WO2014047996A1 - New crystalline form of rosuvastatin methyl ester and preparation method thereof - Google Patents
New crystalline form of rosuvastatin methyl ester and preparation method thereof Download PDFInfo
- Publication number
- WO2014047996A1 WO2014047996A1 PCT/CN2012/083419 CN2012083419W WO2014047996A1 WO 2014047996 A1 WO2014047996 A1 WO 2014047996A1 CN 2012083419 W CN2012083419 W CN 2012083419W WO 2014047996 A1 WO2014047996 A1 WO 2014047996A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- isopropyl
- fluorophenyl
- amino
- dihydroxyhept
- pyrimidin
- Prior art date
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- SUTPUCLJAVPJRS-NDZBKKTDSA-N methyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 SUTPUCLJAVPJRS-NDZBKKTDSA-N 0.000 title claims abstract 4
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 238000002425 crystallisation Methods 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 37
- 230000008025 crystallization Effects 0.000 claims abstract description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 144
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 120
- 239000000203 mixture Substances 0.000 claims description 109
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 102
- 238000000034 method Methods 0.000 claims description 58
- 239000013078 crystal Substances 0.000 claims description 56
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 25
- 229960000672 rosuvastatin Drugs 0.000 claims description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 10
- 150000002576 ketones Chemical class 0.000 claims description 9
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 5
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 4
- CWGIFURHYMAUMX-RNFRBKRXSA-N methyl (3r,5s)-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)C=C CWGIFURHYMAUMX-RNFRBKRXSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 3
- 239000012043 crude product Substances 0.000 claims 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- OYYVAFIUFYBJRB-UHFFFAOYSA-N methyl 2-hydroxyhept-6-enoate Chemical compound COC(=O)C(O)CCCC=C OYYVAFIUFYBJRB-UHFFFAOYSA-N 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 11
- 238000004537 pulping Methods 0.000 abstract description 4
- 125000001041 indolyl group Chemical group 0.000 description 126
- -1 rosuvastatin oxime ester Chemical class 0.000 description 105
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 62
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 40
- 239000012065 filter cake Substances 0.000 description 28
- MMTXSCWTVRMIIY-PHDIDXHHSA-N (3r,5s)-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)C=C MMTXSCWTVRMIIY-PHDIDXHHSA-N 0.000 description 27
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 13
- 229930182558 Sterol Natural products 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 150000003432 sterols Chemical class 0.000 description 11
- 235000003702 sterols Nutrition 0.000 description 11
- KHIPEWLRUGVKIC-UHFFFAOYSA-N 4-Mercapto-2-pentanone Chemical compound CC(S)CC(C)=O KHIPEWLRUGVKIC-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 238000002156 mixing Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- JQJBQVRTSMGDJX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxy]decane Chemical compound CCCCCCCCCCOC(C)(C)C JQJBQVRTSMGDJX-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- IMSVBNQVZVQSND-UHFFFAOYSA-N 1,5-bis(sulfanyl)pentan-3-one Chemical compound SCCC(=O)CCS IMSVBNQVZVQSND-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 150000003505 terpenes Chemical class 0.000 description 3
- 235000007586 terpenes Nutrition 0.000 description 3
- HXZUUPAHSHVFDZ-UHFFFAOYSA-N 2-methyl-2-sulfanyloxypropane Chemical compound CC(C)(C)OS HXZUUPAHSHVFDZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 229930004069 diterpene Natural products 0.000 description 2
- 150000004141 diterpene derivatives Chemical class 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 2
- 229960004796 rosuvastatin calcium Drugs 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- IKWXJJICTWDYPP-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxy]nonane Chemical compound CCCCCCCCCOC(C)(C)C IKWXJJICTWDYPP-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- UUWFCRDPOPYJDH-UHFFFAOYSA-N 2-hydroxyhept-6-enoic acid Chemical compound OC(=O)C(O)CCCC=C UUWFCRDPOPYJDH-UHFFFAOYSA-N 0.000 description 1
- FFAADXOKPZHULO-UHFFFAOYSA-N 2-methylpropanethioic s-acid Chemical compound CC(C)C(S)=O FFAADXOKPZHULO-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- SOEGVMSNJOCVHT-VEUZHWNKSA-N Rosuvastatin lactone Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC(N(C)S(C)(=O)=O)=NC=1C1=CC=C(F)C=C1 SOEGVMSNJOCVHT-VEUZHWNKSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical compound C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- RWNJOXUVHRXHSD-UHFFFAOYSA-N hept-6-enoic acid Chemical compound OC(=O)CCCCC=C RWNJOXUVHRXHSD-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Definitions
- This invention relates to the field of compound preparation, and in particular to novel crystalline forms of rosuvastatin oxime ester and methods for their preparation. Background technique
- Rosuvastatin calcium bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-indolyl sulfonylaminopyrimidine)-5-yl] ( 3R,5S)-dihydroxy-(E)-6-hept-enoic acid] calcium salt, the structure of which is shown in formula I,
- Rosuvastatin Calcium is a super statin drug that is comparable to first-cholesterol and triglycerides.
- Rosuvastatin and the intermediate rosuvastatin oxime esters have enantiomers and diastereomers with molecules having two chiral centers at positions 3 and 5.
- ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5R)-3 the structure of 5-dihydroxyhept-6-enoic acid decyl ester is as shown in Formula II
- the structure of decyl sulfonylamino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate is as shown in Formula III
- WO 2005/040134 reports reducing rosuvastatin by lactonization or by converting amorphous rosuvastatin and an intermediate into a crystalline rosuvastatin intermediate and subsequent conversion to an amorphous form. The diastereomeric content of the intermediate.
- the method disclosed in WO 2007/040940 is to reduce the content of diastereomers of the rosuvastatin intermediate by recovering rosuvastatin diol ester and crystallizing rosuvastatin ketone-ester. Chiral purity of the rosuvastatin intermediate. However, it is very difficult to remove unreacted starting materials from the reaction.
- the present invention provides rosuvastatin oxime ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine -5-yl]
- the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[ ⁇ ] with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30%.
- the present invention provides the following technical solutions:
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidin-5-yl] (3R,5S) Crystal form of -3,5-dihydroxyhept-6-enoate, X-ray powder diffraction pattern at 2 ⁇ 1 The position has a peak, and the 2 ⁇ are 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293.
- the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, wherein the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, wherein the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 0.3, and the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 0.2, wherein the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
- the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystalline form of -3,5-dihydroxyhept-6-enoic acid ester for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof; (E)-7-[4-(4-fluorophenyl) X-ray of -6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate
- the powder diffraction pattern has peaks at 2 ⁇ ⁇ 1 position, which are 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293.
- the present invention also provides the above ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoate to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt according to US Publication No. 2005/080134 get on. This conversion can be carried out by alkaline hydrolysis of the oxime ester.
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for crystallizing a crystalline form of -3,5-dihydroxyhept-6-enoate, comprising the steps of: Step 1: obtaining (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[indolyl(decyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester;
- Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid decyl ester is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
- the solvent is ( 1-4 alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-1 .
- Aromatic hydrocarbon ethylene glycol diethyl ether, ethylene glycol dioxime ether, water, acetonitrile One or a mixture of two or more;
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (
- the solvent in step 2 is decyl alcohol, a mixture of acetonitrile and water, a mixture of acetone and water, MTBE ( ⁇ Tert-butyl ether), a mixture of sterol and water, a mixture of ethanol and water, a mixture of ethanol and MTBE, a mixture of acetonitrile and MTBE, a mixture of decyl alcohol and MTBE, MEK (mercaptoethyl ketone), 4-mercapto a mixture of 2-pentanone, MTBE and terpene, a mixture of one or more of ethyl ketone, MEK (mercaptoethyl ketone), 4-mercapto a mixture of 2-pentanone, MTBE
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidin-5-yl] (3R)
- the solvent used is not limited to the above-mentioned species, and according to the principle that the structural similar properties are similar, it is known that (3 1-4 alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-1 .
- a mixture of one or more of an aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile can be used as a solvent to facilitate The effect of crystallization, therefore, one or both of C M alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-10 aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine- Crystal form of 5-(5R,5S)-3,5-dihydroxyhept-6-enoate
- the solvent in the step 2 is MTBE, MEK, 4-mercapto-2-pentanone, terpene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the solvent in step 2 is 4-mercapto-2-pentanone and/or MTBE.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the solvent is decyl alcohol, in g/mL
- the mass to volume ratio of the crude decyl enoate to sterol is 1:1 to 10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the solvent is a mixture of decyl alcohol and water, wherein the volume ratio of sterol to water Less than 6: 1.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the solvent is a mixture of acetonitrile and MTBE, wherein the volume ratio of acetonitrile to MTBE is less than 1: 10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the solvent is a mixture of decyl alcohol and MTBE, wherein the volume ratio of sterol to MTBE is less than 1: 10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the crystallization in step 2 is specifically taking the first solution and heating to 50 ° C or higher. , cool down.
- (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R) is provided by the present invention.
- the cooling temperature is -20 - 40 °C.
- the cooling temperature is -10 to 30 °C.
- the cooling temperature is -5 to 10 °C.
- the filtration in step 2 is vacuum filtration.
- step 2 After filtration, the filter cake is collected, and the filter cake is dried, and the drying in step 2 is dried under reduced pressure or warmed up. Dry.
- the drying in step 2 is carried out under a negative pressure at 40 to 50 °C.
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-5 which is obtained by the above preparation method.
- the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for preparing a crystal form of -3,5-dihydroxyhept-6-enoate, comprising the steps of: Step 1: obtaining (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester;
- Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5 at 0-40 °C a solution of (3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester is suspended in an excess of a second solvent, and is obtained after separation and drying;
- the second solvent is selected from the group consisting of C M alcohols, C 3-8 esters, C 3-8 ketones, C 3-8 ethers, C 6-1 .
- Aromatic hydrocarbons ethylene glycol diethyl ether, ethylene glycol dioxime ether, acetonitrile, water.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-
- the second solvent is decyl alcohol, a mixture of acetonitrile and water, a mixture of acetone and water.
- MTBE nonyl tert-butyl ether
- sterol and water a mixture of ethanol and water
- a mixture of ethanol and MTBE a mixture of acetonitrile and MTBE
- MEK mercaptoethyl ketone
- 4-mercapto-2-pentanone a mixture of MTBE and toluene, a mixture of one or more of a mixture of ethyl acetate and petroleum ether.
