CN116829523A - Phenol derivative, crystal form and preparation method thereof - Google Patents
Phenol derivative, crystal form and preparation method thereof Download PDFInfo
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- CN116829523A CN116829523A CN202380008068.1A CN202380008068A CN116829523A CN 116829523 A CN116829523 A CN 116829523A CN 202380008068 A CN202380008068 A CN 202380008068A CN 116829523 A CN116829523 A CN 116829523A
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- amino acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000002989 phenols Chemical class 0.000 title abstract description 17
- 239000013078 crystal Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- -1 Boc-amino Chemical group 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 16
- 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 11
- 239000002904 solvent Substances 0.000 claims description 11
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 230000008569 process Effects 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 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 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 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 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- 150000002148 esters Chemical class 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 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
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 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
- 238000006482 condensation 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
- 239000007787 solid Substances 0.000 abstract description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 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 23
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- WLMSWDHYJKAXGN-UHFFFAOYSA-N 2-(1-cyclopropylethyl)phenol Chemical compound C=1C=CC=C(O)C=1C(C)C1CC1 WLMSWDHYJKAXGN-UHFFFAOYSA-N 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
- 239000000047 product Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical group OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 8
- 229940125898 compound 5 Drugs 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229960004134 propofol Drugs 0.000 description 7
- 238000009987 spinning Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000005406 washing Methods 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 150000001413 amino acids Chemical group 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 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 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 238000012360 testing method 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 238000004440 column chromatography Methods 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical group NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring 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
- 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
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 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
- 239000003480 eluent Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 238000002695 general anesthesia Methods 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
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical group [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000002156 mixing Methods 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
- 238000004537 pulping Methods 0.000 description 2
- 238000013094 purity test Methods 0.000 description 2
- 238000000967 suction filtration Methods 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
- 239000011345 viscous material Substances 0.000 description 2
- 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
- OYXZPXVCRAAKCM-SANMLTNESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid Chemical compound C1=NC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 OYXZPXVCRAAKCM-SANMLTNESA-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
- CVZUKWBYQQYBTF-ZDUSSCGKSA-N (4s)-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CCC(O)=O)C(=O)OCC1=CC=CC=C1 CVZUKWBYQQYBTF-ZDUSSCGKSA-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
- BMEARIQHWSVDBS-SNVBAGLBSA-N 2-[(1r)-1-cyclopropylethyl]-6-propan-2-ylphenol Chemical compound CC(C)C1=CC=CC([C@H](C)C2CC2)=C1O BMEARIQHWSVDBS-SNVBAGLBSA-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
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-Phenylalanine Natural products OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-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
- 230000009471 action Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 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
- 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000007730 finishing process Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 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
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 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
- 238000012544 monitoring process Methods 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
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 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 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a phenol derivative, a crystal form and a preparation method thereof, in particular to a solid intermediate for preparing the phenol derivative, and specifically provides a compound shown in a formula (I) or a formula (II), and a stereoisomer, a crystal form and a preparation method thereof.
Description
The present application claims priority from the chinese patent office, application number 202210091223.8 entitled "phenol derivatives, their crystalline forms and methods of preparation," filed on 1 month 26 2022, the entire contents of which are incorporated herein by reference.
The application relates to a phenol derivative, a crystal form and a preparation method thereof, in particular to a solid intermediate for preparing the phenol derivative.
Propofol activates a variety of gamma-aminobutyric acid forms A (GABA) A ) Receptor subtypes are widely used for induction and maintenance of general anesthesia. The remarkable pharmacokinetic and pharmacodynamic properties of propofol are fast onset of action, short duration of maintenance and rapid reversibility. After intravenous administration, propofol rapidly enters high perfusion areas such as heart, lung and liver from blood, and the high fat solubility makes propofol easily cross the blood brain barrier to enter the brain to exert general anesthesia.
In view of the propositionNumerous advantages of phenols, various propofol derivatives have been further developed based on the structure of propofol, in order to obtain a phenol derivative structure with better efficacy and fewer side effects. Patent WO2014180305 describes a class of phenol derivatives, their preparation and their use in the central nervous field, some of which have GABA which is stronger than the commercially available propofol A Agonist activity, and predictable effects of avoiding injection pain. Patent CN202111122520.6 describes another class of phenol derivatives and their use in medicine, and some of the compounds disclosed have stronger potency and lower side effects. However, most of the phenol derivatives based on the structural improvement of propofol are basically in a liquid or oil state, which is not beneficial to quality control and purification of the intermediate or target product and is also not beneficial to mass production and smooth progress of storage and transportation processes.
Chinese patent CN201510255867.6 reports a solid intermediate for synthesizing phenol derivatives, having a structure represented by the following formula (VIII), which is a solid intermediate of formula (VIII) obtained by chiral resolution by introducing-N- ((1R) -1-phenylethyl) carbamate fragment, and applied to synthesizing chiral compound 2- ((1R) -1-cyclopropylethyl) -6-isopropylphenol (i.e., cycloparaffin).
