CN1145625C - ( e ) － ( 6 －{ 2 － [ 4 － ( 4－氟苯基 ) － 6 －异丙基 － 2 － [甲基 (甲磺酰基 )氨基 ]嘧啶 － 5 －基] - Google Patents
( e ) － ( 6 －{ 2 － [ 4 － ( 4－氟苯基 ) － 6 －异丙基 － 2 － [甲基 (甲磺酰基 )氨基 ]嘧啶 － 5 －基] Download PDFInfo
- Publication number
- CN1145625C CN1145625C CNB008037043A CN00803704A CN1145625C CN 1145625 C CN1145625 C CN 1145625C CN B008037043 A CNB008037043 A CN B008037043A CN 00803704 A CN00803704 A CN 00803704A CN 1145625 C CN1145625 C CN 1145625C
- Authority
- CN
- China
- Prior art keywords
- general formula
- compound
- methyl
- methylsulfonyl
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 15
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 22
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- 235000010290 biphenyl Nutrition 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 7
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- ZOFJBHYCGASUQK-UHFFFAOYSA-N sodium;trimethylsilylazanide Chemical compound [Na+].C[Si](C)(C)[NH-] ZOFJBHYCGASUQK-UHFFFAOYSA-N 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical group CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 claims 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 11
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 159000000007 calcium salts Chemical class 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- -1 pyrimidine-5-ylmethyl Chemical group 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 150000003956 methylamines Chemical class 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- OEJBXKXGGWPFEH-UHFFFAOYSA-N [CH2-]C(=O)C(O)O Chemical group [CH2-]C(=O)C(O)O OEJBXKXGGWPFEH-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000008232 de-aerated water Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- IQQDLHGWGKEQDS-UHFFFAOYSA-N methyl hept-2-enoate Chemical class CCCCC=CC(=O)OC IQQDLHGWGKEQDS-UHFFFAOYSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- AEDNGGDZXGFKGS-UHFFFAOYSA-N potassium;trimethylsilylazanide Chemical compound [K+].C[Si](C)(C)[NH-] AEDNGGDZXGFKGS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IIVUJUOJERNGQX-UHFFFAOYSA-N pyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=CN=C1 IIVUJUOJERNGQX-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010792 warming Methods 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及制备(E)-(6-｛2-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基]乙烯基｝(4R，6S)-2，2-二甲基[1，3]二氧杂-4-基)乙酸叔丁酯的方法，在该方法中所用的新原料和在药物制备中该方法的应用。
Description
本发明涉及新的化学方法，更具体地说涉及制备通式为I的(E)-(6-{2-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基]乙烯基}(4R，6S)-2，2-二甲基[1，3]二氧杂-4-基)乙酸叔丁酯(以下称作BEM)的新的化学方法，
通式I
该化合物在例如用于治疗特别是血胆固醇过多、血脂蛋白过多和动脉粥样硬化的药物生产中作为化学中间体是有用的。本发明进一步包括用于该方法的新原料和在制备HMG CoA还原酶抑制剂中该方法的应用。
欧洲专利申请EPA 0521471公开了(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-烯酸及其钠盐和钙盐(以下称作“试剂”，以下进一步说明)，
其是HMG CoA还原酶抑制剂。该试剂通过7-[4-(4-(氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰基-氨基)嘧啶-5-基-(3R)-3-羟基-5-氧-(E)-庚烯酸甲酯的还原和随后的加工而获得。然而，该试剂可以通过用酸处理BEM(裂去丙酮化合物保护基)，接着用碱处理(裂去酯)和(如EPA 0521471所述)将最初形成的盐转化为游离酸或钙盐而获得。