- the present invention provides (E)-7-[ 4- ( 4 -fluorophenyl)-6-isopropyl- 2 -[[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R)
- the solvent used is not limited to the above-mentioned species, and according to the principle that the structural similar properties are similar, it is known that ( ⁇ , alcohol, ester, C) ⁇ 8 ketone, ether, C car aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile or a mixture of two or more can be used as a solvent to facilitate the pulping and thereby obtain the crystal form, therefore, C M alcohol And a mixture of one or more of an aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile, and a mixture of two or more of C, 8 ester
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the second solvent is MTBE, MEK, 4-mercapto-2-pentanone , terpene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl
- the solvent is 4-mercapto-2-pentanone and/or MTBE.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the second solvent is decyl alcohol, in terms of g/mL
- the mass to volume ratio of crude hydroxyhept-6-enoate and sterol is 1: 1 ⁇ 10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the second solvent is a mixture of decyl alcohol and water, wherein sterol and water are The volume ratio is less than 6:1.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the second solvent is a mixture of acetonitrile and MTBE, wherein the volume of acetonitrile and MTBE The ratio is less than 1:10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the second solvent is a mixture of decyl alcohol and MTBE, wherein the volume of sterol and MTBE The ratio is less than 1:10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
- the separation in step 2 is filtration.
- the filtration in step 2 is vacuum filtration.
- step 2 the drying is carried out under reduced pressure or at elevated temperature.
- the drying in the step 2 is drying under a negative pressure of 40 to 50 °C.
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-5 which is obtained by the above preparation method.
- the present invention provides rosuvastatin oxime ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl (3R,5S)-3,5-Dihydroxyhept-6-enoic acid decyl ester and a preparation method thereof.
- the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30% by solvent.
- Figure 1 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 1.
- Figure 2 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 2.
- Figure 3 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 3.
- the invention discloses rosuvastatin oxime ester and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
- the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
- the reagents used in the rosuvastatin oxime ester provided by the present invention and the preparation method thereof can be purchased from the market.
- the present invention determines X-ray powder diffraction spectra by placing a sample in crystalline form on a Siemans single silicon crystal (SSC) wafer mount and coating the sample as a thin layer by means of a microscopic slide.
- the sample was rotated at 30 revolutions per minute (to improve count statistics) and illuminated with X-rays generated by an elongated focusing copper tube operating at a wavelength of 1.5406 angstroms at 40 kV and 40 mA.
- the calibrated X-ray source passes through an automatically adjustable divergence slit set to V20 (20 mm diameter), and the reflected radiation passes directly through a 2 mm anti-scatter slit and a 0.2 mm detection slit.
- the sample received 4 seconds of radiation (continuous scan mode) for every 0.02 degrees 2 turns in the range of 2 to 40 degrees 2 turns in the ⁇ - ⁇ mode.
- the running time is 2 hours, 6 minutes and 40 seconds.
- the instrument is equipped with a scintillation counter as the detector.
- Diffrac AT Socabim
- the invention is not limited, and a suitable temperature range is within the scope of the invention.
- Example 1 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine- 5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate crystallization from benzene
- Example 5 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from MTBE
- Example 6 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) - 3,5-Dihydroxyhept-6-enoate crystallization from MEK
- Example 7 (E)- 7- [4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from ethyl acetate: petroleum ether (1:1)
- Example 8 ( ⁇ )-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid methyl ester crystallized from 4-mercapto-2-pentanone
- Example 9 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) - 3,5-Dihydroxyhept-6-enoate crystallization from ethylene glycol diterpene ether
- Example 10 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-] (3R,5S)- 3,5-Dihydroxyhept-6-enoate crystallization from sterol
- Example 11 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid methyl ester from MEK pulping
- Example 12 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (volume ratio 1:15)
- Example 13 ( ⁇ )-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (5:1 by volume)
- Example 14 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester from a mixture of decyl alcohol and MTBE (volume ratio 1: 20)
- Example 15 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetone and water lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of a mixture of acetone and water, then cooled to room temperature (25 ° C ), and then placed in a
- Example 16 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of ethanol and MTBE
- Example 17 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of 4-mercapto-2-pentanone, MTBE and toluene
- Example 18 (E)- 7 -[ 4 -( 4 -Fluorophenyl)-6-isopropyl- 2 -[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water
- Example 19 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-yl](3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from toluene
- Example 20 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of ethanol and water lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of a mixture of ethanol and water, then cooled to room temperature (30 ° C ), placed in a refrigerator (-10 ° C), frozen and crystallized,
- Example 21 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of MTBE and toluene
- Example 22 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of decyl alcohol and MTBE
- Example 23 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetonitrile and water
- Example 2 4 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from ethyl acetate and petroleum ether
- Example 26 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of ethanol and MTBE
- Example 27 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (1:25 by volume)
- Example 28 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetone and water
- Example 29 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate oxime pulping from MTBE
- Example 30 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from decyl alcohol
- Example 31 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate decylate from a mixture of decyl alcohol and water (1:1 by volume)
- Example 32 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime pulp from a mixture of decyl alcohol and MTBE (volume ratio 1:30)
- Example 33 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (volume ratio of 2:1)
- Example 34 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate decylate from a mixture of decyl alcohol and MTBE (volume ratio less than 1:10)
- Example 35 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (volume ratio less than 6: 1) lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) After heating with a mixture of 20 ml of decyl alcohol and water (volume ratio less than 6:1), The
- Example 36 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (volume ratio less than 1:10)
- Example 37 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from ethylene glycol diterpene ether
- Example 38 (E)- 7- [4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-yl](3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from MEK
- Example 39 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from mercapto tert-butyl ether
Abstract
Provided is a new crystalline form of methyl (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoate and preparation method thereof. The preparation method can obtain the crystalline form of methyl (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoate having less than 0.50% enantiotopic impurities and less than 0.30% diastereoisomeric impurities by solvent crystallization or pulping.
Description
瑞舒伐他汀曱酯的新晶型及其制备方法 New crystal form of rosuvastatin oxime ester and preparation method thereof
技术领域 Technical field
本发明涉及化合物制备领域，特别涉及瑞舒伐他汀曱酯的新晶型及其制 备方法。 背景技术 This invention relates to the field of compound preparation, and in particular to novel crystalline forms of rosuvastatin oxime ester and methods for their preparation. Background technique
瑞舒伐他汀钙 (双 [(E)-7-[4-(4-氟苯基 )-6-异丙基 -2-(N-曱基曱磺酰基氨基 嘧啶) -5-基] (3R,5S)-二羟基 -(E)-6-庚-烯酸]钙盐）， 其结构如式 I所示， 是 Rosuvastatin calcium (bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-indolyl sulfonylaminopyrimidine)-5-yl] ( 3R,5S)-dihydroxy-(E)-6-hept-enoic acid] calcium salt, the structure of which is shown in formula I,
Shionogi公司开发的一种 HMG-CoA还原酶抑制剂， 用于治疗（特别是)高胆 固醇症、 高脂蛋白血症及动脉硬化症等相关病症。 瑞舒伐他汀钙属超级他汀 类药物， 能比第一 -胆固醇和甘油三酯。 An HMG-CoA reductase inhibitor developed by Shionogi for the treatment of (especially) hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. Rosuvastatin Calcium is a super statin drug that is comparable to first-cholesterol and triglycerides.
瑞舒伐他汀及中间体瑞舒伐他汀曱酯存在对映异构体和非对映异构体， 其分子在位置 3和 5具有两个手性中心。 其中， （Ε)-7-[4-(4-氟苯基 )-6-异丙 基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5R)-3,5-二羟庚 -6-烯酸曱酯的结构 如式 II所示， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的结构如式 III所示， （E)-7-[4-(4-氟苯 基) -6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3S,5R)-3,5-二羟庚 -6-烯酸 曱酯的结构如式 IV所示， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨 基]嘧啶 -5-基] (3S,5S)-3,5-二羟庚 -6-烯酸曱酯的结构如式 V所示。这些对映异 构体和非对映异构体可用反相 HPLC检测。
Rosuvastatin and the intermediate rosuvastatin oxime esters have enantiomers and diastereomers with molecules having two chiral centers at positions 3 and 5. Wherein (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5R)-3 , the structure of 5-dihydroxyhept-6-enoic acid decyl ester is as shown in Formula II, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indenyl ( The structure of decyl sulfonylamino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate is as shown in Formula III, (E)-7-[4-( 4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3S,5R)-3,5-dihydroxyhept-6-enoate The structure of the ester is as shown in Formula IV, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] The structure of (3S,5S)-3,5-dihydroxyhept-6-enoic acid ester is as shown in Formula V. These enantiomers and diastereomers can be detected by reverse phase HPLC.
II II
式 V Formula V
US RE37, 314E中公开的瑞舒伐他汀及中间体的合成方法涉及瑞舒伐他 汀重要中间体的合成方法。 该方法将瑞舒伐他汀的酮-酯在碳 5位还原以获 得二醇酯， 在该位置的还原是他汀类药物 (statins)合成中的标准典型步骤。 但是， 这一还原步骤会产生非对映异构杂质。 The synthesis of rosuvastatin and intermediates disclosed in US RE37, 314E involves the synthesis of important intermediates of rosuvastatin. This method reduces the keto-ester of rosuvastatin at the carbon 5 position to obtain the diol ester, and reduction at this position is a standard typical procedure in the synthesis of statins. However, this reduction step produces diastereomeric impurities.
WO 2005/040134公开的方法报道是通过内酯化， 或者通过将无定形瑞 舒伐他汀及中间体转化成结晶型瑞舒伐他汀中间体和随后转化成无定形形 式， 来减少瑞舒伐他汀中间体的非对应异构体含量。 The method disclosed in WO 2005/040134 reports reducing rosuvastatin by lactonization or by converting amorphous rosuvastatin and an intermediate into a crystalline rosuvastatin intermediate and subsequent conversion to an amorphous form. The diastereomeric content of the intermediate.
WO 2007/040940公开的方法 道是通过回收瑞舒伐他汀二醇酯， 并结 晶瑞舒伐他汀酮-酯物， 来减少瑞舒伐他汀中间体的非对映异构体的含量， 从而提高瑞舒伐他汀中间体的手性纯度。但是从该反应中去除未反应的起始 原料存在很大困难。 The method disclosed in WO 2007/040940 is to reduce the content of diastereomers of the rosuvastatin intermediate by recovering rosuvastatin diol ester and crystallizing rosuvastatin ketone-ester. Chiral purity of the rosuvastatin intermediate. However, it is very difficult to remove unreacted starting materials from the reaction.
现有的方法制备的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基] 嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯均为油状物， 无法通过重结晶的 方法提纯。 发明内容 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R, prepared by the existing method) 5S)-3,5-Dihydroxyhept-6-enoic acid decyl ester is an oil and cannot be purified by recrystallization. Summary of the invention
有鉴于此， 本发明提供瑞舒伐他汀曱酯即 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的新晶 型及其制备方法。 该方法能够获得对映异构杂质小于 0.50%, 非对映异构杂 质小于 0.30%的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型。 In view of the above, the present invention provides rosuvastatin oxime ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine -5-yl] New crystal form of (3R,5S)-3,5-dihydroxyhept-6-enoate and its preparation method. The method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[曱] with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30%. Crystal form of decyl (sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate.
