CN103435525B - A kind of method preparing Ezetimibe - Google Patents
A kind of method preparing Ezetimibe Download PDFInfo
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- CN103435525B CN103435525B CN201310319745.XA CN201310319745A CN103435525B CN 103435525 B CN103435525 B CN 103435525B CN 201310319745 A CN201310319745 A CN 201310319745A CN 103435525 B CN103435525 B CN 103435525B
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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
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Abstract
The invention discloses a kind of method preparing Ezetimibe.The method adopts 4-to protect hydroxybenzoate and 3-(4-fluorophenyl)-3-carbonyl chloropropane is raw material, prepares Ezetimibe through 9 steps reactions.Present invention process is stablized, and reaction conditions is gentle, and post-processing operation is simple, and intermediate is easy to be separated, and uses enzyme catalysis to construct chiral centre simultaneously, decreases the generation of the three wastes, can be applied to large-scale production Ezetimibe.
Description
(1) technical field:
The present invention relates to medical synthesis technical field, particularly a kind of synthetic method of Ezetimibe, be specifically related to utilize bio-transformation to construct Ezetimibe chiral intermediate and complete the synthetic method of Ezetimibe drug molecule.
(2) background technology:
Ezetimibe, chemistry is by name: (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone (Compound I), be the exploitation of Schering Plough company and in first cholesterol selective absorbing inhibitor medicaments of listing in 2002, the absorption of cholesterol that it can disturb the cholesterol of food source simultaneously and be synthesized by liver.Can with other Statins anticholesteremic agent coupling, reduce the dosage of statins.Simultaneously no matter individually dosed or with statins coupling, its tolerance is all good, and adverse reaction rate is similar to placebo.
In prior art, the synthetic method of Ezetimibe has a variety of, but all there are some shortcomings.
Yuan Yan producer Schering Plough discloses a kind of Chiral Synthesis in WO200034240; (S)-3-oxy-compound that use chiral reduction obtains is as raw material; by the trimethyl silicon based protection of the hydroxyl of two in product structure while the alpha-position of carbonyl connects side chain, then Cheng Huan, removal protective material obtain Ezetimibe.This synthetic method because hand-type structure is comparatively far away apart from carbonyl, causes selectivity not high when reducing carbonyl, and purge process loss is comparatively large, is not suitable for suitability for industrialized production.
Subsequently, several sections of patents such as WO2007049748, WO2007119106, WO2008032338 and WO2008089984 are improved for prothetic group synthetic route, first construct out the chiral radicals on 2-azetidinone ring, finally use enzyme (WO2000060107; WO2008151324; Or asymmetric catalyst (WO2007030721 WO2009032264); Org.Proc.Res.Dev., 2009,13,907; WO2009067960) carbonyl reduced on side chain, highly selective obtain Ezetimibe.But these route Problems existing are that general line is oversize, employ more expensive reagent, cause high expensive.
Be that initial synthesis Ezetimibe also causes and carrys out the research and development interest (WO2004099132, WO2012173504, WO2010097350) of many drugmakers with chipal compounds.But the difficulty locking into these initial implementation Material synthesis consumption is very large, considers also not too to be applicable to suitability for industrialized production from cost and production operation.
Recently, US7002008, US7498431 and WO2010006954 several sections patent reports and first construct out 3-replacement-2-azetidinone by bio-transformation or asymmetry catalysis, and then carry out the alkylated reaction synthesis Ezetimibe (TetrahedronLetters of 4-position, 1996,37,4095-4098).Because key intermediate is by patent protection, a lot of producer cannot use in actual production.
Therefore, for solving the difficult problem existed in prior art, capture the technology barriers of external drugmaker, suddenly wait to find a technique simple, with low cost, selectivity is good, is easy to be separated and the practicable synthetic route of applicable large-scale production.
(3) summary of the invention:
Technical problem to be solved by this invention is the deficiency overcoming prior art existence, provides a kind of method (see figure 1) preparing Ezetimibe.The method adopts 4-to protect hydroxybenzoate and 3-(4-fluorophenyl)-3-carbonyl chloropropane is raw material, prepares Ezetimibe through 9 steps reactions.Present invention process is stablized, and reaction conditions is gentle, and post-processing operation is simple, and intermediate is easy to be separated, and uses enzyme catalysis to construct chiral centre simultaneously, decreases the generation of the three wastes, can be applied to large-scale production Ezetimibe.
Technical scheme of the present invention: a kind of method preparing Ezetimibe, is characterized in that preparation process is as follows:
(1) 4-protects hydroxyacetophenonum (compound 1) and carbonic diester under the effect of alkali, generate 4-and protects hydroxyl Benzoylacetic acid ester (compound 2); Wherein, 4-protects the blocking group of hydroxyacetophenonum to be R
1, R
1for benzyl, methyl or TBS, the ester group in carbonic diester is R
2, R
2for methyl or ethyl;
(2) 4-protects hydroxyl Benzoylacetic acid ester (compound 2) and the condensation reaction of 4-fluoroaniline to generate N-(4-fluorophenyl)-4-and protects oxybenzene formyl ethanamide (compound 3);
(3) 3-(4-fluorophenyl)-3-carbonyl chloropropane (compound 4) obtains 3-(4-fluorophenyl through asymmetric reduction reaction)-(S)-3-hydroxy chloride propane (compound 5);
(4) to 3-(4-fluorophenyl)-the hydroxyl of (S)-3-hydroxy chloride propane (compound 5) carries out protection and obtains 3-(4-fluorophenyl)-(S)-3-protects hydroxy chloride propane (compound 6); Wherein, 3-(4-fluorophenyl)-(S)-3-protects the protecting group of hydroxy chloride propane to be R
3, R
3for t-Butyldimethylsilyl, triethyl are silica-based, 2H-pyrans or benzyl;
(5) N-(4-fluorophenyl)-4-protects (2-hydroxybenzoyl) ethanamide (compound 3) and 3-(4-fluorophenyl)-(S)-3-protects the alkylated reaction of hydroxy chloride propane (compound 6), obtain two (4-the fluorophenyl)-5-of (S)-N, 5-and protect hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7);
(6) (S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7) to generate (2R through the asymmetric reduction reaction of Dynamic Kinetic Resolution, two (4-the fluorophenyl)-5-of 5S)-N, 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8);
(7) (2R, 5S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8) and Methanesulfonyl chloride to be obtained by reacting (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protection hydroxyl-1-(4-protects hydroxyphenyl) pentyl methanesulfonate (compound 9);
(8) (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate (compound 9) to carry out cyclization generation (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10) under the effect of alkali and phase-transfer catalyst;
(9) (3R; 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10) deprotection base obtains (3R; 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone crude product, crude product obtains qualified target product Ezetimibe through recrystallization.
