CN106278947A - Crystal formation of phenol derivatives and preparation method thereof - Google Patents
Crystal formation of phenol derivatives and preparation method thereof Download PDFInfo
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- CN106278947A CN106278947A CN201510255867.6A CN201510255867A CN106278947A CN 106278947 A CN106278947 A CN 106278947A CN 201510255867 A CN201510255867 A CN 201510255867A CN 106278947 A CN106278947 A CN 106278947A
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- crystal formation
- compound
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- solvent
- crystallization
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- 239000013078 crystal Substances 0.000 title claims abstract description 241
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 170
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 150000002989 phenols Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 103
- 238000002425 crystallisation Methods 0.000 claims description 100
- 230000008025 crystallization Effects 0.000 claims description 98
- 239000002904 solvent Substances 0.000 claims description 95
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- 230000003292 diminished effect Effects 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 44
- 238000002441 X-ray diffraction Methods 0.000 description 31
- 238000000113 differential scanning calorimetry Methods 0.000 description 22
- 238000002411 thermogravimetry Methods 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- 238000011161 development Methods 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 238000001819 mass spectrum Methods 0.000 description 7
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 7
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 238000004296 chiral HPLC Methods 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 6
- BMEARIQHWSVDBS-JTQLQIEISA-N CC(C)c1cccc([C@@H](C)C2CC2)c1O Chemical compound CC(C)c1cccc([C@@H](C)C2CC2)c1O BMEARIQHWSVDBS-JTQLQIEISA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229960004134 propofol Drugs 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- -1 (E)-but-2-ene epoxide Chemical class 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- JJSCUXAFAJEQGB-MRVPVSSYSA-N [(1r)-1-isocyanatoethyl]benzene Chemical class O=C=N[C@H](C)C1=CC=CC=C1 JJSCUXAFAJEQGB-MRVPVSSYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002695 general anesthesia Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CRBJBYGJVIBWIY-UHFFFAOYSA-N 2-isopropylphenol Chemical compound CC(C)C1=CC=CC=C1O CRBJBYGJVIBWIY-UHFFFAOYSA-N 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- JJSCUXAFAJEQGB-QMMMGPOBSA-N [(1s)-1-isocyanatoethyl]benzene Chemical class O=C=N[C@@H](C)C1=CC=CC=C1 JJSCUXAFAJEQGB-QMMMGPOBSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- JUXKGIPJLTZHJR-SNAWJCMRSA-N 1-[(e)-but-2-enoxy]-2-propan-2-ylbenzene Chemical compound C\C=C\COC1=CC=CC=C1C(C)C JUXKGIPJLTZHJR-SNAWJCMRSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- QHJALYUVHVSCRF-SJORKVTESA-N C1(CC1)[C@@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@@H](C)C1=CC=CC=C1)=O Chemical compound C1(CC1)[C@@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@@H](C)C1=CC=CC=C1)=O QHJALYUVHVSCRF-SJORKVTESA-N 0.000 description 1
- QHJALYUVHVSCRF-IAGOWNOFSA-N C1(CC1)[C@@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@H](C)C1=CC=CC=C1)=O Chemical compound C1(CC1)[C@@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@H](C)C1=CC=CC=C1)=O QHJALYUVHVSCRF-IAGOWNOFSA-N 0.000 description 1
- QHJALYUVHVSCRF-IRXDYDNUSA-N C1(CC1)[C@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@@H](C)C1=CC=CC=C1)=O Chemical compound C1(CC1)[C@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@@H](C)C1=CC=CC=C1)=O QHJALYUVHVSCRF-IRXDYDNUSA-N 0.000 description 1
- QHJALYUVHVSCRF-DLBZAZTESA-N C1(CC1)[C@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@H](C)C1=CC=CC=C1)=O Chemical compound C1(CC1)[C@H](C)C1=C(C(=CC=C1)C(C)C)OC(N[C@H](C)C1=CC=CC=C1)=O QHJALYUVHVSCRF-DLBZAZTESA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- GRFUMPFWJKGLQC-SSDOTTSWSA-N [(1r)-1-phenylethyl]carbamic acid Chemical compound OC(=O)N[C@H](C)C1=CC=CC=C1 GRFUMPFWJKGLQC-SSDOTTSWSA-N 0.000 description 1
- GRFUMPFWJKGLQC-ZETCQYMHSA-N [(1s)-1-phenylethyl]carbamic acid Chemical compound OC(=O)N[C@@H](C)C1=CC=CC=C1 GRFUMPFWJKGLQC-ZETCQYMHSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000002035 hexane extract Substances 0.000 description 1
- OAFMYIADTCIEFV-UHFFFAOYSA-N hexane;triethylalumane Chemical compound CCCCCC.CC[Al](CC)CC OAFMYIADTCIEFV-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 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
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides crystal formation of a kind of phenol derivatives and preparation method thereof, specifically provide compound shown in a kind of formula (I) and the crystal formation of isomer thereof and preparation method and they are in the purposes of field of medicaments.Structure is as follows.
Description
Technical field
The present invention relates to crystal formation of compound and isomer thereof and preparation method thereof shown in a kind of formula (I) and they
Purposes at field of medicaments.
Background technology
Propofol can activate multiple GABAAReceptor subtype, is an intravenous anesthetic ripe clinically, extensively uses
Induction and maintenance in general anesthesia.The propofol that clinical dosage is relevant can directly activate in mammalian nervous unit
GABAAReceptor-chloride channel complex, increases chloride conductance, reduces the irritability of neutral net, Jin Eryin
Play general anesthesia (1993) .Anesthesiology, 79,781-788 such as () Manami Hara.The notable medicine generation of propofol
Kinetics and pharmacodynamic properties are rapid-action, short and Rapid reversible of holding time.After intravenously administrable, propofol rapidly from
Blood enters the heart, the contour perfusion area of lung regulating liver-QI, and fat-solubility makes propofol easily cross over blood brain barrier and enters brain performance
General anesthesia effect.2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol is propofol analog, is a kind of high liposoluble
Property material, is directly administered in blood flow, can cause the rapid-onset of anesthesia.
[2-[(1R)-1-cyclopropylethyl]-6-isopropyl phenyl] N-[(1R)-phenylethyl] carbamate (change by formula (I)
Compound) it is the intermediate preparing 2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol, through its solid forms is ground
Study carefully, it has been found that there is the solid-state form of obvious powder x-ray diffraction TuPu method.
Summary of the invention
The present invention relates to a kind of formula (I) compound and the crystal formation I of isomer formula (II) compound thereof.
The present invention relates to a kind of formula (IV) compound and the crystal formation II of isomer formula (III) compound thereof.
The present invention relates to one and prepare formula (I) compound and isomer formula (II), (III), the method for (IV) crystal formation.
The present invention provides formula (I) compound and isomer formula (II) compound thereof to have identical crystal formation, crystal formation i.e.
I, its powder x-ray diffraction collection of illustrative plates is at 19.3 ± 0.2,9.5 ± 0.2,4.8 ± 0.2 and 3.7 ± 0.2 pair in d value
Should there is characteristic diffraction peak；Preferably d value be 19.3 ± 0.2,9.5 ± 0.2,8.7 ± 0.2,4.8 ± 0.2,4.5 ± 0.2,
To there being characteristic diffraction peak at 4.1 ± 0.2 and 3.7 ± 0.2；Preferably there is powder x-ray diffraction figure as shown in Figure 1
Feature representated by spectrum.
