CN104513232A - Preparation process for rosuvastatin ethyl ester - Google Patents
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Abstract
The invention belongs to the field of medicinal chemistry and particularly relates to a preparation process for rosuvastatin ethyl ester. The preparation process comprises the following steps: taking (4R-cis)-6-[(acetoxyl)methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate as an initial raw material, and adding alkali to obtain (4R-cis)-6-hydroxymethyl-2,2-dimethtyl-1,3-dioxane-4-ethyl acetate; reacting with p-nitrobenzenesulfonyl chloride to generate (4R-cis)-6-[(p-nitrobenzenesulfonyl)oxy]-2,2-dimethtyl-1,3-dioxane-4-ethyl acetate; reacting with 2-mercaptobenzothiazole to generate (4R-cis)-6-[(benzothiazolyl)s-methyl]-2,2-dimethtyl-1,3-dioxane-4-ethyl acetate; oxidizing to generate (4R-cis)-6-[(benzothiazolesulfonyl)methyl]-2,2-dimethtyl-1,3-dioxane-4-ethyl acetate; reacting with 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-formyl-1-pyridine to generate a target product. According to the preparation process, the cost is reduced, the difficulty of hydrolysis reaction is lowered, the reaction efficiency is improved, and the raw material risk is lowered.
Description
Technical field:
The invention belongs to medicinal chemistry art, be specifically related to a kind of with (4R-cis)-6-[(acetoxyl group) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is starting raw material synthesis rochovastatin ethyl ester (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(methyl-methylsulfonyl-amino)-pyrimidine-5-base vinyl]-2, the preparation method of 2-dimethyl-1,3-dioxane-4-ethyl acetate.
Background technology:
Rochovastatin; English name Rosuvastatin Calcium; by name pair of chemistry-[E-7-[4-(the fluorine-based phenyl of 4-)-6-sec.-propyl-2-[methyl (methylsulfonyl) is amino]-pyrimidine-5-base] (3R; 5S)-3; 5-dihydroxy heptyl-6-olefin(e) acid] calcium salt (2:1); developed by the wild justice (Osaka Shionogi) of Japanese salt; in April, 1998 transfers AstraZeneca company of Britain, and in August, 2003 is by U.S. FDA approval listing.Rosuvastatin makes liver synthesis cholesterol reduce, and liver L DL-acceptor compensatory raises, and causes LDL-C, vldl, cholesterol and TG level in circulation to decline.From the viewpoint of its existing Clinical results and with like product compare two, rochovastatin is all deserve to be called and being called as " superstatin ", and its lipid-lowering effect is very good, is the most potent fat-reducing medicament up to now.
Summary of the invention:
In order to overcome above-mentioned defect, the present invention aim to provide a kind ofly to reduce costs, the difficulty that reduces hydrolysis reaction, the preparation technology that improves reaction efficiency, reduce the rochovastatin ethyl ester of raw material danger.
In order to realize goal of the invention, the technical solution used in the present invention is: a kind of rochovastatin ethyl ester (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-pyrimidine-5-base vinyl]-2,2-dimethyl-1, the preparation technology of 3-dioxane-4-ethyl acetate, it is characterized in that, comprise the steps:
(1) with (4R-cis)-6-[(acetoxyl group) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is starting raw material, at ambient temperature, in the presence of base, react 3h in a solvent and obtain (4R-Cis)-6-methylol-2,2-dimethyl-1,3-dioxane-4-ethyl acetate;
(2) under 0-5 DEG C of condition, (4R-Cis)-6-methylol-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is under the existence of alkali and solvent, (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2 is generated with 4-Nitrobenzenesulfonyl chloride effect, 2-dimethyl-1,3-dioxane-4-ethyl acetate;
(3) (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is under alkali and solvent exist, react with 2-mercaptobenzothiazole under the condition of 70-80 DEG C and generate (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate;
(4) (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate generates (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2 with hydrogen peroxide oxidation make the condition of catalyzer at Ammonium Molybdate Tetrahydrate under, 2-dimethyl-1,3-dioxane-4-ethyl acetate;
(5) (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2; 2-dimethyl-1; 3-dioxane-4-ethyl acetate in the presence of a base with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-5-formyl radical-1-pyrimidine at-75 DEG C--react at 80 DEG C and generate (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(methyl-methylsulfonyl-amino)-pyrimidine-5-base vinyl]-2; 2-dimethyl-1,3-dioxane-4-ethyl acetate.
Further, in step (5), (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2, 2-dimethyl-1, 3-dioxane-4-ethyl acetate is reacted with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-5-formyl radical-1-pyrimidine and is generated (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(methyl-methylsulfonyl-amino)-pyrimidine-5-base vinyl]-2 under two-(trimethyl silicon based) Lithamide exists at-78 DEG C, 2-dimethyl-1, 3-dioxane-4-ethyl acetate
Preferably, in step (2), the p-nitrophenyl alkylsulfonyl of 4-Nitrobenzenesulfonyl chloride replaces with p-toluenesulfonyl or benzenesulfonyl.
