CN103121964A - Method for preparing atorvastatin calcium key intermediate - Google Patents
Method for preparing atorvastatin calcium key intermediate Download PDFInfo
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- CN103121964A CN103121964A CN2013100172501A CN201310017250A CN103121964A CN 103121964 A CN103121964 A CN 103121964A CN 2013100172501 A CN2013100172501 A CN 2013100172501A CN 201310017250 A CN201310017250 A CN 201310017250A CN 103121964 A CN103121964 A CN 103121964A
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Abstract
The invention belongs to the technical field of medicine, and particularly relates to a method for preparing an atorvastatin calcium key intermediate. According to the method, 5-(4-fluorophenyl)-2-isopropyl-1-(3-formylpropyl)-4-phenyl-1H-pyrryl-3-formic acid phenyl amide used as a raw material is subjected to Aldol condensation with ketene dimer under the action of a chiral catalyst to obtain a chiral compound isopropyl (R)-7-[2-(4-fluorophenyl)-5-isopropyl-phenyl-4-[(phenylamino)formacyl]-1H-pyrryl-1-yl]-5-hydroxy-3-carbonylheptylate. The method has the advantages of accessible raw material and simple technique, and has industrialization value.
Description
Technical field
The invention belongs to medical technical field; be specifically related to a kind of (R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-preparation method of 5-hydroxyl-3-carbonyl enanthic acid isopropyl ester, this (R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-5-hydroxyl-3-carbonyl enanthic acid isopropyl ester can be used as the intermediate of preparation blood lipid-lowering medicine atorvastatincalcuim.
Background technology
Atorvastatincalcuim is the blood lipid regulation medicine of Statins, commodity are called Lipitor, chemistry [R-(R* by name, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxyl-5-(1-methylethyl)-3-phenyl-4-[(anilino) carbonyl]-1H-pyrroles-1-Calcium salt enanthate (2:1) trihydrate.This compound is the inhibitor of effect 3-hydroxy-3-methyl glutaryl base-CoA-reductase (HMG-CoA reductase enzyme), can be used for treating the control of hypercholesterolemia and combined hyperlipidemia familial, coronary heart disease and cerebral apoplexy.
(R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-5-hydroxyl-3-carbonyl enanthic acid isopropyl ester (I) can be used as the intermediate of preparation blood lipid-lowering medicine atorvastatincalcuim, and structural formula is shown below:
（I）
United States Patent (USP) (US5273995) has been reported by 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide and has been induced asymmetric Aldol reaction through the chirality auxiliary, transesterify, the Claisen condensation reaction makes (R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-5-hydroxyl-3-carbonyl enanthic acid tert-butyl ester, but this method corresponding selection is low, must be through polystep reaction, total recovery low (lower than 40%), severe reaction conditions, need to carry out under low temperature (78 ℃), complicated operation.
Based on the pharmacy value of atorvastatincalcuim and good market outlook, the effective ways of seeking the high enantioselectivity of a kind of energy ground synthetic compound (I) are imperative.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art; provide a kind of raw material cheap and easy to get; syntheti c route is short; easy and simple to handle, (the R)-7-[2-that is easy to produce (4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-preparation method of 5-hydroxyl-3-carbonyl enanthic acid isopropyl ester.
Synthetic route of the present invention is as follows:
（II） （I）
preparation method of the present invention is: by 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide (II) preparation (R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-5-hydroxyl-3-carbonyl enanthic acid isopropyl ester (I), concrete steps are as follows: add 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide in chiral catalyst, drip again ketene dimer, carry out asymmetric Aldol reaction.
In the present invention, the preparation of chiral catalyst is metering Ti (O-
i-Pr)
4: the west is alkali=1:1 times of molar weight not, under nitrogen atmosphere, with Ti (O-
i-Pr)
4Dropwise join in the organic solution of western not alkali, stirring at room 1-1.5 hour, obtain chiral catalyst.
In the present invention, chiral catalyst used is selected from a kind of of three kinds of following A, B, C, and chiral catalyst A, B, C are as follows:
（A） （B） （C）
In formula, R
1=R
2=H, C
1~ C
4Straight chain and branched-chain alkyl, R
3=R
4=H, C
1~ C
4Straight chain and branched-chain alkyl, phenyl.
In the present invention, not the alkali structure is as follows in preferred west:
In the present invention, the mol ratio of 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide and chiral catalyst is 1:0.1 ~ 1, and preferred mol ratio is 1:1.
In the present invention, the mol ratio of 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide and ketene dimer is 1:4-1:6, preferred 1:5.
In the present invention, organic solvent used is halohydrocarbon such as methylene dichloride, chloroform or 1,2-ethylene dichloride, ethers such as tetrahydrofuran (THF), ether or methyl tertiary butyl ether.Preferred methylene dichloride.
In the present invention, the Aldol temperature of reaction is-80 ℃ ~ 25 ℃.Preferable reaction temperature is-40 ℃.
In the present invention, the Aldol reaction times is 48 ~ 96 hours.The preferred time is 72 hours.
The present invention has overcome the many deficiencies in existing method, mild condition, and easy and simple to handle, raw material is easy to get.
Embodiment
Following embodiment illustrates content of the present invention better.But the invention is not restricted to following embodiment.