Further, the characteristic XRD peak of the crystal formation I of formula of the present invention (I) compound, with ° 2 θ and d
Value represents:
| Sequence number | °2θ | D value |
| 01 | 4.616 | 19.128 |
| 02 | 9.394 | 9.407 |
| 03 | 10.165 | 8.695 |
| 04 | 11.840 | 7.469 |
| 05 | 15.608 | 5.673 |
| 06 | 16.459 | 5.381 |
| 07 | 17.091 | 5.184 |
| 08 | 18.413 | 4.814 |
| 09 | 19.796 | 4.481 |
| 10 | 21.887 | 4.057 |
| 11 | 23.880 | 3.723 |
Further, the characteristic XRD peak of the crystal formation I of formula of the present invention (II) compound, with ° 2 θ and d
Value represents:
| Sequence number | °2θ | D value |
| 01 | 4.535 | 19.467 |
| 02 | 9.257 | 9.545 |
| 03 | 10.087 | 8.762 |
| 04 | 16.994 | 5.213 |
| 05 | 17.430 | 5.084 |
| 06 | 18.394 | 4.819 |
| 07 | 19.736 | 4.495 |
| 08 | 21.810 | 4.072 |
| 09 | 23.781 | 3.738 |
| 10 | 24.017 | 3.702 |
| 11 | 24.235 | 3.669 |
| 12 | 25.339 | 3.512 |
| 13 | 25.773 | 3.454 |
The present invention provides formula (IV) compound and isomer formula (III) compound thereof to have identical crystal formation, crystalline substance i.e.
Type II, its powder x-ray diffraction collection of illustrative plates is 10.3 ± 0.2,9.4 ± 0.2,7.7 ± 0.2,6.2 ± 0.2 Hes in d value
To there being characteristic diffraction peak at 4.6 ± 0.2, preferably d value be 10.3 ± 0.2,9.4 ± 0.2,8.4 ± 0.2,7.7 ± 0.2,
To there being characteristic diffraction peak at 6.2 ± 0.2,5.8 ± 0.2,5.0 ± 0.2,4.6 ± 0.2 and 3.9 ± 0.2；Preferably have as
The feature representated by powder x-ray diffraction collection of illustrative plates shown in Fig. 2；
Further, the characteristic XRD peak of the crystal formation II of formula of the present invention (IV) compound, with ° 2 θ and d
Value represents:
| Sequence number | °2θ | D value |
| 01 | 8.566 | 10.314 |
| 02 | 9.375 | 9.426 |
| 03 | 10.578 | 8.356 |
| 04 | 11.505 | 7.685 |
| 05 | 14.368 | 6.160 |
| 06 | 15.176 | 5.833 |
| 07 | 17.269 | 5.131 |
| 08 | 17.645 | 5.022 |
| 09 | 18.908 | 4.690 |
| 10 | 19.242 | 4.609 |
| 11 | 20.803 | 4.266 |
| 12 | 21.099 | 4.207 |
| 13 | 22.952 | 3.872 |
| 14 | 23.268 | 3.820 |
| 15 | 24.236 | 3.669 |
Further, the characteristic XRD peak of the crystal formation II of formula of the present invention (III) compound, with ° 2 θ and d
Value represents:
| Sequence number | °2θ | D value |
| 01 | 8.545 | 10.339 |
| 02 | 9.354 | 9.447 |
| 03 | 10.556 | 8.374 |
| 04 | 11.447 | 7.724 |
| 05 | 14.329 | 6.176 |
| 06 | 15.138 | 5.848 |
| 07 | 17.229 | 5.142 |
| 08 | 17.624 | 5.028 |
| 09 | 18.869 | 4.699 |
| 10 | 19.202 | 4.618 |
| 11 | 20.802 | 4.267 |
| 12 | 21.078 | 4.211 |
| 13 | 22.913 | 3.878 |
| 14 | 23.229 | 3.826 |
| 15 | 24.178 | 3.678 |
In one embodiment, (quality contains the crystal formation I content of formula (I) compound of the preparation that the present invention provides
Amount) generally higher than 70%, preferably greater than 80%, the most most preferably greater than 90%.
In one embodiment, (quality contains the crystal formation I content of formula (II) compound of the preparation that the present invention provides
Amount) generally higher than 70%, preferably greater than 80%, further preferably greater than 90%.
In one embodiment, (quality contains the crystal formation II content of formula (IV) compound of the preparation that the present invention provides
Amount) generally higher than 70%, preferably greater than 80%, further preferably greater than 90%.
In one embodiment, (quality contains the crystal formation II content of formula (III) compound of the preparation that the present invention provides
Amount) generally higher than 70%, preferably greater than 80%, further preferably greater than 90%.
The present invention provides one to prepare formula (I) compound and isomer formula (II), (III), the method for (IV) crystal formation,
Including:
1. magma crystallization process: after formula (I) compound or its isomer mix with single solvent or combination solvent, room temperature
Under ultrasonic obtain suspension, then by the ultrasonic suspension obtained at room temperature magma 3 days.Take the turbid solution after magma
Filtration under diminished pressure, obtains target crystal formation after drying.
2. volatilization crystallization process: after formula (I) compound or its isomer mix with single solvent, ultrasonic under room temperature obtain
Molten clear liquid or close to molten clear liquid, uncovered placement is volatilized the most naturally, then obtains target crystal formation after drying.
3. crystallisation by cooling method: after formula (I) compound or its isomer mix with combination solvent, ultrasonic under room temperature obtains
Suspension, to molten by suspension heated and stirred clearly or be positioned over close to molten and be stirred at room temperature clearly, have filtration under diminished pressure after crystallization,
Obtain target crystal formation after drying.
4. antisolvent crystallization method: in formula (I) compound or its isomer add good solvent, under room temperature ultrasonic obtain molten
Clear liquid or close to molten clear liquid, the mode then using forward to add adds the solvent resistant of corresponding proportion in the molten clear liquid of sample
And stir, stir to there being filtration under diminished pressure after crystallization, obtain target crystal formation after drying.
Preferred version of the present invention, one prepares formula (I) compound and isomer formula (II), (III), (IV) crystal formation
Method, the method includes: formula (I) compound or its isomer mix with solvent, ultrasonic under room temperature obtains suspension,
Suspension at room temperature magma 3 days, take the turbid solution filtration under diminished pressure after magma, are dried；Described solvent is selected from water and second
The combination of one or more in alcohol, isopropanol, acetone or 1,4-dioxane；
A kind of combination in water and ethanol, isopropanol, acetone or Isosorbide-5-Nitrae-dioxane of the preferably described solvent,
And the ratio of two kinds of solvents is 5:1～0:1；
The ratio of further preferred two kinds of solvents is 1:1；
Preferred version of the present invention, one prepares formula (I) compound and isomer formula (II), (III), (IV) crystal formation
Method, the method includes: formula (I) compound or its isomer mix with solvent, ultrasonic under room temperature obtains molten clear liquid
Or close to molten clear liquid, uncovered placement is the most naturally volatilized, then is dried；Described solvent selected from ethanol, acetone, 1,4-
The combination of one or more in dioxane, diisopropyl ether, normal hexane or normal heptane；
The preferably described combination that solvent is two kinds, the ratio of two kinds of solvents is 5:1～0:1；
The ratio of further preferred two kinds of solvents is 0:1.
