CN101768102A - New preparation method of atorvastatin calcium 1H-pyrrole derivatives - Google Patents
New preparation method of atorvastatin calcium 1H-pyrrole derivatives Download PDFInfo
- Publication number
- CN101768102A CN101768102A CN200910001856A CN200910001856A CN101768102A CN 101768102 A CN101768102 A CN 101768102A CN 200910001856 A CN200910001856 A CN 200910001856A CN 200910001856 A CN200910001856 A CN 200910001856A CN 101768102 A CN101768102 A CN 101768102A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- solvent
- formula
- thf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthetic route and a method for preparing (R)-5-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylamino formyl-1H-pyrrole-1-ethyl)-3-hydroxyvalerate. The (R)-5-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylamino formyl-1H-pyrrole-1-ethyl)-3-hydroxyvalerate is obtained through seven steps by using (R)-2,3-dihydroxy-chloropropane as raw material. The method provided by the invention has low cost, simple operation, and is suitable for industrialization.
Description
Technical field
The present invention relates to the synthetic route and the preparation method of a kind of preparation (R)-5-(2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-1H-pyrroles-1-yl)-3-hydroxyl valerate, belong to chemical pharmacy field.
Background technology
Compound (R)-5-(2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-1H-pyrroles-1-yl)-3-hydroxyl valerate is synthetic blood lipid-lowering medicine atorvastatincalcuim, and commodity are by name
Key intermediate.The chemistry of atorvastatincalcuim is called [R-(R
*, R
*)]-2-(4-fluorophenyl)-β; δ-dihydroxyl-5-sec.-propyl-3-phenyl-4-formic acid phenyl amide-1H-pyrroles-1-Calcium salt enanthate (2: 1) trihydrate; this compound can act on 3-hydroxy-3-methyl glutaryl base-CoA-reductase (HMG-CoA reductase enzyme) inhibitor, therefore can be used as reducing blood-fat and/or hypocholesterolemic medicine.
Patent US 4681893 discloses trans-6-[2-(3-or 4-formamido-replacement-pyrroles-1-yl) alkyl first]-preparation method of 4-hydroxyl-pyran-2-ones.
Document Tetrahedron Lett, 1992,33 (17), 2283-2284, patent US 5003080, US5155251 etc. disclose
Synthetic method; promptly with (4R-cis)-6-(2-aminoethyl)-2; 2-dimethyl-1; 3-dioxane-4-tert.-butyl acetate and 1; 4-dicarbonyl compound α-isobutyryl-β-fluorobenzene acyl group-β-phenylpropionyl aniline and its is carried out the Paal-knorr condensation; dehydroxylation protecting group then, the hydrolysis ester group obtains
Patent US2002133026, US0220254, CN01822509.8 etc. disclose 5-(4-fluorophenyl)-1-[2-(2R, 4R)-4-hydroxyl-6-oxo-tetrahydropyrans-2-yl)-ethyl]-the improvement synthetic method of 2-sec.-propyl-4-phenyl-1H-pyrroles-3-formic acid phenyl amide, promptly carry out the Paal-knorr condensation with amido acid amides and dicarbonyl compound, under the highly basic condition, increase chain and generate the 1H-pyrroles 3 who replaces, 5-dicarbapentaborane carboxylicesters obtains product by steps such as asymmetric reduction or fractionations again.
Patent EP1705175, US 5097045, and US 5103024, and US 5124482, US5149837, US5216174, US5245047, US5248793, US5273995d, US5280126, US5397792, US5342952, US5298627, US5446054, US5470981, US5489690, US5489691, US5510488, US5998633, US6087511, US2004068121, US20060194867, WO2005/118536, WO2006/097909 etc. disclose
Multiple preparation method.These synthetic methods mainly contain linear and assemble two kinds of strategies, and linear synthetic method is lower mainly due to productive rate, mostly is not suitable for industrial production; And the synthetic method of assembling is mostly with C-5 or the C-7 compound and the dicarbonyl compound condensation of chirality.Expensive chirality C-5 or C-7 compound are restrictions
The major cause of producing.