我们已发现了制备BEM有用具有益的方法。
本发明提供了制备BEM的方法，该方法包括通式III的氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基甲基]膦(以下称作DPPO)，
通式III
与通式II的2[(4R，6S)-6-甲酰基-2，2-二甲基-1，3-二氧杂-4-基}乙酸叔丁酯(以下称作BFA)，在强碱存在下反应，
通式II
该方法在适当的溶剂或溶剂混合物中进行，例如，醚类或芳族溶剂或其混合物。特别适合的溶剂包括，例如，四氢呋喃(THF)，二甲氧基乙烷和甲苯，或其混合物。特别优选的溶剂包括，例如THF和THF和甲苯。
用于该方法的适合的碱包括，例如，酰胺碱，烷基金属和金属氢化物。优选的碱包括，例如，二(三甲基硅烷基)酰胺，二(三甲基硅烷基)氨基钾，二(三甲基硅烷基)氨基锂，丁基锂和氢化钠。特别优选的碱是，例如，二(三甲基硅烷基)氨基钠(NaHMDS)。
反应可以在例如-20°--90℃范围，如-40°--90℃，-40°--80℃进行。进行该反应的适宜温度是，例如，丙酮和固体二氧化碳的混合物的温度(约-75℃)。
该方法以每当量DPPO 1.0-1.2当量碱有益地进行，例如，1.05-1.2当量和优选1.05-1.12当量。虽然BFA可以大过量存在，但是，每当量DPPO使用1.0-1.35当量是适宜的，优选1.05-1.3当量，特别优选1.05-1.15当量。
本发明方法与使用相应的磷酸二烷基酯(-PO(O烷基)2)作原料而不是DPPO的方法比较，提供了明显改进的产品产率和质量。
本发明的另一方面，原料DPPO可以按以下实施例所述方法获得，从2-氨基-4-(4-氟苯基)-6-异丙基嘧啶-5-甲酸烷基酯开始，例如，按日本专利申请06-256318所述方法可得到甲酯，或按EPA 0521471所述方法可得到乙酯。BFA可按EPA 0319847(实施例6)所述方法获得。
本发明另一方面是通式IV化合物的制备方法，
通式IV
其中R1是氢或药物可接受的阳离子，
该方法包括
(1)在强碱(如上述)存在下，DPPO与BFA反应得到BEM；
(2)断开二羟基(丙酮化合物)保护基(例如经酸性水解，如在THF或乙腈中用盐酸)；和
(3)在碱性条件下，断开叔丁酯基团，形成其中R1是药物可接受的阳离子的通式IV化合物，例如用在极性溶剂中的金属氢氧化物的溶液(如用在乙醇或乙腈中的氢氧化钠水溶液，形成钠盐)；
任意地接着中和，得到其中R1是氢的通式IV化合物；
和/或任意地接着转化成其中R1是药物可接受的阳离子的另一种通式IV化合物(例如，通过在含水条件下用水溶性钙盐(如氯化钙)处理，将钠盐转化成钙盐)。
步骤(2)、(3)和接着的任意步骤的适宜条件类似于EPA 0521471和/或EPA 0319847中公开的同样条件，因此，合并这些文献于本文中作参考。要得到通式IV化合物的钙盐，如实施例7所述优选进行步骤(2)和(3)并经甲胺盐转化成钙盐，该步骤构成本发明的又一方面。
在上述方法中，BFA可以用通式V化合物代替，
通式V
其中P1和P2是醇保护基，或P1和P2一起是1，3-二醇保护基，如EPA0319847和GB 2244705所述，这两篇文献合并入本文作参考，和P3是羧基保护基，例如(1-8C)烷基(1-4C烷基)，形成通式VI化合物，
通式VI
通过断开醇或二醇保护基通式VI化合物可转化成所说试剂，并转化COOP3成为COOH基或其药用盐。这种一般方法构成本发明的又一特征。
本发明由以下实施例进一步阐明，但本发明不限于此。
制备1
DPPO的制备
在甲苯(55ml)中的4-(4-氟苯基-6-异丙基)-2-[甲基(甲磺酰基)氨基]嘧啶-5-羧酸甲酯(12.0g)被冷至-10℃，并于2小时内在维持0℃以下，向其中加入氢化二异丁基铝(50ml在甲苯中的1.5M溶液)。加完后，于0℃下搅拌混合物30分钟。在维持0℃下向混合物中加甲醇(0.64ml)。然后，在维持40℃下于两小时内，将该混合物加到搅拌着的浓盐酸(23.3ml)、水(40.5ml)和乙腈(24ml)的混合物中。加完后，于40℃下再搅拌该混合物30分钟，然后以氮气吹扫(除去任何异丁烷)。将该混合物冷至20℃并放置20分钟。分出有机相并用浓盐酸(0.7ml)和水(30ml)洗此混合物。向有机相中加乙腈(24ml)并用在水(120ml)中的碳酸氢钠(0.038g)溶液洗此混合物。
有机相加热至40℃，然后，于40°-80℃以氮气吹扫。在大气压下蒸馏以浓缩该混合物，收集54ml馏分。向浓缩液中加乙腈(24ml)并于维持混合物20℃并搅拌下加三溴化磷(1.2ml)。加完后，于20℃搅拌混合物30分钟。于20℃下30分钟内将混合物加到水(36ml)中。搅拌混合物5分钟并分出有机相。用在水(36ml)中的碳酸氢钠(0.027g)溶液，接着用水(36ml)洗有机相。减压蒸馏有机相直至收集29ml馏分。将混合物冷至60℃并加二苯基次膦酸乙酯(7.47ml)。于60℃搅拌混合物3小时，然后，加热回流。和甲苯(40ml)并于2小时内将混合物冷至0℃。过滤收集产物，用冷的甲苯(10ml)洗并于50℃下真空干燥，得到DPPO(14.66g)；
1H NMR(CDCl3，270MHz)：7.42[m，10H，P(C6H5)2]，7.12[m，2H，Ar-H]，6.92[m，2H，Ar-H]，3.92[d.2H，CH2P]，3.51，3.46(2xs，6H，NCH3SO2CH3]，3.43[hept.，1H，CH(CH3)2]，1.25[d、6H、CH(CH3)2]
4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基)嘧啶-5-甲酸甲酯如下制备：
于25℃下搅拌2-氨基-4-(4-氟苯基)-6-异丙基嘧啶-5-甲酸甲酯(19.0g)、叔戊醇钠(22.95g)和二甲氧基乙烷(190ml)的混合物30分钟。将搅拌着的混合物冷至-10℃并滴加甲磺酰氯(8.4ml)，维持混合物温度于-5℃。20分钟后，加硫酸二(8.1ml)并温热该混合物至25℃。于25℃搅拌混合物1小时并加在二甲氧基乙烷(10ml)中的叔戊醇钠(1.91g)溶液。于25℃下搅拌混合物1小时。加在水(133ml)中氯化钠(13.3g)的溶液并于25℃下搅拌混合物10分钟。放置混合物15分钟，分出下层水相并弃掉。向剩余混合物中加水(38ml)并于25℃下搅拌混合物30分钟。加热混合物得到完全溶液。于1小时内慢慢冷却混合物至25℃。冷却混合物至0℃并搅拌1小时。过滤收集悬浮的固体，以50∶50的水/二甲氧基乙烷(20ml)的冷溶液(0℃)洗固体。于60℃下真空干燥固体，得到4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基)-5-甲酸甲酯(19.35g)。
1H NMR(270MHz，CDCl3)：7.69(m，2H)，7.14(m，2H)，3.71，3.60，3.51(3xs，9H)，3.20(m，1H)，1.32(d，6H).