The concrete operations of step described above (1) are as follows: in reaction flask, add 4-protect hydroxyacetophenonum (compound 1), ether solvent and carbonic diester, be cooled to-20 ~ 10 DEG C, add alkali in batches, then be warming up to 0 ~ 30 DEG C, system cancellation is in buffered soln after completion of the reaction, adds organic solvent extraction, organic phase uses saturated sodium-chloride water solution washing, be concentrated into the dry 4-that obtains and protect hydroxyl Benzoylacetic acid ester (compound 2) crude product, yield 90 ~ 100%, purity 85 ~ 95%; Wherein, 4-protects the blocking group of hydroxyacetophenonum to be R
1, R
1for benzyl, methyl or TBS, the ester group in carbonic diester is R
2, R
2for methyl or ethyl.
In step described above (1), carbonic diester is methylcarbonate or diethyl carbonate; Carbonic diester and 4-protect the mol ratio of hydroxyacetophenonum (compound 1) to be 1.5 ~ 3:1; Alkali is n-Butyl Lithium, sodium hydride, potassium hydride KH, lithium diisopropylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium methylate, sodium ethylate or potassium tert.-butoxide, and alkali and 4-protect the mol ratio of hydroxyacetophenonum (compound 1) to be 1.0 ~ 2.0:1; Ether solvent is at least one in tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, methylcyclopentyl ether, 2-methyltetrahydrofuran or n-butyl ether, and ether solvent and 4-protect the amount ratio of hydroxyacetophenonum to be 5 ~ 15mL/g; Cancellation reaction use buffered soln for saturated ammonium chloride or 3 ~ 10% aqueous citric acid solution, buffered soln and 4-protect the amount ratio of hydroxyacetophenonum to be 3 ~ 10mL/g; The organic solvent that extraction uses is selected from toluene, ethyl acetate or isopropyl acetate, and organic solvent and 4-protect the amount ratio of hydroxyacetophenonum to be 5 ~ 15mL/g; The saturated sodium-chloride water solution that washing organic phase uses and 4-protect the amount ratio of hydroxyacetophenonum to be 5 ~ 15mL/g.
The concrete operations of step described above (2) are as follows: in reaction flask, add 4-successively protect hydroxyl Benzoylacetic acid ester (compound 2), para-fluoroaniline and reaction solvent; system back flow reaction; be cooled to-10 ~ 25 DEG C of stirring and crystallizing after completion of the reaction; obtain product N-(4-fluorophenyl)-4-after suction filtration and protect oxybenzene formyl ethanamide (compound 3); yield 80 ~ 90%, liquid chromatography purity >95%.
In step described above (2), para-fluoroaniline and 4-protect the mol ratio of hydroxyl Benzoylacetic acid ester (compound 2) to be 1 ~ 2:1; Reaction solvent is at least one in toluene, dimethylbenzene, normal heptane and hexanaphthene, and reaction solvent and 4-protect the amount ratio of hydroxyl Benzoylacetic acid ester to be 5 ~ 15mL/g; Temperature of reaction is backflow.
The concrete operations of step described above (3) are as follows: in reaction flask, add 3-(4-fluorophenyl successively)-3-carbonyl chloropropane (compound 4) and solubility promoter, add crude enzyme liquid and the β-NAD of carbonyl reductase after stirring
+then reductive agent and damping fluid adjust ph to 6 ~ 8 are added, insulation reaction after being warming up to 25 ~ 50 DEG C, add organic solvent extraction product after completion of the reaction, concentrated after aftertreatment, add crystallization solvent recrystallization and obtain product 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane (compound 5), yield 75 ~ 90%, purity >98%, corresponding selection >98%.
In step described above (3), solubility promoter is ethylene glycol, dimethyl sulfoxide (DMSO), ethanol, acetone, PEG-4000 or PEG-8 00, solubility promoter and 3-(4-fluorophenyl) amount ratio of-3-carbonyl chloropropane is 1 ~ 2mL/g; Reductase enzyme is carbonyl reductase, and enzyme lives 8 ~ 32, the crude enzyme liquid of carbonyl reductase and 3-(4-fluorophenyl) amount ratio of-3-carbonyl chloropropane is 10 ~ 40mL/g; β-NAD
+with 3-(4-fluorophenyl) amount ratio of-3-carbonyl chloropropane is 0.01 ~ 0.05g/g; Reductive agent is Virahol, glucose or ammonium formiate, reductive agent and 3-(4-fluorophenyl) mol ratio of-3-carbonyl chloropropane is 1 ~ 4:1; Described damping fluid is formic acid/ammonium formiate, acetic acid/ammonium acetate, acetic acid/sodium acetate or dipotassium hydrogen phosphate/potassium primary phosphate, damping fluid and 3-(4-fluorophenyl) amount ratio of-3-carbonyl chloropropane is 5 ~ 20mL/g; The organic solvent that extraction uses is methyl tertiary butyl ether, methylcyclopentyl ether, ethyl acetate, isopropyl acetate or toluene, organic solvent and 3-(4-fluorophenyl) amount ratio of-3-carbonyl chloropropane is 5 ~ 20mL/g; Crystallization solvent is sherwood oil, normal hexane, normal heptane or hexanaphthene, crystallization solvent and 3-(4-fluorophenyl) amount ratio of-3-carbonyl chloropropane is 2 ~ 10mL/g.
The concrete operations of step described above (4) are as follows: in reaction flask, add 3-(4-fluorophenyl successively)-(S)-3-hydroxy chloride propane (compound 5), organic solvent, hydroxy protecting agent and catalyzer; then 30 ~ 50 DEG C of reactions are warming up to; organic phase washing after completion of the reaction; concentrated dryly obtaining product 3-(4-fluorophenyl)-(S)-3-protects hydroxy chloride propane (compound 6); yield >95%; wherein, 3-(4-fluorophenyl)-(S)-3-protects the protecting group of hydroxy chloride propane to be R
3, R
3for t-Butyldimethylsilyl, triethyl are silica-based, 2H-pyrans or benzyl.
In step described above (4), hydroxyl protecting group reagent is TERT-BUTYL DIMETHYL CHLORO SILANE, chlorotriethyl silane, 3,4-dihydro-2H-pyrans or cylite, hydroxy protecting agent and 3-(4-fluorophenyl) mol ratio of-(S)-3-hydroxy chloride propane is 1 ~ 2:1; Organic solvent is methylene dichloride, 1,2-ethylene dichloride, 2-methyltetrahydrofuran or toluene, organic solvent and 3-(4-fluorophenyl) consumption of-(S)-3-hydroxy chloride propane is 5 ~ 15mL/g; Catalyzer is imidazoles, azabicyclic, triethylamine, N, N-diisopropyl ethylenediamine or N-methylmorpholine, catalyzer and 3-(4-fluorophenyl) mol ratio of-(S)-3-hydroxy chloride propane is 1 ~ 2:1.