The present invention is with 3; 4-dihydroxyl fourth cyanogen is brand-new route through the route of important intermediate (R)-5-(2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-1H-pyrroles-1-yl)-3-hydroxyl valerate of the synthetic atorvastatin of steps such as protection, reduction, condensation, and this method avoids using expensive chirality C-5 or C-7 compound.In addition, the total important reaction Paal-knorr condensation in the present invention and the art methods is because reactor product is single, and the productive rate height is easy to handle, and reaction result obviously improves.
Summary of the invention
The present invention has overcome the defective of above-mentioned prior art, and the synthetic route and the preparation method of a kind of preparation formula (9) compound (R)-5-(2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-1H-pyrroles-1-yl)-3-hydroxyl valerate is provided.
R wherein
1Be C
1-C
4Alkyl
Comprise the steps:
Steps A formula (1) compound and alkali metal cyanide in 20 ℃ of-100 ℃ of reactions, get formula (2) compound in solvent;
Step B in the presence of acid, formula (2) compound and 2,2-Propanal dimethyl acetal or acetone react in solvent, formula (3) compound;
Step C is in the presence of catalyzer and ammonia, and formula (3) compound and hydrogen react in solvent, gets formula (4) compound;
Step D in the presence of catalyzer, formula (4) compound and formula (5) compound back flow reaction in organic solvent, dewater formula (6) compound;
Step e is in the presence of acid, and formula (6) compound reacts in solvent, gets formula (7) compound;
Step F formula (7) compound and sulfur oxychloride react in solvent, react in solvent with alkali metal cyanide subsequently, get formula (8) compound
Step G is in the presence of hydrogenchloride, and formula (8) compound reacts in solvent, gets formula (9) compound.
Technical scheme of the present invention, synthetic route and design synoptic diagram be (following reaction scheme only is a synoptic diagram, and only limitation of the scope of the invention can not be explained or be interpreted as to representative reaction special case and part) shown in scheme one.
Scheme one: atorvastatin hydroxy ester analogue and serial intermediate synthetic route synoptic diagram
Steps A: formula (1) compound and alkali metal cyanide (sodium cyanide for example, potassium cyanide) in solvent in 20 ℃ of-100 ℃ of reactions, optional one of following or their arbitrary combination of described solvent: methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), methane amide, N, dinethylformamide etc., be preferably N, the mixing solutions of dinethylformamide and methyl alcohol gets formula (2) compound.
Described temperature of reaction can be 20 ℃-100 ℃, is preferably 60 ℃.Reaction has just begun heat release, and temperature can raise automatically, and is stable after a while.
Also can add a spot of TEBA in the reaction.The boiling point of formula (2) compound is higher, and distillation loss is big, can select directly to carry out next step reaction without underpressure distillation.
Step B: in the presence of acid, formula (2) compound and 2,2-Propanal dimethyl acetal or acetone react in solvent, get formula (3) compound.
The optional sulfuric acid of described acid, hydrochloric acid, Hydrogen bromide, methylsulfonic acid, tosic acid, Phenylsulfonic acid, phenylformic acid, toluylic acid etc. are preferably tosic acid.The optional methylene dichloride of described solvent, chloroform, tetracol phenixin, ethylene dichloride, benzene, toluene, ethylbenzene, tetrahydrofuran (THF) etc. are preferably methylene dichloride.This reaction room temperature just can obtain yield preferably.
Step C: in the presence of catalyzer and ammonia, formula (3) compound and hydrogen react in solvent, get formula (4) compound.
Described catalyzer is Raney's nickel, palladium carbon, is preferably Raney's nickel, and catalyst levels is the 1%-5% of the weight of formula (3) compound.
The optional methyl alcohol of described solvent, ethanol, propyl alcohol, Virahol, butanols etc. are preferably Virahol.
Step D: in the presence of catalyzer, formula (4) compound and formula (5) compound react in solvent, by chemical drier molecular sieve etc. for example, or use Dean-Stark trap, or the component distillation removal water that uses suitable solvent for example to wait, get formula (6) compound.Described catalyzer is formic acid, acetate, propionic acid, butyric acid, valeric acid, trimethylacetic acid, toluylic acid etc., is preferably trimethylacetic acid.