Preferred version of the present invention, one prepares formula (I) compound and isomer formula (II), (III), (IV) crystal formation
Method, the method includes: formula (I) compound or its isomer mix with solvent, ultrasonic under room temperature obtains suspension,
Suspension heated and stirred clearly to molten or be positioned over close to molten and be stirred at room temperature clearly, has filtration under diminished pressure after crystallization, be dried；
Described solvent is in water, normal heptane, normal hexane, diisopropyl ether, ethanol, 1,4-dioxane, acetone or acetonitrile
The combination of one or more；
The preferably described combination that solvent is two kinds, the ratio of two kinds of solvents is 5:1～0:1；
When wherein said solvent is the combination of two kinds, can be selected from water, normal heptane, normal hexane, diisopropyl ether, ethanol,
In 1,4-dioxane, acetone or acetonitrile any two kinds；
In the certain preferred embodiments of the present invention, described solvent is water and selected from normal heptane, normal hexane, different
Any one combination in propyl ether, ethanol, 1,4-dioxane, acetone and acetonitrile；
The ratio of further preferred two kinds of solvents is 3:1～1:2.
Preferred version of the present invention, one prepares formula (I) compound and isomer formula (II), (III), (IV) crystal formation
Method, the method includes: in formula (I) compound or its isomer add good solvent, under room temperature ultrasonic obtain molten clearly
Liquid or close to molten clear liquid, the mode then using forward to add adds the solvent resistant of corresponding proportion also in the molten clear liquid of sample
Stirring, stirs to there being filtration under diminished pressure after crystallization, is dried；Described good solvent is selected from ethanol, isopropanol, acetone, 1,4-
The combination of one or more in dioxane, acetonitrile, diisopropyl ether, described solvent resistant is selected from water or normal heptane
Kind or multiple combination；
Wherein when solvent resistant is water, good solvent can be selected from ethanol, isopropanol, acetone, Isosorbide-5-Nitrae-dioxane, second
The combination of one or more in nitrile, diisopropyl ether；
Wherein when solvent resistant is normal heptane, good solvent can be selected from ethanol, isopropanol, acetone, Isosorbide-5-Nitrae-dioxane,
The combination of one or more in acetonitrile, diisopropyl ether；
The most described good solvent is selected from ethanol, isopropanol, acetone, Isosorbide-5-Nitrae-dioxane, acetonitrile, diisopropyl ether, described
Solvent resistant is selected from water or normal heptane, and the ratio of solvent resistant and good solvent is 5:1～0:1；
Further preferably solvent resistant is 4:1～1:1 with the ratio of good solvent.
Accompanying drawing explanation
Fig. 1 is the XRD figure spectrum of formula (I) compound crystal form I.
Fig. 2 is the XRD figure spectrum of formula (IV) compound crystal form II.
Fig. 3 is the XRD figure spectrum of formula (II) compound crystal form I.
Fig. 4 is the XRD figure spectrum of formula (III) compound crystal form II.
Fig. 5 is differential scanning calorimetry (DSC) curve of formula (I) compound crystal form I.
Fig. 6 is thermogravimetry (TGA) curve of formula (I) compound crystal form I.
Fig. 7 is differential scanning calorimetry (DSC) curve of formula (IV) compound crystal form II.
Fig. 8 is thermogravimetry (TGA) curve of formula (IV) compound crystal form II.
Detailed description of the invention
Implementation process and the beneficial effect of generation of the present invention is described in detail, it is intended to help to read below by way of specific embodiment
Reader is more fully understood that essence and the feature of the present invention, not as can the restriction of practical range to this case.
The structure of compound by nuclear magnetic resonance, NMR (NMR) or (with) mass spectrum (MS) determines.NMR position
Move (δ) with 10-6(ppm) unit is given.The mensuration of NMR is with (Bruker Avance III 400 and Bruker
Avance 300) nuclear magnetic resonance spectrometer, measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3),
Deuterated methanol (CD3OD), tetramethylsilane (TMS) inside it is designated as.
X-ray powder diffractometer is Bruker D8Advance diffractometer with the instrument used, and uses
Cu-Ka radiation source, unless stated otherwise, sample is the most ground.
Differential thermal analysis scanner (DSC) data are picked up from TA Instruments Q200DSC, and sample is with 10 DEG C/min
Programming rate be dried N at 40mL/min2Protection under sample is warming up to 200 DEG C from 0 DEG C.
Thermogravimetric analyzer (TGA) data are picked up from TA Instruments Q500TGA, and sample is with the liter of 10 DEG C/min
Temperature speed is heated to 300 DEG C.
Fourier infrared (FT-IR) data are picked up from Bruker Tensor27.
The mensuration of MS uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
The mensuration of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6
mm)。
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography
(TLC) specification that the silica gel plate used uses is 0.15mm～0.20mm, and the isolated and purified product of thin layer chromatography uses
Specification is 0.4mm～0.5mm.
It is carrier that column chromatography generally uses Yantai Huanghai Sea silica gel 200～300 mesh silica gel.
The initiation material that oneself of the present invention knows can use or synthesize according to methods known in the art, or commercially available in
The public affairs such as safe smooth science and technology, resistance to Jilin Chemical of pacifying, Shanghai moral are silent, Chengdu section dragon chemical industry, splendid remote chemistry science and technology, lark prestige science and technology
Department.
Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
The usual evacuation of hydrogenation, is filled with hydrogen, repeatable operation 3 times.
Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 DEG C～30 DEG C.
Embodiment 1:2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol (compound 1)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol
The first step: 1-[(E)-but-2-ene epoxide]-2-isopropyl-benzene (1B)
1-[(E)-but-2-enoxy]-2-isopropyl-benzene
10L reactor adds 2-isopropyl-phenol 1A (3000g, 22.0mol) and DMF (9.0
L), ice-water bath is cooled to 10 DEG C.It is dividedly in some parts solid sodium hydroxide (969g, 24.2mol), maintains the temperature at
Between 10 DEG C～15 DEG C, finish, the DMF (6.0 of the dropping chloro-2-butylene of 1-(2595g, 28.7mol)
L) solution.Drip complete, maintain the temperature at 10 DEG C～15 DEG C and react 5 hours.Reactant liquor is poured in frozen water, with just
Hexane extracts, and after organic facies is washed with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and filtration is concentrated under reduced pressure to give bright
Title product 1-[(E)-but-2-ene epoxide]-2-isopropyl-benzene 1B (3985g, productivity 95.08%) of yellow liquid.