实施例1
温热DPPO(19.17g)和THF(227ml)的混合物至40℃直至得透明溶液，然后经顺序抽真空和充氮气(5次循环)使溶液惰性。将混合物浸入丙酮/二氧化碳浴中冷却至-75℃。从温度保持于-74℃以下的均压滴液漏斗中，于10分钟内向反应混合物中加二(三甲基硅烷基)氨基钠(37.4ml，1.0M的THF溶液)，形成红色阴离子溶液。经滴液漏斗向混合物中淋洗THF(10ml)并于-76℃下搅拌混合物另1小时，形成红色悬浮液。从温度保持于-73℃以下的均压滴液漏斗中，于20分钟内分批向悬浮液中加BFA(80ml～13.5％ W/W的甲苯溶液)。经滴液漏斗向混合物中淋洗甲苯(20ml)并于-76℃下搅拌混合物另15分钟。撤去冷却，于1.5小时 温热混合物至10℃。一次加入在水(15g)中的冰醋酸(3.21g)，升温至18℃并溶解所有固体，再搅拌混合物5分钟。
在大气压下蒸馏(套管110℃)以浓缩混合物至94℃，收集总共274ml馏出物。冷却浓缩后的混合物，加水(40ml)，搅拌混合物5分钟后放置5分钟。弃掉下层水相。加在水(40ml)中的碳酸氢钠(2.99g)，搅拌混合物5分钟后再放置15分钟。弃掉下层水相，加水(30ml)，再搅拌5分钟后，再放置15分钟，弃掉下层水相。
将有机相转入有甲苯(20ml)的蒸馏设备中，于大气压下蒸馏(套管125-130℃)浓缩至116℃，收集85ml蒸馏物。真空(400-500mbar)蒸馏，至111℃收集另16.5M蒸馏物。释放真空并将浓缩后的混合物冷至80℃。在迅速搅拌下加温热的甲醇(140ml，50℃)，于30分钟内使溶温自冷却至20℃，并在此期间沉积固体。于30分钟内进一步冷却悬浮液至2℃，在烧结漏斗上过滤收集固体并尽可能地抽干。用冷甲醇(60ml，2℃)洗固体并再抽干后，在真空干燥箱中干燥过夜(50℃，200mbar)，得到BEM(14.01g，67.7％)。1H NMR(CDCl3，270MHz)7.65[m，2H，Ar-H]，7.09[m，2H，Ar-H]，6.52[dd，1H，ArCH＝C
H]，5.47[dd，1H，ArCH＝CH]，3.57，3.50[2xs，6H，NCH3，SO2CH3]，3.38[hept.，1H，Ar-CHMe2]，2.45，2.30[2xdd，2H，CH2CO2tBu]，1.55，1.13[dt，dd，2H，acetonide CH2]，1.50，1.40[2xs，6H，acetonide C(CH3)2]，1.45[s，9H，CO2C(CH3)3]，1.27[dd，6H，ArCH(CH3)2]
实施例2-6
以表1给出的反应剂比和温度，进行实施例1所述过程，得到所给产率的BEM。
表1
| DPPO重 | 温度(℃) | 当量NaHMDS | 当量BFA | BEM产率 |
| 10.00g | -75 | 1.12 | 1.20 | 69.2％ |
| 18.12g | -75 | 1.12 | 1.20 | 69.6％ |
| 12.08g | -75 | 1.06 | 1.26 | 72.8％ |
| 19.17g | -40 | 1.05 | 1.06 | 56.7％ |
| 9.57g | -90 | 1.05 | 1.10 | 72.0％ |
| 9.57g | -60 | 1.05 | 1.10 | 70.1％ |
实施例7
于惰性气氛中40℃下，搅拌BEM(5.0g)和乙腈(35ml)的混合物。于35°-42℃下30分钟内向所得溶液中加0.02M盐酸(9.5ml)。于40℃下搅拌混合物3小时后，冷却至25℃。于25℃搅拌下加1.0M氢氧化钠溶液(9.5ml)并于25℃下搅拌混合物另1小时。加氯化钠(4.7g)并于1小时内冷却混合物至-5℃。于-5℃加1M盐酸(9.5ml)和氯化钠(2.4g)的溶液，达pH3.4-4.0并于此温度下搅拌混合物5分钟。于-5℃放置混合物10分钟，分成两层。分出下层并弃掉。于-5℃加乙腈(65ml)于剩余溶液中，过滤混合物。在水(1.1ml)中的40％甲胺溶液于-5℃下加到混合物中并于40分钟内温热至30℃，保持该温度90分钟。然后，于40分钟内冷却混合物至0℃并于此温度下保持90分钟。过滤收集所得固体并用乙腈(2×12ml)洗。该固体为通式IV化合物(R1＝MeNH3 +)的甲胺盐，于35℃下真空干燥(3.87g)。于20℃下加8％ W/W氢氧化钠水溶液(5.44ml)于搅拌着的在脱气水(30ml)中的用胺盐(6.0g)混合物中并搅拌混合物1小时。过滤混合物并于40℃下减压浓缩混合物直至收集24ml馏出物。加水(24ml)并于40℃下再减压浓缩混合物直至收集24ml馏出物。加水(30ml)并于20℃下滴加在水(6ml)中的二水合氯化钙(1.03g)溶液。搅拌混合物45分钟，过滤所得固体。用水(36ml)洗固体并于40℃下真空干燥，得到(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-烯酸的钙盐。
Claims (14)
1.通式VI化合物的制备方法，
通式VI
该方法包括，在强碱存在下，氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基甲基]膦与通式V的化合物反应，
通式V
其中P1和P2是醇保护基，或P1和P2一起是1，3-二醇保护基，和P3是羧酸保护基。
2.权利要求1的方法，其中P3是C1-8烷基。
3.权利要求1或2的方法，其中P1与P2一起形成丙酮化合物保护基。
4.权利要求1的方法，该方法包括，在强碱存在下，氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基甲基]膦与2-[(4R，6S)-6-甲酰基-2，2-二甲基-1，3-二氧杂-4-基]乙酸叔丁酯反应制备(E)-(6-{2-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基]乙烯基}(4R，6S)-2，2-二甲基[1，3]二氧杂-4-基)乙酸叔丁酯。
5.权利要求1、2或4的方法，其中该反应在-20℃--90℃的温度下进行。
6.权利要求1、2或4的方法，其中强碱是二(三甲基硅烷基)氨基钠。
7.权利要求1、2或4的方法，其中该反应在选自四氢呋喃、二甲氧基乙烷和甲苯及其混合物的溶剂中进行。
8.权利要求1、2或4的方法，其中每当量氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基甲基]膦使用1.0-1.2当量碱。
9.权利要求4的方法，其中每当量氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基甲基]膦使用1.0-1.35当量2-[(4R，6S)-6-甲酰基-2，2-二甲基-1，3-二氧杂-4-基]乙酸叔丁酯。
10.化合物氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基甲基]膦。
11.通式VI化合物，
其中P1和P2是醇保护基，或P1和P2一起是1，3-二醇保护基，和P3是羧酸保护基。
12.权利要求11的化合物，其为(E)-(6-{2-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基]乙烯基}(4R，6S)-2，2-二甲基[1，3]二氧杂-4-基)乙酸叔丁酯。
13.通式IV化合物的制备方法，
通式IV
其中R1是氢或药物可接受的阳离子，该方法包括
(1)在强碱存在下，氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基甲基]膦与如下的通式V化合物反应，得到如下的通式VI化合物；
通式V
通式VI
(2)断开步骤(1)产物的二羟基保护基；
(3)在碱性条件下，断开步骤(2)产物的烷基酯基团，形成其中R1是药物可接受的阳离子的通式IV的化合物；任意地接着中和，得到其中R1是氢的通式IV化合物；和/或任意地接着转化成其中R1是药物可接受的阳离子的另一种通式IV化合物。