Described solvent can be one of following or their mixed solvent: benzene, toluene, halogeno-benzene, tetrahydrofuran (THF), 1,4-dioxane, C
1-C
6Alkane etc., be preferably the mixed solvent of tetrahydrofuran (THF) and normal hexane.
Step e: in the presence of strong acid, formula (6) compound reacts in solvent, gets formula (7) compound.
Described strong acid is sulfuric acid, hydrochloric acid, Hydrogen bromide, methylsulfonic acid, tosic acid, Phenylsulfonic acid, and phenylformic acid, toluylic acid etc. are preferably hydrochloric acid.
Described solvent is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene, toluene, ethylbenzene, tetrahydrofuran (THF) etc., is preferably tetrahydrofuran (THF).
Step F: formula (7) compound and sulfur oxychloride react in solvent, react in solvent with alkali metal cyanide (for example sodium cyanide, potassium cyanide) subsequently, get formula (8) compound.
Described solvent with the sulfur oxychloride reaction is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene, toluene, ethylbenzene, tetrahydrofuran (THF) etc., is preferably methylene dichloride.
Described solvent with the alkali metal cyanide reaction is methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), methane amide, N, and dinethylformamide etc. are preferably N, dinethylformamide.
In the presence of hydrogenchloride (drying), formula (8) compound reacts in methyl alcohol or ethanol, gets formula (9) compound.
Embodiment
For essence, preparation thinking and the design that proves absolutely patent of the present invention, verify preparation method of the present invention in the following embodiments, these embodiment only for illustrating and the special case representative, should not explained or be interpreted as the restriction to the present invention's protection.
Steps A:
Embodiment 1
Add compound 1221.0g (2.0mol), NaCN 113.5g (2.2mol), 550mlDMF, 75ml CH in the there-necked flask of 1L
3OH is warming up to 60 ℃ of reactions, and the blocks of solid in the system fades away and forms the white powder solid.Behind the reaction 8h, filter solid NaClO solution-treated.Mother liquor concentrates (distillation temperature is no more than 100 ℃) through underpressure distillation, solvent in the evaporate to dryness system of trying one's best, the recycled solvent that steams, drip the pH=1-2 of the dense HCl regulation system of 40ml, add the acetone of 200-250ml again, stir, filter, solid NaClO solution-treated is collected mother liquor, concentrates.(T=130 ℃) cut is collected in underpressure distillation, gets yellow oily liquid.Yield: 55%
Embodiment 2
Add compound 1221.0g (2.0mol), NaCN 113.5g (2.2mol), 500ml acetonitrile, 70ml CH in the there-necked flask of 1L
3OH is warming up to 60 ℃ of reactions, and the blocks of solid in the system fades away and forms the white powder solid.Behind the reaction 10h, filter solid NaClO solution-treated.Mother liquor concentrates (distillation temperature is no more than 100 ℃) through underpressure distillation, solvent in the evaporate to dryness system of trying one's best, the recycled solvent that steams, drip the pH=1-2 of the dense HCl regulation system of 40ml, add the acetone of 200-250ml again, stir, filter, solid NaClO solution-treated is collected mother liquor, concentrates.(T=130 ℃) cut is collected in underpressure distillation, gets yellow oily liquid.Yield: 45%.
Embodiment 3
Add compound 1221.0g (2.0mol) in the there-necked flask of 1L, KCN143g (2.2mol), 600mlDMF is warming up to 60 ℃ of reactions, and the blocks of solid in the system fades away and forms the white powder solid.Behind the reaction 10h, filter solid NaClO solution-treated.Mother liquor concentrates (distillation temperature is no more than 100 ℃) through underpressure distillation, solvent in the evaporate to dryness system of trying one's best, the recycled solvent that steams, drip the pH=1-2 of the dense HCl regulation system of 40ml carefully, add the acetone of 200-250ml again, stir, filter, solid is used the NaClO solution-treated carefully, collects mother liquor, concentrates.(T=130 ℃) cut is collected in underpressure distillation, gets yellow oily liquid.Yield: 50%.