1H NMR(400MHz,CDCl3) δ 7.20 (dd, 1H), 7.16～7.07 (m, 1H), 6.90 (t, 1H), 6.82
(dd, 1H), 5.89～5.67 (m, 2H), 4.50～4.39 (m, 2H), 3.35 (m, 1H), 1.79～1.69 (m, 3H), 1.21
(dd,6H)。
Second step: (R, S)-2-isopropyl-6-(1-methacrylic) phenol (1C)
(R,S)-2-isopropyl-6-(1-methylallyl)phenol
5L reactor adds 1-[(E)-but-2-ene epoxide]-2-isopropyl-benzene 1B (3985g, 20.5mol) and potassium carbonate
(28.3g, 0.205mol), nitrogen is protected, and is warming up to 200 DEG C and reacts 7 hours.Reactant liquor is cooled to room temperature, uses
After the mixed solvent (v:v=1:1) of ethylene glycol and methanol dissolves, add n-hexane extraction 3 times, separate lower floor.Lower floor adds
Saturated nacl aqueous solution, with n-hexane extraction, merges normal hexane layer, after washing with saturated nacl aqueous solution, and anhydrous sulfur
Acid sodium is dried.Filtering and concentrating, residue column chromatography (eluant is normal hexane: ethyl acetate (v:v)=100:1～20:1)
Rear decompression distill colorless oil title product (R, S)-2-isopropyl-6-(1-methacrylic) phenol 1C (1340g,
Productivity 33.63%, HPLC:98.22%).
1H NMR(400MHz,CDCl3)δ7.10(d,1H),6.98(d,1H),6.88(t,1H),6.07(m,1H),
5.20 (m, 3H), 3.69～3.56 (m, 1H), 3.24 (m, 1H), 1.40 (d, 3H), 1.23 (dd, 6H).
3rd step: (R, S)-2-(1-cyclopropylethyl)-6-isopropyl-phenol (1D)
(R,S)-2-(1-cyclopropylethyl)-6-isopropyl-phenol
Under nitrogen air-flow protection, in 100L glass reaction still add 1.0M triethyl aluminum hexane solution (64.00L,
64.00mol), cool to-5 DEG C～5 DEG C.Lower dropping (R, S)-2-isopropyl-6-(1-the methacrylic)-phenol of stirring
Dichloromethane (13.56kg) solution of 1C (4.06kg, 21.34mol), finishes for 3 hours；Dropping diiodomethane
(20.00kg, 74.67mol), finishes for about 40 minutes；The complete holding 30 DEG C～35 DEG C that feeds is reacted 48 hours.Stir
Mix down, reactant liquor is dropped to cancellation in the sodium hydrate aqueous solution of 10.0%.After cancellation liquid stratification, separate
Machine layer；Water layer with n-hexane extraction once, after separating aqueous alkali layer, merges organic layer；Organic layer successively with deionized water,
After sodium chloride solution washing, anhydrous sodium sulfate is dried.After filtering and concentrating, decompression distillation obtains faint yellow oily title and produces
Thing (R, S)-2-(1-cyclopropylethyl)-6-isopropyl-phenol 1D (3.52kg, productivity 80.73%, HPLC:96.59%).
1H NMR(400MHz,CDCl3)δ7.11(d,1H),7.06(d,1H),6.89(t,1H),4.92(s,1H),
3.15 (m, 1H), 2.57～2.39 (m, 1H), 1.35～1.19 (m, 9H), 1.04 (m, 1H), 0.55 (m, 1H),
0.51～0.38 (m, 1H), 0.29～0.09 (m, 2H).
4th step: [2-[(1R, 1S)-(1-cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1R)-1-phenethyl] carbamic acid
Ester (1E)
[2-[(1R,1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate
50L glass reaction still puts into normal heptane (25.00kg), (R, S)-2-(1-cyclopropylethyl)-6-isopropyl successively
-phenol 1D (5.00kg, 24.47mol), (R)-(+)-1-phenethyl isocyanates (4.69kg, 31.87mol) and three second
Amine (1.24kg, 12.26mol), 28～33 DEG C are reacted 48 hours.Reaction terminates, and reaction feed liquid filters, and sucking filtration is the most dry,
Obtain wet product.By wet product acetic acid ethyl dissolution, after stirring 2 hours, add normal hexane, continue stirring 1 hour.Silicon
Diatomaceous earth filters, and collects filtrate.After filtrate reduced in volume, vacuum drying obtains the title product of off-white color solid fraction
[2-[(1R, 1S)-(1-cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1R)-1-phenethyl] carbamate 1E (2.68
kg)。
5th step: [2-[(1R)-1-cyclopropylethyl]-6-isopropyl phenyl] N-[(1R)-phenylethyl] carbamate
(1F)
[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate
By [2-[(1R, 1S)-(1-cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1R)-1-phenethyl] carbamate 1E
(2.68kg) using normal heptane recrystallization 3 times, filter, filter cake dries the title product obtaining off-white color solid, shaped
[2-[(1R)-1-cyclopropylethyl]-6-isopropyl phenyl] N-[(1R)-phenylethyl] carbamate 1F, off-white color solid
(2.00kg, fourth, fifth step two step gross production rate 46.52%, HPLC:97.31%, chiral-HPLC:99.90%).
1H NMR(400MHz,CDCl3) δ 7.45～7.01 (m, 8H), 5.27 (d, 1H), 4.91 (m, 1H),
3.15～2.86 (m, 1H), 2.08 (s, 1H), 1.55 (d, 3H), 1.33～0.86 (m, 10H), 0.49 (s, 1H), 0.31 (s,
1H), 0.15～-0.04 (m, 2H).
6th step: 2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol (compound 1)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol
50L glass reaction still, is passed through nitrogen stream, puts into Isosorbide-5-Nitrae-dioxane (10.17kg) and [2-[(1R)-1-ring third
Base ethyl]-6-isopropyl phenyl] N-[(1R)-phenylethyl] carbamate 1F (1.99kg), drip 6.0% hydroxide
Sodium water solution (10.17kg), finishes, and is warming up to 65 DEG C～75 DEG C and reacts 2 hours.Normal hexane is added the anti-of cooling
Answer in liquid, spread kieselguhr after stirring and filter, collect filtrate.Filtrate proceeds in 100L glass kettle, adds deionized water,
After stirring stratification, separate water layer, then with n-hexane extraction once, merge organic layer；Organic layer is successively with 3.6%
After aqueous hydrochloric acid solution, deionized water, 10.0% sodium bicarbonate aqueous solution and sodium-chloride water solution washing, anhydrous sodium sulfate
It is dried.After filtering and concentrating, decompression distillation obtains faint yellow oily title product 2-[(1R)-1-cyclopropylethyl]-6-isopropyl
Base-oxybenzene compound 1 (1.00kg, productivity 86.45%, HPLC:99.93%, chiral-HPLC:99.91%).
1H NMR(400MHz,CDCl3)δ7.11(d,2H),7.06(d,2H),6.89(t,1H),4.91(s,1H),
3.15 (m, 1H), 2.49 (m, 1H), 1.35～1.19 (m, 9H), 1.10～0.98 (m, 1H), 0.55 (m, 1H),
0.50～0.41 (m, 1H), 0.19 (m, 2H).
Embodiment 2:2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenol (compound 2)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenol
The first step: [2-[(1R, 1S)-(1-cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1S)-1-phenethyl] carbamic acid
Ester (2A)
[2-[(1R,1S)-cyclopropylethyl)]-6-isopropyl-phenyl]N-[(1S)-1-phenylethyl]carbamate
(R, S)-2-(1-cyclopropylethyl)-6-isopropyl-phenol 1D (42.00g, 205.57mmol) is added in reaction bulb
With oxolane (200mL), dropping triethylamine (58.00g, 573.18mmol), be stirring evenly and then adding into (S)-(-)-1-
Phenethyl isocyanates (45.00g, 308.36mmol), is heated to 63 DEG C and stirs 6 hours, and concentrating under reduced pressure uses second
Acetoacetic ester dissolves, and reduce pressure sucking filtration, and filtrate reduced in volume obtains title product [2-[(1R, the 1S)-(1-of white solid
Cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1S)-1-phenethyl] carbamate 2A (80.00g).
