20 bar, preferably 2-15 bar, more preferably 3-10 bar such as 3, 4, 5, 6, 7, 8, 9 and 10 bar.
- the obtained compound of formula (la) may be used to the next step b) directly or purified by known process such as crystallization and/or filtration.
- the compound of formula (II) may be prepared by any process known in the art in-situ or ex-situ, for example, by treating the compound of formula (I la) with a strong base such as sodium methoxide, sodium ethoxide, sodium hydride (NaH) and sodium amide.
- a strong base such as sodium methoxide, sodium ethoxide, sodium hydride (NaH) and sodium amide.
- the compound of formula (II) maybe produced from nitriles such as acetonitrile as disclosed in US 5187297 A.
- R is defined as above.
- the compound of formula (I) according to the present invention can be used for producing oxazole compounds.
- the whole process for producing oxazole compounds avoid toxic and unsafe reagents while providing high yield and high selectivity.
- the present invention provides a process for producing an oxazole compound comprising the step of producing the compound of formula (I) as defined above.
- the process of the present invention avoids toxic phosphate reagents and saves steps compared to the processes known in the art and thus provides a new process.
- the present invention will be further illustrated by the following examples.
- a dried four necked round bottom flask was charged with liquid ammonia (15 mL, 0.615 mol, 11 eq). After the flask was flushed with argon, sodium (1.5 g, 65 mmol, 1.1 eq) was added and stirred for 30 mins at - 40°C to -50°C. At the same temperature compound 1 (4.85 g, 59 mmol, 1 eq) in THF (20 mL) was added dropwise in 15 mins. Then the reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a white suspension of the compound 2.
- This suspension was filtrated over a paper filter (7 cm diameter) and washed with TBME (200 mL) to obtain filter cake containing the compound 2 (19.40 g, 67.1wt% purity, 97% yield).
- a dried autoclave was charged at -40°C to -50°C with liquid ammonia (887 mL, 36 mol, 46 eq) and iron nitrate nonahydrate (210 mg, 0.97 mmol, 0.001 eq). Then sodium (18.0 g, 783 mmol, 1.0 eq) was added, and the reaction mixture stirred for 30 min at -40°C to -50°C until complete cessation of hydrogen evolution. The reaction mixture was heated to 20°C over a period of 45 min, whereas a pressure of 8 bar formed. At the same temperature anhydrous acetonitrile (64.2 g, 1,564 mmol, 2.0 eq) was pumped over a period of 15 min, and the reaction mixture was stirred for 150 min.
- Example 9 The filter cake obtained according to the same procedures of Example 9 was loaded in a four necked round bottom flask under argon atmosphere. Butyl acetate (100 mL) was added and acetic acid (7.75 g, 129 mmol, 1.0 eq) was added dropwise in 5 mins. The reaction mixture was stirred for 30 mins at room temperature and then filtered over a paper filter (7 cm diameter). The filtrate was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 4 (13.22 g, 98.8wt% purity,
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Abstract
The present invention provides a substituted enamine compound of formula (I), and a process for producing oxazole compounds from the compound of formula (I). According to the processes of the present invention, it can produce substituted enamine compounds with high yield and selectivity while avoiding toxic or unsafe reagents for producing oxazole compounds.wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.
Description
A process for preparation of substituted enamine compounds
Technical Field
The present invention is related to a new process for producing substituted enamine compounds.
Background of the Invention
Oxazole compounds represent a vast class of heterocyclic aromatic organic compounds. Oxazole compounds have become increasingly important because of biological activities and their use as intermediates for the preparation of new biological materials. The wide range of biological activities of oxazole compounds includes anti-inflammatory, analgesic, antibacterial, antifungal, hypoglycemic, antiproliferative, anti-tuberculosis, muscle relaxant and HIV inhibitor activity. In addition, oxazole derivatives are important intermediates for preparation of biological compounds such as vitamin B6.
Various processes for the preparation of oxazole compounds have been developed. One preferred process in industry is from alanine and oxalic acid in ethanol carried out by azeotropic distillation with benzene. Following this concept, the ring closure reaction to obtain 5-ethoxy-4-methyloxazole can also be carried out using phosgene or triphosgene, which is toxic and not environment friendly (see CN 104725262 B, CN 102898321 A and CN 105985297 A)
In recent years, one attractive process is direct cyclodehydration of acyloxy enamines because acyloxy enamines have been introduced early N-atom and installed the carboxylic acids. It was reported that acyloxy enamines can be synthesized by intermolecular oxidative coupling of an enamine compound with carboxylic acid by using iodosobenzene as the oxidant. However, the oxidant iodosobenzene is highly flammable and has explosion risk. In addition, iodosobenzene is not soluble in solvents and thus results in unstable yields of the process (see Xin Liu et al., Org. Lett., Vol. 14, No. 21, 2012).