The present application provides another solid intermediate for synthesizing phenol derivatives, which has a structure as shown in formula (I) or formula (II), wherein formula (II) is a solid intermediate prepared by introducing an amino acid protecting group to form an ester with a phenolic hydroxyl group, and the present inventors have found through a great deal of creative experimental exploration that by introducing an amino acid protecting group fragment of a specific configuration to conduct chiral resolution, a solid intermediate having high optical purity can be obtained, and further synthesis of phenol derivatives of high optical purity is facilitated. Compared with the solid intermediate obtained by forming the ester by the amino acid protecting group and the phenolic hydroxyl group in the prior art and forming the carbamate by the (R) - (+) -1-phenethyl isocyanate and the phenolic hydroxyl group, the solid intermediate provided by the application has the advantages of good resolution effect, high optical purity of the obtained product, relatively cheap raw materials for introducing the amino acid protecting group, lower production cost and easiness in realizing industrial production.
Disclosure of Invention
In order to overcome the defects in the prior art, the application provides an intermediate for synthesizing the phenol derivative through a great deal of creative experimental exploration by researchers, and through researching the solid form of the intermediate, the solid form with obvious powder X-ray diffraction pattern characteristics is discovered. The intermediate provided by the application has high optical purity, is more favorable for synthesizing phenol derivatives with high optical purity, and has more industrial production value. The resolution method of the synthetic intermediate reduces resolution difficulty, has high resolution purity and high yield, is stable in compound in the resolution process, can be recycled for multiple times, achieves optimal material utilization, and has lower cost when the intermediate is adopted to synthesize the phenol derivative target product.
The application provides a compound shown as a formula (I) or a formula (II), or a stereoisomer thereof:
wherein:
r is a hydroxyl protecting group selected from amino acid protecting groups selected from Boc-amino acid protecting groups, cbz-amino acid protecting groups and Fmoc-amino acid protecting groups;
or R is the structural formula:
n is selected from 1,2 and 3.
In some embodiments, the compound has a structure according to formula (iii):
wherein n is selected from 1,2, 3.
In some embodiments, the compound has a structure represented by the following formula (IV) or formula (IV-I) or an isomer thereof:
in some preferred embodiments, the compounds have the structure of formula (III-I):
the application also provides an X-ray powder diffraction pattern of a crystalline form of the compound formula (III-I) in 2 θ The values are: 7.280 Diffraction peaks are present at positions 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, 30.819, 31.761, 34.979, 37.741, 42.400, 44.257.
Further, the X-ray powder diffraction pattern of the crystalline form of the compound formula (III-I) is also at 2 θ The values are: 10.616 One or more of 15.583, 27.321, 29.902, 32.942, 33.503, 36.239, 39.601, 48.303 has a diffraction peak.
The application also provides an X-ray powder diffraction pattern of a crystal form of the structure shown in the formula (IV) or an isomer thereof, which is shown in the specification 2 θ The values are: 9.316 The diffraction peaks at positions 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.
Further, the X-ray powder diffraction pattern of the crystalline form of the structure represented by the formula (IV) or an isomer thereof is also shown in 2 θ The values are: 15.780 One or more of 19.499, 21.899, 27.542, 28.122, 35.338, 36.001 has a diffraction peak.
In another aspect, the application also provides a method for preparing the compound shown in the formula (III),the method is characterized in that the compound shown in the formula (V) is prepared by esterification reaction with cyclic anhydride;
preferably, a solvent is used in the reaction, wherein the solvent is selected from any one or a mixture of a plurality of proportions of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene and acetone;
adding a catalyst in the reaction, wherein the catalyst is selected from DMAP;
the reaction is carried out by adding alkaline reagent, which is selected from any one or mixture of several of triethylamine, N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, lithium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate and sodium bicarbonate.
In another aspect, the application also provides a method for preparing a compound shown in formula (IV), wherein the method is prepared by performing condensation reaction on a compound shown in formula (VI) and Boc-D-alanine to prepare an ester;
preferably, a solvent is used in the reaction, and the solvent is selected from any one or a mixture of a plurality of proportions of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene and acetone;
adding a condensing agent in the reaction, wherein the condensing agent is selected from any one of N, N ' -dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethyl urea hexafluorophosphate and 1-hydroxybenzotriazole;
more preferably, the condensing agent is selected from any one of N, N' -dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide;
the reaction is added with an alkaline reagent selected from the group consisting of: DMAP, triethylamine, N-diisopropylethylamine, pyridine.
Preferably, the preparation method of the compound shown in the formula (VI) comprises the following steps:
step a: hydrolyzing the compound of formula (III-1) under basic conditions to produce a compound of formula (V);
step b: reducing the compound of formula (V) to produce a compound of formula (VI);
in the step a, an alkaline reagent and a reaction solvent are used, wherein the alkaline reagent is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate, and the reaction solvent is selected from any one or a mixture of any two of methanol, ethanol, tetrahydrofuran and water;
in the step b, a reducing agent and a catalyst are used, wherein the reducing agent is hydrogen, and the catalyst is (4R, 5R) - (+) -O- [ 1-benzyl-1- (5-methyl-2-phenyl-4, 5-dihydro-oxazol-4-yl) -2-phenylethyl ] (dicyclohexylphosphine) (1, 5-cyclopentadiene) iridium (I) tetra (3, 5-bis (trifluoromethyl) phenylborate.
