WO2012140490A2 - Procédé de préparation de dérivé de quinoléine - Google Patents

Procédé de préparation de dérivé de quinoléine Download PDF

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WO2012140490A2
WO2012140490A2 PCT/IB2012/000721 IB2012000721W WO2012140490A2 WO 2012140490 A2 WO2012140490 A2 WO 2012140490A2 IB 2012000721 W IB2012000721 W IB 2012000721W WO 2012140490 A2 WO2012140490 A2 WO 2012140490A2
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acid
formula
compound
process according
calcium
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PCT/IB2012/000721
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WO2012140490A3 (fr
Inventor
Sukumar Nandi
Balanarasimha Reddy Gona
Naresh Akkina
Narayan Krishna Anjaneya Subramanya Sambho GORIMELLA
Joseph Prabahar Koilpillai
Sivakumaran Meenakshisunderam
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Aurobindo Pharma Limited
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Publication of WO2012140490A2 publication Critical patent/WO2012140490A2/fr
Publication of WO2012140490A3 publication Critical patent/WO2012140490A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to a novel process for preparing Pitavastatin calcium salt of formula I.
  • Pitavastatin calcium chemically known as (3-3 ⁇ 45S,62s)-7-[2-cyclopropyl-4-(4- fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid calcium (2: 1) salt, is a synthetic lipid lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMG-CoA reductase).
  • Pitavastatin is being marketed under the brand name Livalo , as an oral tablet in 1 MG, 2 MG and 4 MG strengths.
  • Pitavastatin calcium is used to lower the lipid levels including cholesterol in blood and can be used for the prevention or treatment of hyperlipidemia and artheriosclerosis.
  • R is hydrogen or protecting group
  • US 5,284,953 discloses a process for the preparation of Pitavastatin calcium, which employs optically active a-methylbenzylamine as a resoluting agent.
  • Y represents P + RnRi 2 Ri3Hal " or P(W)Ri 4 R 15 ;
  • R 9a , R % and R ]0 are protecting groups each of Rn, Rj 2> R ⁇ , Ri 4 and R15 which are independent of one another, is optionally substituted alkyl or optionally substituted aryl group;
  • R14 and Rj 5 together form a 5- or 6-membered ring;
  • Hal is chlorine, bromine or iodine; and W is O or S.
  • Trifluoroacetic acid or hydrochloric acid is used to break the acetonide and the Pitavastatin ester formed is converted in situ to its corresponding alkali salt by treating with base, such as sodium hydroxide.
  • the objective of the present invention is to provide a novel process for preparing (3 ?,55,6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6- heptenoic acid, calcium (2:1) salt with high yield and high purity, which is simple, industrially applicable and economically viable.
  • Another objective of the present invention is to provide a novel process for preparing (3 ?,5iS',6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6- heptenoic acid, calcium (2:1) salt from novel intermediates.
  • Yet another objective of the present invention is to provide a process for preparing (3if,55,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6- heptenoic acid, calcium (2: 1) salt, containing least amount of diastereomeric impurity.
  • Present invention provides a novel process for preparing (3R,5S,6E)-7-[2- cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2: 1) salt of formula I,
  • Ri represents a hydroxy protecting group
  • R,0 wherein R 2 represents C straight chain or branched chain alkyl, aryl, substituted aryl, aralkyl; M represents Mg, Zn, Ca or Cu; n represents an integer selected from 1 -2; R 3 represents alkyl or alkoxy; m represents an integer selected from 0 or 1
  • R 2 is same as defined above;
  • R 2 is same as defined above;
  • step (e) treating the compound obtained in step (e) with calcium ion source to give Pitavastatin calcium of Formula I.