The concrete operations of step described above (5) are as follows: in reaction flask, add N-(4-fluorophenyl)-4-successively protect (2-hydroxybenzoyl) ethanamide (compound 3), dry organic solvent and 3-(4-fluorophenyl)-(S)-3-protection hydroxy chloride propane (compound 6), then-10 ~ 20 DEG C are cooled to, be incubated-60 ~ 40 DEG C of reactions after adding alkali in batches, add 10% sodium chloride aqueous solution cancellation reaction after completion of the reaction, organic solvent extraction, organic phase merges, saturated sodium-chloride water solution washing organic phase, concentrated after activated carbon decolorizing, with an organic solvent recrystallization obtains (S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7), yield 75 ~ 85%.
In step described above (5), 3-(4-fluorophenyl)-(S)-3-(tertiary butyl dimethyl silyl hydroxyl) mol ratio of chloropropane and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 1 ~ 1.5:1; Dry organic solvent is at least one in tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, methylcyclopentyl ether, 2-methyltetrahydrofuran, n-butyl ether, DMF or toluene; Dry organic solvent and the amount ratio of N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide are 5 ~ 15mL/g; Alkali is n-Butyl Lithium, sodium hydride, potassium hydride KH, lithium diisopropylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium methylate, sodium ethylate, potassium tert.-butoxide, salt of wormwood, hydrogen-oxygen agent, cesium carbonate, sodium carbonate or sodium hydroxide, and the consumption mole of alkali and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 1.5 ~ 3:1; The organic solvent that extraction uses is 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tertiary butyl ether, methylcyclopentyl ether, dibutyl ether or glycol dimethyl ether, and the consumption of the organic solvent that extraction uses and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 10 ~ 30mL/g; The washing saturated sodium-chloride water solution of organic phase and the amount ratio of N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide are 3 ~ 15mL/g; Decolouring uses the model of activated carbon to be GA-T1, and the amount ratio of activated carbon and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 0.05 ~ 0.5g/g; The organic solvent that recrystallization uses is normal heptane, hexanaphthene, normal hexane or sherwood oil, and the amount ratio of the organic solvent that recrystallization uses and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 3 ~ 12mL/g.
The concrete operations of step described above (6) are as follows: in reaction flask, add (S)-N successively; two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7) and solubility promoter, adds the thick liquid of enzyme and the β-NAD of carbonyl reductase after stirring
+then reductive agent and damping fluid adjust ph to 6 ~ 8 are added; heat up insulation reaction after 25 ~ 50 DEG C; add organic solvent extraction after completion of the reaction; concentrated; add crystallization solvent recrystallization and obtain (2R; 5S)-N; two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8); yield 80 ~ 90%; purity >99%, corresponding selection >98.5%.
In step described above (6), solubility promoter is ethylene glycol, dimethyl sulfoxide (DMSO), ethanol, acetone, PEG-4000 or PEG-8 00, solubility promoter protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 1 ~ 2mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; Reductase enzyme is carbonyl reductase, and enzyme lives 8 ~ 32, and the crude enzyme liquid of carbonyl reductase protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 10 ~ 40mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; β-NAD
+with 3-(4-fluorophenyl) amount ratio of-3-carbonyl chloropropane is 0.01 ~ 0.05g/g; Reductive agent is Virahol, glucose or ammonium formiate, reductive agent and 3-(4-fluorophenyl) mol ratio of-3-carbonyl chloropropane is 1 ~ 4:1; Described damping fluid is formic acid/ammonium formiate, acetic acid/ammonium acetate, acetic acid/sodium acetate or dipotassium hydrogen phosphate/potassium primary phosphate, damping fluid protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 5 ~ 20mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; The organic solvent that extraction uses is methyl tertiary butyl ether, methylcyclopentyl ether, ethyl acetate, isopropyl acetate or toluene, organic solvent protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 5 ~ 20mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; Crystallization solvent is sherwood oil, normal hexane, normal heptane or hexanaphthene, and crystallization solvent protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 2 ~ 10mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-.
The concrete operations of step described above (7) are as follows: add (2R in reaction flask successively, 5S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8), organic solvent and organic bases, mode by dripping continuously after being cooled to-40 ~ 0 DEG C adds Methanesulfonyl chloride, be incubated-30 ~ 10 DEG C of reactions, obtain (1R after completion of the reaction, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects hydroxyl-1-(4-protects hydroxyphenyl) pentyl methanesulfonate (compound 9) solution, aftertreatment is not needed to be directly used in next step reaction.
In step described above (7), organic solvent is toluene or dimethylbenzene, organic solvent and (2R, two (4-the fluorophenyl)-5-of 5S)-N, 5-protects the amount ratio of hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide to be 5 ~ 20mL/g; Organic bases is triethylamine, diisopropylethylamine, tri-n-butylamine, azabicyclic, 4-dimethylamino pyridine, pyridine, 2,6-lutidine or N, accelerine, organic bases and (2R, two (4-the fluorophenyl)-5-of 5S)-N, 5-protects the mol ratio of hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8) to be 1.0 ~ 2.0:1; Methanesulfonyl chloride and (2R; two (4-the fluorophenyl)-5-of 5S)-N, 5-protects the mol ratio of hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8) to be 1.0 ~ 1.5:1.
The concrete operations of step described above (8) are as follows: add inorganic base aqueous solution and phase-transfer catalyst successively in the solution obtained to step (7) at temperature control-20 ~ 10 DEG C, then-30 ~ 10 DEG C of reactions are incubated to (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate (compound 9) to be exhausted, the cancellation that adds water is reacted, separate organic phase, decolorizing with activated carbon is used after washing, then be concentrated into dry, product (3R is obtained after adding recrystallization solvent recrystallization, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10), yield 85 ~ 95%.
In step described above (8), mineral alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium carbonate, inorganic base aqueous solution concentration is 20 ~ 60%, inorganic base aqueous solution and (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects the amount ratio of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 0.5 ~ 1mL/g; Phase-transfer catalyst is tetrabutylammonium chloride, Tetrabutyl amonium bromide or benzyltriethylammoinium chloride, phase-transfer catalyst accounts for (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects the mass percent of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 0.5 ~ 3%; The water that cancellation reaction uses protects the amount ratio of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 2 ~ 10mL/g with (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-; Activated carbon accounts for (1R, 2R, 5S), and-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects the mass percent of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 1 ~ 10%; Recrystallization solvent is normal hexane, normal heptane or hexanaphthene; recrystallization solvent and (1R; 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate amount ratio to be 3 ~ 10mL/g.