Preferably, in step (1)-(3), described alkali is salt of wormwood or triethylamine; Described solvent is methyl alcohol; In step (2), described alkali is triethylamine; Described solvent is toluene; In step (3), described alkali is salt of wormwood, and described solvent is DMF.
Preferably, in step (5), described alkali is two-(trimethyl silicon based) Lithamide, sodium hydride or LDA.
In step (1), the mol ratio of (4R-cis)-6-[(acetoxyl group) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate and alkali is 1:1-2:1.
In step (2), the mol ratio of (4R-Cis)-6-methylol-2,2-dimethyl-1,3-dioxane-4-ethyl acetate, alkali and 4-Nitrobenzenesulfonyl chloride is 1:0.5:1-1:1:2.
In step (3), the mol ratio of (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate and 2-mercaptobenzothiazole is 2:1-1:1.
In step (4), the mol ratio of (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate and hydrogen peroxide is 2:1-1:1.
In step (5); (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2; the mol ratio of 2-dimethyl-1,3-dioxane-4-ethyl acetate and 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-5-formyl radical-1-pyrimidine is 2:1-1:1.
Concrete, the present invention is with (4R-cis)-6-[(acetoxyl group) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is starting raw material, under room temperature, salt of wormwood does alkali, methyl alcohol is solvent reaction 3h and obtains (4R-Cis)-6-methylol-2,2-dimethyl-1,3-dioxane-4-ethyl acetate; (4R-Cis)-6-methylol-2,2-dimethyl-1,3-dioxane-4-ethyl acetate triethylamine does alkali toluene and makees solvent, first reinforced at 0-5 DEG C, (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2 is at room temperature generated again with 4-Nitrobenzenesulfonyl chloride effect, 2-dimethyl-1,3-dioxane-4-ethyl acetate; (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate salt of wormwood is alkali DMF and makees solvent, and react with 2-mercaptobenzothiazole under the condition of 70-80 DEG C and generate (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate; (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate generates (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2 with hydrogen peroxide oxidation do the condition of catalyzer at Ammonium Molybdate Tetrahydrate under, 2-dimethyl-1,3-dioxane-4-ethyl acetate; (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2; 2-dimethyl-1; 3-dioxane-4-ethyl acetate is reacted with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-5-formyl radical-1-pyrimidine and is generated (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(methyl-methylsulfonyl-amino)-pyrimidine-5-base vinyl]-2 under two-(trimethyl silicon based) Lithamide exists at-78 DEG C; 2-dimethyl-1,3-dioxane-4-ethyl acetate.
The 1-7 of above reaction formula refers to compound 1-7, or is intermediate 1-7.
This technique solves the problem that processing condition are harsh and raw material danger is high, avoids the protection of other patents simultaneously, also has following advantage:
1) intermediate 1 obtains for fermentation, and cost is lower, can on source Controlling Technology cost;
2) when preparing intermediate 7, sodium hydride is used to do alkali, more the reducing costs of energy;
3) in the reaction preparing intermediate 7, the specific activity tert-butyl ester of ethyl ester is high, and reaction is cleaner, and reaction preference is very high, can obtain the trans-isomer(ide) close to 100%;
4) ethyl ester is than the tert-butyl ester more facile hydrolysis, can reduce the difficulty of hydrolysis reaction.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described.
Embodiment one: (compound
2synthesis)
In the single port flask of a 250ml, add compound
1(18g), methyl alcohol (144ml), salt of wormwood (4.2g), stirring at room temperature is reacted.After 3 hours, TLC detects (PE:EA=5:1), and raw material reaction is complete, cross and filter insolubles, filtrate is concentrated into dry, adds 40ml water and 40ml methyl tertiary butyl ether, after stirring 10min, separatory, collects organic phase, aqueous phase is again with the extraction of 20ml methyl tertiary butyl ether, merge organic phase, wash with water (40ml), saturated aqueous common salt (40ml) is washed, anhydrous sodium sulfate drying, is concentrated into dry compound
2(13g), yield 84%.
Example two: (compound
3synthesis)
In the there-necked flask of a 500ml, add compound
2(23.1g), toluene (130ml), after stirring and dissolving, add triethylamine (22.4g), ice bath is cooled to 0-5 DEG C, dropwise add 4-Nitrobenzenesulfonyl chloride (23.6g is dissolved in 45ml toluene), after dropwising, rise to room temperature reaction 3h, TLC detects, raw material reaction is complete, reaction system is poured in 250ml frozen water, stir 5min, separatory, aqueous phase is extracted with ethyl acetate, merge organic phase, wash with dilute acetic acid (15ml acetic acid is dissolved in 200ml water), washing (200ml*2 time), anhydrous sodium sulfate drying, when being concentrated into quick-drying, add sherwood oil (150ml), stir 30min, filter, filter cake sherwood oil rinses, collect and dry compound
3(36g), yield 91%, purity 99%.