Therefore, there is still demand of a new process for the preparation of substituted enamines, which can be converted to oxazole compounds, in industry.
Summary of the Invention
The present invention provides a substituted enamine compound of formula (I), which can be converted to an oxazole compound,
wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.
The present invention also provides a process for producing the compound of formula (I) and a process for producing oxazole compounds from the compound of formula (I).
According to the processes of the present invention, it can produce substituted enamine compounds with high yield and selectivity, while avoiding toxic or unsafe reagents for producing oxazole compounds.
Detailed Description of the Invention
In the present invention, the term "lower alkyl" as used refers to Ci-Cio alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms. Preferably, the "lower alkyl" is Ci-C6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert- butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclononyl, decyl, isodecyl, tert-decyl, cyclodecyl. More preferably, the "lower alkyl" is methyl or ethyl.
In the present invention, the term "aryl" as used refers to aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthalenyl.
In the present invention, the term "lower alkoxyl" as used refers to the structure represented by (lower alkyl)-0-, wherein the lower alkyl is defined as above.
In the present invention, the term "halo" or "halogen" as used refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br.
In the present invention, the term "substituents" or "substituent" as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH2, -N02, cyano or isocyano.
In the present invention, a compound represented by a formula or a name also cover stereoisomers thereof, including diastereomers and enantiomers, such as cis/trans-isomers or E/Z-isomers.
In the first aspect of the present invention, it provides a process for producing a compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III) to produce the compound of formula (I),
wherein
R is H, lower alkyl or aryl, optionally substituted by one or more substituents; and
R' is H; and any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, lower alkyl, lower alkoxyl, aryl, or NR4R4' (wherein R and R ' are dependently H or lower alkyl), optionally substituted by one or more substituents; or R', Ri, R2 and R3, together with the carbon they connect, form carbon monoxide (Cº0).
Preferably, R is H or Ci-C6 alkyl, optionally substituted by one or more substituents. More preferably, R is H, methyl, ethyl, propyl or butyl, optionally substituted by one or more substituents. The most preferably, R is H or methyl.
Preferably, any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, Ci-C6 lower alkyl, Ci-C6 lower alkoxyl, aryl, or NR4R4' (wherein R and R ' are dependently H or Ci-C6 lower alkyl), optionally substituted by one or more substituents. More preferably, the rest one is hydroxyl, methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, or NR4R4' (wherein R and R ' are dependently H, methyl, ethyl, propyl or butyl), optionally substituted by one or more substituents. The most preferably, the rest one is hydroxyl, methoxyl, ethoxyl, or NR4R4' (wherein R and R ' are dependently H, methyl or ethyl), optionally substituted by one or more substituents.
More preferably, R', Ri, R2 and R3, together with the carbon they connect, form carbon monoxide (C=0).
In one embodiment,
R is H, methyl, ethyl or phenyl; and any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, or NR R ' (wherein R and R ' are dependently H, methyl or ethyl).
In another embodiment,
R is H, methyl, ethyl or phenyl; and
The compound of formula (III) is carbon monoxide.
In one preferable embodiment,
R is H or methyl; and any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, -NH2 or -NHCH3.
In the present invention, the compound of formula (I) and (II) may be in a form of any salt of formula (G) and (IG) respectively:
wherein R is defined as above, and X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), potassium (K), and cesium (Cs)), or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), and barium (Ba)), or Iron (ll/lll); or ammonium (NH ) or substituted ammonium. Preferably, X and Y are dependently Na or K.
In the process of the present invention, the compound of formula (III) may be added in an amount of from 0.01 mols to 20 moles, preferably from 0.05 moles to 15 moles, more preferably from 0.1 mole to 10
moles such as 0.2, 0.5, 0.8, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10 moles, per 1 mole of the compound of formula (II).