为了实现上述发明目的， 本发明提供以下技术方案： In order to achieve the above object, the present invention provides the following technical solutions:
本发明提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型，其 X射线粉末衍射图于 2Θ±1
位置有峰值，所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 The present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidin-5-yl] (3R,5S) Crystal form of -3,5-dihydroxyhept-6-enoate, X-ray powder diffraction pattern at 2Θ±1 The position has a peak, and the 2Θ are 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293.
应该理解， X射线粉末衍射图的 2Θ值可在机器之间或样品之间稍有变 化， 其数值可能相差大约 1个单位， 或者相差大约 0.8个单位， 或者相差大 约 0.5个单位， 或者相差大约 0.3个单位， 或者相差大约 0.1个单位， 因此所 引用的数值不能解释为绝对值。 同样应该理解， 峰的相对强度可根据测试中 样品的方位而变化， 因此包括于本发明中的 XRD迹线 (trace)强度为说明性 的， 并非意欲用于绝对比较。 It should be understood that the XΘ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
作为优选，本发明提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型，其 X射线粉末衍射 图于 2Θ±0.8位置有峰值， 所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 Preferably, the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ester having an X-ray powder diffraction pattern having a peak at 2Θ±0.8, wherein the 2Θ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
作为优选，本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型，其 X射线粉末衍射 图于 2Θ±0.5位置有峰值， 所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 Preferably, the present invention provides (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at 2Θ±0.5, wherein the 2Θ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
作为优选，本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型，其 X射线粉末衍射 图于 2Θ±0.3位置有峰值， 所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 Preferably, the present invention provides (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at a position of 2Θ±0.3, and the 2Θ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
作为优选，本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型，其 X射线粉末衍射 图于 2Θ±0.2位置有峰值， 所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 Preferably, the present invention provides (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at a position of 2Θ±0.2, wherein the 2Θ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
本发明还提供了（Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧 啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型用于制备瑞舒伐他汀或其药 物可接受盐； 上述 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2-[曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 X射线粉末衍射图于 2Θ±1位 置有峰值,所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 The present invention also provides (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystalline form of -3,5-dihydroxyhept-6-enoic acid ester for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof; (E)-7-[4-(4-fluorophenyl) X-ray of -6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate The powder diffraction pattern has peaks at 2 Θ ± 1 position, which are 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293.
本发明还提供的上述 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨 基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型向瑞舒伐他汀或瑞舒 伐他汀内酯或药物可接受盐的转化的方法， 可按照美国公开号 2005/080134 进行。 该转化可由曱酯的碱水解来进行。 （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱
基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3 ,5-二羟基庚 -6-烯酸曱酯的碱水解可由 一个或多个当量的碱金属或碱土金属碱， 如 NaOH或 Ca(OH)2,在诸如以下 的有机溶剂中进行水解： 四氢呋喃、 ACN (乙腈）、 （1-4C)醇 (MeOH、 EtOH、 IPA (异丙醇)、 丙醇、 丁醇等）、 （3-8C)酮或 (3-8C)酯（丙酮、 曱基乙基酮、 曱基 异丙基酮、 乙酸乙酯）。 水解还可由水或者上述溶剂的混合物或者水和上述 溶剂的混合物， 优选在室温下或者通过加热来进行。 The present invention also provides the above (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoate to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt according to US Publication No. 2005/080134 get on. This conversion can be carried out by alkaline hydrolysis of the oxime ester. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[曱 Base hydrolysis of (3R,5S)-3,5-dihydroxyhept-6-enoate, one or more equivalents of an alkali or alkaline earth metal base , such as NaOH or Ca(OH) 2, is hydrolyzed in an organic solvent such as: tetrahydrofuran, ACN (acetonitrile), (1-4C) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol Et.), (3-8C) ketone or (3-8C) ester (acetone, mercaptoethyl ketone, mercapto isopropyl ketone, ethyl acetate). The hydrolysis can also be carried out from water or a mixture of the above solvents or a mixture of water and the above solvents, preferably at room temperature or by heating.
本发明还提供了（E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧 啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的结晶方法，包括如下步骤： 步骤 1 : 获得 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品； The present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for crystallizing a crystalline form of -3,5-dihydroxyhept-6-enoate, comprising the steps of: Step 1: obtaining (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[indolyl(decyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester;
步骤 2: 取 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品与过量的溶剂混合后获得第一溶 液， 结晶、 分离、 干燥后即得； Step 2: Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid decyl ester is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
溶剂为（ 1-4醇、 C3-8酯、 C3-8酮、 C3-8醚、 C6-1。芳烃、 乙二醇二乙醚、 乙 二醇二曱醚、 水、 乙腈中的一种或两者以上的混合物； The solvent is ( 1-4 alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-1 . Aromatic hydrocarbon, ethylene glycol diethyl ether, ethylene glycol dioxime ether, water, acetonitrile One or a mixture of two or more;
上述 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 X射线粉末衍射图于 2Θ±1位置 有峰值， 所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, The crystalline X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid decyl ester has a peak at 2 Θ ± 1 position, and the 2 Θ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293.
为了利于结晶，本发明提供的 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺 酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的结晶方法 中， 步骤 2中溶剂为曱醇， 乙腈和水的混合物， 丙酮和水的混合物， MTBE (曱基叔丁基醚）， 曱醇和水的混合物， 乙醇和水的混合物， 乙醇和 MTBE 的混合物， 乙腈和 MTBE的混合物， 曱醇和 MTBE的混合物， MEK (曱基 乙基酮）， 4-曱基 -2-戊酮、 MTBE 和曱苯的混合物， 乙酸乙酯和石油醚的混 合物中的一种或两者以上的混合物。 可以理解， 本发明提供的 (E)-7-[4-(4-氟 苯基) -6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯 酸曱酯的晶型的制备方法中， 所用溶剂不仅限于上述种类， 根据结构相近性 质相近的原则， 可知（31-4醇、 C3-8酯、 C3-8酮、 C3-8醚、 C6-1。芳烃、 乙二醇二 乙醚、 水、 乙腈中的一种或两者以上的混合物均可作为溶剂起到利于结晶的 效果， 因此， CM醇、 C3-8酯、 C3-8酮、 C3-8醚、 C6-10芳烃、 乙二醇二乙醚、 水、 乙腈中的一种或两者以上的混合物均在本发明的保护范围内。 In order to facilitate crystallization, the present invention provides (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] ( In the crystallization method of the crystal form of 3R,5S)-3,5-dihydroxyhept-6-enoate, the solvent in step 2 is decyl alcohol, a mixture of acetonitrile and water, a mixture of acetone and water, MTBE (曱Tert-butyl ether), a mixture of sterol and water, a mixture of ethanol and water, a mixture of ethanol and MTBE, a mixture of acetonitrile and MTBE, a mixture of decyl alcohol and MTBE, MEK (mercaptoethyl ketone), 4-mercapto a mixture of 2-pentanone, MTBE and terpene, a mixture of one or more of ethyl acetate and petroleum ether. It can be understood that the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidin-5-yl] (3R) In the preparation method of the crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ester, the solvent used is not limited to the above-mentioned species, and according to the principle that the structural similar properties are similar, it is known that (3 1-4 alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-1 . A mixture of one or more of an aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile can be used as a solvent to facilitate The effect of crystallization, therefore, one or both of C M alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-10 aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile The above mixtures are all within the scope of the present invention.
在本发明的一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型
的结晶方法中， 步骤 2中溶剂为 MTBE, MEK, 4-曱基 -2-戊酮， 曱苯， 丙酮 和水的混合物， 乙腈和水的混合物中的一种或两者以上的混合物。 In some embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine- Crystal form of 5-(5R,5S)-3,5-dihydroxyhept-6-enoate In the crystallization method, the solvent in the step 2 is MTBE, MEK, 4-mercapto-2-pentanone, terpene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的结晶方法中， 步骤 2中溶剂为 4-曱基 -2-戊酮和 /或 MTBE。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the crystallization method of the crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid ester, the solvent in step 2 is 4-mercapto-2-pentanone and/or MTBE.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的结晶方法中，溶剂为曱醇， 以 g/mL计，（E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱 基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品与曱醇的 质量体积比为 1:1 ~ 10。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the crystallization method of the crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the solvent is decyl alcohol, in g/mL, (E)-7- [4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyheptane-6 The mass to volume ratio of the crude decyl enoate to sterol is 1:1 to 10.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的结晶方法中，溶剂为曱醇和水的混合物，其中，曱醇与水的体积比小于 6: 1。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the crystallization method of the crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the solvent is a mixture of decyl alcohol and water, wherein the volume ratio of sterol to water Less than 6: 1.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的结晶方法中， 溶剂为乙腈和 MTBE的混合物， 其中， 乙腈和 MTBE的体 积比小于 1: 10。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the crystallization method of the crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the solvent is a mixture of acetonitrile and MTBE, wherein the volume ratio of acetonitrile to MTBE is less than 1: 10.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的结晶方法中， 溶剂为曱醇和 MTBE的混合物， 其中， 曱醇和 MTBE的体 积比小于 1: 10。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the crystallization method of the crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the solvent is a mixture of decyl alcohol and MTBE, wherein the volume ratio of sterol to MTBE is less than 1: 10.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的结晶方法中， 步骤 2中结晶具体为取第一溶液， 加热至 50°C以上， 冷却。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the crystallization method of the crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the crystallization in step 2 is specifically taking the first solution and heating to 50 ° C or higher. , cool down.
作为优选，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的结晶方法中，冷却 温度为 -20 - 40 °C。 Preferably, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R) is provided by the present invention. In the crystallization method of the crystal form of 5S)-3,5-dihydroxyhept-6-enoate, the cooling temperature is -20 - 40 °C.
优选的， 冷却温度为 -10 ~ 30 °C。 Preferably, the cooling temperature is -10 to 30 °C.
更优选的， 冷却温度为 -5 ~ 10 °C。 More preferably, the cooling temperature is -5 to 10 °C.
本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的结晶方法中， 结晶后， 步骤 2中分离为过滤。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) provided by the present invention In the crystallization method of the crystal form of -3,5-dihydroxyhept-6-enoate, after crystallization, it is separated into a filtration in the step 2.
作为优选， 步骤 2中过滤为减压过滤。 Preferably, the filtration in step 2 is vacuum filtration.
过滤后收集滤饼， 并对滤饼进行干燥， 步骤 2中干燥为减压干燥或升温
干燥。 After filtration, the filter cake is collected, and the filter cake is dried, and the drying in step 2 is dried under reduced pressure or warmed up. Dry.
作为优选， 步骤 2中干燥为在负压力、 40 ~ 50°C的条件下干燥。 Preferably, the drying in step 2 is carried out under a negative pressure at 40 to 50 °C.