MS m/z(ESI):352.5[M+1]+。
1HNMR(400MHz,CDCl3): δ 7.38～7.11 (m, 8H), 5.27～5.08 (m, 1H), 4.94～4.87 (m,
1H), 3.00～2.97 (m, 1H), 2.08 (s, 1H), 1.55 (d, 3H), 1.23～1.13 (m, 9H), 0.95 (s, 1H),
0.49(s,1H),0.31(s,1H),0.05(s,1H)。
Second step: [2-[(1S)-1-cyclopropylethyl]-6-isopropyl phenyl] N-[(1S)-phenylethyl] carbamate (2B)
[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1S)-1-phenylethyl]carbamate
By [2-[(1R, 1S)-(1-cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1S)-1-phenethyl] obtained by previous step
Carbamate 2A (80.00g) uses normal hexane recrystallization 4 times, filters, and filter cake dries the mark obtaining white powder
Topic product [2-[(1S)-1-cyclopropylethyl]-6-isopropyl phenyl] N-[(1S)-1-phenethyl] carbamate 2B (39g,
Productivity: 54.93%, HPLC:97.62%, chiral-HPLC:99.84%).
Compound 1D contains 1 chiral centre, can only obtain two isomers, i.e. compound 1 and chemical combination after fractionation
Thing 2.Compound 2B contains two chiral centres, wherein 1 chiral centre by (S)-(-)-1-phenethyl isocyanates
Introducing, the chiral carbon atom that cyclopropane base is connected is consistent with the chirality of compound 2.
3rd step: 2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenol (compound 2)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenol
By [2-[(1S)-1-cyclopropylethyl]-6-isopropyl phenyl] N-[(1S)-1-phenethyl] carbamate 2B (39.00
G, 110.96mmol) it is dissolved in oxolane (390mL), addition 1.0M sodium hydrate aqueous solution (190mL,
190mmol), nitrogen is protected, and is heated to 70 DEG C and reacts 4 hours, stratification, collected organic layer, water layer 1M
Salt acid for adjusting pH is 7, is extracted with ethyl acetate, and merges organic facies, and saturated sodium-chloride water solution washs, anhydrous slufuric acid
Sodium is dried, and filters, by filtrate reduced in volume, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate
(v/v)=100:1) obtain title product 2-[(1S)-1-the cyclopropylethyl]-6-isopropyl-phenolated of weak yellow liquid shape
Compound 2 (17.2g, productivity: 75.80%, HPLC:97.67%, chiral-HPLC:99.86%).Compound 1D
For containing a chiral centre, after fractionation, and two isomers, i.e. compound 1 and compound 2 can be can only obtain.
MS m/z(ESI):203.1[M-1]-。
1HNMR(400MHz,CDCl3):δ7.14(dd,1H),7.08(dd,1H),6.93(t,1H),4.93(s,
1H), 3.22～3.15 (m, 1H), 2.55～2.48 (m, 1H), 1.32 (d, 6H), 1.28 (d, 3H), 1.10～1.04 (m,
1H), 0.60～0.58 (m, 1H), 0.49～0.46 (m, 1H), 0.25～0.18 (m, 2H).
Embodiment 3:[2-[(1S)-(1-cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1R)-1-phenethyl] carbamate
(compound 3)
[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate
In reaction bulb add 2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenol (compound 2) (5.00g, 24.47
And oxolane (50mL) mmol), dropping triethylamine (4.95g, 48.95mmol), it is stirring evenly and then adding into
(1R)-1-phenethyl isocyanates (5.40g, 36.71mmol), is heated to 63 DEG C and is stirred overnight, and concentrating under reduced pressure uses second
Acetoacetic ester (10mL) dissolves, and reduce pressure sucking filtration, by filtrate reduced in volume, obtains [2-[(1S)-1-ring of white solid
Ethyl]-6-isopropyl phenyl] N-[(1R)-1-phenethyl] carbamate (compound 3) (9.00g, HPLC:
98.4%, chiral-HPLC:97.3%).
MS m/z(ESI):352.5[M+1]。
1HNMR (400MHz, CDCl3): δ 7.36～7.13 (m, 8H), 5.26 (d, 1H), 4.94～4.87 (m, 1H),
3.01～2.98 (m, 1H), 2.04～2.09 (m, 1H), 1.55 (d, 3H), 1.20～1.15 (m, 9H), 0.96～0.93 (m, 1H),
0.45～0.43 (m, 1H), 0.37～0.30 (m, 1H), 0.18～0.09 (m, 2H).
Embodiment 4:[2-[(1R)-(1-cyclopropylethyl)]-6-isopropyl-phenyl] N-[(1S)-1-phenethyl] carbamate
(compound 4)
[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]N-[(1S)-1-phenylethyl]carbamate
In reaction bulb add 2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol (compound 1) (5.00g, 24.47
And oxolane (50mL) mmol), dropping triethylamine (4.95g, 48.95mmol), it is stirring evenly and then adding into
(1S)-1-phenethyl isocyanates (5.40g, 36.71mmol), is heated to 63 DEG C and is stirred overnight, and concentrating under reduced pressure uses second
Acetoacetic ester (10mL) dissolves, and reduce pressure sucking filtration, by filtrate reduced in volume, obtains [2-[(1R)-1-ring of white solid
Ethyl]-6-isopropyl phenyl] N-[(1S)-1-phenethyl] carbamate (compound 4) (9.50g, HPLC:
99.4%, chiral-HPLC:99.5%).
MS m/z(ESI):352.5[M+1]。
Embodiment 5:[2-[(1R)-1-cyclopropylethyl]-6-isopropyl phenyl] N-[(1R)-phenylethyl] carbamate
(1F) X-ray single crystal diffraction test
Choose from the off-white color solid that the 5th step of embodiment 1 prepares size be 0.30mm × 0.20mm ×
The colorless plate single crystal sticky of 0.20mm is together on glass fiber, and diffraction experiment crystal is anorthic system, and space group is P1,
Cell parameter: a=5.3665 (3), b=10.3493 (11),α=97.598 (9) °, β=
96.660 (7) °, γ=90.165 (6) °, unit cell volumeAsymmetric cell number is Z=2.?
On Xcalibur tetra-circular single crystal diffractometer in 293.15K with Mo K alpha ray (λ=0.7107, ray tube pipe pressure: 50kv,
Pipe flow: 40ma) collect diffracted intensity data, distance D=45mm between crystal and ccd detector, scanning side
Formula: 2 θ (6.32 ° < θ < 52.744 °), altogether collect 8385 point diffractions (-6≤h≤6 ,-12≤k≤12 ,-21≤l≤
23), the most independent point diffraction is 5645 [Rint=0.0372, Rsigma=0.0588].Crystal diffraction intensity data
Collection and reduction employ diffractometer software kit: CrysAlisPro, crystallographic structural analysis employ Olex2 and
SHElXS-13 (direct method), to the coordinate of whole atoms and anisotropic parameters SHElXL-13 refine (
Little square law).Final its residual error factor R of crystal structure obtained1=0.0850, wR2=0.2088 [I >=2 σ (I)],
R1=0.1115, wR2=0.2405 [all data], S=1.064, refined parameters 480, constraints 3.