Step B
Embodiment 4
Add compound 2101.0g (1.0mol) in the there-necked flask of 500ml, 250mlCH without distillation purifying
2Cl
2And the 5.0g tosic acid, under the room temperature, drip 2,2-Propanal dimethyl acetal 104.1g (1.0mol), after dropwising, stirring at room 4h.Add saturated sodium bicarbonate solution regulation system pH=8, tell organic phase, water layer 100ml CH
2Cl
2Extraction, the merging organic phase, with the saturated common salt washing of 200ml * 2, organic phase adds anhydrous sodium sulfate drying, filters, and the concentrating under reduced pressure solvent gets dark oil liquid, and underpressure distillation is collected (T=80-90 ℃) cut, gas phase content 96%, yield: 70%.
Embodiment 5
Add the compound 2101.0g (1.0mol) without distillation purifying in the there-necked flask of 500ml, 250ml toluene and 5.0g toluylic acid under the room temperature, drip 2,2-Propanal dimethyl acetal 104.1g (1.0mol), and after dropwising, stirring at room 4h.Add saturated sodium bicarbonate solution regulation system pH=8, tell organic phase, water layer 100mlCH
2Cl
2Extraction, the merging organic phase, with the saturated common salt washing of 200ml * 2, organic phase adds anhydrous sodium sulfate drying, filters, and the concentrating under reduced pressure solvent gets dark oil liquid, and underpressure distillation is collected (T=80-90 ℃) cut, gas phase content 94%, yield: 60%.
Embodiment 6
Add the compound 2101.0g (1.0mol) without distillation purifying in the there-necked flask of 500ml, 250ml THF and 5.0g tosic acid under the room temperature, drip 2,2-Propanal dimethyl acetal 104.1g (1.0mol), and after dropwising, stirring at room 4h.Add saturated sodium bicarbonate solution regulation system pH=8, tell organic phase, water layer 100ml CH
2Cl
2Extraction, the merging organic phase, with the saturated common salt washing of 200ml * 2, organic phase adds anhydrous sodium sulfate drying, filters, and the concentrating under reduced pressure solvent gets dark oil liquid, and underpressure distillation is collected (T=80-90 ℃) cut, gas phase content 95%, yield: 62%.
Step C:
Embodiment 7
Add compound 342.0g (0.3mol) in the 500ml autoclave, 210ml Virahol and 1.0g Ni (Mo) catalyzer close still, use nitrogen respectively, and hydrogen exchange three times feeds P then
NH3=0.02Mpa and P
H2=0.5Mpa, 40 ℃ of continuously logical H-H reaction 20h of the hierarchy of control.Filter, reclaim catalyzer, the concentrating under reduced pressure solvent gets the light green oily liquids.Yield: 75%, gas phase content 94%, (T=90-100 ℃) cut is collected in underpressure distillation.Yield: 70%, gas phase content 98%.
Embodiment 8
Add compound 342.0g (0.3mol) in the 500ml autoclave, 210ml methyl alcohol and 1.0g Pd/C catalyzer close still, use nitrogen respectively, and hydrogen exchange three times feeds P then
NH3=0.02Mpa and P
H2=0.5Mpa, 40 ℃ of continuously logical H-H reaction 20h of the hierarchy of control.Filter, reclaim catalyzer, the concentrating under reduced pressure solvent gets the light green oily liquids.Yield: 73%, (T=90-100 ℃) cut is collected in underpressure distillation.Yield: 68%, gas phase content 97%.
Step D:
Embodiment 9
In there-necked flask, add compound (4) 17.8g (0.12mol), trimethylacetic acid 12.2g (0.12mol), triethylamine 12.1g (0.12mol), compound (5) 41.7g (0.1mol), tetrahydrofuran (THF) 150ml and normal hexane 75ml.(63 ℃) reaction that refluxes under vigorous stirring, HPLC follows the tracks of, when reaction solution starting compound (5) (about 90h) less than 5% time, stopped reaction.