本发明还提供了由上述制备方法制得的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型； 其 X射线粉末衍射图于 2Θ±1 位置有峰值， 所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 The present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-5 which is obtained by the above preparation method. a crystal form of (3R,5S)-3,5-dihydroxyhept-6-enoate; its X-ray powder diffraction pattern has a peak at 2Θ±1, and the 2Θ is 9.3280, 17.4066, 17.9806 , 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
本发明还提供了（Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧 啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的制备方法，包括如下步骤： 步骤 1 : 获得 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3 ,5-二羟基庚 -6-烯酸曱酯粗品； The present invention also provides (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for preparing a crystal form of -3,5-dihydroxyhept-6-enoate, comprising the steps of: Step 1: obtaining (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester;
步骤 2: 在 0 ~ 40°C下， 取 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰 基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的溶液悬浮于过量的第 二溶剂中制浆， 分离、 干燥后即得； Step 2: Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5 at 0-40 °C a solution of (3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester is suspended in an excess of a second solvent, and is obtained after separation and drying;
第二溶剂选自 CM醇、 C3-8酯、 C3-8酮、 C3-8醚、 C6-1。芳烃、 乙二醇二乙 醚、 乙二醇二曱醚、 乙腈、 水。 The second solvent is selected from the group consisting of C M alcohols, C 3-8 esters, C 3-8 ketones, C 3-8 ethers, C 6-1 . Aromatic hydrocarbons, ethylene glycol diethyl ether, ethylene glycol dioxime ether, acetonitrile, water.
在本发明的一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的制备方法中， 第二溶剂为曱醇， 乙腈和水的混合物， 丙酮和水的混合物， MTBE (曱基叔丁基醚）， 曱醇和水的混合物， 乙醇和水的混合物， 乙醇和 MTBE的混合物， 乙腈和 MTBE的混合物， 曱醇和 MTBE的混合物， MEK (曱基乙基酮）， 4-曱基 -2-戊酮、 MTBE 和曱苯的混合物， 乙酸乙酯和石油 醚的混合物中的一种或两者以上的混合物。 可以理解， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸曱酯的晶型的制备方法中， 所用溶剂不仅限于上述种类，根 据结构相近性质相近的原则， 可知(^^醇、 酯、 C^8酮、 醚、 Cwo芳 烃、 乙二醇二乙醚、 水、 乙腈中的一种或两者以上的混合物均可作为溶剂起 到利于制浆进而获得晶型的效果， 因此， CM醇、 C^8酯、 酮、 C^8醚、 C6_i。芳烃、 乙二醇二乙醚、 水、 乙腈中的一种或两者以上的混合物均在本发 明的保护范围内。 In some embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine- In the preparation method of the crystal form of 5-amino](3R,5S)-3,5-dihydroxyhept-6-enoate, the second solvent is decyl alcohol, a mixture of acetonitrile and water, a mixture of acetone and water. , MTBE (nonyl tert-butyl ether), a mixture of sterol and water, a mixture of ethanol and water, a mixture of ethanol and MTBE, a mixture of acetonitrile and MTBE, a mixture of decyl alcohol and MTBE, MEK (mercaptoethyl ketone), 4-mercapto-2-pentanone, a mixture of MTBE and toluene, a mixture of one or more of a mixture of ethyl acetate and petroleum ether. It is understood that the present invention provides (E)-7-[ 4- ( 4 -fluorophenyl)-6-isopropyl- 2 -[[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R) In the preparation method of the crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ester, the solvent used is not limited to the above-mentioned species, and according to the principle that the structural similar properties are similar, it is known that (^^, alcohol, ester, C) ^ 8 ketone, ether, C car aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile or a mixture of two or more can be used as a solvent to facilitate the pulping and thereby obtain the crystal form, therefore, C M alcohol And a mixture of one or more of an aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile, and a mixture of two or more of C, 8 ester, ketone, C 8 ether, and C 6 — i are all within the scope of the present invention.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙 基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶 型的制备方法中， 第二溶剂为 MTBE, MEK, 4-曱基 -2-戊酮， 曱苯， 丙酮和 水的混合物， 乙腈和水的混合物中的一种或两者以上的混合物。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the preparation method of the crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid ester, the second solvent is MTBE, MEK, 4-mercapto-2-pentanone , terpene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙
基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶 型的制备方法中， 第二溶剂为 4-曱基 -2-戊酮和 /或 MTBE。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl In the preparation method of the crystalline form of keto-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid ester, second The solvent is 4-mercapto-2-pentanone and/or MTBE.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙 基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶 型的制备方法中， 第二溶剂为曱醇， 以 g/mL计， 所述 (E)-7-[4-(4-氟苯基 )-6- 异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯 粗品与曱醇的质量体积比为 1 : 1 ~ 10。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the method for preparing a crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the second solvent is decyl alcohol, in terms of g/mL, the (E )-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-di The mass to volume ratio of crude hydroxyhept-6-enoate and sterol is 1: 1 ~ 10.
在本发明的另一些实施例中， 本发明提供的 (E)-7- [4-(4-氟苯基 )-6-异丙 基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶 型的制备方法中， 第二溶剂为曱醇和水的混合物， 其中， 曱醇与水的体积比 小于 6: 1。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the method for preparing a crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the second solvent is a mixture of decyl alcohol and water, wherein sterol and water are The volume ratio is less than 6:1.
在本发明的另一些实施例中， 本发明提供的 (E)-7- [4-(4-氟苯基 )-6-异丙 基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶 型的制备方法中， 第二溶剂为乙腈和 MTBE的混合物， 其中， 乙腈和 MTBE 的体积比小于 1 : 10。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the preparation method of the crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the second solvent is a mixture of acetonitrile and MTBE, wherein the volume of acetonitrile and MTBE The ratio is less than 1:10.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙 基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶 型的制备方法中， 第二溶剂为曱醇和 MTBE的混合物， 其中， 曱醇和 MTBE 的体积比小于 1 : 10。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the preparation method of the crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the second solvent is a mixture of decyl alcohol and MTBE, wherein the volume of sterol and MTBE The ratio is less than 1:10.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型 的制备方法中， 步骤 2中分离为过滤。 In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine In the method for preparing a crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoate, the separation in step 2 is filtration.
作为优选， 步骤 2中过滤为减压过滤。 Preferably, the filtration in step 2 is vacuum filtration.
过滤后收集滤饼， 并对滤饼进行干燥。 步骤 2中干燥为减压干燥或升温 干燥。 After filtration, the filter cake was collected and the filter cake was dried. In step 2, the drying is carried out under reduced pressure or at elevated temperature.
作为优选， 步骤 2中干燥的为在负压力、 40 ~ 50°C的条件下干燥。 Preferably, the drying in the step 2 is drying under a negative pressure of 40 to 50 °C.
本发明还提供了由上述制备方法制得的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型； 其 X射线粉末衍射图于 2Θ士 1 位置有峰值， 所述 2Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 The present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-5 which is obtained by the above preparation method. a crystal form of (3R,5S)-3,5-dihydroxyhept-6-enoate; its X-ray powder diffraction pattern has a peak at 2 士士1 position, and the 2Θ is 9.3280, 17.4066, 17.9806 , 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
本发明提供瑞舒伐他汀曱酯即 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱 磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯及其制备方法。 该 方法通过将溶剂能够获得对映异构杂质小于 0.50% , 非对映异构杂质小于 0.30%的（E)-7-[4-(4-氟苯基) -6-异丙基 -2- [曱基（曱磺酰基）氨基]嘧啶 -5-
基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型； 通过对溶剂的选择能够获得对 映异构杂质小于 0.30% , 非对映异构杂质小于 0.10%的 (E)-7-[4-(4-氟苯基 )-6- 异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯 的晶型； 通过对溶剂的更优选择能够获得对映异构杂质小于 0.10% , 非对映 异构杂质小于 0.10%的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基] 嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型。 附图说明 The present invention provides rosuvastatin oxime ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl (3R,5S)-3,5-Dihydroxyhept-6-enoic acid decyl ester and a preparation method thereof. The method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30% by solvent. - [Indolyl (sulfonyl) amino]pyrimidine-5- a crystal form of (3R,5S)-3,5-dihydroxyhept-6-enoic acid ester; by enantioselection of the solvent, it is possible to obtain an enantiomeric impurity of less than 0.30% and a diastereomeric impurity of less than 0.10. % of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a crystalline form of 5-dihydroxyhept-6-enoic acid ester; (E)-7 having an enantiomeric impurity of less than 0.10% and a diastereomeric impurity of less than 0.10% by better selection of a solvent -[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyheptane- Crystal form of 6-enoate. DRAWINGS
图 1示实施例 1中制得的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的 X射线粉末衍射 图； Figure 1 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 1. X-ray powder diffraction pattern of the crystalline form of (3R,5S)-3,5-dihydroxyhept-6-enoate;
图 2示实施例 2中制得的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的 X射线粉末衍射 图； Figure 2 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 2. X-ray powder diffraction pattern of the crystalline form of (3R,5S)-3,5-dihydroxyhept-6-enoate;
图 3示实施例 3中制得的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基) 氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的晶型的 X射线粉末衍射 图。 具体实施方式 Figure 3 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 3. X-ray powder diffraction pattern of the crystal form of (3R,5S)-3,5-dihydroxyhept-6-enoate. detailed description
本发明公开了瑞舒伐他汀曱酯及其制备方法，本领域技术人员可以借鉴 本文内容， 适当改进工艺参数实现。 特别需要指出的是， 所有类似的替换和 改动对本领域技术人员来说是显而易见的， 它们都被视为包括在本发明。 本 发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱 离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更 与组合， 来实现和应用本发明技术。 The invention discloses rosuvastatin oxime ester and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
本发明提供的瑞舒伐他汀曱酯及其制备方法中所用试剂均可由市场购 付。 The reagents used in the rosuvastatin oxime ester provided by the present invention and the preparation method thereof can be purchased from the market.
本发明通过在 Siemans单硅晶体 (SSC)晶圓贴片（wafter mounts)上安放结 晶形式的样品并借助显微载物片将该样品涂布为一薄层来测定 X射线粉末 衍射光谱。将样品以每分钟 30转来旋转 (以改进计数统计）， 用通过在 1.5406 埃波长以 40kV及 40mA操作的一细长聚焦铜管产生的 X射线来照射。校准 的 X射线源通过设置为 V20(20毫米径长)的自动可调发散狭缝， 而反射放射 线直接通过 2毫米的抗散射狭缝及 0.2毫米的检测狭缝。 样品在 Θ-Θ方式中 经 2至 40度 2Θ角范围内每增加 0.02度 2Θ角接受 4秒辐射 (连续扫描模式)。
运行时间为 2小时 6分钟 40秒。该仪器配有闪烁计数器作为检测仪。用 Diffrac AT (Socabim)软件通过 DECpc LPv 433sx个人电脑来警醒控制及获得数据。 The present invention determines X-ray powder diffraction spectra by placing a sample in crystalline form on a Siemans single silicon crystal (SSC) wafer mount and coating the sample as a thin layer by means of a microscopic slide. The sample was rotated at 30 revolutions per minute (to improve count statistics) and illuminated with X-rays generated by an elongated focusing copper tube operating at a wavelength of 1.5406 angstroms at 40 kV and 40 mA. The calibrated X-ray source passes through an automatically adjustable divergence slit set to V20 (20 mm diameter), and the reflected radiation passes directly through a 2 mm anti-scatter slit and a 0.2 mm detection slit. The sample received 4 seconds of radiation (continuous scan mode) for every 0.02 degrees 2 turns in the range of 2 to 40 degrees 2 turns in the Θ-Θ mode. The running time is 2 hours, 6 minutes and 40 seconds. The instrument is equipped with a scintillation counter as the detector. Use Diffrac AT (Socabim) software to alert and control data with the DECpc LPv 433sx PC.