The absolute configuration of 16 carbon atoms of compound 1F by known (R)-(+)-1-phenethyl isocyanates introduce,
Therefore the absolute configuration of the 16 of compound 1F carbon atoms is known R configuration, according to X-ray single crystal diffraction collection of illustrative plates (figure
1) display: the absolute configuration of C-7 is consistent with the absolute configuration of 16-C, so being also R configuration.By compound 1F's
Absolute configuration thus to confirm the absolute configuration of the C-7 of compound 1 be R configuration.
Embodiment 1:
Magma crystallization process prepares formula (I) compound and isomer formula (II), (III), (IV) crystal formation.
Take about 50mg study sample to be positioned in 10mL vial, by 5.0mL single solvent or solvent orange 2 A and molten
The mixed solvent that agent B is formed in varing proportions adds to the vial of above-mentioned placement sample, then will place sample
The vial of product and solvent is put the most ultrasonic 10min and is ensured to obtain suspension, then by ultrasonic obtain outstanding
Turbid liquid at room temperature magma 3 days.Taking the turbid solution filtration under diminished pressure after magma, crystal samples XRD, DSC after drying
Characterize with TGA.Result of study is shown in Table 1-table 8.
Table 1 formula (I) compound prepares crystal formation result
| Numbering | Temperature | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | Room temperature | Water | Ethanol | 1:1 | There is crystallization | Crystal formation I |
| 2 | Room temperature | Water | Isopropanol | 1:1 | There is crystallization | Crystal formation I |
| 3 | Room temperature | Water | Acetone | 1:1 | There is crystallization | Crystal formation I |
| 4 | Room temperature | Water | 1,4-dioxane | 1:1 | There is crystallization | Crystal formation I |
Formula (I) compound crystal form result of study display crystal is same crystal formation I, does not finds other novel crystal forms.
Such as DSC curve finding in Fig. 5, crystal formation I has good heat stability, DSC curve display crystal formation I heat absorption heat
The starting point (enthalpy is 102.2J/g) at about 112.6 DEG C of stream.DSC and TGA curve (Fig. 6) data explanation crystal formation I
Middle without mixed crystal, solvent and water of crystallization phenomenon.
Characteristic powder X-ray diffraction (XRD) peak (Fig. 1) of table 2 formula (I) compound crystal form I
| Sequence number | °2θ | D value |
| 01 | 4.616 | 19.128 |
| 02 | 9.394 | 9.407 |
| 03 | 10.165 | 8.695 |
| 04 | 11.840 | 7.469 |
| 05 | 15.608 | 5.673 |
| 06 | 16.459 | 5.381 |
| 07 | 17.091 | 5.184 |
| 08 | 18.413 | 4.814 |
| 09 | 19.796 | 4.481 |
| 10 | 21.887 | 4.057 |
| 11 | 23.880 | 3.723 |
Table 3 formula (IV) compound prepares crystal formation result
| Numbering | Temperature | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | Room temperature | Water | Ethanol | 1:1 | There is crystallization | Crystal formation II |
| 2 | Room temperature | Water | Isopropanol | 1:1 | There is crystallization | Crystal formation II |
Formula (IV) compound crystal form result of study display crystal is same crystal formation II, does not finds other novel crystal forms.
Such as DSC curve finding in Fig. 7, crystal formation II has good heat stability, DSC curve display crystal formation II heat absorption heat
The starting point (enthalpy is 56.8J/g) at about 76.2 DEG C of stream.In DSC and TGA curve (Fig. 8) data display crystal formation II
Without mixed crystal, solvent and water of crystallization phenomenon.
Characteristic powder X-ray diffraction (XRD) peak (Fig. 2) of table 4 formula (IV) compound crystal form II
| Sequence number | °2θ | D value |
| 01 | 8.566 | 10.314 |
| 02 | 9.375 | 9.426 |
| 03 | 10.578 | 8.356 |
| 04 | 11.505 | 7.685 |
| 05 | 14.368 | 6.160 |
| 06 | 15.176 | 5.833 |
| 07 | 17.269 | 5.131 |
| 08 | 17.645 | 5.022 |
| 09 | 18.908 | 4.690 |
| 10 | 19.242 | 4.609 |
| 11 | 20.803 | 4.266 |
| 12 | 21.099 | 4.207 |
| 13 | 22.952 | 3.872 |
| 14 | 23.268 | 3.820 |
| 15 | 24.236 | 3.669 |
Table 5 formula (II) compound prepares crystal formation result
| Numbering | Temperature | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | Room temperature | Water | Ethanol | 1:1 | There is crystallization | Crystal formation I |
| 2 | Room temperature | Water | Isopropanol | 1:1 | There is crystallization | Crystal formation I |
| 3 | Room temperature | Water | Acetone | 1:1 | There is crystallization | Crystal formation I |
| 4 | Room temperature | Water | 1,4-dioxane | 1:1 | There is crystallization | Crystal formation I |
Formula (II) compound crystal form result of study display crystal is same crystal formation I, does not finds other novel crystal forms,
Without mixed crystal, solvent and water of crystallization phenomenon in DSC and TGA data display crystal formation I.
Characteristic powder X-ray diffraction (XRD) peak (Fig. 3) of table 6 formula (II) compound crystal form I
| Sequence number | °2θ | D value |
| 01 | 4.535 | 19.467 |
| 02 | 9.257 | 9.545 |
| 03 | 10.087 | 8.762 |
| 04 | 16.994 | 5.213 |
| 05 | 17.430 | 5.084 |
| 06 | 18.394 | 4.819 |
| 07 | 19.736 | 4.495 |
| 08 | 21.810 | 4.072 |
| 09 | 23.781 | 3.738 |
| 10 | 24.017 | 3.702 |
| 11 | 24.235 | 3.669 |
| 12 | 25.339 | 3.512 |
| 13 | 25.773 | 3.454 |
Table 7 formula (III) compound prepares crystal formation result
| Numbering | Temperature | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | Room temperature | Water | Ethanol | 1:1 | There is crystallization | Crystal formation II |
| 2 | Room temperature | Water | Isopropanol | 1:1 | There is crystallization | Crystal formation II |
Formula (III) compound crystal form result of study display crystal is same crystal formation II, does not finds other novel crystal forms,
Without mixed crystal, solvent and water of crystallization phenomenon in DSC and TGA data display crystal formation II.
Characteristic powder X-ray diffraction (XRD) peak (Fig. 4) of table 8 formula (III) compound crystal form II
| Sequence number | °2θ | D value |
| 01 | 8.545 | 10.339 |
| 02 | 9.354 | 9.447 |
| 03 | 10.556 | 8.374 |
| 04 | 11.447 | 7.724 |
| 05 | 14.329 | 6.176 |
| 06 | 15.138 | 5.848 |
| 07 | 17.229 | 5.142 |
| 08 | 17.624 | 5.028 |
| 09 | 18.869 | 4.699 |
| 10 | 19.202 | 4.618 |
| 11 | 20.802 | 4.267 |
| 12 | 21.078 | 4.211 |
| 13 | 22.913 | 3.878 |
| 14 | 23.229 | 3.826 |
| 15 | 24.178 | 3.678 |
Embodiment 2:
Volatilization crystallization process prepares formula (I) compound and isomer formula (II), (III), the crystal formation of (IV).