The process of the present invention may be carried out in the presence of a solvent. The solvent may be an inorganic solvent such as liquid ammonia, or an organic solvent including but not limited to
alkane such as pentane, hexane, heptane, cyclopentane and cyclohexane, aromatic hydrocarbon such as benzene and toluene, ester such as methyl formate and ethyl formate, alcohol such as ethanol, ether such as methyl tert-butyl ether (TBME) and cyclopentyl methyl ether, tertiary amine such as N,N-diethylaniline, triethylamine and tributylamine, amide such as dimethylformamide (DMF), diethylformamide (DEF) and dibutylformamide (DBF), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), or mixture thereof.
More preferably, the solvent is liquid ammonia, toluene, THF, heptane, acetonitrile, methyl formate, N,N- diethylaniline, triethylamine, TBME, cyclopentyl methyl ether, toluene, ethanol, or mixture thereof. The most preferably, the solvent is liquid ammonia, toluene, heptane, acetonitrile, methyl formate, TBME, or mixture thereof.
In one embodiment, the compound of formula (III) is methyl formate, and the solvent is selected from the group consisting of liquid ammonia, heptane, acetonitrile, methyl formate, N,N-diethylaniline, triethylamine, TBME, cyclopentyl methyl ether and toluene, and mixture thereof.
In another embodiment, the compound of formula (III) is ethyl formate, and the solvent is selected from the group consisting of liquid ammonia, toluene, THF and heptane, and mixture thereof.
In the process of the present invention, the solvent may be added in an amount of from 0.05 mL to 10 mL, preferably from 0.1 mL to 9 mL, more preferably from 0.15 mL to 5 mL such as 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 2, 3, 4 and 5 mL, per 1 mmol of the compound of formula (II).
The reaction of the present invention may be carried out at the temperature from -50°C to 110°C, preferably from -40°C to 100°C, more preferably from -10°C to 50°C such as -10, -5, 0, 10, 15, 20, 25, 30, 35, 40, 45 and 50°C, under a pressure at 1-20 bar, preferably 2-15 bar, more preferably 3-10 bar such as
3, 4, 5, 6, 7, 8, 9 and 10 bar. After the reaction finishes, the obtained compound of formula (la) may be used to the next step b) directly or purified by known process such as crystallization and/or filtration.
The compound of formula (II) may be prepared by any process known in the art in-situ or ex-situ, for example, by treating the compound of formula (I la) with a strong base such as sodium methoxide, sodium ethoxide, sodium hydride (NaH) and sodium amide.
Wherein Ri is as defined above.
Alternatively, the compound of formula (II) maybe produced from nitriles such as acetonitrile as disclosed in US 5187297 A.
The inventor of the present invention surprisingly discovered that the compound of formula (I) according to the present invention is new. Accordingly, in the second aspect of the present invention, it provides a compound of formula (I),
Wherein R is defined as above.
As described above, the compound of formula (I) according to the present invention can be used for producing oxazole compounds. As a result, the whole process for producing oxazole compounds avoid toxic and unsafe reagents while providing high yield and high selectivity.
In the third aspect of the present invention, it provides a process for producing an oxazole compound comprising the step of producing the compound of formula (I) as defined above. The process of the present invention avoids toxic phosphate reagents and saves steps compared to the processes known in the art and thus provides a new process.
The present invention will be further illustrated by the following examples.
Examples
1 2
A dried four necked round bottom flask was charged with liquid ammonia (15 mL, 0.615 mol, 11 eq). After the flask was flushed with argon, sodium (1.5 g, 65 mmol, 1.1 eq) was added and stirred for 30 mins at - 40°C to -50°C. At the same temperature compound 1 (4.85 g, 59 mmol, 1 eq) in THF (20 mL) was added dropwise in 15 mins. Then the reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a white suspension of the compound 2.
1H NMR of f/Z-isomers of compound 2 (400 MHz, DMSO) d (ppm): 1.74 (3H) (46.7%), 1.53 (3H) (53.3%).
2
A dried four necked round bottom flask was charged with liquid ammonia (50 mL, 2.05 mol, 16 eq). After the flask was flushed with argon, iron nitrate nonahydrate (35 mg, 0.087 mmol, 0.00067 eq) was added. Then sodium (2.96 g, 129 mmol, 1.0 eq) was added and stirred for 30 mins at -40°C to -50°C. At the same temperature anhydrous acetonitrile (11.65 g, 283 mmol, 2.2 eq) was added dropwise in 15 mins and anhydrous toluene (40 mL) was added immediately. The reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a grey suspension.