本发明不做限定， 适宜的温度范围均在本发明的保护范围内。 The invention is not limited, and a suitable temperature range is within the scope of the invention.
下面结合实施例， 进一步阐述本发明： 实施例 1 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱苯中结晶 The invention is further illustrated by the following examples: Example 1 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine- 5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate crystallization from benzene
非对映异构体检测方法： Diastereomer detection method:
HPLC条件： HPLC conditions:
色谱柱： Agilent C8 ( 4.5*15mm, 5謹 ） Column: Agilent C8 (4.5*15mm, 5)
梯度洗脱： A: 1ml 85%磷酸溶于 1000ml水中 Gradient elution: A: 1ml 85% phosphoric acid dissolved in 1000ml water
B: 异丙醇 B: isopropanol
C: 曱醇 C: sterol
具体条件见表 1。 The specific conditions are shown in Table 1.
检测波长 λ=242ηηι Detection wavelength λ=242ηηι
柱温： 30 °C Column temperature: 30 °C
样品制备： Sample Preparation:
取样品适量加 90%曱醇制成 0.5mg/ml的溶液。 进样 20μΙ^。 对映异构体检测方法： A suitable amount of 90% sterol was added to make a 0.5 mg/ml solution. Injection 20μΙ^. Enantiomer detection method:
色谱柱： CHIRALCEL OJ-H (4.6*250mm, 5μηι) Column: CHIRALCEL OJ-H (4.6*250mm, 5μηι)
流动相： （正己烷： 乙醇： 三氟乙酸） - ( 80:20:0.1 ) Mobile phase: (n-hexane: ethanol: trifluoroacetic acid) - (80:20:0.1)
Flow: l.Oml/min λ=242ηηι 柱温： 30°C
样品配制： 取样品适量加流动相制成 0.2mg/ml的溶液。 进样 20μ 。 将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20ml曱苯加热全溶后， 然后冷却至室温（30°C ), 再放入冰箱中 （0°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 8.1g(E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6- 烯酸曱酯， 其中对映异构体水平为 0.32 % , 非对映异构体水平为 0.50 %。 得 到的（E)-7-[4-(4-氟苯基）-6-异丙基 -2-[曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图如图 1所示， 于 2Θ 为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927 和 26.3293位置有峰， 具体数据见表 2。 表 2 X射线粉末衍射图数据 Flow: l.Oml/min λ=242ηηι Column temperature: 30°C Sample preparation: Take a proper amount of the sample and add a mobile phase to make a 0.2 mg/ml solution. Inject 20μ. 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of benzene, then cool to room temperature (30 ° C), then The crystals were frozen and crystallized in a refrigerator (0 ° C), and the crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 8.1 g of (E)-7-[4-(4-fluorophenyl)-6. -isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein the enantiomer The level was 0.32% and the diastereomer level was 0.50%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate, as shown in Figure 1, has peaks at positions of 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293. The data is shown in Table 2. Table 2 X-ray powder diffraction pattern data
非对映异构体和对映异构体的检测方法同实施例 1。 The detection methods of the diastereomers and enantiomers are the same as in the first embodiment.
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20mlMEK加热全溶后， 然后冷却至室温（ 25°C ), 再放入冰箱中 （4°C )
冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.9g(E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6- 烯酸曱酯， 其中对映异构体水平为 0.31 % , 非对映异构体水平为 0.48 %。 得 到的（E)-7-[4-(4-氟苯基）-6-异丙基 -2-[曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图如图 2所示， 于 2Θ 为 9.3578、 17.4561、 18.0215、 19.5603、 20.2484、 21.7248、 24.3535、 24.8001 和 26.3673位置有峰， 具体数据见表 3。 表 3 X射线粉末衍射图数据 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of MEK, then cooled to room temperature (25 ° C), then placed In the refrigerator (4 ° C) After freezing and crystallization, the crystals were precipitated and then filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[ (3R,5S)-3,5-dihydroxyhept-6-enoate, wherein the enantiomeric level is 0.31%, diastereomeric The level of the construct is 0.48%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate, as shown in Fig. 2, has peaks at positions of 9.3578, 17.4561, 18.0215, 19.5603, 20.2484, 21.7248, 24.3535, 24.8001 and 26.3673. The data is shown in Table 3. Table 3 X-ray powder diffraction pattern data
非对映异构体和对映异构体的检测方法同实施例 1。 The detection methods of the diastereomers and enantiomers are the same as in the first embodiment.
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml曱基叔丁基醚于室温（30°C ) 混合后搅拌 0.5小时， 静置 1小 时后， 过滤， 滤饼于 45°C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱 基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 收率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 得到的 (E)-7-[4-(4-氟苯基 )-6-异丙 基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X 射线粉末衍射图如图 2所示， 于 2Θ为 9.4629、 17.5291、 18.1184、 19.6408、
20.2973、 21.7716、 24.3955、 24.8508和 26.4346位置有峰， 具体数据见表 4。 表 4 X射线粉末衍射图数据 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of decyl tert-butyl ether mixed at room temperature (30 ° C), stirred 0.5 After 1 hour, after standing for 1 hour, it was filtered, and the cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate, as shown in Figure 2, at 9.4629, 17.5291, 18.1184, 19.6408, There are peaks at positions 20.2973, 21.7716, 24.3955, 24.8508, and 26.4346. See Table 4 for specific data. Table 4 X-ray powder diffraction pattern data
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20ml 乙腈:曱基叔丁基醚 (2:6)的混合溶剂加热全溶后， 然后冷却至室温 ( 20°C ), 再放入冰箱中 （-5 °C )冷冻析晶， 析出晶体后过滤， 滤饼于 45°C 减压烘干， 得到 7.5g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧 啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.30 % , 非对映异构体水平为 0.52 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) heated with 20 ml of a mixed solvent of acetonitrile: decyl tert-butyl ether (2:6) After dissolution, it was cooled to room temperature (20 ° C), and then placed in a refrigerator (-5 ° C) to freeze and crystallize. The crystals were precipitated and filtered, and the cake was dried at 45 ° C under reduced pressure to obtain 7.5 g (E). -7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy Hept-6-enoate, wherein the enantiomeric level is 0.30% and the diastereomer level is 0.52%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 5 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从 MTBE中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 5: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from MTBE
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-
基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.1%非对映异构体 0.7%对映异构体） 用 50ml MTBE加热全溶后，然后冷却至室温（ 15°C ) ,再放入冰箱中（ -20°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.5g(E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.28 % , 非对映异构体水平为 0.45 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5- (3R,5S)-3,5-Dihydroxyhept-6-enoate (1.1% diastereomer 0.7% enantiomer) After total dissolution with 50 ml MTBE, then cooled to At room temperature (15 ° C), and then placed in the refrigerator (-20 ° C), frozen and crystallized, precipitated crystals, filtered, and the filter cake was dried under reduced pressure at 45 ° C to obtain 7.5 g (E) -7-[4- (4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid The oxime ester has an enantiomeric level of 0.28% and a diastereomer level of 0.45%.
