WO2023143158A1 - Dérivé de phénol, forme cristalline de celui-ci et procédé de préparation associé - Google Patents
Dérivé de phénol, forme cristalline de celui-ci et procédé de préparation associé Download PDFInfo
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- WO2023143158A1 WO2023143158A1 PCT/CN2023/072277 CN2023072277W WO2023143158A1 WO 2023143158 A1 WO2023143158 A1 WO 2023143158A1 CN 2023072277 W CN2023072277 W CN 2023072277W WO 2023143158 A1 WO2023143158 A1 WO 2023143158A1
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- 239000013078 crystal Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000002989 phenols Chemical class 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 238000006243 chemical reaction Methods 0.000 claims description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 44
- -1 Boc-amino Chemical group 0.000 claims description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- QVHJQCGUWFKTSE-RXMQYKEDSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-RXMQYKEDSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 21
- WLMSWDHYJKAXGN-UHFFFAOYSA-N 2-(1-cyclopropylethyl)phenol Chemical compound C=1C=CC=C(O)C=1C(C)C1CC1 WLMSWDHYJKAXGN-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- 239000002994 raw material Substances 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 229960004134 propofol Drugs 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 150000001413 amino acids Chemical group 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 229940125898 compound 5 Drugs 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- JTFAASKLZAZMON-UHFFFAOYSA-N CC(C1CC1)C(C=CC=C1C(C)O)=C1O Chemical compound CC(C1CC1)C(C=CC=C1C(C)O)=C1O JTFAASKLZAZMON-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- WLMSWDHYJKAXGN-MRVPVSSYSA-N 2-[(1R)-1-cyclopropylethyl]phenol Chemical compound C1(CC1)[C@@H](C)C1=C(C=CC=C1)O WLMSWDHYJKAXGN-MRVPVSSYSA-N 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JJSCUXAFAJEQGB-MRVPVSSYSA-N [(1r)-1-isocyanatoethyl]benzene Chemical compound O=C=N[C@H](C)C1=CC=CC=C1 JJSCUXAFAJEQGB-MRVPVSSYSA-N 0.000 description 2
- 239000012445 acidic reagent Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 150000001924 cycloalkanes Chemical class 0.000 description 2
- VRNCRGHDRGGBLW-UHFFFAOYSA-N cyclopenta-1,2-diene Chemical compound C1CC=C=C1 VRNCRGHDRGGBLW-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000002695 general anesthesia Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical group [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000013094 purity test Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- IIKBAAIJWTZALX-UHFFFAOYSA-N tris[3,5-bis(trifluoromethyl)phenyl] borate Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(OB(OC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)OC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 IIKBAAIJWTZALX-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- SJVFAHZPLIXNDH-JOCHJYFZSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-JOCHJYFZSA-N 0.000 description 1
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 1
- URKWHOVNPHQQTM-OAHLLOKOSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-naphthalen-2-ylpropanoic acid Chemical compound C1=CC=CC2=CC(C[C@@H](NC(=O)OC(C)(C)C)C(O)=O)=CC=C21 URKWHOVNPHQQTM-OAHLLOKOSA-N 0.000 description 1
- USPFMEKVPDBMCG-GFCCVEGCSA-N (2r)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-GFCCVEGCSA-N 0.000 description 1
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 description 1
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 1
- UGNIYGNGCNXHTR-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UGNIYGNGCNXHTR-SFHVURJKSA-N 0.000 description 1
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 1
- FODJWPHPWBKDON-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 FODJWPHPWBKDON-IBGZPJMESA-N 0.000 description 1
- CBPJQFCAFFNICX-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 CBPJQFCAFFNICX-IBGZPJMESA-N 0.000 description 1
- BUBGAUHBELNDEW-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylsulfanylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCSC)C(O)=O)C3=CC=CC=C3C2=C1 BUBGAUHBELNDEW-SFHVURJKSA-N 0.000 description 1
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 1
- DMBKPDOAQVGTST-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)COCC1=CC=CC=C1 DMBKPDOAQVGTST-LBPRGKRZSA-N 0.000 description 1
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- AJDUMMXHVCMISJ-ZDUSSCGKSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC(=O)OCC1=CC=CC=C1 AJDUMMXHVCMISJ-ZDUSSCGKSA-N 0.000 description 1
- AHYFYYVVAXRMKB-KRWDZBQOSA-N (2s)-3-(1h-indol-3-yl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)OCC1=CC=CC=C1 AHYFYYVVAXRMKB-KRWDZBQOSA-N 0.000 description 1
- MCRMUCXATQAAMN-HNNXBMFYSA-N (2s)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 MCRMUCXATQAAMN-HNNXBMFYSA-N 0.000 description 1
- TXDGEONUWGOCJG-LBPRGKRZSA-N (2s)-3-[(2-methylpropan-2-yl)oxy]-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound CC(C)(C)OC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 TXDGEONUWGOCJG-LBPRGKRZSA-N 0.000 description 1
- FOXRXVSTFGNURG-VIFPVBQESA-N (2s)-3-amino-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound NC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 FOXRXVSTFGNURG-VIFPVBQESA-N 0.000 description 1
- KRJLRVZLNABMAT-YFKPBYRVSA-N (2s)-3-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CN)C(O)=O KRJLRVZLNABMAT-YFKPBYRVSA-N 0.000 description 1
- LZOLWEQBVPVDPR-VLIAUNLRSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@H](OC(C)(C)C)C)C(O)=O)C3=CC=CC=C3C2=C1 LZOLWEQBVPVDPR-VLIAUNLRSA-N 0.000 description 1
- QXVFEIPAZSXRGM-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 QXVFEIPAZSXRGM-DJJJIMSYSA-N 0.000 description 1
- MFFFBNAPQRDRQW-JTQLQIEISA-N (3s)-4-methoxy-4-oxo-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound COC(=O)[C@H](CC(O)=O)NC(=O)OCC1=CC=CC=C1 MFFFBNAPQRDRQW-JTQLQIEISA-N 0.000 description 1
- HXOVWGDXLFASDW-UHFFFAOYSA-N 2-(1-cyclopropylethenyl)phenol Chemical compound C1(CC1)C(=C)C1=C(C=CC=C1)O HXOVWGDXLFASDW-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- VFRCXEHNAFUTQC-UHFFFAOYSA-N 2-[[2-(phenylmethoxycarbonylamino)acetyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)CNC(=O)OCC1=CC=CC=C1 VFRCXEHNAFUTQC-UHFFFAOYSA-N 0.000 description 1
- XBQADBXCNQPHHY-NSHDSACASA-N 33305-77-0 Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C([N+]([O-])=O)C=C1 XBQADBXCNQPHHY-NSHDSACASA-N 0.000 description 1
- UYOZWZKJQRBZRH-UHFFFAOYSA-N 4-oxo-4-phenylmethoxy-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound C=1C=CC=CC=1COC(=O)C(CC(=O)O)NC(=O)OCC1=CC=CC=C1 UYOZWZKJQRBZRH-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CGJOQVQYJJEWGF-UHFFFAOYSA-N CCSC(C)C1=CC=CC(C(C)C2CC2)=C1O Chemical compound CCSC(C)C1=CC=CC(C(C)C2CC2)=C1O CGJOQVQYJJEWGF-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- DZYBBBYFLOPVOL-UHFFFAOYSA-N methyl 2-(phenylmethoxycarbonylamino)acetate Chemical compound COC(=O)CNC(=O)OCC1=CC=CC=C1 DZYBBBYFLOPVOL-UHFFFAOYSA-N 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- BFFLLBPMZCIGRM-MRVPVSSYSA-N tert-butyl (2r)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1CO BFFLLBPMZCIGRM-MRVPVSSYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
- C07C69/40—Succinic acid esters
-
- 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
Definitions
- the invention relates to a phenol derivative, its crystal form and a preparation method, in particular to a solid intermediate for preparing the phenol derivative.
- Propofol activates multiple gamma-aminobutyric acid type A (GABA A ) receptor subtypes and is widely used for induction and maintenance of general anesthesia.
- GABA A gamma-aminobutyric acid type A
- the remarkable pharmacokinetic and pharmacodynamic properties of propofol are rapid onset of action, short duration of action and rapid reversibility.
- propofol quickly enters hyperperfused areas such as the heart, lungs, and liver from the blood, and its high fat solubility makes it easy for propofol to cross the blood-brain barrier and enter the brain to exert general anesthesia.
- Patent WO2014180305 describes a class of phenol derivatives and their preparation methods and uses in the central nervous system, some of which have stronger GABA A agonistic activity than commercially available propofol, and can be predicted to have the effect of avoiding injection pain.
- Patent CN202111122520.6 describes another class of phenol derivatives and their application in medicine. Some compounds disclosed in it have stronger medicinal effects and lower side effects.
- the present invention provides another solid intermediate for synthesizing phenol derivatives, which has a structure shown in formula (I) or formula (II), wherein formula (II) is formed by introducing amino acid protecting groups and phenolic hydroxyl groups into esters
- formula (II) is formed by introducing amino acid protecting groups and phenolic hydroxyl groups into esters
- the solid intermediate formula (II) obtained by forming an ester of an amino acid protecting group and a phenolic hydroxyl group is compared with that obtained by forming a carbamate between (R)-(+)-1-phenylethyl isocyanate and a phenolic hydroxyl group in the prior art.
- the solid intermediate obtained by the present invention has a good resolution effect, and the obtained product has high optical purity, and the raw materials used for introducing amino acid protecting groups are relatively cheap, the production cost is low, and industrial production is easy to realize.
- the present invention provides an intermediate for the synthesis of phenol derivatives through a large number of creative experiments by the researchers. After studying its solid state, we found a solid state with obvious powder X-ray diffraction pattern characteristics form.
- the intermediate provided by the invention has high optical purity, is more conducive to the synthesis of phenol derivatives with high optical purity, and has more industrial production value.
- the method for splitting synthetic intermediates provided by the invention reduces the difficulty of splitting, has high splitting purity and high yield, and the compound is stable during the splitting process, and the compound can be recycled and utilized many times to achieve the optimization of material utilization.
- the intermediate provided by the invention synthesizes the target product of the phenol derivative, and the cost is lower.
- the present invention provides a compound represented by formula (I) or formula (II), or a stereoisomer thereof:
- R is a hydroxyl protecting group, the hydroxyl protecting group is selected from amino acid protecting groups, and the amino acid protecting group is selected from Boc-amino acid protecting group, Cbz-amino acid protecting group, Fmoc-amino acid protecting group;
- R is the following structural formula:
- n is selected from 1,2,3.
- the compound has the structure shown in the following formula (III):
- n is selected from 1, 2, 3.
- the compound has the structure shown in the following formula (IV) or formula (IV-I) or its isomer formula:
- the compound has the structure shown in the following formula (III-I):
- the present invention also provides the X-ray powder diffraction pattern of the crystal form of compound formula (III-I), whose values at 2 ⁇ are: 7.280, 10.847, 10.954, 13.641, 14.304, 14.419, 15.161, 15.683, 16.556, 17.659, 18.501 , 18.600, 19.301, 20.558, 20.663, 21.620, 22.060, 22.281, 22.663, 23.941, 25.461, 25.800, 26.500, 27.800, 28.079, 29.142, 29.498, 30.577, 3 Diffraction peaks at 0.819, 31.761, 34.979, 37.741, 42.400, 44.257 .
- the X-ray powder diffraction pattern of the crystal form of the compound formula (III-I) also has a 2 ⁇ value of: 10.616, 15.583, 27.321, 29.902, 32.942, 33.503, 36.239, 39.601, 48.303 or There are many diffraction peaks.
- the present invention also provides the X-ray powder diffraction pattern of the structure shown in compound formula (IV) or the crystal form of its isomer formula, and its value at 2 ⁇ is: 9.316, 12.121, 13.097, 13.599, 15.158, 16.037, 17.222, 18.239 , 18.659, 20.142, 20.519, 20.858, 21.279, 22.261, 23.123, 24.182, 25.002, 25.301, 25.981, 34.839 have diffraction peaks.
- the X-ray powder diffraction pattern of the crystal form of the compound formula (IV) or its isomer formula also has a 2 ⁇ value of: 15.780, 19.499, 21.899, 27.542, 28.122, 35.338, 36.001 or There are many diffraction peaks.
- the present invention also provides a preparation method of the compound represented by the formula (III), the method is obtained by the formula (V)
- the compound is prepared by esterification with cyclic acid anhydride;
- a solvent is used in the reaction, and the solvent is selected from any one of methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone one or a mixture of several proportions;
- Described reaction adds catalyst, and catalyst is selected from DMAP;
- alkaline reagent is added to the reaction, and the alkaline reagent is selected from triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, lithium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate, Any one or a mixture of any of sodium bicarbonate.
- the present invention also provides a preparation method of the compound represented by formula (IV), which is prepared by performing condensation reaction between the compound of formula (VI) and Boc-D-alanine to form an ester;
- a solvent is used in the reaction, and the solvent is selected from any one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone one or a mixture of several proportions;
- a condensing agent is added in the reaction, and the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-(7-azobenzotriazole)-N,N, Any of N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole;
- the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-(3- Any one of dimethylaminopropyl)-3-ethylcarbodiimide;
- alkaline reagent is added to the reaction, and the alkaline reagent is selected from the bases: any one of DMAP, triethylamine, N,N-diisopropylethylamine, and pyridine.
- the preparation method of the compound represented by the formula (VI) comprises the following steps:
- Step a hydrolyzing the compound of formula (III-1) under basic conditions to generate the compound of formula (V);
- Step b reducing the compound of formula (V) to generate the compound of formula (VI);
- described basic reagent is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, described reaction solvent Any one selected from methanol, ethanol, tetrahydrofuran, water or a mixture of any ratio;
- a reducing agent and a catalyst are used in the step b, the reducing agent is hydrogen, and the catalyst is (4R,5R)-(+)-O-[1-benzyl-1-(5-methyl- 2-Phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl](dicyclohexylphosphine)(1,5-cyclopentadiene)iridium(I)tetrakis(3, 5-Bis(trifluoromethyl)phenyl borate.
- the present invention also provides a method for purifying the compound represented by formula (III),
- the purification method is that the crude product of the compound of formula (III) is subjected to beating and purification in an organic solvent, and the organic solvent is selected from alkanes, Any one of cycloalkanes, aromatic hydrocarbons, and ether solvents or a mixture of any ratio;
- the organic solvent is selected from a single solvent of n-hexane, n-heptane or toluene;
- the organic solvent is selected from mixed solvents of n-hexane and methyl tert-butyl ether, n-heptane and methyl tert-butyl ether or toluene and methyl tert-butyl ether.
- the present invention also provides a method for purifying the compound represented by formula (IV),
- the purification method is that the crude product of the compound shown in formula (IV) is recrystallized in an organic solvent, and the organic solvent is selected from any one or a mixture of any ratio in alkane and cycloalkane solvents; preferably, the organic solvent For n-hexane or n-heptane.
- the present invention also provides a compound represented by formula (VII), or its isomer formula (VII-I) or formula (VII-II):
- the present invention also provides a preparation method of the compound represented by formula (VII), comprising the following steps:
- Step c hydrolyzing the compound of formula (IV-I) under basic conditions to generate the compound of formula (VI);
- Step d acylation of the compound of formula (VI) to generate the compound of formula (VII);
- an alkaline reagent and a reaction solvent are used in the step c, the alkaline reagent is selected from sodium hydroxide, and the reaction solvent is selected from methanol and Tetrahydrofuran, methanol and water in any one or a mixture of several ratios;
- an acylating agent, a catalyst and an alkaline agent are used, the acylating agent is selected from paraformaldehyde, the catalyst is selected from magnesium chloride, and the alkaline agent is selected from triethylamine.
- the present invention also provides a preparation method of the compound shown in formula (XI), the preparation process comprising the following steps:
- Step e Grignard reaction of the compound of formula (VII) to generate the compound of formula (IX);
- Step f reacting the compound of formula (IX) with ethanethiol to generate the compound of formula (X);
- Step g oxidizing the compound of formula (X) to generate the compound of formula (XI);
- a Grignard reagent is used in the step e, and the Grignard reagent is selected from methylmagnesium chloride;
- An acid reagent is used in the step f, and the acid reagent is selected from hydrochloric acid;
- oxidizing agent in the described step g is selected from m-chloroperoxybenzoic acid.
- amino acid protecting group in the present invention refers to the group after amino acid reacts with hydroxyl group and carboxylic acid removes hydroxyl group.
- Boc-amino acid protecting group, Cbz-amino acid protecting group, and Fmoc-amino acid protecting group are respectively Boc-amino acid, Cbz-amino acid, Fmoc-amino acid reacting with hydroxyl group after the carboxylic acid removes the hydroxyl group.
- Boc-amino acids include, but are not limited to, N-(tert-butoxycarbonyl)-L-glutamate-1-benzyl ester, Boc-L-proline, N-Boc-O-benzyl-L-serine, S- Acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N2-[tert-butoxycarbonyl]-N-(trityl base)-D-asparagine, Boc-D-alanine, N-Boc-N-nitro-L-arginine, tert-butoxycarbonyl-L-2,4-diaminobutyric acid, ( S)-3-amino-2-(tert-butoxycarbonylamino)propionic acid, Boc-glycine, N-tert-butoxycarbonyl-L-glutamic acid-5-benzyl ester, N-Boc-N'-triphenyl Methyl-L-histidine,
- Cbz-amino acids include but are not limited to N-benzyloxycarbonyl-L-arginine cyclohexylamine salt, N-benzyloxycarbonyl-glycyl-glycine, N-benzyloxycarbonyl-D-leucine, N-benzyloxycarbonyl Oxycarbonyl-L-glutamic acid-5-tert-butyl ester, N-benzyloxycarbonyl-L-leucine, N-[(benzyloxy)carbonyl]-1-(triphenylmethyl)-L -Histidine, N-alpha-benzyloxycarbonyl-L-2,3-diaminopropionic acid, Cbz-L-phenylglycine, N-benzyloxycarbonyl-O-tert-butyl-L-serine, Cbz-glycine Methyl Ester, N-Benzyloxycarbonyl-L-Tryptophan, Cbz
- Fmoc-amino acids include, but are not limited to, Fmoc-O-tert-butyl-L-threonine, Fmoc-L-aspartic acid-beta-tert-butyl ester, Fmoc-O-tert-butyl-L-glutamine Amino acid, Fmoc-O-tert-butyl-L-tyrosine, N-alpha-fluorenylmethoxycarbonyl-N-epsilon-tert-butoxycarbonyl-L-lysine, Fmoc-Pbf-arginine, N -alpha-Fmoc-N-in-tert-Butoxycarbonyl-L-Tryptophan, Fmoc-L-Proline, N-Fmoc-L-Alanine, Fmoc-L-Valine acid, Fmoc-L-methionine, Fmoc-L-phenylalanine, F
- Fig. 1 is the XRD pattern of formula (III-I) compound crystal form
- Fig. 2 is the XRD pattern of formula (IV) compound crystal form
- Fig. 3 is an ellipsoid diagram of the three-dimensional molecular structure of the compound of formula (IV).
- Chemical purity test adopt high performance liquid chromatography (HPLC) to detect the chemical purity of the product;
- Optical purity test chrial-HPLC test.
- Powder X-ray diffraction (XRD) test The characteristic powder X-ray diffraction (XRD) peaks of the compound III-I crystal form prepared in Example 1 are shown in Table 1; the powder X-ray diffraction pattern is shown in Figure 1.
- Powder X-ray diffraction (XRD) test The characteristic powder X-ray diffraction (XRD) peaks of the compound IV crystal form prepared in Example 5 are shown in Table 2; the powder X-ray diffraction pattern is shown in Figure 2.
- compound X (200mg, 0.798mmol) was dissolved in DCM (10mL) and m-chloroperoxybenzoic acid (m-CPBA, 325mg, 1.60mmol, 2.0 eq) was added to the reaction, and the reaction was allowed to react at 10°C for 0.5 hours.
- m-CPBA m-chloroperoxybenzoic acid
- the SADABS program was used to perform empirical absorption correction on the data; the SHELXT2014 software was used to analyze the single crystal structure by the direct method, and the structure was refined by the least square method.
- the isotropic calculation process is obtained, and the hydrogen atoms on C-H are obtained by calculation hydrogenation, and the riding model is used to refine it.
- the Flack constant is 0.14 (11), the chirality can be confirmed, and C7 and C13 are R configurations ( Figure 3).
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Abstract
La présente invention concerne un dérivé de phénol, une forme cristalline de celui-ci et un procédé de préparation associé, en particulier un intermédiaire solide utilisé pour préparer le dérivé de phénol, et concerne en particulier un composé représenté par la formule (I) ou la formule (II), un stéréoisomère de celui-ci, une forme cristalline de celui-ci et un procédé de préparation associé.
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WO2016188490A1 (fr) * | 2015-05-28 | 2016-12-01 | 四川海思科制药有限公司 | Procédé de préparation de 1,2-dicyclopropyléthylphénol et de son isomère optique |
CN106187702A (zh) * | 2015-05-28 | 2016-12-07 | 四川海思科制药有限公司 | 一种2‑[1‑环烷基乙烯基]苯酚的制备方法及其中间体 |
CN106278947A (zh) * | 2015-05-19 | 2017-01-04 | 四川海思科制药有限公司 | 苯酚衍生物的晶型及其制备方法 |
CN113248482A (zh) * | 2020-02-10 | 2021-08-13 | 中国药科大学 | 含苯并五元杂环结构的化合物及其制备方法与用途 |
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WO2016188490A1 (fr) * | 2015-05-28 | 2016-12-01 | 四川海思科制药有限公司 | Procédé de préparation de 1,2-dicyclopropyléthylphénol et de son isomère optique |
CN106187702A (zh) * | 2015-05-28 | 2016-12-07 | 四川海思科制药有限公司 | 一种2‑[1‑环烷基乙烯基]苯酚的制备方法及其中间体 |
CN113248482A (zh) * | 2020-02-10 | 2021-08-13 | 中国药科大学 | 含苯并五元杂环结构的化合物及其制备方法与用途 |
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