14.权利要求13的方法，其中所用的通式V化合物是2-[(4R，6S)-6-甲酰基-2，2-二甲基-1，3-二氧杂-4-基]乙酸叔丁酯。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9903472.0A GB9903472D0 (en) | 1999-02-17 | 1999-02-17 | Chemical process |
| GB9903472.0 | 1999-02-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1340052A CN1340052A (zh) | 2002-03-13 |
| CN1145625C true CN1145625C (zh) | 2004-04-14 |
Family
ID=10847843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008037043A Expired - Lifetime CN1145625C (zh) | 1999-02-17 | 2000-02-15 | ( e ) － ( 6 －{ 2 － [ 4 － ( 4－氟苯基 ) － 6 －异丙基 － 2 － [甲基 (甲磺酰基 )氨基 ]嘧啶 － 5 －基] |
Country Status (34)
| Country | Link |
|---|---|
| US (2) | US6844437B1 (zh) |
| EP (1) | EP1155015B1 (zh) |
| JP (3) | JP2003518474A (zh) |
| KR (1) | KR100648160B1 (zh) |
| CN (1) | CN1145625C (zh) |
| AR (1) | AR022600A1 (zh) |
| AT (1) | ATE415398T1 (zh) |
| AU (1) | AU760145B2 (zh) |
| BR (1) | BRPI0008301B8 (zh) |
| CA (1) | CA2362594C (zh) |
| CL (1) | CL2003002336A1 (zh) |
| CY (1) | CY1108733T1 (zh) |
| CZ (1) | CZ299844B6 (zh) |
| DE (1) | DE60040905D1 (zh) |
| DK (1) | DK1155015T3 (zh) |
| EE (2) | EE05531B1 (zh) |
| ES (1) | ES2316349T3 (zh) |
| GB (1) | GB9903472D0 (zh) |
| HK (1) | HK1041265B (zh) |
| HU (1) | HU229835B1 (zh) |
| IL (2) | IL144793A0 (zh) |
| IS (1) | IS2711B (zh) |
| MX (1) | MXPA01008235A (zh) |
| NO (1) | NO320739B1 (zh) |
| NZ (1) | NZ513261A (zh) |
| PL (1) | PL218518B1 (zh) |
| PT (1) | PT1155015E (zh) |
| RU (1) | RU2243969C2 (zh) |
| SI (1) | SI1155015T1 (zh) |
| SK (1) | SK286988B6 (zh) |
| TR (2) | TR200401874T2 (zh) |
| TW (1) | TWI285202B (zh) |
| WO (1) | WO2000049014A1 (zh) |
| ZA (1) | ZA200106370B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100436428C (zh) * | 2005-08-22 | 2008-11-26 | 鲁南制药集团股份有限公司 | 瑞舒伐他汀及其盐的制备方法 |
| CN103232398A (zh) * | 2012-04-28 | 2013-08-07 | 天津滨江药物研发有限公司 | 一种瑞舒伐他汀氨基酸盐及其制备方法和应用 |
| CN108997324A (zh) * | 2018-08-21 | 2018-12-14 | 南京欧信医药技术有限公司 | 瑞舒伐他汀钙中间体的制备方法 |
Families Citing this family (80)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9902202D0 (sv) * | 1999-06-10 | 1999-06-10 | Astra Ab | Production of aggregates |
| GB0003305D0 (en) * | 2000-02-15 | 2000-04-05 | Zeneca Ltd | Pyrimidine derivatives |
| GB0011120D0 (en) * | 2000-05-09 | 2000-06-28 | Avecia Ltd | Process |
| NL1015744C2 (nl) | 2000-07-19 | 2002-01-22 | Dsm Nv | Werkwijze voor de bereiding van 2-(6-gesubstitueerde-1,3-dioxan-4-yl) azijnzuurderivaten. |
| EP1417180B1 (en) * | 2001-07-13 | 2006-12-27 | AstraZeneca UK Limited | Preparation of aminopyrimidine compounds |
| SK1402004A3 (sk) * | 2001-08-16 | 2005-01-03 | Teva Pharmaceutical Industries Ltd. | Spôsob prípravy vápenatých solí statinov |
| EP1323717A1 (en) * | 2001-12-27 | 2003-07-02 | Dsm N.V. | Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives |
| EP1375493A1 (en) | 2002-06-17 | 2004-01-02 | Dsm N.V. | Process for the preparation of an dioxane acetic acid ester |
| GB0218781D0 (en) * | 2002-08-13 | 2002-09-18 | Astrazeneca Ab | Chemical process |
| AU2003288443B2 (en) | 2002-12-16 | 2007-10-25 | Astrazeneka Uk Limited | Process for the preparation of pyrimidine compounds |
| GB0312896D0 (en) * | 2003-06-05 | 2003-07-09 | Astrazeneca Ab | Chemical process |
| WO2005023778A2 (en) | 2003-08-28 | 2005-03-17 | Teva Pharmaceutical Industries Ltd. | Process for preparation of rosuvastatin calcium |
| UY28501A1 (es) * | 2003-09-10 | 2005-04-29 | Astrazeneca Uk Ltd | Compuestos químicos |