The concrete operations of step described above (9) are as follows: in reaction flask, add (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10), the reagent of organic solvent and deprotection base, reaction terminates to add acid in backward reaction system, then be incubated 0 ~ 50 DEG C and continue stirring 2 ~ 4 hours, then add purified water and separate out solid crude product (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone, qualified Ezetimibe is obtained after adding recrystallization solvent recrystallization, yield 70 ~ 85%, purity >99.0%.
In above-mentioned steps (9), the reagent of deprotection base is chosen from Pd/C/H according to the difference of protecting group
2, HCl, aluminum chloride or boron tribromide, the reagent of deprotection base and the mol ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10) are 0.1 ~ 4.0:1; Organic solvent is at least one in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), toluene or methylene dichloride, alcoholic solvent is 5 ~ 20mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone; The acid that treating product uses for concentration be hydrochloric acid or the sulfuric acid of 2 ~ 5mol/L, acid is 0.5 ~ 2mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone; Crystallization uses purified water to be 2 ~ 5mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone; The solvent that recrystallization uses is ethyl acetate, at least one in isopropyl acetate, normal hexane, hexanaphthene or normal heptane; recrystallization solvent is 5 ~ 20mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone.
Superiority of the present invention: provide a kind of novel method preparing Ezetimibe.The reagent that this inventive method not only uses is cheap, and process stabilizing, and reaction conditions is gentle; and post-processing operation is simple, intermediate is easy to be separated, and uses enzyme catalysis to construct chiral centre simultaneously; decrease the generation of the three wastes, large-scale production Ezetimibe can be applied to.
(4) accompanying drawing illustrates:
Fig. 1 is a kind of chemical reaction process figure preparing the method for Ezetimibe involved by the present invention.
Composition graphs 1 can understand the technical scheme of foregoing invention more intuitively.
(5) embodiment:
In order to absolutely prove essence, the preparation thinking and design of patent of the present invention, verify preparation method of the present invention in the following embodiments, the restriction to the present invention's protection should not explained or be interpreted as to these embodiments only for illustrating and special case representative.
The present invention's all tests material is commercially available purchase product if no special instructions.Although the description of the inventive method starts with initial compounds, it will be appreciated by those skilled in the art that when a certain intermediate product can obtain, technological process of the present invention can from any one intermediate and step.
Embodiment 1: a kind of method preparing Ezetimibe, is characterized in that concrete preparation process is as follows:
(1) synthesis of 4-benzyl hydroxyl methyl benzoylacetate
4-benzyloxy acetophenone 226g(1mol is added successively in the four-hole bottle of 5L), tetrahydrofuran (THF) 1.8L(8mL/g) and methylcarbonate 180g(2mol), be cooled to-10 ~ 0 DEG C, add 28.8gNaH(1.2mol in batches), be then warming up to 0 ~ 10 DEG C.System joins 1.13L(5mL/g after completion of the reaction) 5% aqueous citric acid solution in cancellation reaction, add 2.26L isopropyl acetate (10mL/g) extracted products.Organic phase uses the washing of 1.13L saturated sodium-chloride water solution, and be concentrated into dry, the crude product 4-benzyl (2-hydroxybenzoyl) methyl acetate obtained with quantitative yield, purity >90%, is directly used for casting single step reaction.
(2) synthesis of N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide
Four-hole bottle to 5L adds 4-benzyl (2-hydroxybenzoyl) methyl acetate 284.3g(1mol successively), para-fluoroaniline 133.2g(1.2mol) and normal heptane 2.8L(10mL/g).System back flow reaction 12h, is cooled to-10 DEG C, stirs 2h.Suction filtration, drying obtains product N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide 309g, yield 85%, HPLC purity 98.0%.
(3) 3-(4-fluorophenyl) synthesis of-(S)-3-hydroxy chloride propane
3-(4-fluorophenyl is added successively in the four-hole bottle of 10L)-3-carbonyl chloropropane 373g(2mol), 600mL PEG-4000, adds crude enzyme liquid, the 11.2g β-NAD of 7L ketoreductase after stirring homogeneous phase
+with 126g ammonium formiate, adjust system pH6.5 ~ 7.0 with 20% aqueous formic acid, be warming up to 30 ~ 35 DEG C of reactions.After completion of the reaction, add 3.7L methyl tertiary butyl ether extracted products, organic phase crosses silicagel pad, concentrated, uses 1.9L normal heptane (5mL/g) recrystallization to obtain product 306g, yield 81%, HPLC purity 99%, enantioselectivity 99.0%.
(4) 3-(4-fluorophenyl)-(S)-3-(tertiary butyl dimethyl silyl hydroxyl) synthesis of chloropropane
3-(4-fluorophenyl is added successively in 5L four-hole bottle)-(S)-3-hydroxy chloride propane 189g(0.5mol), methylene dichloride 1.9L, TERT-BUTYL DIMETHYL CHLORO SILANE 181g(1.2mol) and imidazoles 136g(2mol), be warming up to back flow reaction 12 hours.Wash organic phase 4 times by 900mL purified water after completion of the reaction at every turn.Organic phase is concentrated into dry, and quantitative obtains crude product 3-(4-fluorophenyl)-(S)-3-(tertiary butyl dimethyl silyl hydroxyl) chloropropane, HPLC purity is 98%.This crude product can be directly used in next step reaction.
(5) two (4-the fluorophenyl)-5-(tertiary butyl dimethyl silyl hydroxyl of (S)-N, 5-) synthesis of-2-(4-benzyl oxybenzene formyl radical) valeramide
N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide 182g(0.5mol is added successively) in the four-hole bottle of 5L, dry DMF1.8L(10mL/g), 3-(4-fluorophenyl)-(S)-3-(tertiary butyl dimethyl silyl hydroxyl) chloropropane 182g(0.6mol), temperature control 0 ~ 10 DEG C, the THF solution 1L containing 112g potassium tert.-butoxide (1mol) is dripped, then insulation reaction in 2 ~ 3 hours.After completion of the reaction, add the sodium chloride aqueous solution 1.8L of 10%, use 1.8L methyl tertiary butyl ether extracted products twice, merge organic phase, use the washing of 1.8L saturated sodium-chloride.Organic phase uses the activated carbon decolorizing of 18gGA-T1 model; be concentrated into dry; 1.8L normal heptane recrystallization obtains two (4-the fluorophenyl)-5-(tertiary butyl dimethyl silyl hydroxyl of (S)-N, 5-)-2-(4-benzyl oxybenzene formyl radical) valeramide 250g, yield 79%.