得到的 (E)-7-[4-(4-氟笨基 )-6-异丙基 -2-[曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 6: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)- 3,5-二羟基庚 -6-烯酸曱酯从 MEK中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 6: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) - 3,5-Dihydroxyhept-6-enoate crystallization from MEK
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 0.52%非对映异构体 0.3%对映异构体） 用 20ml MEK加热全溶后， 然后冷却至室温（ 28°C ) ,再放入冰箱中（ -10°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7g(E)-7-[4-(4-氟 苯基) -6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3，5-二羟基庚 -6- 烯酸甲酯， 其中对映异构体水平为 0.12 %， 非对映异构体水平为 0.25 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (0.52% diastereomer 0.3% enantiomer) after total dissolution with 20 ml MEK, then cooled to room temperature (28 ° C), and then It was frozen in a refrigerator (-10 ° C), crystallized, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7 g of (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid methyl ester, wherein the enantiomeric level It was 0.12% and the diastereomer level was 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2-[曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 7: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙酸乙酯:石油醚 (1: 1)中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 7: (E)- 7- [4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from ethyl acetate: petroleum ether (1:1)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯 （0.52%非对映异构体， 0.3%对映异构 体）用 20ml 乙酸乙酯:石油醚 (1 : 1)的混合溶剂加热全溶后， 然后冷却至室温 ( 23 °C ), 再放入冰箱中 （0°C )冷冻析晶， 析出晶体后过滤， 滤饼于 45°C 减压烘干， 得到 7.6g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧 啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.13 % , 非对映异构体水平为 0.28 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (0.52% diastereomer, 0.3% enantiomer) heated in 20 ml of ethyl acetate: petroleum ether (1:1) in a solvent Thereafter, it was cooled to room temperature (23 ° C), and then placed in a refrigerator (0 ° C) to freeze and crystallize, crystals were precipitated, filtered, and the cake was dried at 45 ° C under reduced pressure to obtain 7.6 g (E)-7. -[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyheptane- 6-enoate, wherein the enantiomeric level is 0.13 % and the diastereomer level is 0.28%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰，
2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at 2 Θ, The value of 2 is similar to that of Embodiment 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 8 : (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸甲酯从 4-曱基 -2-戊酮中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 8: (Ε)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid methyl ester crystallized from 4-mercapto-2-pentanone
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯 （0.52%非对映异构体， 0.3%对映异构 体）用 30ml 4-曱基 -2-戊酮加热全溶后， 然后冷却至室温（ 10°C ), 再放入冰 箱中 （-10°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7.8g(E)-7-[4-(4-氟苯基）-6-异丙基 -2-[甲基（甲磺酰基）氨基]嘧啶- 5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.10 % , 非对 映异构体水平为 0.20 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (0.52% diastereomer, 0.3% enantiomer) was completely dissolved in 30 ml of 4-mercapto-2-pentanone, then cooled to At room temperature (10 ° C), put it into the refrigerator (-10 ° C) to freeze and crystallize, precipitate crystals, filter, filter cake at 45 ° C under reduced pressure to obtain 7.8 g (E) -7-[4- (4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid The oxime ester has an enantiomeric level of 0.10% and a diastereomer level of 0.20%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的^ r测方法同实施例 1。 实施例 9: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)- 3，5-二羟基庚 -6-烯酸曱酯从乙二醇二曱醚中结晶 The method for measuring diastereomers and enantiomers is the same as in Example 1. Example 9: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) - 3,5-Dihydroxyhept-6-enoate crystallization from ethylene glycol diterpene ether
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 0.52%非对映异构体 0.3%对映异构体） 用 15ml乙二醇二曱醚加热全溶后， 然后冷却至室温（40°C ), 再放入冰箱中 ( -5 °C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 8.0g(E)-7-[4-(4-氟苯基）-6-异丙基 -2-[曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.05 % , 非对 映异构体水平为 0.08 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (0.52% diastereomer 0.3% enantiomer) was completely dissolved by heating with 15 ml of ethylene glycol dioxime ether, and then cooled to room temperature (40°). C), and then placed in a refrigerator (-5 °C) to freeze and crystallize, precipitate crystals, filter, filter cake at 45 °C under reduced pressure to obtain 8.0g (E)-7-[4-(4-fluoro Phenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein The enantiomeric level was 0.05% and the diastereomer level was 0.08%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 10: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- ] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 10: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-] (3R,5S)- 3,5-Dihydroxyhept-6-enoate crystallization from sterol
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-
基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20ml曱醇加热全溶后， 然后冷却至 30°C , 再放入冰箱中 （-5°C )冷冻析 晶，析出晶体后过滤，滤饼于 45°C减压烘干，得到 7.9g(E)-7-[4-(4-氟苯基 )-6- 异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱 酯， 其中对映异构体水平为 0.31 % , 非对映异构体水平为 0.48 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5- (3R,5S)-3,5-Dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of decyl alcohol, then cooling After 30 ° C, it was placed in a refrigerator (-5 ° C) to freeze and crystallize, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g (E) -7-[4-(4 -fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate , wherein the enantiomeric level is 0.31% and the diastereomer level is 0.48%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3 ,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 11 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸甲酯从 MEK中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 11: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid methyl ester from MEK pulping
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml MEK于室温 （40°C ) 混合后搅拌 0.5小时， 静置 1小时后， 过 滤， 滤饼于 45°C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺 酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 收率 85%。 对映异 构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml MEK mixed at room temperature (40 ° C), stirred for 0.5 hour, allowed to stand 1 After an hour, it was filtered and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 12: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙腈和 MTBE 的混合物（体积比为 1: 15 ) 中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 12: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (volume ratio 1:15)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体）与 50ml乙腈和 MTBE的混合物（体积比为 1 : 15 )于室温（30°C ) 混合 后搅拌 0.5小时，静置 1小时后，过滤，滤饼于 45°C减压烘干。得到 (E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6- 烯酸曱酯， 收率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of acetonitrile and MTBE (volume ratio 1:15) at room temperature (30 °C) After mixing, the mixture was stirred for 0.5 hour, allowed to stand for 1 hour, filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoate, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰，
2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at 2 Θ, The value of 2 is similar to that of Embodiment 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 13 : (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和水的混合物（体积比为 5: 1 ) 中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 13: (Ε)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (5:1 by volume)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 0.52%非对映异构体 0.3%对映异构体） 用 20ml 曱醇和水的混合物 （体积比为 5: 1 )加热全溶后， 然后冷却至室温 ( 30°C ), 再放入冰箱中（0°C )冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减 压烘干，得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.12 % , 非对 映异构体水平为 0.25 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (0.52% diastereomer 0.3% enantiomer) After heating and total dissolution with 20 ml of a mixture of decyl alcohol and water (volume ratio of 5:1), Then, it was cooled to room temperature (30 ° C), and then placed in a refrigerator (0 ° C) to freeze and crystallize. The crystals were precipitated and filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7 g (E) -7-[4 -(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-ene The acid ester had an enantiomeric level of 0.12% and a diastereomer level of 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 14: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和 MTBE 的混合物（体积比为 1 : 20 ) 中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 14: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester from a mixture of decyl alcohol and MTBE (volume ratio 1: 20)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体 )与 50ml曱醇和 MTBE的混合物（体积比为 1 :20 )于 0 °C混合后搅拌 0.5 小时，静置 1小时后，过滤，滤饼于 45 °C减压烘干。得到 (E)-7-[4-(4-氟苯基 )-6- 异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯， 收率 85%。 对映异构体 0.35%， 非对应异构体 0.61 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5 - dihydroxyhepta-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of decyl alcohol and MTBE (volume ratio 1:20) at 0 °C After mixing, the mixture was stirred for 0.5 hour, allowed to stand for 1 hour, filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)- 7- [4- (4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)- 7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 15 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯从丙酮和水的混合物中结晶
将 lOg (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20ml丙酮和水的混合物加热全溶后， 然后冷却至室温（25 °C ), 再放入冰 箱中 （-5 °C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基）-6-异丙基 -2-[甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.31 % , 非对 映异构体水平为 0.48 %。 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 15: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetone and water lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of a mixture of acetone and water, then cooled to room temperature (25 ° C ), and then placed in a refrigerator (-5 ° C) to freeze and crystallize, crystallize and filter, and the filter cake is dried under reduced pressure at 45 ° C to obtain 7.9 g of (E)-7-[4-(4-fluorobenzene). (6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein The level of the isomer was 0.31% and the level of diastereomer was 0.48%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2-[曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 16: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙醇和 MTBE的混合物中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 16: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of ethanol and MTBE
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体 )与 50ml, 乙醇和 MTBE的混合物于室温（ 20°C ) 混合后搅拌 0.5小时， 静置 1小时后， 过滤， 滤饼于 45 °C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异 丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯，收 率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of a mixture of ethanol and MTBE at room temperature (20 ° C) and stirred 0.5 After 1 hour, after standing for 1 hour, it was filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 17: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从 4-曱基 -2-戊酮、 MTBE和曱苯的混合 物中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 17: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of 4-mercapto-2-pentanone, MTBE and toluene
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml4-甲基 -2-戊酮、 MTBE和甲苯的混合物于室温（25 °C ) 混合后 搅拌 0.5小时，静置 1小时后，过滤，滤饼于 45 °C减压烘干。得到 (E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6- 烯酸曱酯， 收率 85%。 对映异构体 0.35% , 非对应异构体 0.61%。
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) with 50 ml of 4-methyl-2-pentanone, MTBE and toluene at room temperature ( After stirring at 25 ° C for 0.5 hour, after standing for 1 hour, it was filtered, and the cake was dried at 45 ° C under reduced pressure. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoate, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 18: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯从曱醇和水的混合物中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 18: (E)- 7 -[ 4 -( 4 -Fluorophenyl)-6-isopropyl- 2 -[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯（ 0.52%非对映异构体 0.3%对映异构体 ) 用 20ml曱醇和水的混合物加热全溶后， 然后冷却至室温（20°C )， 再放入冰 箱中 （4°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基）-6-异丙基 -2-[曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.12 % , 非对 映异构体水平为 0.25 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (0.52% diastereomer 0.3% enantiomer) After total dissolution with 20 ml of a mixture of decyl alcohol and water, then cooled to room temperature (20 ° C ), placed in a refrigerator (4 ° C), frozen and crystallized, precipitated crystals, filtered, and the filter cake was dried under reduced pressure at 45 ° C to obtain 7 g of (E)-7-[4-(4-fluorophenyl). -6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein the enantiomer The level of the construct was 0.12% and the level of diastereomer was 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 19: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶- 5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯从曱苯中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 19: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-yl](3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from toluene
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml曱苯于室温（35 °C ) 混合后搅拌 0.5小时， 静置 1 小时后， 过 滤， 滤饼于 45 °C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺 酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 收率 85%。 对映异 构体 0.35% , 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of hydrazine mixed at room temperature (35 ° C), stirred for 0.5 hours, allowed to stand After 1 hour, it was filtered and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的 ^则方法同实施例 1。 实施例 20: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯从乙醇和水的混合物中结晶
将 lOg (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20ml乙醇和水的混合物加热全溶后， 然后冷却至室温（30°C ), 再放入冰 箱中 （-10°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基）-6-异丙基 -2-[曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.31 % , 非对 映异构体水平为 0.48 %。 The method for the diastereomers and enantiomers is the same as in Example 1. Example 20: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of ethanol and water lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of a mixture of ethanol and water, then cooled to room temperature (30 ° C ), placed in a refrigerator (-10 ° C), frozen and crystallized, precipitated crystals, filtered, and the filter cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (E)-7-[4-(4-fluorobenzene). (6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein The level of the isomer was 0.31% and the level of diastereomer was 0.48%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 21 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从 MTBE和曱苯的混合物中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 21: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of MTBE and toluene
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体）与 50mlMTBE和曱苯的混合物于室温（ 15 °C )混合后搅拌 0.5小时， 静 置 1小时后， 过滤， 滤饼于 45°C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙 基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯，收率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5-dihydroxyheptane-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of MTBE and toluene at room temperature (15 ° C) and stirred for 0.5 hour. After standing for 1 hour, it was filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 22: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和 MTBE的混合物中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 22: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of decyl alcohol and MTBE
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体 ) 与 50ml曱醇和 MTBE的混合物于室温（ 20°C ) 混合后搅拌 0.5小时， 静置 1小时后， 过滤， 滤饼于 45°C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异 丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯，收 率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of a mixture of decyl alcohol and MTBE were mixed at room temperature (20 ° C) and stirred for 0.5 hour. After standing for 1 hour, it was filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-
基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5- The X-ray powder diffraction pattern of (3R,5S)-3,5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 23 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙腈和水的混合物中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 23: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetonitrile and water