  • the present invention also provides a process for preparing (3R,5S,6E)-7-[2- cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2: 1) salt of formula I, which comprises,
  • R 2 is same as defined above
  • R 2 is same as defined above and X represents monobasic or dibasic acid
  • M represents Na, K, Li
  • present invention provides a process to prepare pitavastatin calcium comprising protecting (3.S , ,4E)-5-[2-cyclopropyl-4-(4-fluorophenyl)quinolin- 3-yl]-3-hydroxypentenoic acid of formula II with a suitable hydroxy protecting group selected from tertiarybutyldimethylsilyl, dihydropyran, trimethylsilyl, methoxymethyl, more preferably tert-butyldimethylsilyl in the presence of an organic solvent selected from toluene, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, N-methylpyrrolidinone, sulfolane or mixtures thereof with or without acid or base catalysts at a temperature ranging from 0 to 50°C; preferably at 0-30°C.
  • a suitable hydroxy protecting group selected from tertiarybutyldimethylsilyl, dihydropyran, tri
  • the acid catalyst is selected from pyridinium p-toluene sulfonate, p-toluene sulfonic acid, acetic acid, etc. and base catalyst is selected from triethylamine, pyridine, imidazole, etc.
  • a suitable additive is added to accelerate the reaction, which is selected from sodium iodide, potassium iodide, lithium iodide etc.
  • (3S,4E)-5-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3-(protected hydroxy )pentenoic acid of formula III is treated with acid activator like 1 ,1- carbonylimidazole, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, 4-methoxyphenylchloroformate, 2,4-dinitrophenyl chloroformate, 4- trifluoromethylchloroformate, 4-nitrophenylchloroformate, etc.; more preferably with 1,1-carbonylimidazole in the presence or absence of organic base which is selected from triethylamine, pyridine, etc.
  • the resulting activated imidazolimide intermediate is subsequently treated with metal complex of alkyl malonate selected from magnesium, zinc, calcium or copper complex.
  • Magnesium complex of monoalkyl malonate is prepared by treating 2 moles of malonic acid mono alkyl ester with 1 mole of magnesium ethoxide in the presence of an organic solvent selected from tetrahydrofuran, N,N-dimethylformamide, methylene chloride, acetonitrile or mixture thereof and the reaction is conducted at a temperature between 0-100°C, preferably at ambient temperature.
  • Zinc complex of monoalkyl malonate is prepared by using different methods known in the art, such as process I or II.
  • Zinc complex is prepared by reacting dialkyl zinc with 2 moles of lower alcohol, preferably ethanol in an inert solvent selected from tetrahydrofuran, toluene, hexane, methyl tert-butyl ether, isopropyl ether or mixture thereof, at -10°C to 40°C. 1-5 mole of monoalkyl malonate, preferably 2 to 3 mole are added to this reaction mixture and stirred for 1 - 15 h, preferably for 1 -3 h.
  • lower alcohol preferably ethanol
  • an inert solvent selected from tetrahydrofuran, toluene, hexane, methyl tert-butyl ether, isopropyl ether or mixture thereof
  • Zinc complex is prepared by reacting zinc oxide with 1 to 5 moles of monoalkyl malonate in an inert solvent selected from tetrahydrofuran, toluene, hexane, methyl tert-butyl ether, isopropyl ether or mixture thereof, at ambient temperature for 2h to 6h.
  • an inert solvent such as toluene.
  • the metal complex of formula IV is reacted with acid activated compound of formula III in an inert solvent such as tetrahydrofuran, acetonitrile, toluene, methyl tert-butyl ether, isopropyl ether or mixtures thereof at 0°C to 40°C, preferably at 10°C to 25°C for 8h to 24h, preferably lOh to 24h to yield (5S,6E)-7-[2-cyclopropyl-4-(4- fluorophenyl)-quinolin-3-yl]-5-(protectedhydroxy)-3-oxo-6-heptenoate of formula V.
  • an inert solvent such as tetrahydrofuran, acetonitrile, toluene, methyl tert-butyl ether, isopropyl ether or mixtures thereof at 0°C to 40°C, preferably at 10°C to 25°C for 8h to 24h, preferably lOh
  • metal borohydride selected from sodium borohydride, more preferably sodium borohydride in the presence of chelating agents like trialkylborane or boronates selected from dialkylalkoxyborane such as diethylmethoxyborane, diethylethoxyborane, dimethylmethoxyborane, more preferably with diethylmethoxyborane, in a mixture of inert solvent selected from tetrahydrofuran, a lower alkanol, more preferably methanol and C alkyl ester like methyl acetate, ethyl acetate, propyl acetate, more preferably ethyl acetate at -78°C to -0°C.