In another aspect, the present application also provides a method for purifying a compound of formula (III),
the purification method comprises pulping and purifying crude product of compound of formula (III) in organic solvent selected from one or more of alkanes, cycloalkanes, aromatic hydrocarbons and ethers;
preferably, the organic solvent is selected from a single solvent of n-hexane, n-heptane or toluene;
more preferably, the organic solvent is selected from the group consisting of mixed solvents of n-hexane and methyl tert-butyl ether, n-heptane and methyl tert-butyl ether, or toluene and methyl tert-butyl ether.
In another aspect, the application also provides a method for purifying a compound shown in formula (IV),
the purification method comprises recrystallizing crude product of the compound shown in formula (IV) in organic solvent selected from one or more of alkane and naphthene hydrocarbon solvents; preferably, the organic solvent is n-hexane or n-heptane.
In another aspect, the present application also provides a compound of formula (VII), or an isomer thereof of formula (VII-I) or formula (VII-II):
further, the application also provides a preparation method of the compound shown in the formula (VII), which comprises the following steps:
step c: hydrolyzing a compound of formula (IV-I) under basic conditions to produce a compound of formula (VI);
step d: acylating the compound of formula (VI) to produce a compound of formula (VII);
preferably, in the preparation method of the compound shown in the formula (VII), in the step c, an alkaline reagent and a reaction solvent are used, wherein the alkaline reagent is selected from sodium hydroxide, and the reaction solvent is selected from any one or a mixture of a plurality of proportions of methanol and tetrahydrofuran, methanol and water;
in the step d, an acylating agent, a catalyst and an alkaline agent are used, wherein the acylating agent is selected from paraformaldehyde, the catalyst is selected from magnesium chloride, and the alkaline agent is selected from triethylamine.
The application also provides a preparation method of the compound shown in the formula (XI), wherein the preparation process comprises the following steps:
step e: reacting the compound of formula (VII) in a format to form a compound of formula (IX);
step f: reacting a compound of formula (IX) with ethanethiol to produce a compound of formula (X);
step g: oxidizing a compound of formula (X) to produce a compound of formula (XI);
preferably, a formative reagent is used in step e, wherein the formative reagent is selected from methyl magnesium chloride;
the acid reagent is used in the step f, and the acid reagent is selected from hydrochloric acid;
the oxidizing agent is used in the step g, and the oxidizing agent is selected from m-chloroperoxybenzoic acid.
The term "amino acid protecting group" as used herein refers to a group obtained by reacting an amino acid with a hydroxyl group to remove the hydroxyl group from the carboxylic acid. The Boc-amino acid protecting group, the Cbz-amino acid protecting group and the Fmoc-amino acid protecting group are groups obtained by reacting Boc-amino acid, cbz-amino acid and Fmoc-amino acid with hydroxyl and removing hydroxyl by carboxylic acid.
Boc-amino acids include, but are not limited to, N- (tert-butoxycarbonyl) -L-glutamic acid-1-benzyl ester, boc-L-proline, N-Boc-O-benzyl-L-serine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N2- [ tert-butoxycarbonyl ] -N- (trityl) -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' -trityl-L-histidine, boc-L-4-nitrophenylalanine, boc-D-prolol, boc-3- (2-naphthyl) -D-alanine.
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-L-glutamic acid-5-tert-butyl ester, N-benzyloxycarbonyl-L-leucine, N- [ (phenylmethoxy) 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-L-tyrosine, benzyloxycarbonyl-L-alanine, N-benzyloxycarbonyl-L-aspartic acid-1-methyl ester, N-benzyloxycarbonyl-L-aspartic acid-1-benzyl ester.
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-glutamic acid, fmoc-O-tert-butyl-L-tyrosine, N-alpha-fluorenylmethoxycarbonyl-N-epsilon-tert-butoxycarbonyl-L-lysine, fmoc-Pbf-arginine, N-alpha-fluorenylmethoxycarbonyl-N-in-tert-butoxycarbonyl-L-tryptophan, fmoc-L-proline, N-fluorenylmethoxycarbonyl-L-alanine, fmoc-L-valine, fmoc-L-methionine, fmoc-L-phenylalanine, fmoc-L-leucine, fmoc-L-isoleucine, fmoc-S-trityl-L-cysteine.
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application and do not constitute a limitation on the application.
FIG. 1 is an XRD pattern of a crystalline form of a compound of formula (III-I);
FIG. 2 is an XRD pattern of a crystalline form of the compound of formula (IV);
FIG. 3 is an ellipsoidal diagram of the molecular steric structure of the compound of formula (IV).
The following detailed description of the application and the advantages achieved by the embodiments are intended to assist the reader in better understanding the nature and characteristics of the application and are not intended to limit the scope of the application. Starting materials known in the present application may be synthesized using or according to methods known in the art or may be purchased commercially.
As used herein, room temperature (rt) refers to about 20-30 ℃;1M, 1N:1mol/L; eq: equivalent weight; ee: enantiomeric excess; yield = actual synthetic product mass/theoretical synthetic product mass x 100%; chemical purity test: detecting the chemical purity of the product by High Performance Liquid Chromatography (HPLC); optical purity test: and (3) testing by using a chiral-HPLC.