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 0.52%非对映异构体 0.3%对映异构体 ) 用 20ml乙腈和水的混合物加热全溶后， 然后冷却至室温（ 18°C ), 再放入冰 箱中 （4°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基）-6-异丙基 -2-[曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.12 % , 非对 映异构体水平为 0.25 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (0.52% diastereomer 0.3% enantiomer) was heated and dissolved in a mixture of 20 ml of acetonitrile and water, then cooled to room temperature (18 ° C) ), placed in a refrigerator (4 ° C), frozen and crystallized, precipitated crystals, filtered, and the filter cake was dried under reduced pressure at 45 ° C to obtain 7 g of (E)-7-[4-(4-fluorophenyl). -6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein the enantiomer The level of the construct was 0.12% and the level of diastereomer was 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 24： (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙酸乙酯和石油醚中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 2 4 : (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from ethyl acetate and petroleum ether
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml 乙酸乙酯和石油醚于室温（40 °C ) 混合后搅拌 0.5小时， 静置 1 小时后， 过滤， 滤饼于 45 °C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 收率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of ethyl acetate and petroleum ether were mixed at room temperature (40 ° C) and stirred 0.5 After 1 hour, after standing for 1 hour, it was filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 25 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- ] (3R,5S)-3,5-二羟基庚 -6-烯酸甲酯从曱苯中结晶 Example 25: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-] (3R,5S)- Methyl 3,5-dihydroxyhept-6-enoate crystallized from toluene
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体）
用 20ml曱苯加热全溶后， 然后冷却至室温（ 10°C )， 再放入冰箱中 （-20°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7.9g(E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.31 % , 非对映异构体水平为 0.48 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After completely dissolving with 20 ml of hydrazine, it was cooled to room temperature (10 ° C), and then placed in a refrigerator (-20 ° C) to freeze and crystallize. The crystals were precipitated and filtered, and the cake was dried under reduced pressure at 45 ° C. 7.9 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)- 3,5-Dihydroxyhept-6-enoate, wherein the enantiomeric level is 0.31% and the diastereomer level is 0.48%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2-[甲基（曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(indolyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 26: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙醇和 MTBE的混合物中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 26: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of ethanol and MTBE
将 10g (E)-7-[4-(4-氟笨基 )-6-异丙基 -2- [甲基（曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml乙醇和 MTBE的混合物于室温（ 30°C ) 混合后搅拌 0.5小时， 静置 1小时后， 过滤， 滤饼于 45 °C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异 丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯，收 率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(indolyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of a mixture of ethanol and MTBE were mixed at room temperature (30 ° C) and stirred for 0.5 hour. After standing for 1 hour, it was filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 27: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙腈和 MTBE 的混合物（体积比为 1:25 ) 中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 27: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (1:25 by volume)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体）与 50ml乙腈和 MTBE的混合物（体积比为 1 :25 )于室温（ 20°C ) 混合 后搅拌 0.5小时，静置 1小时后，过滤，滤饼于 45°C减压烘干。得到 (E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6- 烯酸曱酯， 收率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5 - dihydroxyhepta-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of acetonitrile and MTBE (volume ratio 1:25) at room temperature (20 °C) After mixing, the mixture was stirred for 0.5 hour, allowed to stand for 1 hour, filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoate, yield 85%. The enantiomer is 0.35% and the non-isomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 28: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从丙酮和水的混合物中结晶 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1. The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 28: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetone and water
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（甲磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸甲酯（ 0.52%非对映异构体 0.3%对映异构体） 用 20ml丙酮和水的混合物加热全溶后， 然后冷却至室温（23 °C ), 再放入冰 箱中 （-15 °C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基）-6-异丙基 -2-[曱基（曱磺酰基）氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.12 % , 非对 映异构体水平为 0.25 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid methyl ester (0.52% diastereomer 0.3% enantiomer), after total dissolution with 20 ml of a mixture of acetone and water, then cooled to room temperature (23 ° C ), and then placed in a refrigerator (-15 ° C) to freeze and crystallize, crystallize and filter, and filter cake is dried under reduced pressure at 45 ° C to obtain 7 g of (E)-7-[4-(4-fluorophenyl) -6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester, which is mirrored The isomer level was 0.12% and the diastereomer level was 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 29: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从 MTBE中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 29: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate oxime pulping from MTBE
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体）与 50mlMTBE于 5 °C混合后搅拌 0.5小时， 静置 1小时后， 过滤， 滤饼 于 45°C减压烘干。得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (曱磺酰基)氨基] 嘧啶 -5-基] (3R,5S)-3，5-二羟基庚 -6-烯酸曱酯， 收率 85%。对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of MTBE mixed at 5 ° C, stirred for 0.5 hours, allowed to stand for 1 hour, filtered The filter cake was dried under reduced pressure at 45 °C. (E) -7- [ 4- ( 4 -Fluorophenyl)-6-isopropyl- 2 -([methyl(indolyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 30: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 30: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from decyl alcohol
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20ml曱醇加热全溶后， 然后冷却至室温（20°C ), 再放入冰箱中 （-8°C )
冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减压烘干， 得到 7.9g(E)-7-[4-(4- 氟苯基 )-6-异丙基 -2-[曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.31 % , 非对映异构体水平为 0.48 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of decyl alcohol, then cooled to room temperature (20 ° C), then Put in the refrigerator (-8 ° C) After freezing and crystallization, the crystals were precipitated and filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[ (3R,5S)-3,5-dihydroxyhept-6-enoate, wherein the enantiomeric level is 0.31%, diastereomeric The level of the construct is 0.48%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2-[曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 31 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和水的混合物（体积比为 1 : 1 ) 中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 31: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate decylate from a mixture of decyl alcohol and water (1:1 by volume)
将 10g (E)-7-[4-(4-氟笨基 )-6-异丙基 -2- [甲基（曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml曱醇和 MTBE的混合物 （体积比为 1 : 1 ) 于室温（28 °C ) 混合 后搅拌 0.5小时，静置 1小时后，过滤，滤饼于 45 °C减压烘干。得到 (E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6- 烯酸曱酯， 收率 85%。 对映异构体 0.35% , 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(indolyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) with 50 ml of decyl alcohol and MTBE (volume ratio of 1:1) at room temperature (28 °C) After mixing, the mixture was stirred for 0.5 hours, allowed to stand for 1 hour, filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoate, yield 85%. The enantiomer is 0.35% and the diastereomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 32: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和 MTBE 的混合物（体积比为 1 : 30 ) 中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 32: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime pulp from a mixture of decyl alcohol and MTBE (volume ratio 1:30)
将 10g (E)-7-[4-(4-氟笨基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体）与 50ml曱醇和 MTBE的混合物（体积比为 1 :30 )于室温（32 °C ) 混合 后搅拌 0.5小时，静置 1小时后，过滤，滤饼于 45 °C减压烘干。得到 (E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6- 烯酸曱酯， 收率 85%。 对映异构体 0.35% , 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of crude 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) and 50 ml of decyl alcohol and MTBE (volume ratio 1:30) at room temperature (32 °C) After mixing, the mixture was stirred for 0.5 hours, allowed to stand for 1 hour, filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoate, yield 85%. The enantiomer is 0.35% and the diastereomer is 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 33 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和水的混合物（体积比为 2: 1 ) 中结晶 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3. The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 33: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (volume ratio of 2:1)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 0.52%非对映异构体 0.3%对映异构体） 用 20ml 曱醇和水的混合物 （体积比为 2: 1 )加热全溶后， 然后冷却至室温 ( 25 °C ), 再放入冰箱中（5 °C )冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减 压烘干，得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.12 % , 非对 映异构体水平为 0.25 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (0.52% diastereomer 0.3% enantiomer) After heating with a mixture of 20 ml of a mixture of decyl alcohol and water (volume ratio of 2:1), Then, it was cooled to room temperature (25 °C), and then placed in a refrigerator (5 °C) to freeze and crystallize. The crystals were precipitated and filtered. The cake was dried under reduced pressure at 45 ° C to obtain 7 g (E) -7-[4 -(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-ene The acid ester had an enantiomeric level of 0.12% and a diastereomer level of 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 34: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和 MTBE的混合物（体积比小于 1 : 10 ) 中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 34: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate decylate from a mixture of decyl alcohol and MTBE (volume ratio less than 1:10)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体）与 50ml曱醇和 MTBE的混合物 （体积比小于 1 : 10 )于室温（ 18 °C )混 合后搅拌 0.5 小时， 静置 1 小时后， 过滤， 滤饼于 45 °C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸曱酯， 收率 85%。对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of crude 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) and 50 ml of decyl alcohol and MTBE (volume ratio less than 1:10) at room temperature (18 °C) After mixing, stir for 0.5 hours, let stand for 1 hour, filter, and filter cake at 45 °C under reduced pressure. (E)-7-[ 4 -( 4 -Fluorophenyl)-6-isopropyl- 2 -[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoate, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 35 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱醇和水的混合物（体积比小于 6: 1 ) 中结晶
将 lOg (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 1.0%非对映异构体 0.7%对映异构体） 用 20ml曱醇和水的混合物（体积比小于 6: 1 )加热全溶后， 然后冷却至室温 ( 20°C ), 再放入冰箱中 （0°C )冷冻析晶， 析出晶体后过滤， 滤饼于 45°C 减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧 啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 其中对映异构体水平为 0.31 % , 非对映异构体水平为 0.48 %。 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 35: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (volume ratio less than 6: 1) lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) After heating with a mixture of 20 ml of decyl alcohol and water (volume ratio less than 6:1), Then, it was cooled to room temperature (20 ° C), and then placed in a refrigerator (0 ° C) to freeze and crystallize. The crystals were precipitated and filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (E)-7-[ 4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6- The decanoate ester has an enantiomeric level of 0.31% and a diastereomer level of 0.48%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2-[曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 36: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙腈和 MTBE的混合物（体积比小于 1: 10 ) 中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 36: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (volume ratio less than 1:10)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体）与 50ml乙腈和 MTBE的混合物 （体积比小于 1 : 10 )于室温（20°C )混 合后搅拌 0.5 小时， 静置 1 小时后， 过滤， 滤饼于 45°C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸曱酯， 收率 85%。对映异构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , a mixture of 5 - dihydroxyhepta-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 50 ml of acetonitrile and MTBE (volume ratio less than 1: 10) at room temperature (20 °C) After mixing, stir for 0.5 hours, let stand for 1 hour, filter, and filter cake at 45 ° C under reduced pressure. (E)-7-[ 4 -( 4 -Fluorophenyl)-6-isopropyl- 2 -[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoate, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 37: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从乙二醇二曱醚中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 37: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from ethylene glycol diterpene ether
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 100ml乙二醇二曱醚于室温（23 °C ) 混合后搅拌 0.5小时， 静置 1小 时后， 过滤， 滤饼于 45°C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱 基 (曱磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 收率 85%。 对映异构体 0.35%, 非对应异构体 0.61%。
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-D-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) and 100 ml of ethylene glycol dioxime mixed at room temperature (23 ° C), stirred 0.5 After 1 hour, after standing for 1 hour, it was filtered, and the cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 38: (E)- 7-[4-(4-氟苯基 )- 6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶- 5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从 MEK中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 38: (E)- 7- [4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-yl](3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from MEK
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯（ 0.52%非对映异构体 0.3%对映异构体） 用 20ml MEK加热全溶后， 然后冷却至室温（ 15°C ) ,再放入冰箱中（ -20°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干，得到 7g(E)-7-[4-(4-氟苯 基) -6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3，5-二羟基庚 -6-烯酸 曱酯， 其中对映异构体水平为 0.12 %， 非对映异构体水平为 0.25 %。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (0.52% diastereomer 0.3% enantiomer), after total dissolution with 20 ml of MEK, then cooled to room temperature (15 ° C), and then In a refrigerator (-20 ° C), the crystals were frozen and precipitated, and the crystals were precipitated and filtered. The cake was dried under reduced pressure at 45 ° C to obtain 7 g of (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein the enantiomeric level It was 0.12% and the diastereomer level was 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 39: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯从曱基叔丁基醚中制浆 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 39: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from mercapto tert-butyl ether
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯粗品（ 1.0%非对映异构体 0.7%对映异构 体） 与 50ml曱基叔丁基醚于 10°C混合后搅拌 0.5小时， 静置 1小时后， 过 滤， 滤饼于 45°C减压烘干。 得到 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基 (曱磺 酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯， 收率 85%。 对映异 构体 0.35%, 非对应异构体 0.61%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester crude (1.0% diastereomer 0.7% enantiomer) and 50 ml of decyl tert-butyl ether mixed at 10 ° C, stirred for 0.5 hours, static After 1 hour, it was filtered, and the filter cake was dried under reduced pressure at 45 °C. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-Dihydroxyhept-6-enoic acid decyl ester, yield 85%. The enantiomer was 0.35% and the non-isomer was 0.61%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [曱基（曱磺酰基)氨基]嘧啶 -5- 基] (3R,5S)-3,5-二羟基庚 -6-烯酸曱酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 3类似。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 3.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 以上所述仅是本发明的优选实施方式， 应当指出， 对于本技术领域的普通技 术人员来说， 在不脱离本发明原理的前提下， 还可以做出若干改进和润饰， 这些改进和润饰也应视为本发明的保护范围。
The method for detecting diastereomers and enantiomers is the same as in Example 1. The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.
Claims
1、 (E) -7- [4- (4 -氟苯基) _6_异丙基 _2_ [甲基（甲磺酰基)氨基]嘧啶 _5_ 基 ] (3R，5S)_3，5-二羟基庚 -6-烯酸甲酯的晶型， 其特征在于， 其 X射线粉末 衍射图于 2 Θ ± 1 位置有峰值， 所述 2 Θ为 9.3280、 17.4066、 17.9806、 19.5084、 20.2123、 21.6525、 24.3325、 24.6927和 26.3293。 1. (E) -7-[4-(4-fluorophenyl)_6_isopropyl_2_[methyl(methanesulfonyl)amino]pyrimidin_5_yl] (3R,5S)_3,5-di The crystal form of hydroxyhept-6-enoic acid methyl ester is characterized in that its X-ray powder diffraction pattern has a peak at the 2Θ ± 1 position, and the 2Θ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325 , 24.6927 and 26.3293.
2、 根据权利要求 1 所述的（E)-7-[4-(4-氟苯基 )_6-异丙基 -2- [甲基（甲 磺酰基）氨基]嘧啶 -5-基] (3R, 5S) -3, 5-二羟基庚 -6-烯酸甲酯的晶型用于制 备瑞舒伐他汀或其药物可接受盐。 2. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] according to claim 1 ( The crystalline form of 3R, 5S)-3,5-dihydroxyhept-6-enoic acid methyl ester is used to prepare rosuvastatin or its pharmaceutically acceptable salt.
3、 根据权利要求 1 所述的（E)-7-[4-(4-氟苯基 )_6-异丙基 -2- [甲基（甲 磺酰基）氨基]嘧啶 -5-基] (3R，5S) -3， 5-二羟基庚 -6-烯酸甲酯的晶型的结晶 方法， 其特征在于， 包括如下步骤： 3. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] according to claim 1 ( The crystallization method of the crystal form of 3R, 5S)-3, 5-dihydroxyhept-6-enoic acid methyl ester is characterized in that it includes the following steps:
步骤 1: 获得（E)- 7- [4- (4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基] 嘧啶 _5 -基] (3R， 5S)-3, 5 -二羟基庚 _6 -烯酸甲酯粗品； Step 1: Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] (3R, 5S) -Crude product of -3, 5-dihydroxyhept-6-enoic acid methyl ester;
步骤 2: 取所述（E) -7- [4- (4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨 基]嘧啶 -5-基] (3R, 5S)-3, 5-二羟基庚 -6-烯酸甲酯粗品与过量的溶剂混合后 获得第一溶液， 结晶、 分离、 干燥后即得； Step 2: Take the (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] (3R, 5S)-3, 5-Dihydroxyhept-6-enoic acid methyl ester crude product is mixed with excess solvent to obtain a first solution, which is obtained after crystallization, separation, and drying;
所述溶剂为 d-4醇、 C3-8酯、 C3-8酮、 C3-8醚、 C6-1()芳烃、 乙二醇二乙醚、 乙 二醇二甲醚、 水、 乙腈中的一种或两者以上的混合物。 The solvent is d- 4 alcohol, C 3 - 8 ester, C 3 - 8 ketone, C 3 - 8 ether, C 6 - 1() aromatic hydrocarbon, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, water, One or a mixture of more than two acetonitriles.
4、 根据权利要求 3 所述晶型的结晶方法， 其特征在于， 步骤 2 中所述 溶剂为甲醇， 乙腈和水的混合物， 丙酮、 水和 MTBE 的混合物， 甲醇和水的 混合物， 乙醇和水的混合物， 乙醇和 MTBE 的混合物， 乙腈和 MTBE 的混合 物， 甲醇和 MTBE 的混合物， MEK, 4-甲基 -2-戊酮、 MTBE和甲苯的混合物， 乙酸乙酯和石油醚的混合物中的一种或两者以上的混合物。 4. The crystallization method of the crystal form according to claim 3, wherein the solvent in step 2 is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, ethanol and water A mixture of ethanol and MTBE, a mixture of acetonitrile and MTBE, a mixture of methanol and MTBE, MEK, a mixture of 4-methyl-2-pentanone, MTBE and toluene, a mixture of ethyl acetate and petroleum ether species or a mixture of two or more.
5、 根据权利要求 3 所述的晶型的结晶方法， 其特征在于， 步骤 2 中所 述溶剂为 MTBE, MEK, 4-甲基 -2-戊酮， 甲苯， 丙酮和水的混合物， 乙腈和 水， 甲醇的混合物中的一种或两者以上的混合物。 5. The crystallization method of the crystal form according to claim 3, wherein the solvent in step 2 is a mixture of MTBE, MEK, 4-methyl-2-pentanone, toluene, acetone and water, acetonitrile and One or a mixture of more than two of water and methanol.
6、 根据权利要求 3 所述的晶型的结晶方法， 其特征在于， 步骤 2 中所 述结晶具体为取所述第一溶液， 加热至 50°C以上， 冷却。 6. The crystallization method of the crystal form according to claim 3, wherein the crystallization in step 2 specifically involves taking the first solution, heating it to above 50°C, and cooling it.
7、 根据权利要求 6 所述的晶型的结晶方法， 其特征在于， 所述冷却温 度为 _20~40°C。 7. The crystallization method of the crystal form according to claim 6, characterized in that the cooling temperature is -20~40°C.
8、 根据权利要求 1 所述的（E)-7-[4-(4-氟苯基 )_6-异丙基 -2- [甲基（甲 磺酰基）氨基]嘧啶 -5-基] (3R，5S) -3， 5-二羟基庚 -6-烯酸甲酯的晶型的制备 方法， 其特征在于， 包括如下步骤： 8. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] according to claim 1 ( A method for preparing the crystalline form of 3R, 5S)-3, 5-dihydroxyhept-6-enoic acid methyl ester, which is characterized in that it includes the following steps:
步骤 1: 获得（E)- 7- [4- (4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基] 嘧啶 _5 -基] (3R， 5S)-3, 5 -二羟基庚 _6 -烯酸甲酯粗品；
步骤 2 : 在 0 ~ 40 °C下， 取所述（E) _7_ [4_ (4_氟苯基）_6_异丙基 _2 - [甲 基（甲磺酰基）氨基]嘧啶 -5-基] (3R, 5S) -3, 5-二羟基庚 -6-烯酸甲酯的溶液悬 浮于过量的第二溶剂中制浆， 分离、 干燥后即得； Step 1: Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] (3R, 5S) -Crude product of -3, 5-dihydroxyhept-6-enoic acid methyl ester; Step 2: At 0 ~ 40 ° C, take the (E) _7_[4_(4_fluorophenyl)_6_isopropyl_2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl ] (3R, 5S) -3, 5-Dihydroxyhept-6-enoic acid methyl ester solution is suspended in excess second solvent to make a slurry, separated and dried to obtain;
所述第二溶剂选自 醇、 酯、 酮、 醚、 。芳烃、 乙二醇二乙 醚、 乙二醇二甲醚、 乙腈、 水。 The second solvent is selected from alcohol, ester, ketone, ether. Aromatic hydrocarbons, glycol diethyl ether, glycol dimethyl ether, acetonitrile, water.
9、 根据权利要求 8 所述的晶型的制备方法， 其特征在于， 所述第二溶 剂为甲醇， 乙腈和水的混合物， 丙酮、 水和 MTBE 的混合物， 甲醇和水的混 合物， 乙醇和水的混合物， 乙醇和 MTBE的混合物， 乙腈和 MTBE的混合物， 甲醇和 MTBE 的混合物， MEK, 4_甲基- 2_戊酮、 MTBE 和甲苯的混合物， 乙酸 乙酯和石油醚的混合物中的一种或两者以上的混合物。 9. The method for preparing the crystal form according to claim 8, wherein the second solvent is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, ethanol and water A mixture of ethanol and MTBE, a mixture of acetonitrile and MTBE, a mixture of methanol and MTBE, MEK, a mixture of 4-methyl-2-pentanone, MTBE and toluene, a mixture of ethyl acetate and petroleum ether species or a mixture of two or more.
10、 根据权利要求 8 所述的晶型的制备方法， 其特征在于， 所述第二溶 剂为 MTBE, MEK, 4-甲基 -2-戊酮， 甲苯， 甲醇和水的混合物， 乙酸乙酯和石 油醚的混合物中的一种或两者以上的混合物。
10. The method for preparing the crystal form according to claim 8, wherein the second solvent is MTBE, MEK, 4-methyl-2-pentanone, toluene, a mixture of methanol and water, ethyl acetate One or more mixtures of petroleum ether and petroleum ether.
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| CN201210379910.6A CN103709107B (en) | 2012-09-29 | 2012-09-29 | New crystal of Rosuvastatin methyl esters and preparation method thereof |
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| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
| WO2012073055A1 (en) * | 2010-11-29 | 2012-06-07 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Method for the preparation of high-purity pharmaceutical intermediates |
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| CN101591301B (en) * | 2008-05-27 | 2011-01-12 | 常州制药厂有限公司 | Preparation method of 3, 5-dihydroxy heptyl-6-gadoleic acid derivative |
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| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
| WO2012073055A1 (en) * | 2010-11-29 | 2012-06-07 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Method for the preparation of high-purity pharmaceutical intermediates |
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