Take about 25mg study sample to be positioned in 10ml or 25mL vial, single molten by 0.25～20.0mL
Agent adds to the vial of above-mentioned placement sample, is then put at room temperature by the vial placing sample and solvent
Ultrasonic 30min obtains molten clear liquid or close to molten clear liquid (if formed after ultrasonic is layering suspension, then take molten clear layer),
Direct uncovered placement is volatilized the most naturally.Gained crystal samples XRD, DSC and TGA after drying and characterizes.
The results are shown in Table 9-12.
Table 9 formula (I) compound prepares crystal formation result
| Numbering | Temperature | Solvent B | Development results | XRD result |
| 1 | Room temperature | Ethanol | There is crystallization | Crystal formation I |
| 2 | Room temperature | Acetone | There is crystallization | Crystal formation I |
| 3 | Room temperature | 1,4-dioxane | There is crystallization | Crystal formation I |
| 4 | Room temperature | Diisopropyl ether | There is crystallization | Crystal formation I |
| 5 | Room temperature | Normal hexane | There is crystallization | Crystal formation I |
| 6 | Room temperature | Normal heptane | There is crystallization | Crystal formation I |
Formula (I) compound crystal form result of study display crystal is same crystal formation I, DSC and TGA data and shows
Show in crystal formation I without mixed crystal, solvent and water of crystallization phenomenon.
Table 10 formula (IV) compound prepares crystal formation result
| Numbering | Temperature | Solvent B | Development results | XRD result |
| 1 | Room temperature | Ethanol | There is crystallization | Crystal formation II |
| 2 | Room temperature | Acetone | There is crystallization | Crystal formation II |
| 3 | Room temperature | 1,4-dioxane | There is crystallization | Crystal formation II |
| 4 | Room temperature | Diisopropyl ether | There is crystallization | Crystal formation II |
| 5 | Room temperature | Normal hexane | There is crystallization | Crystal formation II |
| 6 | Room temperature | Normal heptane | There is crystallization | Crystal formation II |
Formula (IV) compound crystal form result of study display crystal is same crystal formation II, DSC and TGA data
Without mixed crystal, solvent and water of crystallization phenomenon in display crystal formation II.
Table 11 formula (II) compound prepares crystal formation result
| Numbering | Temperature | Solvent B | Development results | XRD result |
| 1 | Room temperature | Ethanol | There is crystallization | Crystal formation I |
| 2 | Room temperature | Acetone | There is crystallization | Crystal formation I |
| 3 | Room temperature | 1,4-dioxane | There is crystallization | Crystal formation I |
| 4 | Room temperature | Diisopropyl ether | There is crystallization | Crystal formation I |
| 5 | Room temperature | Normal hexane | There is crystallization | Crystal formation I |
| 6 | Room temperature | Normal heptane | There is crystallization | Crystal formation I |
Formula (II) compound crystal form result of study display crystal is same crystal formation I, DSC and TGA data and shows
Show in crystal formation I without mixed crystal, solvent and water of crystallization phenomenon.
Table 12 formula (III) compound prepares crystal formation result
| Numbering | Temperature | Solvent B | Development results | XRD result |
| 1 | Room temperature | Ethanol | There is crystallization | Crystal formation II |
| 2 | Room temperature | Acetone | There is crystallization | Crystal formation II |
| 3 | Room temperature | 1,4-dioxane | There is crystallization | Crystal formation II |
| 4 | Room temperature | Diisopropyl ether | There is crystallization | Crystal formation II |
| 5 | Room temperature | Normal hexane | There is crystallization | Crystal formation II |
| 6 | Room temperature | Normal heptane | There is crystallization | Crystal formation II |
Formula (III) compound crystal form result of study display crystal is same crystal formation II, DSC and TGA data
Without mixed crystal, solvent and water of crystallization phenomenon in display crystal formation II.
Embodiment 3:
Crystallisation by cooling method formula (I) compound and isomer (II), (III), the crystal formation of (IV).
Take about 50mg study sample to be positioned in 10mL or 25ml vial, by 2.0～10.0mL solvent orange 2 As and
The mixed solvent that solvent B is formed in varing proportions adds to the vial of above-mentioned placement sample, then will place
The vial of sample and solvent is put the most ultrasonic 30min and is obtained suspension, will be equipped with the vial of suspension
Be directly placed into be heated in the water-bath of 60 DEG C and stir to the most molten clear or close to molten clearly, be positioned over and be stirred at room temperature.There is crystallization
Rear filtration under diminished pressure, samples XRD, DSC and TGA after drying and characterizes.The results are shown in Table 13-table 16.
Table 13 formula (I) compound prepares crystal formation result
| Numbering | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | / | Normal heptane | / | There is crystallization | Crystal formation I |
| 2 | / | Normal hexane | / | There is crystallization | Crystal formation I |
| 3 | / | Diisopropyl ether | / | There is crystallization | Crystal formation I |
| 4 | Water | Ethanol | 1:2 | There is crystallization | Crystal formation I |
| 5 | Water | 1,4-dioxane | 3:1 | There is crystallization | Crystal formation I |
| 6 | Water | Acetone | 1:1 | There is crystallization | Crystal formation I |
| 7 | Water | Acetonitrile | 3:2 | There is crystallization | Crystal formation I |
Formula (I) compound crystal form result of study display crystal is same crystal formation I, DSC and TGA data and shows
Show in crystal formation I without mixed crystal, solvent and water of crystallization phenomenon.
Table 14 formula (IV) compound prepares crystal formation result
| Numbering | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | / | Normal heptane | / | There is crystallization | Crystal formation II |
| 4 | Water | Ethanol | 1:2 | There is crystallization | Crystal formation II |
Formula (IV) compound crystal form result of study display crystal is same crystal formation II, DSC and TGA data
Without mixed crystal, solvent and water of crystallization phenomenon in display crystal formation II.
Table 15 formula (II) compound prepares crystal formation result
| Numbering | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | / | Normal heptane | / | There is crystallization | Crystal formation I |
| 2 | / | Normal hexane | / | There is crystallization | Crystal formation I |
| 3 | / | Diisopropyl ether | / | There is crystallization | Crystal formation I |
| 4 | Water | Ethanol | 1:2 | There is crystallization | Crystal formation I |
| 5 | Water | 1,4-dioxane | 3:1 | There is crystallization | Crystal formation I |
| 6 | Water | Acetone | 1:1 | There is crystallization | Crystal formation I |
| 7 | Water | Acetonitrile | 3:2 | There is crystallization | Crystal formation I |
Formula (II) compound crystal form result of study display crystal is same crystal formation I, DSC and TGA data and shows
Show in crystal formation I without mixed crystal, solvent and water of crystallization phenomenon.