| GB0321827D0 (en) * | 2003-09-18 | 2003-10-15 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0322552D0 (en) | 2003-09-26 | 2003-10-29 | Astrazeneca Uk Ltd | Therapeutic treatment |
| GB0324791D0 (en) * | 2003-10-24 | 2003-11-26 | Astrazeneca Ab | Chemical process |
| TW200526596A (en) * | 2003-11-24 | 2005-08-16 | Teva Pharma | Crystalline ammonium salts of rosuvastatin |
| CA2546894C (en) | 2003-12-02 | 2009-09-08 | Teva Pharmaceutical Industries Ltd. | Reference standard for characterization of rosuvastatin |
| US7241800B2 (en) | 2004-03-17 | 2007-07-10 | Mai De Ltd. | Anhydrous amorphous form of fluvastatin sodium |
| GB0406757D0 (en) | 2004-03-26 | 2004-04-28 | Avecia Ltd | Process and compounds |
| JP2007508379A (ja) | 2004-07-13 | 2007-04-05 | テバ ファーマシューティカル インダストリーズ リミティド | Ｔｅｍｐｏ媒介型酸化段階を包含するロスバスタチンの調製方法 |
| GB0427491D0 (en) | 2004-12-16 | 2005-01-19 | Avecia Ltd | Process and compounds |
| GB0428328D0 (en) * | 2004-12-24 | 2005-02-02 | Astrazeneca Uk Ltd | Chemical process |
| CN100351240C (zh) * | 2005-01-19 | 2007-11-28 | 安徽省庆云医药化工有限公司 | 瑞舒伐他汀钙的合成方法 |
| TWI353981B (en) | 2005-02-22 | 2011-12-11 | Teva Pharma | Preparation of rosuvastatin |
| US20090124803A1 (en) * | 2005-03-22 | 2009-05-14 | Pandurang Balwant Deshpande | Process for preparation of rosuvastatin |
| EP1869005A1 (en) * | 2005-04-04 | 2007-12-26 | Unichem Laboratories Limited | Process for preparation of calcium salt of rosuvastatin |
| HU227120B1 (hu) * | 2005-05-26 | 2010-07-28 | Richter Gedeon Nyrt | Eljárás rosuvastatin kalciumsójának elõállítására új intermediereken keresztül |
| JP5146965B2 (ja) * | 2005-06-24 | 2013-02-20 | レツク・フアーマシユーテイカルズ・デー・デー | 不純物を含まない非晶質ロスバスタチンカルシウムの調製方法 |
| SI1915349T1 (sl) * | 2005-06-24 | 2016-05-31 | Lek Pharmaceuticals D.D. | Postopek za pripravo čistega amorfnega rosuvastatin kalcija |
| GB0514078D0 (en) * | 2005-07-08 | 2005-08-17 | Astrazeneca Uk Ltd | Chemical process |
| EP1912953B1 (en) | 2005-07-28 | 2016-08-17 | LEK Pharmaceuticals d.d. | Process for the synthesis of rosuvastatin calcium |
| JP2008515931A (ja) | 2005-08-16 | 2008-05-15 | テバ ファーマシューティカル インダストリーズ リミティド | 結晶形ロスバスタチン中間体 |
| CN100352821C (zh) * | 2005-08-22 | 2007-12-05 | 鲁南制药集团股份有限公司 | 一种瑞舒伐他汀钙中间体的制备方法 |
| WO2007125547A2 (en) * | 2006-05-03 | 2007-11-08 | Manne Satyanarayana Reddy | Novel process for statins and its pharmaceutically acceptable salts thereof |
| US8404841B2 (en) * | 2006-10-09 | 2013-03-26 | Msn Laboratories Limited | Process for the preparation of statins and their pharmaceutically acceptable salts thereof |
| EP2079712A2 (en) | 2006-10-31 | 2009-07-22 | Aurobindo Pharma Limited | An improved process for preparing rosuvastatin calcium |
| TW200831469A (en) * | 2006-12-01 | 2008-08-01 | Astrazeneca Uk Ltd | Chemical process |
| WO2008072078A1 (en) | 2006-12-13 | 2008-06-19 | Aurobindo Pharma Limited | An improved process for preparing rosuvastatin caclium |
| US8212035B2 (en) | 2007-02-08 | 2012-07-03 | Aurobindo Pharma Ltd. | Process for preparation of rosuvastatin calcium field of the invention |
| WO2008130678A2 (en) | 2007-04-18 | 2008-10-30 | Teva Pharmaceutical Industries Ltd. | Rosuvastatin intermediates and process for the preparation of rosuvastatin |
| JP2010533188A (ja) | 2007-07-12 | 2010-10-21 | テバ ファーマシューティカル インダストリーズ リミティド | ロバスタチン中間体及びその製法 |
| CA2696381A1 (en) | 2007-08-28 | 2009-03-05 | Ratiopharm Gmbh | Process for preparing pentanoic diacid derivatives |
| CN101376647B (zh) * | 2007-08-31 | 2010-12-08 | 中山奕安泰医药科技有限公司 | 一种用于合成瑞舒伐他汀中间体及瑞舒伐他汀的合成方法 |