This suspension was filtrated over a paper filter (7 cm diameter) and washed with TBME (200 mL) to obtain filter cake containing the compound 2 (19.40 g, 67.1wt% purity, 97% yield).
2
A dried four necked round bottom flask was charged with liquid ammonia (50 mL, 2.05 mol, 18.4 eq). After the flask was flushed with argon, iron nitrate nonahydrate (32 mg, 0.078 mmol, 0.0007 eq) was added. Then, potassium (4.36 g, 112 mmol, 1.0 eq) was added at -50°C and stirred for 30 mins at -40°C to -50°C. At the same temperature anhydrous acetonitrile (10.07 g, 245 mmol, 2.2 eq) was added dropwise in 15 mins and anhydrous acetonitrile (35 mL) was added immediately. The reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a grey suspension.
This suspension was filtrated over a paper filter (7 cm diameter) and washed with TBME (200 mL) to obtain filter cake containing the compound 2 (12.56 g, 93% yield).
A dried four necked round bottom flask was charged with liquid ammonia (50 mL, 2.05 mol, 16 eq) and anhydrous heptane (5 mL, 34.1 mmol, 0.26 eq). After the flask was flushed with argon, iron nitrate nonahydrate (35 mg, 0.087 mmol, 0.00067 eq) was added. Then sodium (2.96 g, 129 mmol, 1.0 eq) was added and stirred for 30 mins at -40°C to -50°C. At the same temperature anhydrous acetonitrile (11.65 g, 283 mmol, 2.2 eq) was added dropwise in 15 mins and anhydrous heptane (35 mL) was added immediately. The reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a grey suspension.
Heptane (30 mL) was added to the grey suspension, and then ethyl formate (11.69 g, 154.8 mmol, 1.2 eq) dissolved in anhydrous heptane (20 mL) was added dropwise to the grey suspension during 20 mins. The reaction mixture was stirred for 2 hours to obtain a grey and thick suspension. N-butyl acetate (100 mL) was added and the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (19.30 g, 83 w/w% purity, 93% yield).
JH NMR of E -isomer of compound 3 (400 MHz, DMSO) d (ppm): 8.81 (1H), 3.73 (1H), 1.82 (1H). NMR of Z-isomer of compound 3 (400 MHz, DMSO) d (ppm): 8.58 (1H), 4.21 (1H), 1.93 (3H).
2 3
A dried autoclave was charged at -40°C to -50°C with liquid ammonia (887 mL, 36 mol, 46 eq) and iron nitrate nonahydrate (210 mg, 0.97 mmol, 0.001 eq). Then sodium (18.0 g, 783 mmol, 1.0 eq) was added, and the reaction mixture stirred for 30 min at -40°C to -50°C until complete cessation of hydrogen evolution. The reaction mixture was heated to 20°C over a period of 45 min, whereas a pressure of 8 bar formed. At the same temperature anhydrous acetonitrile (64.2 g, 1,564 mmol, 2.0 eq) was pumped over a period of 15 min, and the reaction mixture was stirred for 150 min. Ethyl formate (71.7 g, 949 mmol, 1.2 eq) was pumped over a period of 60 min and the reaction mixture was stirred for 8 h. All volatiles were evaporated to obtain compound 3 (76.8 g, 582 mmol, 74% yield).
Ethyl formate (2.14 g, 29 mmol, 1.2 eq) was added dropwise to compound 2 (2.50 g, 24 mmol, 1.0 eq) obtained according to the same procedures of Example 2 in 20 min. The reaction mixture was stirred for 1.5 hours to obtain a grey slurry. TBME (30 mL) was added. Then, the mixture was filtrated over a paper filter to obtain a filter cake containing compound 3 (2.60 g, 82% yield).
Ethyl formate (2.14 g, 29 mmol, 1.2 eq) was added dropwise to the grey suspension obtained according to the same procedures of Example 2 (2.50 g, 24 mmol, 1.0 eq) in 20 min. The reaction mixture was stirred for 1.5 hours to obtain a grey and thick suspension. TBME (30 mL) was added. Then, the mixture was filtrated over a paper filter (4.5 cm diameter) to obtain a filter cake containing compound 3 (2.65 g, 83% yield).
2
3
Ethyl formate (10.49 g, 142 mmol, 1.1 eq) dissolved in acetonitrile (20 mL) was added dropwise to the grey suspension obtained according to the same procedures of Example 2 (13.43 g, 129 mmol, 1.0 eq) in 30 min. The reaction mixture was stirred over night to obtain a white and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (15.84 g, 93% yield).