(6) two (4-the fluorophenyl)-5-(tertiary butyl dimethyl silyl hydroxyl of (2R, 5S)-N, 5-) synthesis of-2-((R)-hydroxyl (4-benzyl hydroxyphenyl) methyl) valeramide
(S)-N is added successively in the four-hole bottle of 5L; two (4-the fluorophenyl)-5-(tertiary butyl dimethyl silyl hydroxyl of 5-)-2-(4-benzyl oxybenzene formyl radical) valeramide 158g(0.25mol); 300mL PEG-4000; add 3L ketoreductase crude enzyme liquid after stirring, then add 4.74g β-NAD
+with 31.5g ammonium formiate, adjust system pH6.5 ~ 7.0 with 20% aqueous formic acid, be warming up to 30 ~ 35 DEG C of reactions.After completion of the reaction, add 1.6L methyl tertiary butyl ether extracted products, organic phase uses 8gGA-T1 activated carbon decolorizing, concentrated, use 800mL normal heptane (5mL/g) recrystallization to obtain (2R, 5S)-N, two (4-the fluorophenyl)-5-(tertiary butyl dimethyl silyl hydroxyl of 5-)-2-((R)-hydroxyl (4-benzyl hydroxyphenyl) methyl) valeramide 136g, yield 86%, HPLC purity 99%, selectivity >99.0%.
(7) (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-(tertiary butyl dimethyl silyl hydroxyl)-1-(4-benzyl hydroxyphenyl) pentyl methanesulfonate
(2R is added successively in 2L four-hole bottle, 5S)-N, two (4-the fluorophenyl)-5-(tertiary butyl dimethyl silyl hydroxyl of 5-)-2-((R)-hydroxyl (4-benzyl hydroxyphenyl) methyl) valeramide 63g(0.1mol), toluene 630mL, triethylamine 11.1g(0.11mol), be cooled to-20 ~-10 DEG C, slowly drip Methanesulfonyl chloride 12.6g(0.11mol), and be incubated at such a temperature to reacting complete.Reaction system does not need aftertreatment, directly casts single step reaction.
(8) synthesis of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-tertiary butyl dimethyl silyl hydroxypropyl)-4-(4-benzyl hydroxyphenyl)-2-azetidinone
Temperature control-10 ~ 0 DEG C, adds the KOH aqueous solution 50mL of 50%, then adds benzyltriethylammoinium chloride 0.2g in the reaction system that step (7) obtains, and the raw material consumption being then incubated-10 ~ 0 DEG C of reaction is complete.Add 300mL purified water cancellation reaction, separate organic phase, use the washing of 30mL0.5N hydrochloric acid, 300mL purified water and 300mL saturated sodium-chloride respectively.Organic phase uses 6g activated carbon decolorizing, be concentrated into dry, 300mL hexanaphthene recrystallization is used to obtain (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-tertiary butyl dimethyl silyl hydroxypropyl)-4-(4-benzyl hydroxyphenyl)-2-azetidinone 54g, yield 89%.
(9) synthesis of (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone
(3R is added successively in the reaction flask of 1L, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-tertiary butyl dimethyl silyl hydroxypropyl)-4-(4-benzyl hydroxyphenyl)-2-azetidinone 30.3g(0.05mol), the Pd/C1.5g of 10% and methyl alcohol 300mL.Nitrogen replacement 3 times, after this hydrogen exchange 3 is warming up to 35 ~ 40 DEG C of reaction to raw materials and disappears.Filtering Pd/C catalyzer, filtrate uses the activated carbon decolorizing of 1.5gGA-T1 model.Filtrate is transferred in 1L reaction flask, and temperature control 10 ~ 20 DEG C, adds the aqueous hydrochloric acid of 25mL4mol/L, be stirred to and react completely.Be incubated 10 ~ 20 DEG C, drip 90mL purified water, then continue stirring and within 2 hours, ensure that crystallization is abundant.Collected by suction solid, washing, dry.Solid uses 150mL isopropyl acetate/hexanaphthene (1:6, v/v) recrystallization, obtain (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone 16.8g, yield 82%, purity >99.5%.
Embodiment 2: a kind of preparation method of Ezetimibe, is characterized in that concrete preparation process is as follows:
(1) synthesis of 4-methoxybenzoyl ethyl acetate
4-methoxyacetophenone 150g(1mol is added successively in the four-hole bottle of 5L), tetrahydrofuran (THF) 1.5L(8mL/g) and diethyl carbonate 236g(2mol), be cooled to-10 ~ 0 DEG C, add 36.0gNaH(1.5mol in batches), be then warming up to 0 ~ 10 DEG C.System joins 1.2L(8mL/g after completion of the reaction) 5% aqueous citric acid solution in cancellation reaction, add 2.26L isopropyl acetate (10mL/g) extracted products.Organic phase uses the washing of 1.13L saturated sodium-chloride water solution, and be concentrated into dry, the crude product 4-methoxybenzoyl ethyl acetate obtained with quantitative yield, purity >90%, is directly used for casting single step reaction.
(2) synthesis of N-(4-fluorophenyl)-4-methoxyl group formyl ethanamide
Four-hole bottle to 5L adds 4-methoxybenzoyl ethyl acetate 222g(1mol successively), para-fluoroaniline 133.2g(1.2mol) and normal heptane 3.3L(15mL/g).System back flow reaction 12h, is cooled to-10 DEG C, stirs 2h.Suction filtration, drying obtains product N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide 309g, yield 85%, HPLC purity 98.5%.
The present embodiment step (3)-(8) are with reference to embodiment 1.
Embodiment 3: a kind of preparation method of Ezetimibe, is characterized in that concrete preparation process is as follows:
(9) 3R, 4S) synthesis of-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone
(3R is added successively in the reaction flask of 500mL, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-tertiary butyl dimethyl silyl hydroxypropyl)-4-(4-p-methoxy-phenyl)-2-azetidinone 26.9g(0.05mol), aluminum chloride 20.0g(1.5mol) and methylene dichloride 270mL, be warming up to 35 ~ 40 DEG C of reaction to raw materials and disappear.Use 270mL purified water cancellation reaction, separatory, organic phase is concentrated into dry, and add 270mL dissolve with methanol and be transferred in 1L reaction flask, temperature control 10 ~ 20 DEG C, adds the aqueous hydrochloric acid of 25mL4mol/L, be stirred to and react completely.Be incubated 10 ~ 20 DEG C, drip 135mL purified water, then continue stirring and within 2 hours, ensure that crystallization is abundant.Collected by suction solid, washing, dry.Solid uses 135mL isopropyl acetate/hexanaphthene (1:6, v/v) recrystallization, obtain (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone 15.6g, yield 76%, purity >99.5%.