| WO2009143776A1 (zh) | 2008-05-27 | 2009-12-03 | 常州制药厂有限公司 | 瑞舒伐他汀钙盐的制备方法及其中间体 |
| EP2138165A1 (en) | 2008-06-27 | 2009-12-30 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising a statin |
| SI2309992T1 (en) | 2008-06-27 | 2018-03-30 | Krka, Tovarna Zdravil, D.D., Novo Mesto | A pharmaceutical composition comprising a statin |
| WO2010029561A1 (en) * | 2008-09-09 | 2010-03-18 | Biocon Limited | A process for preparation of rosuvastatin acetonide calcium |
| EP2350025A1 (en) * | 2008-09-30 | 2011-08-03 | Aurobindo Pharma Limited | An improved process for preparing pyrimidine propenaldehyde |
| CN102186869A (zh) * | 2008-10-20 | 2011-09-14 | 株式会社钟化 | 新嘧啶衍生物及HMG-CoA还原酶抑制剂中间体的制造方法 |
| EP2327682A1 (en) | 2009-10-29 | 2011-06-01 | KRKA, D.D., Novo Mesto | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates |
| SI2373609T1 (sl) | 2008-12-19 | 2013-12-31 | Krka, D.D., Novo Mesto | Uporaba amfifilnih spojin za kontrolirano kristalizacijo statinov in intermediatov statinov |
| KR20100080432A (ko) * | 2008-12-29 | 2010-07-08 | 한미약품 주식회사 | 스타틴 화합물의 신규 제조방법 및 이에 사용되는 벤조티아졸릴 술폰 화합물 |
| EA019995B1 (ru) | 2009-01-14 | 2014-07-30 | Крка, Товарна Здравил, Д.Д., Ново Место | Соль розувастатина, способ ее получения и способ получения фармацевтически приемлемой соли розувастатина |
| WO2010089770A2 (en) | 2009-01-19 | 2010-08-12 | Msn Laboratories Limited | Improved process for the preparation of highly pure (3r,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3,5-dihydroxy-6(e)-heptenoic acid and pharmaceutically acceptable salts thereof |
| KR101157314B1 (ko) * | 2009-06-05 | 2012-06-15 | 주식회사종근당 | 로수바스타틴의 신규한 제조방법, 이 제조에 유용한 중간체 화합물 및 그의 제조방법 |
| EP2526099B1 (en) | 2010-01-18 | 2016-03-30 | MSN Laboratories Limited | Improved process for the preparation of amide intermediates and their use thereof |
| WO2011104725A2 (en) | 2010-02-23 | 2011-09-01 | Cadila Healthcare Limited | Hmg-coa reductase inhibitors and process for the preparation thereof |
| WO2012011129A2 (en) * | 2010-07-22 | 2012-01-26 | Msn Laboratories Limited | Novel polymorph of bis[(e)-7-[4-(4-fluorophenyl)-6-iso-propyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid] calcium salt |
| WO2012073256A1 (en) | 2010-11-29 | 2012-06-07 | Cadila Healthcare Limited | Salts of rosuvastatin |
| CN103313983B (zh) * | 2011-01-18 | 2016-06-29 | 中化帝斯曼制药有限公司荷兰公司 | 在碱存在下制备他汀类化合物的方法 |
| US8865900B2 (en) | 2011-01-18 | 2014-10-21 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Methyltetrazole sulfides and sulfones |
| US9150562B2 (en) | 2011-01-18 | 2015-10-06 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for the preparation of diol sulfones |
| WO2012172564A1 (en) * | 2011-05-25 | 2012-12-20 | Dr. Reddy's Laboratories Limited | Process for preparation of rosuvastatin calcium |
| WO2013083718A1 (en) | 2011-12-09 | 2013-06-13 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for the preparation of a statin precursor |
| HUE032936T2 (en) | 2011-12-09 | 2017-11-28 | Dsm Sinochem Pharm Nl Bv | A method for producing thioprecursors of statins |
| KR20130087153A (ko) * | 2012-01-27 | 2013-08-06 | 코오롱생명과학 주식회사 | 로수바스타틴의 제조방법 및 이에 사용되는 중간체 화합물 |
| KR101292743B1 (ko) * | 2012-05-17 | 2013-08-02 | (주) 에프엔지리서치 | 신규한 스타틴 중간체 및 이를 이용한 피타바스타틴, 로수바스타틴, 세리바스타틴 및 플루바스타틴의 제조 방법 |
| CN103864697A (zh) * | 2012-12-11 | 2014-06-18 | 润泽制药(苏州)有限公司 | 瑞舒伐中间体主链醇的制备方法 |
| WO2014108795A2 (en) | 2013-01-10 | 2014-07-17 | Aurobindo Pharma Limited | An improved process for the preparation of chiral diol sulfones and statins |
| CN103420919B (zh) * | 2013-08-22 | 2015-07-08 | 南京欧信医药技术有限公司 | 一种嘧啶类衍生物的合成方法 |
| WO2015037018A1 (en) * | 2013-09-14 | 2015-03-19 | Ind-Swift Laboratories Limited | Process for the preparation of rosuvastatin via novel intermediates |
| PT3115367T (pt) | 2014-03-07 | 2018-01-04 | Asymchem Laboratories Fuxin Co Ltd | Composto intermediário para preparar rosuvastatina cálcica e método para preparar rosuvastatina cálcica a partir deste |
| CN103936680B (zh) * | 2014-04-18 | 2016-08-24 | 润泽制药(苏州)有限公司 | 瑞舒伐他汀钙已知杂质的制备方法 |
| CN104788387A (zh) * | 2015-04-17 | 2015-07-22 | 浙江海森药业有限公司 | 高纯度瑞舒伐他汀钙的制备方法 |
| KR20160126700A (ko) | 2015-04-24 | 2016-11-02 | 미래파인켐 주식회사 | 스타틴의 중간체, 이의 제조방법 및 이를 이용한 로수바스타틴의 제조방법 |
| CN105461636A (zh) * | 2015-12-30 | 2016-04-06 | 安徽美诺华药物化学有限公司 | 一种瑞舒伐他汀甲酯的合成方法 |
| CN106478518A (zh) * | 2016-09-27 | 2017-03-08 | 南通常佑药业科技有限公司 | 一种庚烯酸环戊酯衍生物的制备方法 |
| KR101953575B1 (ko) | 2016-10-24 | 2019-05-24 | 한양대학교 에리카산학협력단 | 스타틴계 고지혈증 치료제 합성을 위한 새로운 중간체 합성 및 이를 이용한 로수바스타틴 합성 공정 개발 |
| CN109651259B (zh) * | 2018-12-29 | 2020-05-19 | 浙江永太科技股份有限公司 | 一种瑞舒伐他汀钙关键中间体的纯化方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3741509A1 (de) | 1987-12-08 | 1989-06-22 | Hoechst Ag | Verfahren zur herstellung optisch aktiver 3-desmethylmevalonsaeurederivate sowie zwischenprodukte |
| JP2648897B2 (ja) | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | ピリミジン誘導体 |
| FR2741620B1 (fr) | 1995-11-28 | 1997-12-26 | Oreal | Procede de preparation de composes a groupement beta-hydroxy -delta-lactone analogues de la (+) compactine et de la (+) mevinoline |
-
1999
- 1999-02-17 GB GBGB9903472.0A patent/GB9903472D0/en not_active Ceased
-
2000
- 2000-02-15 CN CNB008037043A patent/CN1145625C/zh not_active Expired - Lifetime
- 2000-02-15 US US09/913,539 patent/US6844437B1/en not_active Expired - Lifetime
- 2000-02-15 PL PL350185A patent/PL218518B1/pl unknown
- 2000-02-15 BR BRPI0008301A patent/BRPI0008301B8/pt not_active IP Right Cessation
- 2000-02-15 KR KR1020017010439A patent/KR100648160B1/ko active IP Right Grant
- 2000-02-15 SI SI200031016T patent/SI1155015T1/sl unknown
- 2000-02-15 MX MXPA01008235A patent/MXPA01008235A/es active IP Right Grant
- 2000-02-15 CZ CZ20012930A patent/CZ299844B6/cs not_active IP Right Cessation
- 2000-02-15 WO PCT/GB2000/000481 patent/WO2000049014A1/en active IP Right Grant
- 2000-02-15 IL IL14479300A patent/IL144793A0/xx not_active IP Right Cessation
- 2000-02-15 EE EEP200900043A patent/EE05531B1/xx unknown
- 2000-02-15 RU RU2001125421/04A patent/RU2243969C2/ru active
- 2000-02-15 EE EEP200100430A patent/EE05150B1/xx unknown
- 2000-02-15 TR TR2004/01874T patent/TR200401874T2/xx unknown
- 2000-02-15 PT PT00903810T patent/PT1155015E/pt unknown
- 2000-02-15 ES ES00903810T patent/ES2316349T3/es not_active Expired - Lifetime
- 2000-02-15 DE DE60040905T patent/DE60040905D1/de not_active Expired - Lifetime
- 2000-02-15 HU HU0200301A patent/HU229835B1/hu unknown
- 2000-02-15 NZ NZ513261A patent/NZ513261A/en not_active IP Right Cessation
- 2000-02-15 JP JP2000599753A patent/JP2003518474A/ja not_active Withdrawn
- 2000-02-15 AU AU25573/00A patent/AU760145B2/en not_active Expired
- 2000-02-15 CA CA002362594A patent/CA2362594C/en not_active Expired - Fee Related
- 2000-02-15 AR ARP000100642A patent/AR022600A1/es active IP Right Grant
- 2000-02-15 DK DK00903810T patent/DK1155015T3/da active
- 2000-02-15 TR TR2001/02360T patent/TR200102360T2/xx unknown
- 2000-02-15 AT AT00903810T patent/ATE415398T1/de active
- 2000-02-15 SK SK1183-2001A patent/SK286988B6/sk not_active IP Right Cessation
- 2000-02-15 EP EP00903810A patent/EP1155015B1/en not_active Expired - Lifetime
- 2000-03-10 TW TW089104365A patent/TWI285202B/zh not_active IP Right Cessation
-
2001
- 2001-07-31 IS IS6029A patent/IS2711B/is unknown
- 2001-08-02 ZA ZA200106370A patent/ZA200106370B/xx unknown
- 2001-08-16 NO NO20013994A patent/NO320739B1/no not_active IP Right Cessation
-
2002
- 2002-04-22 HK HK02103022.4A patent/HK1041265B/zh not_active IP Right Cessation
-
2003
- 2003-07-02 US US10/610,700 patent/US6784171B2/en not_active Expired - Lifetime
- 2003-11-12 CL CL200302336A patent/CL2003002336A1/es unknown
-
2004
- 2004-08-05 IL IL163375A patent/IL163375A/en not_active IP Right Cessation
-
2007
- 2007-05-08 JP JP2007123108A patent/JP4130844B2/ja not_active Expired - Lifetime
-
2008
- 2008-03-17 JP JP2008067100A patent/JP2008255114A/ja active Pending
-
2009
- 2009-01-29 CY CY20091100107T patent/CY1108733T1/el unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100436428C (zh) * | 2005-08-22 | 2008-11-26 | 鲁南制药集团股份有限公司 | 瑞舒伐他汀及其盐的制备方法 |
| CN103232398A (zh) * | 2012-04-28 | 2013-08-07 | 天津滨江药物研发有限公司 | 一种瑞舒伐他汀氨基酸盐及其制备方法和应用 |
| CN103232398B (zh) * | 2012-04-28 | 2016-04-06 | 上海科州药物研发有限公司 | 一种瑞舒伐他汀氨基酸盐及其制备方法和应用 |
| CN108997324A (zh) * | 2018-08-21 | 2018-12-14 | 南京欧信医药技术有限公司 | 瑞舒伐他汀钙中间体的制备方法 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1145625C (zh) | ( e ) － ( 6 －{ 2 － [ 4 － ( 4－氟苯基 ) － 6 －异丙基 － 2 － [甲基 (甲磺酰基 )氨基 ]嘧啶 － 5 －基] | |
| KR101099934B1 (ko) | 로수바스타틴 칼슘염의 향상된 제조 | |
| TWI260982B (en) | Methods for preparing O-desmethylvenlafaxine | |
| CN101454304B (zh) | 用于制造苯并吡喃-2-醇衍生物的方法 | |
| CN1106396A (zh) | 用于制备具有抗糖尿病和抗肥胖症性能的芳香氨基醇衍生物的中间化合物 | |
| CN1759093A (zh) | 用于制备1,2－二氨基化合物的不使用叠氮化物的方法 | |
| JP6316282B2 (ja) | イソシアナートシランの作製 | |
| KR100877849B1 (ko) | 3-히드록시테트라히드로퓨란의 효율적 제조방법 | |
| CN101321770A (zh) | 由雷帕霉素42-酯硼酸酯制备雷帕霉素42-酯的可放大方法 | |
| EP0131435B1 (en) | Process for preparing 3-phenoxy-1-azetidines and carboxamide derivatives | |
| CN1091743A (zh) | 吡咯衍生物，其制备方法及其在治疗上的应用 | |
| WO2017093973A1 (en) | Process for the preparation of pure sofosbuvir | |
| CN1146547C (zh) | 4,6-二氯-5-氟嘧啶的制备方法 | |
| JP4375943B2 (ja) | 粉末ｎ−長鎖アシルイミノ二塩基酸塩の製造方法 | |
| CN1211356C (zh) | 偶氮亚氨基醚和偶氮羧酸酯的制备方法以及偶氮羧酸的新的混合酯 | |
| JPS6121624B2 (zh) | ||
| JP2011098934A (ja) | Ｌ−カルニチンに含まれる不純物の除去方法 | |
| CN1281596C (zh) | 制备4－氧代四氢吡喃－2－酮的方法 | |
| KR101006003B1 (ko) | 이상계 반응을 이용한 폴리옥시 알킬렌 알케닐 에테르의제조 방법 | |
| WO2016016446A1 (en) | Process for preparing 2-fluoropropionaldehyde | |
| US20090118507A1 (en) | Method for Preparing (3-Chloro-4-Fluorophenyl)-(4-Fluoro-4--Piperidin-1-Yl)-Methanone and Novel Intermediate Pyrimidine Derivatives | |
| CN1057652A (zh) | 一种制备取代的无环核苷及其有关中间体的方法 | |
| JPH07258183A (ja) | Ｎ，Ｎ−ジエチル−α，β−不飽和カルボン酸アミドの製造方法 | |
| CN1206415A (zh) | 3－苯基－1－亚甲二氧基苯基－1,2－二氢化茚－2－羧酸衍生物的制备方法 | |
| CN114621126A (zh) | 一种改进的依折麦布的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: ASTRAZENECA AB Free format text: FORMER NAME: ASTRA ZENECA AKTIEBOLAG |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Swedish Sodertalje Patentee after: Astrazeneca (Sweden) AB Patentee after: Shionogi & Co., Ltd. Address before: Swedish Sodertalje Patentee before: Astra Zeneca Aktiebolag Patentee before: Shionogi & Co., Ltd. |
|
| CX01 | Expiry of patent term |
Granted publication date: 20040414 |
|
| CX01 | Expiry of patent term |