Decompression and solvent recovery, add 100ml water and 200ml toluene, add saturated sodium hydrogen carbonate solution 100ml, fully stirred reaction mixture, extracted organic phase, divide extraction water liquid 2 times with toluene 200ml again, combining methylbenzene solution washes with water three times, dried over sodium sulfate, reclaim solvent and obtain faint yellow solid 68g, HPLC detection level 91.88% is used for next step without further separating.
Embodiment 10
In there-necked flask, add compound (4) 17.8g (0.12mol), formic acid 5.52g (0.12mol), triethylamine 12.1g (0.12mol), compound (5) 41.7g (0.1mol), toluene 200ml.(63 ℃) reaction that refluxes under vigorous stirring, HPLC follows the tracks of, when reaction solution starting compound (5) (about 100h) less than 5% time, stopped reaction.
Decompression and solvent recovery, add 100ml water and 200ml toluene, add saturated sodium hydrogen carbonate solution 100ml, abundant stirred reaction mixture, extracted organic phase, divide extraction water liquid 2 times with toluene 200ml again, combining methylbenzene solution washes dried over sodium sulfate with water three times, reclaim solvent and obtain faint yellow solid 58g, can be directly used in next step reaction.
Step e:
Embodiment 11
Crude product 68g, tetrahydrofuran (THF) 300ml, the concentrated hydrochloric acid 40ml of adding formula (6) compound in the there-necked flask.At 25 ℃ of following stirring reaction 24h, react 1.5h down in 65 ℃ again.Reclaim tetrahydrofuran (THF) under the decompression in 40 ℃ of water-baths, residuum adds 200ml methylene dichloride and 200ml water, gets organic phase, and water extracts at twice with the 100ml methylene dichloride again, merges organic phase.Wash organic phase with water to neutral, dried over sodium sulfate, the filtration drying agent is reclaimed solvent and is got 66.2g, and HPLC detection level 91.09% is used it in the next step without further separating.
Embodiment 12
Crude product 68g, the CH of adding formula (6) compound in the there-necked flask
2Cl
2300ml, concentrated hydrochloric acid 40ml.At 25 ℃ of following stirring reaction 24h, reaction 1.5h under 65 ℃ tells organic phase again, and water extracts at twice with the 100ml methylene dichloride again, merges organic phase.Wash organic phase with water to neutral, dried over sodium sulfate, the filtration drying agent is reclaimed solvent and is got 64g, uses it in the next step without further separating.
Embodiment 13
Crude product 68g, toluene 300ml, the concentrated hydrochloric acid 40ml of adding formula (6) compound in the there-necked flask.At 25 ℃ of following stirring reaction 24h, reaction 1.5h under 65 ℃ tells organic phase again, and water extracts at twice with the 100ml methylene dichloride again, merges organic phase.Wash organic phase with water to neutral, dried over sodium sulfate, the filtration drying agent is reclaimed solvent and is got 60g, uses it in the next step without further separating.
Step F:
Embodiment 14
In there-necked flask, add 66.2g formula (7) compound crude product, methylene dichloride 500ml, stirring and dissolving sample, cryosel is bathed and is cooled to below-5 ℃ then, drip thionyl chloride (34.7g) solution of 150ml methylene dichloride dilution, 30min dropwises, and is raised to 25 ℃ of reaction 12h then naturally, the reclaim under reduced pressure methylene dichloride, further evaporate to dryness thionyl chloride, with sample dissolution, add the 14.7g sodium cyanide with DMF 300ml, 25 ℃ of reaction 48h.
Add 300ml water, adding concentrated hydrochloric acid under the water-bath cooling regulates about PH to 3, add the 200ml dichloromethane extraction again, extract at twice with the 100ml methylene dichloride again, merge organic phase, organic phase washes neutrality with water, dried over sodium sulfate, reclaim solvent and get 60g formula (8) compound crude product, HPLC detection level 74%.
Purifying crude: the 60g crude product is joined in the there-necked flask, add 90ml toluene and boil 1h for 80 ℃, cold filtration, solid washs with normal hexane, obtains the 26g product, HPLC detection level 91%.Can be used for next reaction.