Example 1
Synthesis of 4- (2- (1-cyclopropylvinyl) phenoxy) -4-oxobutanoic acid (Compound III-I)
Compound V (47.0 g,293.75mmol,1.0 eq), 4-dimethylaminopyridine (DMAP, 15mg, catalytic amount) and triethylamine (TEA, 29.7g,293.75mmol,1.0 eq) were added to 250mL of Dichloromethane (DCM), succinic anhydride (29.4 g,293.75mmol,1.0 eq) was added and stirred at room temperature for 1h, thin Layer Chromatography (TLC) monitored the starting material was essentially complete, the reaction stopped, the reaction solution was poured into 100mL of water, pH was adjusted to 3 with 2M hydrochloric acid, the solution was separated, the aqueous phase was extracted with DCM (100 mL. Times.2), the organic phases were combined and dried by spin to give compound III-1, n-hexane: 250mL of a mixed solvent of methyl tert-butyl ether at 15:1 was slurried twice to give a crystalline form of compound III-I (white solid, 62.4g, yield: 81.7%).
1 H NMR(400MHz,Chloroform-d)δ7.35-7.29(m,2H),7.27-7.19(m,1H),7.10-7.03(m,1H),5.07(d,J=1.4Hz,1H),4.92(d,J=1.4Hz,1H),2.92-2.77(m,4H),1.60(m,1H),0.79-0.66(m,2H),0.59-0.47(m,2H)。
Powder X-ray diffraction (XRD) test: the characteristic powder X-ray diffraction (XRD) peaks of the crystalline form III-I of the compound prepared in example 1 are shown in table 1; the powder X-ray diffraction pattern is shown in FIG. 1.
TABLE 1
Example 2
Synthesis of (R) -2- (1-cyclopropylvinyl) phenyl 2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3-phenylpropionate (Compound 1)
After compound v (35.2 g,220mmol,1.0 eq) and Fmoc-D-phenylalanine (85.2 g,220mmol,1.0 eq) were dissolved in DCM (250 mL), the reaction was placed under ice, DMAP (279 mg,2.2mmol,0.01 eq) and N, N' -dicyclohexylcarbodiimide (DCC, 45.3g,220mmol,1.0 eq) were added to the reaction in this order, after which the reaction was stirred at room temperature for 2 hours, TLC monitored the consumption of the starting material for a large part, the reaction was stopped, the reaction was dried by spinning, 200mL of methyl tert-butyl ether was added and stirred for 5min, after filtering off the solids, the filtrate was dried by spinning to give crude product, with a volume ratio of N-hexane: 150mL of the mixed solvent of methyl tertiary butyl ether at 15:1 was slurried to give compound 1 (white solid, 75.0g, yield: 70.8%).
[M+Na] + :552.1; 1 H NMR(400MHz,CD 3 Cl)δ7.76(m,2H),7.55(m,2H),7.42-7.20(m,12H),6.98(m,1H),5.28(m,1H),5.04(s,1H),4.89(m,2H),4.47-4.19(m,3H),3.36-3.15(m,2H),1.57(m,1H),0.69(m,2H),0.45(m,2H)。
Example 3
Synthesis of 2- (1-cyclopropylvinyl) phenyl (t-butoxycarbonyl) -D-alanine ester (Compound 2)
After compound V (5.0 g,31.25mmol,1.0 eq) and Boc-D-alanine (6.2 g,32.81mmol,1.05 eq) were dissolved in DCM (50 mL), the reaction was placed under ice, DMAP (38 mg,0.31mmol,0.01 eq) and DCC (6.4 g,31.25mmol,1.0 eq) were added to the reaction in this order, after which the reaction was stirred at room temperature for 2 hours, TLC monitored that the starting material was mostly consumed, the reaction was stopped, the reaction was dried by spinning, 50mL of methyl tert-butyl ether was added and stirred for 5min, the solid was filtered off, and the filtrate was dried by spinning to give crude product, using the volume ratio n-hexane: 50mL of the mixed solvent of methyl tert-butyl ether (15:1) was slurried to give compound 2 (white solid, 6.2g, yield: 59.9%).
1 H NMR(400MHz,CD 3 Cl)δ7.36-7.29(m,2H),7.27-7.19(m,1H),7.10-7.03(m,1H),5.11(d,J=7.1Hz,1H),5.07(d,J=1.3Hz,1H),4.92(d,J=1.4Hz,1H),4.62-4.54(m,1H),1.60(m,1H),1.57(d,J=7.2Hz,3H),1.49(s,9H),0.78-0.66(m,2H),0.60-0.48(m,2H)。
Example 4
2- ((R) -1-cyclopropylethyl) phenyl (t-butoxycarbonyl)) Synthesis of L-phenylalanine ester (Compound 3)
Compound VI (15.0 g,92.6mmol,1.0 eq) and Boc-L-phenylalanine (25.8 g,97.23mmol,1.05 eq) were dissolved in dichloromethane, DMAP (113 mg,0.93mmol,0.1 eq) and DMAP (20.1 g,97.23mmol,1.05 eq) were added sequentially, then stirred at room temperature for 2 hours, monitored by TLC, and after completion of the reaction; concentrating under reduced pressure to dryness, adding methyl tert-butyl ether (80 mL), stirring for 5min, vacuum filtering, washing filter cake with methyl tert-butyl ether, and concentrating filtrate to obtain light yellow viscous substance 38.5g; n-hexane (577.5 mL,15 mL/g) was added, heated to 40deg.C and stirred for clearing, then slowly cooled to-10deg.C and stirred for 1 hour, and suction filtered to obtain 28.0g of white solid; the recrystallization was repeated in the same manner until the optical purity was not less than 99.5%, to obtain compound 3 (18.5 g, yield 47.5%).