Table 16 formula (III) compound prepares crystal formation result
| Numbering | Solvent orange 2 A | Solvent B | A:B | Development results | XRD result |
| 1 | / | Normal heptane | / | There is crystallization | Crystal formation II |
| 2 | / | Normal hexane | / | There is crystallization | Crystal formation II |
| 4 | Water | Ethanol | 1:2 | There is crystallization | Crystal formation II |
| 5 | Water | 1,4-dioxane | 3:1 | There is crystallization | Crystal formation II |
Formula (III) compound crystal form result of study display crystal is same crystal formation II, DSC and TGA data
Without mixed crystal, solvent and water of crystallization phenomenon in display crystal formation II.
Embodiment 4:
Antisolvent crystallization method formula (I) compound and isomer (II), (III) crystal formation.
Take about 50mg study sample to be positioned in 5mL or 10ml vial, 1.0mL good solvent is added extremely
In the vial of above-mentioned placement sample, then the vial placing sample and good solvent is put the most ultrasonic
30min obtains molten clear liquid or close to molten clear liquid, the mode then using forward to add is added in the molten clear liquid of sample accordingly
The solvent resistant of ratio also stirs, and stirs to there being filtration under diminished pressure after crystallization, samples XRD, DSC and TGA after drying
Characterize.Result is shown in 17-table 19.
Table 17 formula (I) compound prepares crystal formation result
| Numbering | Solvent resistant | Good solvent | Solvent resistant: good solvent | Development results | XRD result |
| 1 | Water | Ethanol | 4:1 | There is crystallization | Crystal formation I |
| 2 | Water | Isopropanol | 2:1 | There is crystallization | Crystal formation I |
| 3 | Water | Acetone | 4:1 | There is crystallization | Crystal formation I |
| 4 | Water | 1,4-dioxane | 4:1 | There is crystallization | Crystal formation I |
| 5 | Water | Acetonitrile | 4:1 | There is crystallization | Crystal formation I |
| 6 | Normal heptane | Diisopropyl ether | 1:1 | There is crystallization | Crystal formation I |
Formula (I) compound crystal form result of study display crystal is same crystal formation I, DSC and TGA data and shows
Show in crystal formation I without mixed crystal, solvent and water of crystallization phenomenon.
Table 18 formula (II) compound prepares crystal formation result
| Numbering | Solvent resistant | Good solvent | Solvent resistant: good solvent | Development results | XRD result |
| 1 | Water | Ethanol | 4:1 | There is crystallization | Crystal formation I |
| 2 | Water | Isopropanol | 2:1 | There is crystallization | Crystal formation I |
| 3 | Water | Acetone | 4:1 | There is crystallization | Crystal formation I |
| 4 | Water | 1,4-dioxane | 4:1 | There is crystallization | Crystal formation I |
| 5 | Water | Acetonitrile | 4:1 | There is crystallization | Crystal formation I |
| 6 | Normal heptane | Diisopropyl ether | 1:1 | There is crystallization | Crystal formation I |
Formula (II) compound crystal form result of study display crystal is same crystal formation I, DSC and TGA data and shows
Show in crystal formation I without mixed crystal, solvent and water of crystallization phenomenon.
Table 19 formula (III) compound prepares crystal formation result
| Numbering | Solvent resistant | Good solvent | Solvent resistant: good solvent | Development results | XRD result |
| 1 | Water | Ethanol | 4:1 | There is crystallization | Crystal formation II |
| 2 | Water | Isopropanol | 2:1 | There is crystallization | Crystal formation II |
| 3 | Water | Acetone | 4:1 | There is crystallization | Crystal formation II |
Formula (III) compound crystal form result of study display crystal is same crystal formation II, DSC and TGA data
Without mixed crystal, solvent and water of crystallization phenomenon in display crystal formation II.
Claims (8)
1. the identical crystal formation that formula (I) compound and isomer formula (II) compound thereof have, i.e. crystal formation I,
It is characterized in that its powder x-ray diffraction collection of illustrative plates d value be 19.3 ± 0.2,9.5 ± 0.2,4.8 ± 0.2 and 3.7 ±
To there being characteristic diffraction peak at 0.2；
Crystal formation the most according to claim 1, it is characterised in that its powder x-ray diffraction collection of illustrative plates is 19.3 in d value
To feature should be had to spread out at ± 0.2,9.5 ± 0.2,8.7 ± 0.2,4.8 ± 0.2,4.5 ± 0.2,4.1 ± 0.2 and 3.7 ± 0.2
Penetrate peak.
3. the identical crystal formation that formula (IV) compound and isomer formula (III) compound thereof have, i.e. crystal formation II, its
It is characterised by that its powder x-ray diffraction collection of illustrative plates is 10.3 ± 0.2,9.4 ± 0.2,7.7 ± 0.2,6.2 ± 0.2 in d value
With 4.6 ± 0.2 to there being characteristic diffraction peak；
Crystal formation the most according to claim 3, it is characterised in that its powder x-ray diffraction collection of illustrative plates is 10.3 in d value
± 0.2,9.4 ± 0.2,8.4 ± 0.2,7.7 ± 0.2,6.2 ± 0.2,5.8 ± 0.2,5.0 ± 0.2,4.6 ± 0.2 and 3.9
To there being characteristic diffraction peak at ± 0.2.
5. prepare formula (I) compound and a crystal formation for isomer formula (II), (III) and (IV) compound thereof, i.e.
Crystal formation I and the method for crystal formation II, the method includes: formula (I) compound or its isomer mix with solvent, under room temperature
The ultrasonic suspension that obtains, suspension at room temperature magma 3 days, take the turbid solution filtration under diminished pressure after magma, be dried；Institute
State solvent selected from water and the combination of one or more in ethanol, isopropanol, acetone or 1,4-dioxane.
6. prepare formula (I) compound and a crystal formation for isomer formula (II), (III) and (IV) compound thereof, i.e.
Crystal formation I and the method for crystal formation II, the method includes: formula (I) compound or its isomer mix with solvent, under room temperature
Ultrasonic obtaining molten clear liquid, uncovered placement is the most naturally volatilized, then is dried；Described solvent selected from ethanol, acetone,
The combination of one or more in 1,4-dioxane, diisopropyl ether, normal hexane or normal heptane.
7. prepare formula (I) compound and a crystal formation for isomer formula (II), (III) and (IV) compound thereof, i.e.
Crystal formation I and the method for crystal formation II, the method includes: formula (I) compound or its isomer mix with solvent, under room temperature
Ultrasonic obtain suspension, suspension heated and stirred be positioned over to the most molten and be stirred at room temperature clearly, has filtration under diminished pressure after crystallization,
It is dried；Described solvent is selected from water, normal heptane, normal hexane, diisopropyl ether, ethanol, 1,4-dioxane, acetone or second
The combination of one or more in nitrile.
8. prepare formula (I) compound and a crystal formation for isomer formula (II), (III) and (IV) compound thereof, i.e.
Crystal formation I and the method for crystal formation II, the method includes: add good solvent, room temperature in formula (I) compound or its isomer
Under ultrasonic obtain molten clear liquid, be subsequently adding solvent resistant and stir, stirring to there being filtration under diminished pressure after crystallization, be dried；Described
Good solvent is selected from ethanol, isopropanol, acetone, Isosorbide-5-Nitrae-dioxane, acetonitrile, diisopropyl ether, and described solvent resistant is selected from water
Or normal heptane.
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