Embodiment 15
In there-necked flask, add 66.2g formula (7) compound crude product, THF500ml, stirring and dissolving sample, cryosel is bathed and is cooled to below-5 ℃ then, drip thionyl chloride (34.7g) solution of 150mlTHF dilution, dropwised in 30 minutes, and be raised to 25 ℃ of reaction 12h then naturally, reclaim under reduced pressure THF, further evaporate to dryness thionyl chloride, with sample dissolution, add the 14.7g sodium cyanide with acetonitrile 300ml, 25 ℃ of reaction 48h.Add 300ml water, under the water-bath cooling, add concentrated hydrochloric acid and regulate about PH to 3, add the 200ml dichloromethane extraction again, extract at twice with the 100ml methylene dichloride, merge organic phase, organic phase washes neutrality with water, dried over sodium sulfate reclaims solvent and gets 55g formula (8) compound crude product.
Embodiment 16
In there-necked flask, add 66.2g formula (7) compound crude product, toluene 500ml, the stirring and dissolving sample, cryosel is bathed and is cooled to below-5 ℃ then, drip thionyl chloride (34.7g) solution of 150ml dilution with toluene, 30min dropwises, naturally be raised to 25 ℃ of reaction 12h then, reclaim under reduced pressure toluene, further the evaporate to dryness thionyl chloride with sample dissolution, adds the 14.7g sodium cyanide with methyl alcohol 300ml, 25 ℃ of reaction 48h, recovery part methyl alcohol, residuum adds 300ml water, adds concentrated hydrochloric acid and regulate about PH to 3 under the water-bath cooling, add the 200ml dichloromethane extraction again, extract at twice with the 100ml methylene dichloride, merge organic phase, organic phase washes neutrality with water, dried over sodium sulfate reclaims solvent and gets 45g formula (8) compound crude product.
Step G
Embodiment 17
In the 500ml there-necked flask, add hydroxyl nitrile formula (8) compound 15 grams, methyl alcohol 150ml, stir the cooling bath cooling down (15 ℃) feed exsiccant HCl gas 6 hours to saturated, then in 25 ℃ of following stirring reaction 24-48h, the back adding 150ml water that reacts completely stirred 10 minutes, and a large amount of solids are separated out.The back adds the 100ml dichloromethane extraction, separatory, twice of 30ml*2 dichloromethane extraction of water layer.Merge organic phase, wash 3 times, anhydrous sodium sulfate drying is sloughed solvent and is got yellow viscous material formula (9) compound 16.2 grams.
The recrystallization experiment of formula (9) compound
With 7g crude product hydroxy ester recrystallization.Be dissolved in 12ml ethanol, be warming up to 60 ℃, add normal hexane, till having precipitation to separate out.When rising to 60 ℃, temperature adds the 10ml normal hexane.Stir for a moment.Adding 10ml adularescent solid again separates out.Slowly drip the shared normal hexane 51ml that goes.Stop to be stirred to stirring at normal temperature, solution is yellow.The adularescent solid is separated out when the near room temperature of temperature.Stop to stir.Suction filtration gets filter cake 4.1g.Purity got about 73% by former not re-crystallization and brings up to about 93%.
Claims (16)
1. the method for a preparation formula (9) compound (R)-5-(2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-1H-pyrroles-1-yl)-3-hydroxyl valerate is characterized in that comprising the steps:
R wherein
1Be C
1-C
4Alkyl
Steps A formula (1) compound and alkali metal cyanide in 20 ℃ of-100 ℃ of reactions, get formula (2) compound in solvent;
Step B in the presence of acid, formula (2) compound and 2,2-Propanal dimethyl acetal or acetone react in solvent, formula (3) compound;
Step C is in the presence of catalyzer and ammonia, and formula (3) compound and hydrogen react in solvent, gets formula (4) compound;
Step D in the presence of catalyzer, formula (4) compound and formula (5) compound back flow reaction in organic solvent, dewater formula (6) compound;
Step e is in the presence of acid, and formula (6) compound reacts in solvent, gets formula (7) compound;
Step F formula (7) compound and sulfur oxychloride react in solvent, react in solvent with alkali metal cyanide subsequently, get formula (8) compound
Step G is in the presence of hydrogenchloride, and formula (8) compound reacts in solvent, gets formula (9) compound.