Ethyl formate (10.71 g, 142 mmol, 1.1 eq) dissolved in anhydrous toluene (20 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) obtained according to the same procedures of Example 2 in 20 mins. The reaction mixture was stirred overnight to obtain a grey and thick suspension. TBME (100
mL) was added and the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (49.68 g, 31.6wt% purity, 92% yield).
Ethyl formate (4.82 g, 65 mmol, 0.5 eq) dissolved in THF (10 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) obtained according to the same procedures of Example 2 except that toluene was replaced with THF in 20 mins. The reaction mixture was stirred overnight to obtain a grey and thick suspension. TBME (100 mL) was added and the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (7.40 g, 82% yield).
2 3
Methyl formate (9.28 g, 155 mmol, 1.2 eq) dissolved in heptane (20 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) obtained according to the same procedures of Example 2 except that toluene was replaced with heptane in 30 min. The reaction mixture was stirred over night to obtain a white and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (15.46 g, 91% yield).
2
3
Methyl formate (8.51 g, 142 mmol, 1.1 eq) dissolved in acetonitrile (20 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) obtained according to the same procedures of Example 2 except that toluene was replaced with acetonitrile in 15 min. The reaction mixture was stirred over night to obtain a white and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (15.98 g, 94% yield).
2
3
Methyl formate (8.51 g, 142 mmol, 1.1 eq) dissolved in N,N-diethylaniline (20 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) obtained according to the same procedures of Example 2 except that toluene was replaced with N,N-diethylaniline in 20 min and stirred for 10 min. Afterwards, additional methyl formate (47.0 g, 183 mmol, 6.1 eq) was added. The reaction mixture was stirred over night to obtain a grey and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (11.44 g, 67.2% yield).
2 3
Methyl formate (8.51 g, 142 mmol, 1.1 eq) dissolved in triethylamine (20 mL) was added dropwise to the grey suspension (13.43g, 129 mmol, 1.0 eq) obtained according to the same procedures as Example 2 except that toluene was replaced with triethylamine in 20 min. The reaction mixture was stirred over night to obtain a white and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (13.97 g, 82% yield).
Methyl formate (9.28 g, 155 mmol, 1.2 eq) dissolved in TBME (20 mL) was added dropwise to the grey suspension (13.43g, 129 mmol, 1.0 eq) obtained according to the same procedures as Example 2 except that toluene was replaced with TBME (13.43g, 129 mmol, 1.0 eq) in 30 min. The reaction mixture was stirred over night to obtain a white and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (15.19 g,
89% yield).
Example 16
©
2 3
Methyl formate (9.28 g, 155 mmol, 1.2 eq) dissolved in cyclopentyl methyl ether (20 mL) was added dropwise to the grey suspension (13.43g, 129 mmol, 1.0 eq) obtained according to the same procedures as Example 2 except that toluene was replaced with cyclopentyl methyl ether in 30 min. The reaction mixture was stirred over night to obtain a white and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (13.47 g, 79% yield).
Dimethyl formamide (6.95 g, 95 mmol, 3 eq) dissolved in toluene (5 mL) was added dropwise to the grey suspension obtained according to the same procedures of Example 2 (3.3g, 31.7 mmol, 1.0 eq) in 10 min.
The reaction mixture was stirred for 3 days at 40°Cto obtain a white suspension. TBME (50 mL) was added. Then, the mixture was filtrated over a paper filter (4 cm diameter) to obtain a filter cake containing compound 3 (1.98 g, 47% yield).
Carbon monoxide (50 bar overpressure) was added to ethanol (10 mL) and the filter cake obtained according to the same procedures of Example 2 (347 mg, 3.33 mmol, 1.0 eq). The reaction mixture was shaked over 19 h at 70°C to obtain a yellow suspension. TBME (20 mL) was added. Then, the mixture was filtrated over a paper filter (2 cm diameter) to obtain a filter cake containing compound 3 (248 mg, 56% yield).
The filter cake obtained according to the same procedures of Example 9 was loaded in a four necked round bottom flask under argon atmosphere. Butyl acetate (100 mL) was added and acetic acid (7.75 g, 129 mmol, 1.0 eq) was added dropwise in 5 mins. The reaction mixture was stirred for 30 mins at room temperature and then filtered over a paper filter (7 cm diameter). The filtrate was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 4 (13.22 g, 98.8wt% purity,
92% yield).
To a solution of the compound 4 (220 mg, 2.0 mmol) in dried 1,2-dichloroethane (20 mL) was added BF3-Et20 (4.0 mmol, 2.0 eq). The reaction mixture was heated to reflux, and then phenyliodine(lll) diacetate (838 mg, 2.6 mmol, 1.3 eq) was added in one portion rapidly. After stirring under refluxing
condition for 0.5-3 hours, the reaction mixture was cooled down to room temperature, quenched with saturated aqueous NaHC03, and then extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na2S0 and concentrated by the rotary evaporator. The crude product was purified by flash column chromatography to give the compound 5 (140 mg, 65% yield).
Claims
1. A process for producing a compound of formula (I), comprising: reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula
R is H, lower alkyl or aryl, optionally substituted by one or more substituents; and
R' is H; and any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, lower alkyl, lower alkoxyl, aryl, or NR R ' (wherein R and R ' are dependently H or lower alkyl), optionally substituted by one or more substituents; or R', Ri, R2 and R3, together with the carbon they connect, form carbon monoxide (Cº0).
2. The process of claim 1, wherein R is H, methyl, ethyl, propyl or butyl, optionally substituted by one or more substituents.
3. The process of claim 1, wherein any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, or NR4R4' (wherein R and R ' are dependently H, methyl, ethyl, propyl or butyl), optionally substituted by one or more substituents
4. The process of claim 1, wherein R', Ri, R2 and R3, together with the carbon they connect, form carbon monoxide (Cº0).
5. The process of claim 1, wherein R is H, methyl, ethyl or phenyl; and any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, or NR4R4' (wherein R and R ' are dependently H, methyl or ethyl).
6. The process of claim 1, wherein R is H, methyl, ethyl or phenyl; and the compound of formula (III) is carbon monoxide.
7. The process of claim 1, wherein R is H or methyl; and any two of Ri, R2 and R3, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, -NH2 or -NHCH3.
8. The process of claim 1, wherein the compound of formula (I) and (II) are in a form of any salt of formula (G) and (IG) respectively:
(I·) (II·) wherein R is defined as any one of claims 1-7, and X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), potassium (K), and cesium (Cs)), or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), and barium (Ba)), or Iron (ll/lll); or ammonium (NH ) or substituted ammonium.
9. The process of any one of claims 1-8, wherein the reaction is carried out in the presence of a solvent.
10. The process of claim 9, wherein The solvent is an inorganic solvent such as liquid ammonia, or an organic solvent including but not limited to C5-Ci2 alkane such as pentane, hexane, heptane, cyclopentane and cyclohexane, aromatic hydrocarbon such as benzene and toluene, ester such as methyl formate and ethyl formate, alcohol such as ethanol, ether such as methyl tert-butyl ether (TBME) and cyclopentyl methyl ether, tertiary amine such as N,N-diethylaniline, triethylamine and tributylamine, amide such as dimethylformamide (DMF), diethylformamide (DEF) and dibutylformamide (DBF), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), or mixture thereof.
11. The process of claim 9, wherein the solvent is liquid ammonia, toluene, THF, heptane, acetonitrile, methyl formate, N,N-diethylaniline, triethylamine, TBME, cyclopentyl methyl ether, toluene, ethanol, or mixture thereof.
12. The process of any one of claims 1-8, wherein the reaction is carried out at the temperature from - 50°C to 110°C, preferably from -40°C to 100°C, more preferably from -10°C to 50°C such as -10, -5, 0, 10, 15, 20, 25, 30, 35, 40, 45 and 50°C, under a pressure at 1-20 bar, preferably 2-15 bar, more preferably 3- 10 bar such as 3, 4, 5, 6, 7, 8, 9 and 10 bar.
13. The process of any one of claims 1-8, wherein the compound of formula (II) is prepared from the compound of formula (lla) or nitriles such as acetonitrile:
H2N
R ,/CN
(lla)
Wherein Ri is defined as any one of claims 1-8.
Wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.
15. A process for producing an oxazole compound comprising the step of producing the compound of formula (I) according to any one of claims 1-13.
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-
2022
- 2022-04-04 WO PCT/EP2022/058839 patent/WO2022218734A1/en active Application Filing
- 2022-04-04 EP EP22720626.5A patent/EP4323333A1/en active Pending
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