  • metal borohydride selected from sodium borohydride, more preferably sodium borohydride in the presence of chelating agents like trialkylborane or boronates selected from dialkylalkoxyborane such as diethylmethoxyborane,
  • 2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde of formula XIII is reacted with a phosphorous compound of formula XIV optionally in the presence of a base such as organic base selected from sodium methoxide, lithium diisopropylamide, n-butyllithium, lithium hexamethyldisilazane, sodium hexamethyldisilazane, etc.
  • a base such as organic base selected from sodium methoxide, lithium diisopropylamide, n-butyllithium, lithium hexamethyldisilazane, sodium hexamethyldisilazane, etc.
  • a base selected from sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, a solvent selected from acetonitrile, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol and mixture thereof, at a temperature ranging from 20-90°C, preferably at 40-80°C for 1 -8 h to yield (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]acrylate of formula XV, which is reduced using a reducing agent such as diisobutylaluminium hydride (DIBAL), Vitride, Lithium aluminium hydride (LAH), etc.
  • DIBAL diisobutylaluminium hydride
  • LAH Lithium aluminium hydride
  • (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]propen-l-ol of formula XVI is oxidized using an oxidizing agent such as pyridinium dicromate (PDC), Pyridinium chlorocromate (PCC), manganese dioxide (Mn0 2 ), and tetrapropylammoniumperrutheniante (TPAP), sodium hypochlorite (NaOCl) / TEMPO, N-methylmorpholine-N-oxide (MNO) and the like, at a temperature ranging from 0-100°C preferably at 0-25°C to yield (2£)-3-[2-cyclopropyl-4-(4- fluorophenyl)quinolin-3-yl]-2-propenal of formula XVII, which is condensed with a compound of formula XVIIIa or XVIIIb in presence of base selected from n- butyllithium, lithium
  • lithium hexamethyldisilazane in an organic solvent selected from tetrahydrofuran, ether, hydrocarbon solvents such as heptane, hexane or mixture thereof, preferably tetrahydrofuran and hexane and the reaction is carried out at a temperature ranging from -78°C to 25°C.
  • present invention relates to novel organic acid salts of Pitavastatin alkyl ester of formula VIII.
  • R 2 is same as defined above.
  • the organic acid salt of Pitavastatin ester is selected from trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzene sulphonic acid, 4-nitrobenzene sulfonic acid, etc.
  • the process to prepare organic acid salt of Pitavastatin ester of formula VIII according to present invention comprises reacting Pitavastatin ester of formula VII in an organic solvent selected from C 1-C5 alcohol such as methanol, ethanol, butanol; C 3 -C 8 esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate; C 3 -C 8 ketones such as methyl ethyl ketone, methyl isobutyl ketone, acetone; C 6 -Cio aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, methyl ethyl ether; acetonitrile and mixture thereof, with an organic acid, selected from monobasic, dibasic, or tribasic acid, such as trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid
  • the organic acid salt of formula VIII is prepared using organic acid and ester compound of VII in molar ratio within the range from 1.25:1 to 0.8 : 1 ; preferably 1.1 : 1.
  • the present invention provides Pitavastatin ethyl ester organic acid salt of formula VIII, containing less than -0.3% of its anti-isomer of formula VIII(a) and least amount of Pitavastatin lactone salt of formula X or less than 0.5% corresponding Pitavastatin acid salt of formula XI.
  • Non-polar solvent selected from hexane, heptane, cyclohexane, ethers such as diisopropyl ether etc. is added and isolated the organic acid salt of Pitavastatin ester of formula VIII.
  • the obtained organic acid salt of Pitavastatin ester of formula VIII is optionally purified using organic solvent or from a mixture of solvent selected from ethanol, methanol, isopropyl alcohol, methyl tert-butyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene, acetonitrile, water, hexanes, heptane, pentane, cyclohexane etc.