2. according to the method for claim 1, it is characterized in that alkalimetal hydride described in steps A and the step F is KCN or NaCN.
3. according to the described method of claim 1, it is characterized in that the described solvent of steps A is one of following or their arbitrary combination: methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, methane amide, N, dinethylformamide etc., be preferably N, the mixing solutions of dinethylformamide and methyl alcohol.
4. according to the described method of claim 1, it is characterized in that the steps A temperature of reaction is preferably 60 ℃.
5. according to the method for claim 1, it is characterized in that the acid among the step B includes but not limited to tosic acid, Phenylsulfonic acid, phenylformic acid, toluylic acid; Be preferably tosic acid.
6. according to the method for claim 1, it is characterized in that solvent is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene, toluene, ethylbenzene, tetrahydrofuran (THF) etc. described in the step B, be preferably methylene dichloride.
7. according to the method for claim 1, it is characterized in that catalyzer described in the step C is Raney's nickel, palladium carbon, is preferably Raney's nickel.
8. according to the method for claim 1, it is characterized in that solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols etc. described in the step C, be preferably Virahol.
9. according to the method for claim 1, it is characterized in that catalyzer is formic acid, acetate, propionic acid, butyric acid, valeric acid, trimethylacetic acid, toluylic acid etc. described in the step D, be preferably trimethylacetic acid.
10. according to the method for claim 1, it is characterized in that solvent described in the step D can be one of following or their mixed solvent: benzene, toluene, halogeno-benzene, tetrahydrofuran (THF), 1,4-dioxane, C
1-C
6Alkane etc., be preferably the mixed solvent of tetrahydrofuran (THF) and normal hexane.
11. according to the method for claim 1, it is characterized in that strong acid described in the step e is sulfuric acid, hydrochloric acid, Hydrogen bromide, methylsulfonic acid, tosic acid, Phenylsulfonic acid, phenylformic acid, toluylic acid etc. are preferably hydrochloric acid.
12., it is characterized in that solvent described in the step e is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene, toluene, ethylbenzene, tetrahydrofuran (THF) etc., is preferably methylene dichloride according to the method for claim 1.
13. according to the method for claim 1, it is characterized in that the solvent that reacts with thionyl chloride described in the step F is methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene, toluene, ethylbenzene, tetrahydrofuran (THF) etc., be preferably tetrahydrofuran (THF).
14. according to the method for claim 1, it is characterized in that the solvent that reacts with alkali metal cyanide described in the step F is methyl alcohol, ethanol, Virahol, acetonitrile, tetrahydrofuran (THF), methane amide, N, dinethylformamide etc. are preferably N, dinethylformamide.
15., it is characterized in that solvent described in the step G is methyl alcohol, ethanol according to the method for claim 1.
16. method according to claim 1; the present invention is not limited only to (R)-2; 3-dihydroxyl chloropropane is feedstock production (R)-5-(2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-1H-pyrroles-1-yl)-3-hydroxyl valerate; also can be according to the route and the preparation method of claim 1; with (S) or (±)-2; 3-dihydroxyl chloropropane is a raw material, preparation (S) or (±)-5-(2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-1H-pyrroles-1-yl)-3-hydroxyl valerate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910001856 CN101768102B (en) | 2009-01-05 | 2009-01-05 | New preparation method of atorvastatin calcium 1H-pyrrole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910001856 CN101768102B (en) | 2009-01-05 | 2009-01-05 | New preparation method of atorvastatin calcium 1H-pyrrole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101768102A true CN101768102A (en) | 2010-07-07 |
| CN101768102B CN101768102B (en) | 2013-08-21 |
Family