1 H NMR(400MHz,CD 3 Cl)δ7.42(dt,J=7.4Hz,2.3Hz,1H),7.37-7.32(m,2H),7.31-7.28(m,1H),7.27(d,J=1.7Hz,1H),7.25(t,J=1.9Hz,1H),7.23-7.16(m,2H),6.86(t,J=7.4Hz,1H),5.02(d,J=7.1Hz,1H),4.81(d,J=8.4Hz,1H),3.27(dd,J=13.9Hz,6.0Hz,1H),3.17(dt,J=13.7Hz,6.3Hz,1H),2.15-2.07(m,1H),1.43(s,9H),1.22(dd,J=7.0Hz,4.2Hz,3H),0.94(dddd,J=14.3Hz,8.2Hz,6.1Hz,4.2Hz,1H),0.55-0.49(m,1H),0.36(tt,J=8.9Hz,4.7Hz,1H),0.17(dq,J=9.9Hz,4.7Hz,1H),0.07(dq,J=15.1Hz,5.0Hz,1H)。
Example 5
Synthesis of 2- ((R) -1-cyclopropylethyl) phenyl (t-butoxycarbonyl) -D-alaninate (Compound IV)
Step 1: synthesis of 2- (1-cyclopropylvinyl) phenol (V)
Compound III-I (62.4 g,240mmol,1.0 eq) was dissolved in 300mL of methanol (MeOH) and 100mL of water, sodium hydroxide (24.0 g,600mmol,2.5 eq) was added, reacted at 25℃for 5 hours, after the starting material had reacted, methanol was removed by spinning, extracted with n-hexane (150 mL. Times.3), the organic phase was washed with 100mL of saturated sodium bicarbonate solution and dried by spinning to give compound V (pale yellow liquid, 38.0g, yield 99.0%).
1 H NMR(400MHz,Chloroform-d)δ7.24-7.10(m,2H),6.99-6.83(m,2H),5.60(s,1H),5.32(d,J=1.4Hz,1H),5.07(d,J=1.5Hz,1H),1.67(m,1H),0.87-0.74(m,2H),0.61-0.50(m,2H)。
Step 2: synthesis of 2- (1-cyclopropylethyl) phenol (VI)
Compound V (47.0 g,293.8.0mmol,1.0 eq) and 150mL DCM were added to a 500mL hydrogenation kettle, and then catalyst ((4R, 5R) - (+) -O- [ 1-benzyl-1- (5-methyl-2-phenyl-4, 5-dihydro-oxazol-4-yl) -2-phenylethyl ] (dicyclohexylphosphine) (1, 5-cyclopentadiene) iridium (I) tetrakis (3, 5-bis (trifluoromethyl) phenylborate, CAS: 880262-14-6) (400 mg,0.23mmol,0.00078 eq) were added, and after the reaction of the starting materials was completed, the reaction solution was poured into 50mL of water, the organic phase was separated and dried by spinning to give crude product, which was dissolved in n-hexane, and suction-filtered, followed by short silica gel (Compound V: silica gel: 1g:1.5g, silica gel height: 8-10 cm), eluting with 1.5L of n-hexane until the filtrate was no more than 45.95% of the pale yellow compound was obtained in the filtrate.
1 H NMR(400MHz,Chloroform-d)δ7.31(dd,J=7.6Hz,1.7Hz,1H),7.11(td,J=7.7Hz,1.7Hz,1H),6.95(td,J=7.5Hz,1.3Hz,1H),6.77(dd,J=7.9Hz,1.3Hz,1H),4.75(s,1H),2.46(dd,J=8.4Hz,6.8Hz,1H),1.33(d,J=7.0Hz,3H),1.08(qt,J=8.2Hz,5.0Hz,1H),0.67-0.51(m,1H),0.46(tdd,J=8.0Hz,5.1Hz,4.0Hz,1H),0.33-0.13(m,2H)。
Step 3: synthesis of 2- ((R) -1-cyclopropylethyl) phenyl (t-butoxycarbonyl) -D-alaninate (IV)
Compound VI (57 g,351 mmol) and Boc-D-alanine (70 g,369 mmol) were dissolved in dichloromethane, DMAP (4.3 g,35 mmol) and DCC (80 g,386 mmol) were added sequentially, then stirred at room temperature for 2 hours, monitored by TLC, and compound VI reacted completely; concentrating under reduced pressure to dryness, adding methyl tert-butyl ether (500 mL), stirring for 5min, suction filtering, washing filter cake with methyl tert-butyl ether, and concentrating filtrate to obtain compound IV (pale yellow viscous substance, 110 g); n-hexane (1650 mL,15 mL/g) was added, heated to 40℃and the solution was stirred, then slowly cooled to-10℃and stirred for 1 hour, and suction filtration was performed to obtain 88g of a white solid; the recrystallization was repeated by the same method until the optical purity was not less than 99.5%, to obtain a crystalline form of the compound IV (white solid, 65g, yield 55.5%).
1 H NMR(400MHz,CD 3 Cl)δ7.46(dd,J=7.3Hz,2.2Hz,1H),7.28-7.18(m,2H),7.05-6.98(m,1H),5.11(d,J=7.1Hz,1H),4.62-4.54(m,1H),2.19(dq,J=9.1Hz,6.9Hz,1H),1.57(d,J=7.2Hz,3H),1.49(s,9H),1.27(d,J=7.0Hz,3H),1.01(m,1H),0.63-0.52(m,1H),0.39(m,1H),0.23(m,1H),0.10(m,1H)。
Powder X-ray diffraction (XRD) test: the characteristic powder X-ray diffraction (XRD) peaks for form IV of compound prepared in example 5 are shown in table 2; the powder X-ray diffraction pattern is shown in figure 2.
TABLE 2
Example 6
Synthesis of (2- (1-cyclopropylethyl) -6- (1- (ethylsulfonic acid) ethyl) phenol) (Compound XI)
Step 1: synthesis of 2- (1-cyclopropylethyl) phenol (VI)
Compound IV-I (164 g,492 mmol) was dissolved in methanol (410 mL) and tetrahydrofuran (THF, 410 mL), and then 4M aqueous sodium hydroxide solution (248 mL,984 mol) was added thereto, and the reaction was stirred at room temperature for 1 hour, and the reaction was completed as monitored by TLC; water (600 mL) was added to the reaction mixture, which was extracted with ethyl acetate (700 mL. Times.2), and the organic phase was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound VI (pale yellow liquid, 79.5g, yield 99.6%, chemical purity 98.24%).
Step 2: synthesis of 3- (1-cyclopropylethyl) -2-hydroxybenzaldehyde (VII)
Compound VI (79.5 g,490 mmol), acetonitrile (ACN, 795 mL), paraformaldehyde (73.6 g,2450 mmol), magnesium chloride (140 g,1470 mmol) and triethylamine (247.9 g,2450 mmol) were added to the flask, heated to 65deg.C and stirred for 2 hours, monitored by TLC, the starting material reacted completely; 2N HCl solution is slowly added at 0 ℃ to adjust pH=3-4, ethyl acetate is used for extraction (600 mL multiplied by 2), then water and saturated saline water are sequentially used for washing an organic phase, anhydrous sodium sulfate is used for drying, silica gel is used for filtering, and filtrate is concentrated to obtain a compound VII (dark red liquid, 86.0g, and chemical purity is 96.97%).
Step 3: synthesis of 2- (1-cyclopropylethyl) -6- (1-hydroxyethyl) phenol (IX)
Compound VII (86.0 g,452 mmol) was dissolved in tetrahydrofuran (430 mL), nitrogen was replaced and protected, cooled to 0 ℃, 3M methyl magnesium chloride (331.5 mL,994.4 mol) was slowly added dropwise, and after addition, the reaction was stirred at room temperature for 1 hour, monitored by TLC, and the starting material was complete; the reaction solution was slowly added to a saturated ammonium chloride solution (600 mL) under stirring, extracted with ethyl acetate (700 mL), and the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered over silica gel, and the filtrate was concentrated to give compound IX (yellow liquid, 92.4g, chemical purity 91.93%).
Step 4: synthesis of (2- (1-cyclopropylethyl) -6- (1- (ethylsulfanyl) ethyl) phenol (X)
Compound IX (1.0 g,4.85 mmol) was dissolved in acetonitrile (ACN, 10 mL), ethanethiol (361 mg,5.81mmol,1.2 eq) was added under nitrogen protection, hydrochloric acid (229 mg,6.30mmol,1.3 eq) was slowly added dropwise to the reaction mixture, the reaction was stirred at 15℃for 10 hours, TLC (V) N-hexane :V Acetic acid ethyl ester =5: 1) The reaction was stopped after the detection of the consumption of most of the raw materials. The reaction solution is reactedDiluting with water, extracting with ethyl acetate (50 mL. Times.3), mixing the organic phases, washing with saturated saline, concentrating, purifying the crude product by column chromatography, eluting with polarity V N-hexane :V Acetic acid ethyl ester =50: 1-20:1 to obtain compound X (yellow oily, 700mg, yield 57.7%).
1 H NMR(400MHz,CD 3 Cl)δ7.50(d,J=8.0Hz,1H),7.27-7.25(m,1H),6.93-6.91(m,1H),6.86-6.83(m,1H),4.18-4.12(m,1H),2.58-2.52(m,1H),2.40-2.34(m,2H),1.64(d,J=8.0Hz,3H),1.31-1.28(m,3H),1.19-1.15(m,3H),1.05-0.97(m,1H),0.55-0.54(m,1H),0.35-0.30(m,1H),0.20-0.16(m,2H)。
Step 5: synthesis of (2- (1-cyclopropylethyl) -6- (1- (ethylsulfonic acid) ethyl) phenol) (XI)
Compound X (200 mg,0.798 mmol) was dissolved in DCM (10 mL) under nitrogen and m-chloroperoxybenzoic acid (m-CPBA, 325mg,1.60mmol,2.0 eq) was slowly added to the reaction at-5-0deg.C and allowed to react for 0.5 hours at 10deg.C. TLC (V) N-hexane :V Acetic acid ethyl ester =1: 1) Detecting consumption of the raw materials, stopping the reaction, diluting the reaction solution with dichloromethane (10 mL), washing with saturated sodium bicarbonate solution, mixing the organic phases, washing with saturated saline solution, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating, purifying the crude product by column chromatography, eluting with eluent V N-hexane :V Acetic acid ethyl ester =1: 1, compound XI was obtained (180.0 mg, yield 82%) as pale yellow oil.
1 H NMR(400MHz,CD 3 Cl)δ7.38-7.33(m,1H),7.12-7.10(m,2H),6.99-6.96(m,1H),4.59-4.55(m,1H),2.94-2.88(m,2H),2.58-2.54(m,1H),1.83(d,J=8.0Hz,3H),1.34-1.32(m,3H),1.30-1.27(m,3H),1.05-1.01(m,1H),0.58-0.56(m,1H),0.42-0.40(m,1H),0.23-0.15(m,2H)。
Example 7
X-ray single crystal diffraction test of 2- ((R) -1-cyclopropylethyl) phenyl (t-butoxycarbonyl) -D-alanine ester (IV)
Crystal data
After the SAINT program is adopted to carry out integral reduction on the diffraction data, the SADABS program is adopted to carry out experience absorption correction on the data; analyzing the monocrystal structure by adopting SHEXT 2014 software through a direct method, finishing the structure by adopting a least square method, obtaining hydrogen atoms through isotropic calculation in the finishing process, obtaining hydrogen atoms on C-H through calculation hydrogenation, and finishing the structure by adopting a riding model. The Flack constant was 0.14 (11), and the chirality was confirmed, with C7 and C13 in the R configuration (FIG. 3).
Example 8
Synthesis of 3- ((1R) -1-cyclopropylethyl) -2-hydroxybenzaldehyde (Compound VII-I)
Step 1: synthesis of 2- ((1R) -1-cyclopropylethyl) phenol (4)
Compound IV (164 g,492 mmol) was dissolved in methanol (410 mL) and tetrahydrofuran (410 mL), and then 4M aqueous sodium hydroxide solution (246 mL,984 mol) was added thereto, and the reaction was stirred at room temperature for 1 hour, monitored by TLC, and the reaction of the starting materials was complete; water (600 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (700 mL. Times.2), the organic phase was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give Compound 4 (pale yellow liquid, 79.5g, yield 99.6%, optical purity 99.32%, chemical purity 98.24%).
Step 2: synthesis of 3- ((1R) -1-cyclopropylethyl) -2-hydroxybenzaldehyde (VII-I)
To the flask was added compound 4 (79.5 g,490 mmol), acetonitrile (795 mL), paraformaldehyde (73.6 g,2450 mmol), magnesium chloride (140 g,1470 mmol) and triethylamine (247.9 g,2450 mmol), and the mixture was heated to 65℃and stirred for 2 hours for reaction, monitored by TLC, and the starting material was reacted completely; slowly adding 2N HCl solution at 0deg.C to adjust pH=3-4, extracting with ethyl acetate (600 mL×2), washing organic phase with water and saturated saline sequentially, drying with anhydrous sodium sulfate, filtering with silica gel, and concentrating filtrate to obtain compound VII-I (dark red liquid, 86.0g, chemical purity 96.97%).
Comparative example 1
Synthesis of 2- ((1R) -1-cyclopropylethyl) phenyl N- ((1R) -1-phenylethyl) carbamate (Compound 5)
The procedure for the preparation of compound V and compound VI in comparative example 1 is identical to that in example 5.
To the flask were added compound VI (4.0 g,24.8mmol,1.0 eq), (R) - (+) -1-phenethyl isocyanate (3.97 g,27.0mmol,1.05 eq), triethylamine (2.6 g,27.0mmol,1.05 eq) and tetrahydrofuran (30 mL), and the mixture was heated to 60℃and stirred for 3 hours. TLC monitoring the reaction of the starting materials complete, pouring the reaction solution into 15mL of water, extracting with dichloromethane (30 mL. Times.3), collecting the organic phase, spin-drying, purifying with column chromatography, eluting with the eluent V N-hexane :V Acetic acid ethyl ester =10:1, yielding 7.8g of a white solid product.
2.0g of the product is recrystallized by 20mL of n-hexane or n-heptane, heated to reflux, most of the product is undissolved and cannot be recrystallized, and the product is pulped by 20mL of n-hexane at room temperature, and the white solid 1.6g (yield: 80%) is obtained by suction filtration, and the detection result is that: compound 5 and diastereoisomer 5-1 ratio listed as 51.77%:48.23% > (compound 5: ee 3.54%), substantially no resolution effect;
2.0g of the product was recrystallized from 20mL of isopropyl alcohol to obtain 1.2g (yield: 60%) of a white solid, detection result: compound 5 and diastereoisomer 5-1 ratio listed as 51.41%:48.59% > (compound 5: ee 2.82%), essentially no resolution;
2.0g of the product was recrystallized from 8mL of toluene to obtain 1.0g of a white solid (yield: 50%) as a result of detection: compound 5 and diastereoisomer 5-1 ratio listed as 52.45%:47.55% > (compound 5: ee 4.90%), with substantially no resolution effect. No good solvent is found in the follow-up process for pulping or recrystallization resolution, and the compound is difficult to resolve.
1 HNMR(400MHz,CD 3 Cl)δ7.44-7.30(m,6H),7.23-7.18(m,2H),7.08(dd,J=6.2,3.2Hz,1H),5.29(s,1H),4.95(p,J=7.1Hz,1H),2.24-2.18(m,1H),1.59(d,J=5.6Hz,3H),1.26(dd,J=13.4,7.0Hz,3H),1.02-0.98(m,1H),0.58-0.50(m,1H),0.40-0.34(m,1H),0.21-0.04(m,2H)。
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (15)
- A compound having the formula (i) or (ii), or a stereoisomer thereof:wherein:r is a hydroxyl protecting group selected from amino acid protecting groups;the amino acid protecting group is selected from a Boc-amino acid protecting group, a Cbz-amino acid protecting group and an Fmoc-amino acid protecting group;or R is the structural formula:n is selected from 1,2 and 3.
- The compound of claim 1, wherein the compound has a structure of formula (iii):wherein n is selected from 1,2, 3.
- The compound of claim 1, wherein the compound has a structure represented by the following formula (IV) or formula (IV-I) or an isomer thereof:
- the compound of claim 2, wherein the compound has a structure of formula (iii-i):
- the compound of claim 4, wherein the compound of formula (III-I) has a crystalline form having an X-ray powder diffraction pattern of 2 θ The values are: 7.280 The diffraction peaks are found in 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, 30.819, 31.761, 34.979, 37.741, 42.400, 44.257.
- The compound of claim 5, wherein the compound of formula (III-I) has an X-ray powder diffraction pattern of 2 θ The values are: 10.616 One or more of 15.583, 27.321, 29.902, 32.942, 33.503, 36.239, 39.601, 48.303 has a diffraction peak.
- A compound according to claim 3, wherein the compound has an X-ray powder diffraction pattern of the crystalline form of the structure of formula (iv) or an isomer thereof in the range of 2 θ The values are: 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 compound of claim 7, wherein the compound has a structure of formula (iv) or an isomeric form thereof, having an X-ray powder diffraction pattern of 2 θ The values are: 15.780 One or more of 19.499, 21.899, 27.542, 28.122, 35.338, 36.001 has a diffraction peak.
- A process for producing a compound represented by the formula (III), which comprises esterifying a compound of the formula (V) with a cyclic acid anhydride;
- a process for the preparation of a compound as claimed in claim 9, wherein,the reaction uses a solvent, wherein the solvent is selected from any one or a mixture of a plurality of proportions of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene and acetone;adding a catalyst to the reaction, wherein the catalyst is selected from DMAP;the reaction is carried out by adding alkaline reagent, which is selected from any one or mixture of several of triethylamine, N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, lithium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate and sodium bicarbonate.
- A preparation method of a compound shown in a formula (IV) is characterized in that the compound shown in the formula (VI) is prepared by performing condensation reaction on the compound shown in the formula (VI) and Boc-D-alanine to form ester;
- a process for the preparation of a compound as claimed in claim 11, wherein,the reaction uses a solvent, wherein the solvent is selected from any one or a mixture of a plurality of proportions of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene and acetone;adding a condensing agent to the reaction, wherein the condensing agent is selected from any one of N, N '-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azobenzotriazole) -N, N, N', N '-tetramethyl urea hexafluorophosphate and 1-hydroxybenzotriazole, and preferably any one of N, N' -dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide;and adding an alkaline reagent in the reaction, wherein the alkaline reagent is selected from any one of DMAP, triethylamine, N-diisopropylethylamine and pyridine.
- The method for producing a compound according to claim 11, wherein the method for producing a compound represented by formula (VI) comprises the steps of:step a: hydrolyzing the compound of formula (III-1) under basic conditions to produce a compound of formula (V);step b: reducing the compound of formula (V) to produce a compound of formula (VI);
- a process for the preparation of a compound of formula (VII), characterized in that it is prepared from a compound of formula (IV-I), comprising the steps of:step c: hydrolyzing a compound of formula (IV-I) under basic conditions to produce a compound of formula (VI);step d: acylating the compound of formula (VI) to produce a compound of formula (VII);
- a compound of formula (VII), or an isomer thereof, formula (VII-i) or formula (VII-II):
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