  • Inorganic base selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, lithium bicarbonate, lithium carbonate; in the presence of an organic solvent selected from-ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran, acetonitrile and water is added to obtain Pitavastatin ester free from acid and then treated with aqueous alkali selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, lithium bicarbonate, lithium carbonate, etc. to obtain Pitavastatin alkali salt of formula IX, which in situ converted to Pitavastatin calcium of formula I by treating with a source of calcium ions selected from calcium chloride, calcium acetate, calcium carbonate.
  • Methyl (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]acrylate (50 g, 0.144 mole) was dissolved in toluene (600 ml) at 25-30°C. It was cooled to -50 to -60°C under nitrogen atmosphere. Diisobutylaluminium hydride (82 g, -25% w/w solution in toluene) was added slowly in - 2 h by keeping the temperature of the reaction mass between -50°C and -60°C. The completion of the reaction was confirmed by TLC and thereafter, water (300 ml) was added to the above reaction mass slowly in -30 min at -50°C and temperature was raised to 25-30°C.
  • Diisobutylaluminium hydride (82 g, -25% w/w solution in toluene) was added slowly in - 2 h by keeping the temperature of the reaction mass between -50°C and -60°C. The
  • the precipitated inorganic salt was filtered through hyflow. From the filtrate, toluene layer was separated and the aqueous layer was extracted with toluene (300 ml). The combined toluene layer was washed with water. Thereafter the toluene layer was partially concentrated to control the water content below 0.1% w/w.
  • Manganese dioxide (100 g) was added to the above partially distilled toluene layer and stirred at 25-30°C for ⁇ 24 h. Thereafter the reaction mass was filtered and the residue was washed with preheated toluene (2 x 150 ml). The filtrate was concentrated at 35-45°C. The crude mass obtained was crystallized from hexanes (250 ml) and dried at 40-45°C till the loss on drying is less than 3% w/w.
  • Hexamethyldisilazane (73.31 g, 0.454 mole) was added to n-butyl lithium (272 ml, -15% w/w solution in hexanes) at 0-5°C over a period of -15 min and thereafter temperature was raised to 20-30°C and stirred for 30 min.
  • the above contents were diluted with tetrahydrofuran (450 ml) and the reaction mass was cooled to -35°C.
  • the resulting aqueous layer was extracted with methylene chloride (2 x 250 ml) at 25-30°C.
  • the pH of the resulting aqueous layer was lowered to 1.5 to 2 with aqueous hydrochloric acid and the product was extracted with methylene chloride (2 x 250 ml).
  • the combined methylene chloride extracts was washed with water (250 ml) and solvent was evaporated.
  • the residue obtained was dissolved in acetonitrile (600 ml) and (R)-oc- Methylbenzyl amine (17.0 g) was added to it.
  • the product precipitated was filtered, washed with acetonitrile (950 ml) and dried at 40-45°C under reduced pressure for 8 h.
  • Part A (35,4E)-5 - [2-Cylopropyl-4-(4-fluorophenyl)quinoline-3 -yl]-3-hydroxy pentenoic acid, (R)-a-methylbenzylamine salt (50 g) was suspended in a mixture of methylene chloride (150 ml) and water (150 ml) and cooled the suspension to 0-5°C. The contents were acidified with ⁇ 1N hydrochloric acid (-100 ml) to pH 2.0 - 2.5. Thereafter, the temperature of the reaction mass was raised to 20-30°C and methylene chloride layer was separated.
  • the aqueous layer was extracted with methylene chloride (150 ml) and the combined methylene chloride extracts was washed with water (250 ml). The washed methylene chloride layer was concentrated to obtain a viscous oily residue.
  • Part B Anhydrous potassium iodide (41.66 g) was suspended in N,N- dimethylformamide (160 ml) at 25-30°C under nitrogen atmosphere, tert- butyldimethylsilyl chloride (37.65 g) was added to the above suspension and temperature was raised to 60-65 °C. It was stirred for 45 min at 60-65 °C and triethyl amine (30.42 g) was added to it slowly over a period of 30 min. The part A product was dissolved in N,N-dimethylformamide (100 ml) and added to the above reaction mass at 60-65°C. The reaction mass was stirred for 30 min and the completion of the reaction was confirmed by TLC.
  • Part C The Part B product was dissolved in methylene chloride at 25-30°C and cooled to 15-20°C. Carbonyldiimidazole (48.80 g) was dissolved in methylene chloride (500 ml) and added to the above reaction mass over a period of 15 min. at 15-20°C. The stirring was continued at this temperature for ⁇ 3h and the completion of the reaction was confirmed by TLC. Thereafter it was quenched by pouring into pre-cooled water (1.0 Lt, 2-5°C). The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride (250 ml).
  • the combined methylene chloride layer was washed with water (250 ml), with -5% w/w aqueous citric acid solution and finally with water (250 ml).
  • the methylene chloride layer was concentrated at 40-45°C under vacuum to obtain the product as an oily residue.
  • reaction mass was diluted with ethyl acetate (500 ml) and temperature of the reaction mass was raised to 15-20°C.
  • the organic layer was separated.
  • the aqueous layer was extracted with ethyl acetate (250 ml) and the combined organic layer was washed with water.
  • Solvent was evaporated to obtain a viscous residue which was re- dissolved in toluene (250 ml), washed with -2% w/w aqueous potassium carbonate solution (2 x 75 ml) and finally with water (75 ml).
  • the toluene layer was concentrated under vacuum to obtain the product as viscous residue which was subsequently crystallized from ethyl acetate- hexane (2:8 ; v/v).
  • the product was dried under vacuum at 40-45°C till the loss on drying is ⁇ 0.5% w/w.
  • the ethyl acetate layer was concentrated under vacuum at 40-45 °C to obtain the crude product. It was co-distilled with methanol (80 ml X 2) and finally with n-heptane (80 ml). The residue obtained after distillation was dissolved in ethyl acetate (50 ml) and ethanol (25 ml) at 20-30°C. n-Heptane (200 ml) was added to it for crystallization. The product was filtered, washed with n-heptane (25 ml) at 0-5 °C and dried at 40-45 °C under vacuum for 8 h till the loss on drying is less than 0.5% w/w.
  • Ethyl (3 ?,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy- 6-heptenoate (25 g, 0.055 mole) was suspended in ethanol (125 ml) and cooled to 0- 5°C.
  • Sodium hydroxide (2.28 g, 97% w/w assay, 0.055 mole) in water (50 ml) was added to the above suspension at 0-5°C and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, solvent was evaporated and water (240 ml) was added to it.
  • aqueous layer was extracted with methyl tert-butyl ether (2 x 50 ml). Carbon (1 g) was added to the aqueous layer and stirred for 30 min. It was filtered through hyflo and a solution of calcium chloride (4.5 g, dihydrate, 0.030 mole) in water (25 ml) was added to it. The Pitavastatin calcium, which precipitated out was filtered and washed with water (2 x 25 ml). The product was dried under vacuum at 40-45°C for 8 h.
  • a solution of diethylmethoxyborane in tetrahydrofuran (8.95 g, 50% solution, 0.044 mole) was added to a cold mixture of tetrahydrofuran (300 ml), methanol (65 ml) and ethyl acetate (25 ml) at -75°C to -80°C.
  • Sodium borohydride (1.36 gm,0.033 mole) was added to the above solution in one lot and stirred for 5 min. at the same temperature.
  • TRIFLUOROACETATE SALT [PITAVASATTIN ETHYL ESTER TRIFLUOROACETATE SALT] The crude Pitavastatin ethyl ester (10 gm, 0.022 mole, anti isomer: 0.85%), was dissolved in a mixture of ethyl acetate (25 ml) and ethanol (10 ml). It was cooled to 0- 5°C. Trifluoacetic acid (1.89 ml, 0.024 mole) was added to the above solution maintaining the temperature below 5°C. The reaction mixture was stirred for 15 min at 0-5°C and thereafter temperature was raised to 20-30°C. Heptane (150 ml) was added to it and stirred for 1 hr. The precipitated Pitavastatin ethyl ester trifluoroacetate salt was isolated by filtration.
  • Anti isomer (JS,55-Isomer): 0.50%.
  • the Pitavastatin ethyl ester, trifluoroacetate salt (10 gm, anti isomer: 0.51%) was dissolved in a mixture of ethyl acetate (25 ml) and ethanol (10ml). n-Heptane (150 ml) was added to it slowly over a period of 30 min. at 20-30°C. The product precipitated was further stirred for 2 hr and filtered.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation de sel calcique de pitavastatine de formule (I).
PCT/IB2012/000721 2011-04-11 2012-04-10 Procédé de préparation de dérivé de quinoléine WO2012140490A2 (fr)

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IN1251/CHE/2011 2011-04-11
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CN102898367A (zh) * 2012-11-15 2013-01-30 江苏阿尔法药业有限公司 一种匹伐他汀钙原料药中间体的制备方法
CN103145613A (zh) * 2013-03-11 2013-06-12 黄河三角洲京博化工研究院有限公司 一种(e)-3-(2-环丙基-4-（4-氟苯基）)喹啉-2-丙烯醛的合成方法
CN103848784A (zh) * 2012-12-05 2014-06-11 安徽省庆云医药化工有限公司 匹伐他汀酯的新晶型及其制备方法
CN104016916A (zh) * 2014-05-16 2014-09-03 南通常佑药业科技有限公司 一种匹伐他汀钙中间体的制备方法
WO2017022846A1 (fr) * 2015-08-05 2017-02-09 株式会社エーピーアイ コーポレーション Procédé de production de pitavastatine calcique
CN106749001A (zh) * 2016-11-21 2017-05-31 黄河三角洲京博化工研究院有限公司 一种(e)‑3‑[2‑环丙基‑4‑(4‑氟苯基)‑3‑喹啉‑2‑丙烯醛的合成方法

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CN102898367A (zh) * 2012-11-15 2013-01-30 江苏阿尔法药业有限公司 一种匹伐他汀钙原料药中间体的制备方法
CN103848784A (zh) * 2012-12-05 2014-06-11 安徽省庆云医药化工有限公司 匹伐他汀酯的新晶型及其制备方法
WO2014086073A1 (fr) * 2012-12-05 2014-06-12 安徽省庆云医药化工有限公司 Nouvelle forme cristalline d'ester de pitavastatine et son procédé de préparation
CN103848784B (zh) * 2012-12-05 2016-12-21 安徽省庆云医药化工有限公司 匹伐他汀酯的晶型及其制备方法
CN103145613A (zh) * 2013-03-11 2013-06-12 黄河三角洲京博化工研究院有限公司 一种(e)-3-(2-环丙基-4-（4-氟苯基）)喹啉-2-丙烯醛的合成方法
CN104016916A (zh) * 2014-05-16 2014-09-03 南通常佑药业科技有限公司 一种匹伐他汀钙中间体的制备方法
WO2017022846A1 (fr) * 2015-08-05 2017-02-09 株式会社エーピーアイ コーポレーション Procédé de production de pitavastatine calcique
CN107949556A (zh) * 2015-08-05 2018-04-20 株式会社Api 生产匹伐他汀钙的方法
US20180222865A1 (en) * 2015-08-05 2018-08-09 Api Corporation Method for producing pitavastatin calcium
US10676441B2 (en) 2015-08-05 2020-06-09 Api Corporation Method for producing pitavastatin calcium
US10815201B2 (en) 2015-08-05 2020-10-27 Api Corporation Method for producing pitavastatin calcium
CN107949556B (zh) * 2015-08-05 2021-12-07 株式会社Api 生产匹伐他汀钙的方法
CN106749001A (zh) * 2016-11-21 2017-05-31 黄河三角洲京博化工研究院有限公司 一种(e)‑3‑[2‑环丙基‑4‑(4‑氟苯基)‑3‑喹啉‑2‑丙烯醛的合成方法

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