ID=42501225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910001856 Active CN101768102B (en) | 2009-01-05 | 2009-01-05 | New preparation method of atorvastatin calcium 1H-pyrrole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101768102B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766136A (en) * | 2012-08-07 | 2012-11-07 | 浙江宏元药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| CN103121964A (en) * | 2013-01-17 | 2013-05-29 | 复旦大学 | Method for preparing atorvastatin calcium key intermediate |
| CN114702425A (en) * | 2022-03-28 | 2022-07-05 | 苏州汉酶生物技术有限公司 | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325844A (en) * | 2000-05-31 | 2001-12-12 | 中国医学科学院药物研究所 | Process for synthesizing (+/-)p-fluoro-2(2-methyl-propionyl)-4-oxy-N,3-diphenyl-phenylbutylamide |
| WO2004089895A1 (en) * | 2003-04-11 | 2004-10-21 | Lek Pharmaceuticals D.D. | Process for the preparation of amorphous calcium salt of atorvastatin |
| WO2005063741A1 (en) * | 2003-12-29 | 2005-07-14 | Lek Pharmaceuticals D.D. | Process for preparing amorphous (4r-cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid |
-
2009
- 2009-01-05 CN CN 200910001856 patent/CN101768102B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325844A (en) * | 2000-05-31 | 2001-12-12 | 中国医学科学院药物研究所 | Process for synthesizing (+/-)p-fluoro-2(2-methyl-propionyl)-4-oxy-N,3-diphenyl-phenylbutylamide |
| WO2004089895A1 (en) * | 2003-04-11 | 2004-10-21 | Lek Pharmaceuticals D.D. | Process for the preparation of amorphous calcium salt of atorvastatin |
| WO2005063741A1 (en) * | 2003-12-29 | 2005-07-14 | Lek Pharmaceuticals D.D. | Process for preparing amorphous (4r-cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid |
Non-Patent Citations (1)
| Title |
|---|
| 王继宇等: "阿托伐他汀的全合成研究进展", 《合成化学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766136A (en) * | 2012-08-07 | 2012-11-07 | 浙江宏元药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| CN103121964A (en) * | 2013-01-17 | 2013-05-29 | 复旦大学 | Method for preparing atorvastatin calcium key intermediate |
| CN114702425A (en) * | 2022-03-28 | 2022-07-05 | 苏州汉酶生物技术有限公司 | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate |
| CN114702425B (en) * | 2022-03-28 | 2024-04-19 | 苏州汉酶生物技术有限公司 | Process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives and intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101768102B (en) | 2013-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102627594A (en) | Preparation method of waterless aziridine compound | |
| CN101768102B (en) | New preparation method of atorvastatin calcium 1H-pyrrole derivatives | |
| CN108586465B (en) | Preparation method of barretinib | |
| CN101747273A (en) | Preparing method of blonanserin intermediate | |
| CN103420908B (en) | The preparation method of montelukast chiral intermediate | |
| CN104530033A (en) | Novel process method for preparing arotinolol hydrochloride | |
| CN107056681B (en) | A kind of support method replaces the preparation method of cloth intermediate | |
| CN103183673A (en) | Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane | |
| CN101941965A (en) | Preparation method of candesartan cilexetil | |
| CN103980105B (en) | A kind of anisic acid prepares the method for aubepine | |
| CN110669014A (en) | Preparation method of oxalagogri intermediate | |
| CN107298683B (en) | A kind of synthetic method of chirality benzodiazepine * compound | |
| CN102391243A (en) | Preparation method of atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate | |
| CN1317268C (en) | 2,6-dimethylpyridine preparation method | |
| CN102531939A (en) | Preparation method of L-methyldopa | |
| CN101423490B (en) | Synthetic method of trandolapril key intermediate (2S,3aR,7as)-octahydro-1H-indole-2-carboxylic acid | |
| CN102807516A (en) | Intermediate in amisulpride and method for preparing amisulpride by using intermediate | |
| CN105968103B (en) | The synthetic method of anti-tumor drug Afatinib | |
| CN104703967A (en) | Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same | |
| CN103012266A (en) | Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine | |
| CN103288671B (en) | Synthetic method of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride | |
| CN103130700A (en) | Preparation method of azelnidipine intermediate | |
| TW202206412A (en) | Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof | |
| CN102827058A (en) | Production method of N-t-butoxycarbonyl-L-pyroglutamate | |
| CN102367228A (en) | Method for synthesizing agomelatine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |