CN115974789A - Rosuvastatin calcium intermediate anhydride impurity, and preparation method and application thereof - Google Patents
Rosuvastatin calcium intermediate anhydride impurity, and preparation method and application thereof Download PDFInfo
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- CN115974789A CN115974789A CN202310062428.8A CN202310062428A CN115974789A CN 115974789 A CN115974789 A CN 115974789A CN 202310062428 A CN202310062428 A CN 202310062428A CN 115974789 A CN115974789 A CN 115974789A
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- methyl
- fluorophenyl
- isopropyl
- methylsulfonyl
- pyrimidine
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- 239000012535 impurity Substances 0.000 title claims abstract description 32
- 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 title claims abstract description 27
- 229960004796 rosuvastatin calcium Drugs 0.000 title claims abstract description 26
- 150000008064 anhydrides Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 230000018044 dehydration Effects 0.000 claims abstract description 11
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 8
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 8
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 229940117975 chromium trioxide Drugs 0.000 claims description 7
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 7
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- -1 anhydride compound Chemical class 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 150000004965 peroxy acids Chemical class 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 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 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940066901 crestor Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- NASVTBDJHWPMOO-UHFFFAOYSA-N n,n'-dimethylmethanediimine Chemical compound CN=C=NC NASVTBDJHWPMOO-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000000192 social effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Images
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of organic synthetic pharmaceutical chemistry, and particularly relates to a preparation method of rosuvastatin calcium intermediate anhydride impurities. The method comprises the steps of taking 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formaldehyde as a raw material, and carrying out oxidation, dehydration and condensation to obtain a target compound, namely 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride. The method has the characteristics of originality, simple operation, rapid reaction, high product purity and high yield. The rosuvastatin calcium intermediate impurity provided by the invention can be used as a reference substance for researching the rosuvastatin calcium impurity, and provides certain help for the research on the quality of rosuvastatin calcium. In addition, the invention provides a new preparation method and an operation means for the synthesis of the same type of compounds as a synthesis method of the anhydride compound.
Description
Technical Field
The invention relates to the field of organic synthetic pharmaceutical chemistry, and particularly relates to a rosuvastatin calcium intermediate anhydride impurity, and a preparation method and application thereof.
Background
Rosuvastatin calcium, chemical name: bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R, 5S) -3,5-dihydroxyhept-6-enoic acid ] calcium salt (2:1), was developed by Nippon salt fiexus corporation at the end of the 20 th century 80S under the code S-4522. Japanese salt-wild-type corporation, 4 months 1998, assigned patents other than in Japan to Aslicon, inc. in the UK. Rosuvastatin calcium tablet is firstly marketed in the netherlands in 11 months in 2002, american FDA approval is obtained in 8 months in 2003 and Japanese is marketed in 1 month in 2005. It is marketed in china in 2007 under the name of Crestor, and has been marketed in sixty several countries such as germany, italy, australia, denmark, portugal, and the like. The structural formula is as follows:
in the preparation of rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-methanol from rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carbaldehyde, an impurity is generated, which has a polarity close to that of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carbaldehyde, so that the impurity cannot be effectively removed in the post-treatment process, thereby possibly affecting the quality of the final product rosuvastatin calcium. Therefore, it is necessary to prepare a standard of the impurities and study the removal of the impurities. The impurity is 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride through research and identification.
Until now, no researchers have been reported on the preparation of the compound 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic anhydride. As no patent is recorded for the impurity at present, and no related literature is researched, the preparation method of the impurity can supplement the defects of the prior art, provide a standard substance of rosuvastatin calcium intermediate anhydride impurity, and provide certain help for the research of quality improvement of rosuvastatin calcium.
Disclosure of Invention
The invention provides a rosuvastatin calcium intermediate anhydride impurity, a preparation method and an application thereof, aiming at overcoming the defects in the prior art. The method has the advantages of short synthetic route, simple process, convenient post-treatment and purification, easy operation and high purity and yield of the target product.
In order to solve the above problems, the technical solution provided by the present invention is as follows:
an impurity of rosuvastatin calcium intermediate anhydride, the impurity having a structural formula:
the chemical name of the impurity is: 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic anhydride.
Further, the preparation method of the impurities comprises the following steps:
(1) The compound 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formaldehyde is used as a raw material, a solvent is added, and the raw material and an oxidant are subjected to oxidation reaction to prepare 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid, wherein the reaction formula is as follows:
(2) The compound 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid is subjected to dehydration condensation reaction in the presence of a solvent to obtain 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride, and the reaction formula is as follows:
(3) And (3) carrying out aftertreatment on the prepared 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride to obtain a crude product, and crystallizing to obtain a final target product, namely an anhydride impurity.
The invention relates to a method for preparing peroxyacid impurity 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid from rosuvastatin calcium key intermediate compound 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formaldehyde, and preparing peroxyanhydride impurity 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid from 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid. The method comprises the steps of oxidizing 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formaldehyde to obtain peroxyacid impurities, and dehydrating and condensing the peroxyacid impurities to obtain peroxyanhydride impurities.
The compound 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formaldehyde compound is selected as a reaction starting material, and the compound has the advantage that the compound is an intermediate product for preparing rosuvastatin calcium, and can be purchased from the market.
Further, in the step (1), the reaction solvent is at least one of ethyl acetate, benzene, toluene, dichloromethane, acetone, methyl tert-butyl ketone, methyl ethyl ketone, tetrachloroethane, xylene and chloroform. Acetone is preferred, and the molar ratio of acetone to 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carbaldehyde is from 50 to 150, preferably from 90 to 110.
Further, in the step (1), the oxidant is at least one of potassium permanganate, potassium dichromate, hydrogen peroxide, trifluoroperacetic acid and chromium trioxide. Preferably chromium trioxide, the molar ratio of the amount of chromium trioxide to 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carbaldehyde used is (1.5-5): 1, preferably (3-4): 1.
Further, the reaction temperature in the step (1) is 0 to 50 ℃, preferably the reaction temperature in the step (1) is 25 to 40 ℃, preferably 30 to 35 ℃, and the reaction time is 0.5 to 2 hours, preferably 0.5 to 1 hour.
Further, the dehydration condensation reaction reagent in the step (2) is at least one of acetic anhydride, thionyl chloride, benzenesulfonyl chloride, phosphorus pentoxide, calcium chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and N, N' -dimethylcarbodiimide. Phosphorus pentoxide is preferred, the molar ratio of phosphorus pentoxide to 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic acid being (1-10): 1, preferably (1-4): 1.
Further, the solvent in the step (2) is toluene, benzene, ethyl acetate, acetic anhydride, acetic acid, N-dimethylformamide. Acetic anhydride is preferred, and the molar ratio of acetic anhydride to 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic acid is (0.1-196) to 1, preferably (0.1-5) to 1, more preferably (0.1-1) to 1.
Further, in the step (2), the dehydration condensation reaction temperature is 50 to 150 ℃, preferably 100 to 130 ℃, and the dehydration condensation reaction time is 10 seconds to 20 hours, preferably 10 seconds to 6 hours, and more preferably 30 seconds to 60 minutes.
Further, the solvent used for crystallization in step (3) is one or more of dichloromethane, toluene, ethanol, methanol, water, isopropanol, tert-butanol and n-propanol.
Further, the application of the rosuvastatin calcium intermediate anhydride impurity as a reference standard for analyzing medicinal compounds is also included.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The method has the beneficial effects that 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formaldehyde is used as a raw material, and the 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride is prepared through oxidation, dehydration and condensation, so that the method is short in synthetic route, simple to operate, rapid in reaction, and high in yield and purity of the obtained product. The invention relates to the synthesis of anhydride with larger volume steric hindrance, which is generally more difficult and has very low yield compared with the synthesis of anhydride with small volume steric hindrance, and compared with the general anhydride synthesis method, the invention has the advantages of simple operation, rapid reaction, good yield and higher purity. Provides a new synthesis idea and a purification method for the synthesis of other bulky and sterically hindered anhydrides. Particularly, the use of, for example, acetic anhydride in the dehydration condensation step allows the reaction to be carried out in a very small amount of liquid phase, increases the reaction rate, and simplifies the post-treatment. The anhydride impurity can be applied to the research of reference substances, is beneficial to improving the quality control level of rosuvastatin calcium, and can also be used for registration declaration of rosuvastatin calcium. The method has important significance for the quality control research of rosuvastatin calcium, is beneficial to improving the quality standard of rosuvastatin calcium and improving the medication safety of people; the method has great promotion effect on the further and extensive research on the safety, reliability and stability of rosuvastatin calcium related medicine and the quality control in the production process, and has good economic and social effects.
Drawings
FIG. 1 is an ESI-MS diagram of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic acid anhydride, a compound obtained in example 2 of the present invention;
FIG. 2 is an IR spectrum of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic anhydride, a compound obtained in example 2 of the present invention;
FIG. 3 is a UV spectrum of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic anhydride, a compound obtained in example 2 of the present invention;
FIG. 4 shows 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methyl) methane, a compound obtained in example 2 of the present inventionSulfonyl) amino groups]Process for preparing (E) -pyrimidine-5-carboxylic anhydride 1 H-NMR spectrum;
FIG. 5 shows 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino group, a compound obtained in example 2 of the present invention]Process for preparing pyrimidine-5-carboxylic anhydride 13 C-NMR spectrum.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
into a 3000mL three-necked flask were added 140g of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carbaldehyde, 2200g of acetone was added, and the mixture was stirred, dispersed and warmed to 28 ℃. A chromium trioxide solution was prepared by dissolving 120mL of chromium trioxide and 98% concentrated sulfuric acid 120mL in 360mL of water. Dropwise adding the chromium trioxide solution into the reaction system within 1 hour, and keeping the temperature at 25-40 ℃ for 30 minutes. After the reaction, the reaction mixture was filtered under suction, and the filtrate was spin-dried at 70 ℃. After spin drying, 93g of dichloromethane are added into the system, stirring is carried out for 5 minutes, then 420g of water is added, pulping is carried out for 30 minutes, pulping is carried out twice, suction filtration is carried out, rinsing is carried out by 53g of dichloromethane, and a filter cake is placed in a 70 ℃ oven and dried to constant weight. To obtain the dried 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic acid with yield of 80.15% and purity of 97.53%.
Example 2:
the prepared 10g of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid is added into a 250mL reaction bottle, 11.59g of phosphorus pentoxide is added, the mixture is stirred and mixed evenly, the temperature is raised to 110 ℃, the mixture is stirred for 30min, and 0.5mL of acetic anhydride is slowly added into the system. Stirring for 30 seconds to ensure that the system becomes purple black, immediately sampling a TLC point plate for central control, taking dichloromethane as a developing agent to generate product points, and stopping heating at the moment because the reaction cannot be continued due to continuous heating and heat preservation. The temperature was reduced to room temperature and 100mL of toluene was added. Quench with 100mL of ice water. And (3) performing suction filtration, extracting a filter cake twice by using 50mL of methylbenzene, combining filtrates, adding 10g of anhydrous sodium sulfate, uniformly stirring, performing suction filtration, and spin-drying methylbenzene at the temperature of below 65 ℃ to obtain an orange-yellow solid. Adding 1mL of dichloromethane, dissolving, adding 250mL of 95% ethanol, slowly dripping, gradually separating out a white solid, performing suction filtration, rinsing a filter cake with 20mL of 95% ethanol, and drying the filter cake at 50 ℃ for 12 hours to obtain a white dry product, wherein the yield is 35.56% and the purity is 99.45%.
The nuclear magnetic characterization data are as follows: 1 H-NMR(500MHz,DMSO):δ1.293-1.280(d,12H),3.291-3.238(m,2H),3.505(s,6H),3.586(s,6H),7.432-7.397(m,4H),7.837-7.808(m,4H);
13 C-NMR (126MHz, DMSO): δ 21.548, 32.748, 33.198, 41.610, 115.159, 115.708, 115.883, 130.602, 130.672, 130.866, 130.939, 157.936, 161.513, 161.540, 168.987, 173.043, 175.188. Mass spectrometry characterization data: obtaining [ M + Na ] by ESI method] + The peak is 739.1821, which corresponds to a molecular weight of 716.1899.
Infrared characterization data: 2972cm -1 -2875cm -1 Is saturated-CH 3 -a stretching vibration absorption peak of CH-; 1789cm -1 ,1731cm -1 The absorption peak of the expansion vibration of anhydride C = O, which is influenced by conjugation and moves to a low wave number; 1789cm -1 -1731cm -1 Is a frequency doubling region of the C-H out-of-plane bending vibration absorption peak of the disubstituted benzene; 1606cm -1 ,1550cm -1 ,1511cm -1 ,1448cm -1 Is benzene ring C = C stretching vibration absorption peak; 812cm -1 Is a C-H out-of-plane bending vibration absorption peak of 1,4-disubstituted benzene; 1384cm -1 is-CH 3 The deformation vibration absorption peak is basically consistent with the characteristic absorption peak in the structural formula.
Ultraviolet characterization data: ultraviolet absorption peaks at 203nm and 253nm indicate that a benzene ring structure exists, and the ultraviolet absorption peaks are consistent with the characteristic absorption peaks in the structural formula.
Example 3:
50g of prepared 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic acid was added to a 3000mL reaction flask, 2500mL of acetic anhydride was added, and the mixture was stirred and mixed. Heating to reflux, reacting for 18h, adding 20mL of toluene every 30 minutes, steaming, concentrating the residual solvent in the reaction bottle at 140 ℃ under reduced pressure until the solvent is dry, adding 500mL of n-hexane, pulping for 30 minutes, performing suction filtration, adding the solid into a 1000mL single-neck bottle, and adding 400mL of toluene. Dissolving 48g of sodium bicarbonate in 500mL of water, adding the solution into a single-mouth bottle, and washing for 30 minutes; layering, adding a sodium bicarbonate aqueous solution prepared by dissolving 48g of sodium bicarbonate in 500mL of water into an organic layer, and washing for 30 minutes; layering, adding 100g of sodium sulfate solid into an organic layer, stirring for 30 minutes, performing suction filtration, concentrating the organic layer at 60 ℃ under reduced pressure until the organic layer is dried to obtain a solid, and drying the solid in a reduced-pressure oven at 50 ℃ for 12 hours to obtain a white dried product 9.30g, wherein the yield is 21.98%, and the purity is 98.12%.
Example 4:
adding prepared 10g of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid into a 250mL reaction bottle, adding 8.5g of phosphorus pentoxide and 150mL of toluene, heating to 100 ℃, stirring for 60 minutes to ensure that the system becomes yellow transparent liquid, the bottom of the system is black solid, and naturally cooling to room temperature. Adding 50mL of ice water, stirring for 10 minutes, filtering, washing the organic layer for 10 minutes by using 50g of 10% liquid alkali solution, and layering; the organic layer was washed with 50g of 10% aqueous alkali solution for 10 minutes; washing for three times totally, adding 10g of anhydrous sodium sulfate into an organic layer, drying for 30 minutes, carrying out suction filtration, concentrating mother liquor at an external temperature of 60 ℃ under reduced pressure until the mother liquor is dried, adding 1mL of dichloromethane, dissolving, adding 250mL of 95% ethanol, slowly dropwise adding, separating out a large amount of white solid, carrying out suction filtration, rinsing a filter cake with 20mL of 95% ethanol, and drying the filter cake in a vacuum drying oven at 50 ℃ for 12 hours to obtain a white dry product, wherein the yield is 42.10%, and the purity is 99.25%.
Example 5:
method for detecting 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid
The HPLC detection method is as follows:
the instrument comprises the following steps: high performance liquid chromatograph and electronic balance
Chromatographic conditions
A chromatographic column: xbridge Phenyl, 4.6X 150mm,3.5 μm or a column of comparable performance
Mobile phase A:0.1% phosphoric acid aqueous solution
Mobile phase B: acetonitrile (ACN)
Diluent (b): acetonitrile
Column temperature: 30 deg.C
Detection wavelength: 242nm
Sample injection amount: 5 μ L
Flow rate: 1.0mL/min
Elution gradient:
time (min) | Mobile phase A (%) | Mobile phase B (%) |
0 | 60 | 40 |
10 | 60 | 40 |
15 | 25 | 75 |
22 | 25 | 75 |
22.1 | 60 | 40 |
25 | 60 | 40 |
Solution preparation
Blank solution: a diluent.
Test solution: taking about 20mg of a test sample, placing the test sample in a 25mL measuring flask, adding a diluent to dissolve the test sample, fixing the volume to a scale, and shaking up to obtain a test sample solution.
Example 6:
detection method HPLC detection method of 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride is as follows:
the instrument comprises the following steps: high performance liquid chromatograph and electronic balance
Chromatographic conditions
A chromatographic column: xbridge Phenyl, 4.6X 150mm,3.5 μm or a column of comparable performance
Mobile phase A: water (W)
And (3) mobile phase B: acetonitrile
Diluent agent: 0.1% acetonitrile phosphate solution
Column temperature: 30 deg.C
Detection wavelength: 242nm
Sample introduction amount: 5 μ L
Flow rate: 1.0mL/min
Elution gradient:
time (min) | Mobile phase A (%) | Mobile phase B (%) |
0 | 60 | 40 |
10 | 60 | 40 |
15 | 25 | 75 |
22 | 25 | 75 |
22.1 | 60 | 40 |
25 | 60 | 40 |
Solution preparation
Blank solution: a diluent.
Test solution: taking about 20mg of a test sample, placing the test sample in a 25mL measuring flask, adding a diluent to dissolve the test sample, fixing the volume to a scale, and shaking up to obtain a test sample solution.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
2. the method of producing the impurity of claim 1, comprising the steps of:
(1) Taking a compound 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formaldehyde as a raw material, adding a solvent, and carrying out oxidation reaction with an oxidant to obtain 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid, wherein the reaction formula is as follows:
(2) The compound 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic acid is subjected to dehydration condensation reaction in the presence of a solvent to obtain 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride, and the reaction formula is as follows:
(3) And (3) carrying out aftertreatment on the prepared 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-formic anhydride to obtain a crude product, and crystallizing to obtain the final target product, namely anhydride impurities.
3. The method of claim 2, wherein the reaction temperature in step (1) is 0 to 50 ℃ and the reaction time is 0.5 to 2 hours; the reaction solvent in the step (1) is at least one of ethyl acetate, benzene, toluene, dichloromethane, acetone, methyl tert-butyl ketone, methyl ethyl ketone, tetrachloroethane, xylene and chloroform; in the step (1), the oxidant is at least one of potassium permanganate, potassium dichromate, hydrogen peroxide, trifluoro peracetic acid and chromium trioxide.
4. The method of claim 2, wherein the dehydration condensation reaction reagent in step (2) is at least one of acetic anhydride, thionyl chloride, benzenesulfonyl chloride, phosphorus pentoxide, calcium chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and N, N' -dicyclohexylcarbodiimide.
5. The method according to claim 4, wherein the dehydrating condensation reagent in step (2) is phosphorus pentoxide, and the molar ratio of phosphorus pentoxide to 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic acid is 1-10.
6. The method according to claim 2, wherein the solvent in the step (2) is toluene, benzene, ethyl acetate, acetic anhydride, acetic acid, N-dimethylformamide.
7. The process according to claim 6, wherein the solvent is acetic anhydride and the molar ratio of acetic anhydride to 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] -pyrimidine-5-carboxylic acid is 0.1 to 196.
8. The method according to claim 2, wherein the dehydration condensation reaction temperature in the step (2) is 50 to 150 ℃ and the dehydration condensation reaction time is 10 seconds to 20 hours.
9. The method according to claim 2, wherein the solvent used for crystallization in step (3) is one or more of dichloromethane, toluene, ethanol, methanol, water, isopropanol, tert-butanol and n-propanol.
10. Use of rosuvastatin calcium intermediate anhydride impurity of claim 1 as a control standard for analysis of pharmaceutical compounds.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080091014A1 (en) * | 2005-01-19 | 2008-04-17 | Anhui Quingyun Pharmaceutical And Chemical Co., Ltd. | Synthetic Method and Intermediates of Rosuvastatin Calcium and Preparation Methods of Intermediates |
CN103936680A (en) * | 2014-04-18 | 2014-07-23 | 润泽制药(苏州)有限公司 | Preparation method of known impurities of rosuvastatin |
CN104844525A (en) * | 2015-04-08 | 2015-08-19 | 江西富祥药业股份有限公司 | Preparation method of rosuvastatin calcium impurity |
CN107698518A (en) * | 2017-06-20 | 2018-02-16 | 迪沙药业集团(天津)药物研究有限公司 | A kind of preparation method of rosuvastain calcium epimer impurity |
CN108191772A (en) * | 2017-12-28 | 2018-06-22 | 江苏悦兴医药技术有限公司 | The synthetic method of rosuvastain calcium intermediate impurities |
CN113292542A (en) * | 2021-05-26 | 2021-08-24 | 乳源东阳光药业有限公司 | Rosuvastatin calcium intermediate impurity and preparation method thereof |
-
2023
- 2023-01-17 CN CN202310062428.8A patent/CN115974789A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080091014A1 (en) * | 2005-01-19 | 2008-04-17 | Anhui Quingyun Pharmaceutical And Chemical Co., Ltd. | Synthetic Method and Intermediates of Rosuvastatin Calcium and Preparation Methods of Intermediates |
CN103936680A (en) * | 2014-04-18 | 2014-07-23 | 润泽制药(苏州)有限公司 | Preparation method of known impurities of rosuvastatin |
CN104844525A (en) * | 2015-04-08 | 2015-08-19 | 江西富祥药业股份有限公司 | Preparation method of rosuvastatin calcium impurity |
CN107698518A (en) * | 2017-06-20 | 2018-02-16 | 迪沙药业集团(天津)药物研究有限公司 | A kind of preparation method of rosuvastain calcium epimer impurity |
CN108191772A (en) * | 2017-12-28 | 2018-06-22 | 江苏悦兴医药技术有限公司 | The synthetic method of rosuvastain calcium intermediate impurities |
CN113292542A (en) * | 2021-05-26 | 2021-08-24 | 乳源东阳光药业有限公司 | Rosuvastatin calcium intermediate impurity and preparation method thereof |
Non-Patent Citations (1)
Title |
---|
张雅然等: "瑞舒伐他汀钙有关物质的合成", 《化学试剂》, no. 12, 31 December 2014 (2014-12-31), pages 1143 - 1146 * |
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