The present embodiment step (1)-(2) are with reference to embodiment 2, and step (3)-(8) are with reference to embodiment 1.
Claims (15)
1. prepare a method for Ezetimibe, it is characterized in that preparation process is as follows:
(1) 4-protects hydroxyacetophenonum (compound 1) and carbonic diester under the effect of alkali, generate 4-and protects hydroxyl Benzoylacetic acid ester (compound 2); Wherein, 4-protects the blocking group of hydroxyacetophenonum to be R
1, R
1for benzyl, methyl or TBS, the ester group in carbonic diester is R
2, R
2for methyl or ethyl;
(2) 4-protects hydroxyl Benzoylacetic acid ester (compound 2) and the condensation reaction of 4-fluoroaniline to generate N-(4-fluorophenyl)-4-and protects oxybenzene formyl ethanamide (compound 3);
(3) 3-(4-fluorophenyl)-3-carbonyl chloropropane (compound 4) obtains 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane (compound 5) through asymmetric reduction reaction;
(4) protection is carried out to the hydroxyl of 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane (compound 5) and obtain 3-(4-fluorophenyl)-(S)-3-protection hydroxy chloride propane (compound 6); Wherein, 3-(4-fluorophenyl)-(S)-3-protects the protecting group of hydroxy chloride propane to be R
3, R
3for t-Butyldimethylsilyl, triethyl are silica-based, 2H-pyrans or benzyl;
(5) N-(4-fluorophenyl)-4-protects (2-hydroxybenzoyl) ethanamide (compound 3) and 3-(4-fluorophenyl)-(S)-3-to protect the alkylated reaction of hydroxy chloride propane (compound 6), obtain two (4-the fluorophenyl)-5-of (S)-N, 5-and protect hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7);
(6) (S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7) to generate (2R through the asymmetric reduction reaction of Dynamic Kinetic Resolution, two (4-the fluorophenyl)-5-of 5S)-N, 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8);
The concrete operations of described step (6) are as follows: in reaction flask, add (S)-N successively; two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7) and solubility promoter, adds the thick liquid of enzyme and the β-NAD of carbonyl reductase after stirring
+then reductive agent and damping fluid adjust ph to 6 ~ 8 are added, heat up insulation reaction after 25 ~ 50 DEG C, add organic solvent extraction after completion of the reaction, concentrated, add crystallization solvent recrystallization and obtain (2R, 5S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8), yield 80 ~ 90%, purity >99%, corresponding selection >98.5%;
(7) (2R, 5S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8) and Methanesulfonyl chloride to be obtained by reacting (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protection hydroxyl-1-(4-protects hydroxyphenyl) pentyl methanesulfonate (compound 9);
The concrete operations of described step (7) are as follows: add (2R in reaction flask successively, 5S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8), organic solvent and organic bases, mode by dripping continuously after being cooled to-40 ~ 0 DEG C adds Methanesulfonyl chloride, be incubated-30 ~ 10 DEG C of reactions, obtain (1R after completion of the reaction, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects hydroxyl-1-(4-protects hydroxyphenyl) pentyl methanesulfonate (compound 9) solution, aftertreatment is not needed to be directly used in next step reaction,
(8) (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate (compound 9) to carry out cyclization generation (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10) under the effect of alkali and phase-transfer catalyst;
The concrete operations of described step (8) are as follows: add inorganic base aqueous solution and phase-transfer catalyst successively in the solution obtained to step (7) at temperature control-20 ~ 10 DEG C, then-30 ~ 10 DEG C of reactions are incubated to (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate (compound 9) to be exhausted, the cancellation that adds water is reacted, separate organic phase, decolorizing with activated carbon is used after washing, then be concentrated into dry, product (3R is obtained after adding recrystallization solvent recrystallization, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10), yield 85 ~ 95%, described recrystallization solvent is normal hexane, normal heptane or hexanaphthene,
(9) (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10) deprotection base obtains (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone crude product, crude product obtains qualified target product Ezetimibe through recrystallization;
The concrete operations of described step (9) are as follows: in reaction flask, add (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10), the reagent of organic solvent and deprotection base, reaction terminates to add acid in backward reaction system, then be incubated 0 ~ 50 DEG C and continue stirring 2 ~ 4 hours, then add purified water and separate out solid crude product (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone, qualified Ezetimibe is obtained after adding recrystallization solvent recrystallization, yield 70 ~ 85%, purity >99.0%, the reagent of described deprotection base is chosen from Pd/C/H according to the difference of protecting group
2, HCl, aluminum chloride or boron tribromide.
2. a kind of method preparing Ezetimibe according to claim 1, it is characterized in that the concrete operations of described step (1) are as follows: in reaction flask, add 4-protect hydroxyacetophenonum (compound 1), ether solvent and carbonic diester, be cooled to-20 ~ 10 DEG C, add alkali in batches, then 0 ~ 30 DEG C is warming up to, system cancellation is in buffered soln after completion of the reaction, add organic solvent extraction, organic phase uses saturated sodium-chloride water solution washing, be concentrated into the dry 4-that obtains and protect hydroxyl Benzoylacetic acid ester (compound 2) crude product, yield 90 ~ 100%, purity 85 ~ 95%, wherein, 4-protects the blocking group of hydroxyacetophenonum to be R
1, R
1for benzyl, methyl or TBS, the ester group in carbonic diester is R
2, R
2for methyl or ethyl.
3. a kind of method preparing Ezetimibe according to claim 2, is characterized in that, in described step (1), carbonic diester is methylcarbonate or diethyl carbonate; Carbonic diester and 4-protect the mol ratio of hydroxyacetophenonum (compound 1) to be 1.5 ~ 3:1; Alkali is n-Butyl Lithium, sodium hydride, potassium hydride KH, lithium diisopropylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium methylate, sodium ethylate or potassium tert.-butoxide, and alkali and 4-protect the mol ratio of hydroxyacetophenonum (compound 1) to be 1.0 ~ 2.0:1; Ether solvent is at least one in tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, methylcyclopentyl ether, 2-methyltetrahydrofuran or n-butyl ether, and ether solvent and 4-protect the amount ratio of hydroxyacetophenonum to be 5 ~ 15mL/g; Cancellation reaction use buffered soln for saturated ammonium chloride or 3 ~ 10% aqueous citric acid solution, buffered soln and 4-protect the amount ratio of hydroxyacetophenonum to be 3 ~ 10mL/g; The organic solvent that extraction uses is selected from toluene, ethyl acetate or isopropyl acetate, and organic solvent and 4-protect the amount ratio of hydroxyacetophenonum to be 5 ~ 15mL/g; The saturated sodium-chloride water solution that washing organic phase uses and 4-protect the amount ratio of hydroxyacetophenonum to be 5 ~ 15mL/g.
4. a kind of method preparing Ezetimibe according to claim 1; it is characterized in that the concrete operations of described step (2) are as follows: in reaction flask, add 4-successively protect hydroxyl Benzoylacetic acid ester (compound 2), para-fluoroaniline and reaction solvent; system back flow reaction; be cooled to-10 ~ 25 DEG C of stirring and crystallizing after completion of the reaction; obtain product N-(4-fluorophenyl)-4-after suction filtration and protect oxybenzene formyl ethanamide (compound 3); yield 80 ~ 90%, liquid chromatography purity >95%.
5. a kind of method preparing Ezetimibe according to claim 4, it is characterized in that in described step (2), para-fluoroaniline and 4-protect the mol ratio of hydroxyl Benzoylacetic acid ester (compound 2) to be 1 ~ 2:1; Reaction solvent is at least one in toluene, dimethylbenzene, normal heptane and hexanaphthene, and reaction solvent and 4-protect the amount ratio of hydroxyl Benzoylacetic acid ester to be 5 ~ 15mL/g; Temperature of reaction is backflow.
6. a kind of method preparing Ezetimibe according to claim 1, it is characterized in that the concrete operations of described step (3) are as follows: in reaction flask, add 3-(4-fluorophenyl)-3-carbonyl chloropropane (compound 4) and solubility promoter successively, after stirring, add crude enzyme liquid and the β-NAD of carbonyl reductase
+then reductive agent and damping fluid adjust ph to 6 ~ 8 are added, insulation reaction after being warming up to 25 ~ 50 DEG C, add organic solvent extraction product after completion of the reaction, concentrated after aftertreatment, add crystallization solvent recrystallization and obtain product 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane (compound 5), yield 75 ~ 90%, purity >98%, corresponding selection >98%.
7. a kind of method preparing Ezetimibe according to claim 6, it is characterized in that in described step (3), solubility promoter is ethylene glycol, dimethyl sulfoxide (DMSO), ethanol, acetone, PEG-4000 or PEG-8 00, and the amount ratio of solubility promoter and 3-(4-fluorophenyl)-3-carbonyl chloropropane is 1 ~ 2mL/g; Reductase enzyme is carbonyl reductase, and enzyme lives 8 ~ 32, and the amount ratio of the crude enzyme liquid of carbonyl reductase and 3-(4-fluorophenyl)-3-carbonyl chloropropane is 10 ~ 40mL/g; β-NAD
+be 0.01 ~ 0.05g/g with the amount ratio of 3-(4-fluorophenyl)-3-carbonyl chloropropane; Reductive agent is Virahol, glucose or ammonium formiate, and the mol ratio of reductive agent and 3-(4-fluorophenyl)-3-carbonyl chloropropane is 1 ~ 4:1; Described damping fluid is formic acid/ammonium formiate, acetic acid/ammonium acetate, acetic acid/sodium acetate or dipotassium hydrogen phosphate/potassium primary phosphate, and the amount ratio of damping fluid and 3-(4-fluorophenyl)-3-carbonyl chloropropane is 5 ~ 20mL/g; The organic solvent that extraction uses is methyl tertiary butyl ether, methylcyclopentyl ether, ethyl acetate, isopropyl acetate or toluene, and the amount ratio of organic solvent and 3-(4-fluorophenyl)-3-carbonyl chloropropane is 5 ~ 20mL/g; Crystallization solvent is sherwood oil, normal hexane, normal heptane or hexanaphthene, and the amount ratio of crystallization solvent and 3-(4-fluorophenyl)-3-carbonyl chloropropane is 2 ~ 10mL/g.
8. a kind of method preparing Ezetimibe according to claim 1, it is characterized in that the concrete operations of described step (4) are as follows: in reaction flask, add 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane (compound 5) successively, organic solvent, hydroxy protecting agent and catalyzer, then 30 ~ 50 DEG C of reactions are warming up to, organic phase washing after completion of the reaction, concentrated dry product 3-(4-fluorophenyl)-(the S)-3-that obtains protects hydroxy chloride propane (compound 6), yield >95%, wherein, 3-(4-fluorophenyl)-(S)-3-protects the protecting group of hydroxy chloride propane to be R
3, R
3for t-Butyldimethylsilyl, triethyl are silica-based, 2H-pyrans or benzyl.
9. a kind of method preparing Ezetimibe according to claim 8, it is characterized in that in described step (4), hydroxyl protecting group reagent is TERT-BUTYL DIMETHYL CHLORO SILANE, chlorotriethyl silane, 3,4-dihydro-2H-pyrans or cylite, the mol ratio of hydroxy protecting agent and 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane is 1 ~ 2:1; Organic solvent is methylene dichloride, 1,2-ethylene dichloride, 2-methyltetrahydrofuran or toluene, and the consumption of organic solvent and 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane is 5 ~ 15mL/g; Catalyzer is imidazoles, azabicyclic, triethylamine, N, N-diisopropyl ethylenediamine or N-methylmorpholine, and the mol ratio of catalyzer and 3-(4-fluorophenyl)-(S)-3-hydroxy chloride propane is 1 ~ 2:1.
10. a kind of method preparing Ezetimibe according to claim 1, it is characterized in that the concrete operations of described step (5) are as follows: in reaction flask, add N-(4-fluorophenyl)-4-successively protect (2-hydroxybenzoyl) ethanamide (compound 3), dry organic solvent and 3-(4-fluorophenyl)-(S)-3-protect hydroxy chloride propane (compound 6), then-10 ~ 20 DEG C are cooled to, be incubated-60 ~ 40 DEG C of reactions after adding alkali in batches, add 10% sodium chloride aqueous solution cancellation reaction after completion of the reaction, organic solvent extraction, organic phase merges, saturated sodium-chloride water solution washing organic phase, concentrated after activated carbon decolorizing, with an organic solvent recrystallization obtains (S)-N, two (4-the fluorophenyl)-5-of 5-protects hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide (compound 7), yield 75 ~ 85%.
11. a kind of methods preparing Ezetimibe according to claim 1, it is characterized in that in described step (5), the mol ratio of 3-(4-fluorophenyl)-(S)-3-(tertiary butyl dimethyl silyl hydroxyl) chloropropane and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 1 ~ 1.5:1; Dry organic solvent is at least one in tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, methylcyclopentyl ether, 2-methyltetrahydrofuran, n-butyl ether, DMF or toluene; Dry organic solvent and the amount ratio of N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide are 5 ~ 15mL/g; Alkali is n-Butyl Lithium, sodium hydride, potassium hydride KH, lithium diisopropylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium methylate, sodium ethylate, potassium tert.-butoxide, salt of wormwood, potassium hydroxide, cesium carbonate, sodium carbonate or sodium hydroxide, and the consumption mole of alkali and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 1.5 ~ 3:1; The organic solvent that extraction uses is 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, methyl tertiary butyl ether, methylcyclopentyl ether, dibutyl ether or glycol dimethyl ether, and the consumption of the organic solvent that extraction uses and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 10 ~ 30mL/g; The washing saturated sodium-chloride water solution of organic phase and the amount ratio of N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide are 3 ~ 15mL/g; Decolouring uses the model of activated carbon to be GA-T1, and the amount ratio of activated carbon and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 0.05 ~ 0.5g/g; The organic solvent that recrystallization uses is normal heptane, hexanaphthene, normal hexane or sherwood oil, and the amount ratio of the organic solvent that recrystallization uses and N-(4-fluorophenyl)-4-benzyl oxybenzene formyl ethanamide is 3 ~ 12mL/g.
12. a kind of methods preparing Ezetimibe according to claim 1, it is characterized in that in described step (6), solubility promoter is ethylene glycol, dimethyl sulfoxide (DMSO), ethanol, acetone, PEG-4000 or PEG-8 00, solubility promoter protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 1 ~ 2mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; Reductase enzyme is carbonyl reductase, and enzyme lives 8 ~ 32, and the crude enzyme liquid of carbonyl reductase protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 10 ~ 40mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; β-NAD
+be 0.01 ~ 0.05g/g with the amount ratio of 3-(4-fluorophenyl)-3-carbonyl chloropropane; Reductive agent is Virahol, glucose or ammonium formiate, and the mol ratio of reductive agent and 3-(4-fluorophenyl)-3-carbonyl chloropropane is 1 ~ 4:1; Described damping fluid is formic acid/ammonium formiate, acetic acid/ammonium acetate, acetic acid/sodium acetate or dipotassium hydrogen phosphate/potassium primary phosphate, damping fluid protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 5 ~ 20mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; The organic solvent that extraction uses is methyl tertiary butyl ether, methylcyclopentyl ether, ethyl acetate, isopropyl acetate or toluene, organic solvent protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 5 ~ 20mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-; Crystallization solvent is sherwood oil, normal hexane, normal heptane or hexanaphthene, and crystallization solvent protects the amount ratio of hydroxyl-2-(4-protects oxybenzene formyl radical) valeramide to be 2 ~ 10mL/g with two (4-the fluorophenyl)-5-of (S)-N, 5-.
13. a kind of methods preparing Ezetimibe according to claim 1, it is characterized in that in described step (7), organic solvent is toluene or dimethylbenzene, organic solvent and (2R, two (4-the fluorophenyl)-5-of 5S)-N, 5-protects the amount ratio of hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide to be 5 ~ 20mL/g; Organic bases is triethylamine, diisopropylethylamine, tri-n-butylamine, azabicyclic, 4-dimethylamino pyridine, pyridine, 2,6-lutidine or N, accelerine, organic bases and (2R, two (4-the fluorophenyl)-5-of 5S)-N, 5-protects the mol ratio of hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8) to be 1.0 ~ 2.0:1; Methanesulfonyl chloride and (2R; two (4-the fluorophenyl)-5-of 5S)-N, 5-protects the mol ratio of hydroxyl-2-((R)-hydroxyl (4-protects hydroxyphenyl) methyl) valeramide (compound 8) to be 1.0 ~ 1.5:1.
14. a kind of methods preparing Ezetimibe according to claim 1, it is characterized in that in described step (8), mineral alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium carbonate, inorganic base aqueous solution concentration is 20 ~ 60%, inorganic base aqueous solution and (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects the amount ratio of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 0.5 ~ 1mL/g; Phase-transfer catalyst is tetrabutylammonium chloride, Tetrabutyl amonium bromide or benzyltriethylammoinium chloride, phase-transfer catalyst accounts for (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects the mass percent of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 0.5 ~ 3%; The water that cancellation reaction uses protects the amount ratio of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 2 ~ 10mL/g with (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-; Activated carbon accounts for (1R, 2R, 5S), and-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protects the mass percent of hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate to be 1 ~ 10%; Recrystallization solvent and (1R, 2R, 5S)-5-(4-fluorophenyl)-2-(4-fluoroaniline formyl radical)-5-protect hydroxyl-1-(4-protects hydroxy phenyl) pentyl methanesulfonate amount ratio to be 3 ~ 10mL/g.
15. a kind of methods preparing Ezetimibe according to claim 1, it is characterized in that in step (9), the reagent of deprotection base and the mol ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone (compound 10) are 0.1 ~ 4.0:1; Organic solvent is at least one in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), toluene or methylene dichloride, alcoholic solvent is 5 ~ 20mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone; The acid that treating product uses for concentration be hydrochloric acid or the sulfuric acid of 2 ~ 5mol/L, acid is 0.5 ~ 2mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone; Crystallization uses purified water to be 2 ~ 5mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone; The solvent that recrystallization uses is ethyl acetate, at least one in isopropyl acetate, normal hexane, hexanaphthene or normal heptane; recrystallization solvent is 5 ~ 20mL/g with the amount ratio of (3R, 4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-protects hydroxypropyl)-4-(4-protects hydroxyphenyl)-2-azetidinone.
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| CN1931838A (en) * | 2006-10-20 | 2007-03-21 | 屠勇军 | Azetidinone derivative and synthetic method thereof |
| WO2009054887A1 (en) * | 2007-10-22 | 2009-04-30 | Merck & Co., Inc. | Process for preparing an anti-hypercholesterolemic compound |
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| US6093812A (en) * | 1991-07-23 | 2000-07-25 | Schering Corporation | Process for the stereospecific synthesis of azetidinones |
| CN1931838A (en) * | 2006-10-20 | 2007-03-21 | 屠勇军 | Azetidinone derivative and synthetic method thereof |
| WO2009054887A1 (en) * | 2007-10-22 | 2009-04-30 | Merck & Co., Inc. | Process for preparing an anti-hypercholesterolemic compound |
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