Embodiment 1 under nitrogen atmosphere protection with the west not aar ligand (289.8mg, 1.1mmol), methylene dichloride (5mL) be placed in reaction flask, add Ti (O-
i-Pr)
4(284.2mg, 1mmol), then stirring at room one hour is cooled to-40 ℃.Add compound (II) (454.2mg, 1mmol), ketene dimer (420.4mg, 5mmol) stirred 72 hours at-40 ℃.Reaction is finished, and adds 1M HCl(20mL), ether (20mL), at room temperature vigorous stirring is one hour, ethyl acetate extraction three times, saturated sodium bicarbonate washing three times, saturated common salt water washing three times, anhydrous sodium sulfate drying, decompression and solvent recovery, crude product get target compound (I) (361.1mg through column chromatography purification, 60.4%), enantiomeric excess (ee% 79%).
1H NMR (400 MHz, CDCl
3) δ 1.23-1.26 (d, 6H), 1.52-1.55 (dd, 6H), 1.62-1.68 (m, 2H), 2.51-2.53 (m, 1H), 2.74 (d, 1H, OH), 3.35 (s, 2H), 3.52-3.60 (m, 1H), 3.90-3.98 (m, 2H), 4.09-4.19 (m, 1H), 6.86 (s, 1H), 6.96-7.20 (m, 14H) ppm。
Embodiment 2 under nitrogen atmosphere protection with the west not aar ligand (289.8mg, 1.1mmol), methylene dichloride (5mL) be placed in reaction flask, add Ti (O-
i-Pr)
4(284.2mg, 1mmol), then stirring at room one hour is cooled to-20 ℃.Add compound (II) (454.2mg, 1mmol), ketene dimer (420.4mg, 5mmol) stirred 72 hours at-20 ℃.Reaction is finished, and adds 1M HCl(20mL), ether (20mL), at room temperature vigorous stirring is one hour, ethyl acetate extraction three times, saturated sodium bicarbonate washing three times, saturated common salt water washing three times, anhydrous sodium sulfate drying, decompression and solvent recovery, crude product get target compound (I) (405.1mg through column chromatography purification, 67.7%), enantiomeric excess (ee% 58%).
1H NMR is consistent with example 1.
Embodiment 3 under nitrogen atmosphere protection with the west not aar ligand (289.8mg, 1.1mmol), methylene dichloride (5mL) be placed in reaction flask, add Ti (O-
i-Pr)
4(284.2mg, 1mmol), then stirring at room one hour is cooled to 0 ℃.Add compound (II) (454.2mg, 1mmol), ketene dimer (420.4mg, 5mmol) stirred 72 hours at 0 ℃.Reaction is finished, and adds 1M HCl(20mL), ether (20mL), at room temperature vigorous stirring is one hour, ethyl acetate extraction three times, saturated sodium bicarbonate washing three times, saturated common salt water washing three times, anhydrous sodium sulfate drying, decompression and solvent recovery, crude product get target compound (I) (418.4mg through column chromatography purification, 70.0%), enantiomeric excess (ee% 41%).
1H NMR is consistent with example 1.
Claims (6)
1. (R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-preparation method of 5-hydroxyl-3-carbonyl enanthic acid isopropyl ester (I), it is characterized in that by 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide (II) preparation (R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-[(phenylamino) formyl radical]-1H-pyrroles-1-yl]-5-hydroxyl-3-carbonyl enanthic acid isopropyl ester (I), synthetic route is as follows:
（II） （I）
Concrete steps are: add 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide in chiral catalyst, then drip ketene dimer, carry out asymmetric Aldol reaction;
Chiral catalyst used is selected from a kind of of three kinds of following A, B, C, and chiral catalyst A, B, C are as follows:
（A） （B） （C）
In formula, R
1=R
2=H, C
1~ C
4Straight chain and branched-chain alkyl, R
3=R
4=H, C
1~ C
4Straight chain and branched-chain alkyl, phenyl.
2. preparation method according to claim 1, is characterized in that the mol ratio of described 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide and chiral catalyst is 1:0.1 ~ 1.
3. preparation method according to claim 1, is characterized in that the mol ratio of described 5-(4-fluorophenyl)-2-sec.-propyl-1-(3-aldehyde radical propyl group)-4-phenyl-1H-pyrroles-3-formic acid phenyl amide and ketene dimer is 1:4-1:6.
4. preparation method according to claim 1, is characterized in that organic solvent used is halohydrocarbon such as methylene dichloride, chloroform or 1,2-ethylene dichloride, ethers such as tetrahydrofuran (THF), ether or methyl tertiary butyl ether.
5. preparation method according to claim 1, is characterized in that described Aldol temperature of reaction is-80 ℃ ~ 25 ℃.
6. preparation method according to claim 1, is characterized in that the described Aldol reaction times is 48 ~ 96 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| CN101768102A (en) * | 2009-01-05 | 2010-07-07 | 浙江华海药业股份有限公司 | New preparation method of atorvastatin calcium 1H-pyrrole derivatives |
-
2013
- 2013-01-17 CN CN2013100172501A patent/CN103121964A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| CN101768102A (en) * | 2009-01-05 | 2010-07-07 | 浙江华海药业股份有限公司 | New preparation method of atorvastatin calcium 1H-pyrrole derivatives |
Non-Patent Citations (2)
| Title |
|---|
| MASAHIKO HAYASHI，等: "Highly Efficient Preparation of Optically Active 5-Hydroxy-3-oxoesters by Enantioselective Reaction of Diketene with Aldehydes Promoted by Novel Chiral Schiff Base-Titanium Alkoxide Complexes", 《TETRAHEDRON: ASYMMETRY》, vol. 6, no. 8, 31 August 1995 (1995-08-31) * |
| MASAHIKO HAYASHI,等: "Novel Enantioselective Reaction of Diketene with Aldehydes Promoted by Chiral Schiff Base-Titanium Alkoxide Complex", 《J. CHEM. SOC., CHEM. COMMUN.》, 1 January 1994 (1994-01-01), pages 341 - 342 * |
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