Example three: (compound
3synthesis)
In the there-necked flask of a 500ml, add compound
2(23.2g), toluene (130ml), after stirring and dissolving, add triethylamine (22.4g), ice bath is cooled to 0-5 DEG C, dropwise add p-methyl benzene sulfonic chloride (21.0g is dissolved in 40ml toluene), after dropwising, rise to room temperature reaction 3h, TLC detects, raw material reaction is complete, reaction system is poured in 250ml frozen water, stir 5min, separatory, aqueous phase is extracted with ethyl acetate, merge organic phase, wash with dilute acetic acid (15ml acetic acid is dissolved in 200ml water), washing (200ml*2 time), anhydrous sodium sulfate drying, when being concentrated into quick-drying, add sherwood oil (120ml), stir 30min, filter, filter cake sherwood oil rinses, collect and dry compound
3(32.8g), yield 85%, purity 98%.
Example four: (compound
3synthesis)
In the there-necked flask of a 500ml, add compound
2(23.2g), toluene (130ml), after stirring and dissolving, add triethylamine (22.4g), ice bath is cooled to 0-5 DEG C, dropwise add benzene sulfonyl chloride (19.5g is dissolved in 35ml toluene), after dropwising, rise to room temperature reaction 3h, TLC detects, raw material reaction is complete, reaction system is poured in 200ml frozen water, stir 5min, separatory, aqueous phase is extracted with ethyl acetate, merge organic phase, wash with dilute acetic acid (15ml acetic acid is dissolved in 200ml water), washing (200ml*2 time), anhydrous sodium sulfate drying, when being concentrated into quick-drying, add sherwood oil (200ml), stir 30min, filter, filter cake sherwood oil rinses, collect and dry compound
3(32.4g), yield 87%, purity 98%.
Example five: (compound
4synthesis)
In the there-necked flask of a 500ml, add compound 3 (36g), DMF (300ml), 2-mercaptobenzothiazole (14.2g), salt of wormwood (22g), under stirring, be warming up to 70-80 DEG C of reaction 3h, HPLC detects, and raw material reaction is complete, after being down to room temperature, add 500ml water and 200ml ethyl acetate, stir 10min, separatory, aqueous phase is extracted with ethyl acetate (200ml*2 time), merge organic phase, with saturated common salt washing (200ml*2 time), anhydrous sodium sulfate drying, be concentrated into dry compound
4(35.6g), purity 98%.
Example six: (compound
4synthesis)
In the there-necked flask of a 500ml, add compound
3(36g), DMF (300ml), 2-mercaptobenzothiazole (14.2g), sodium carbonate (16.4g), under stirring, be warming up to 90 DEG C of reactions 6h, HPLC and detect, raw material reaction is complete, after being down to room temperature, add 500ml water and 200ml ethyl acetate, stir 10min, separatory, aqueous phase is extracted with ethyl acetate (200ml*2 time), merges organic phase, with saturated common salt washing (200ml*2 time), anhydrous sodium sulfate drying, is concentrated into dry compound
4(32g), purity 96%.
Example seven: (compound
4synthesis)
In the there-necked flask of a 500ml, add compound
3(36g), DMF (300ml), 2-mercaptobenzothiazole (14.2g), cesium carbonate (50g), under stirring, heat up 60 DEG C of reaction 2h, HPLC detects, and raw material reaction is complete, after being down to room temperature, add 500ml water and 200ml ethyl acetate, stir 10min, separatory, aqueous phase is extracted with ethyl acetate (200ml*2 time), merges organic phase, with saturated common salt washing (200ml*2 time), anhydrous sodium sulfate drying, is concentrated into dry compound
4(34g), purity 98%.
Example eight: (compound
5synthesis)
In the there-necked flask of a 50ml, add compound
4(4.4g), methylene dichloride (10ml), Virahol (30ml), after stirring and dissolving, is heated to 50 DEG C, add Ammonium Molybdate Tetrahydrate (800mg), dropwise add 30% aqueous hydrogen peroxide solution again, after reaction is spent the night, HPLC detects, raw material reaction is complete, add 50ml water, and add the excessive oxygenant of anhydrous sodium acid sodium cancellation, remove volatile matter under reduced pressure, residue aqueous phase is with dichloromethane extraction (5ml*3 time), merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, be concentrated into dry crude product, then use the compound of recrystallisation from isopropanol
5(2.4g), purity: 99%.
Example nine: (compound
7synthesis)
In the there-necked flask of a 50ml, add compound
5(4.4g), compound
6(3.5g), THF (80ml), after stirring and dissolving, is cooled to-78 DEG C, drip LiHMDS (2.2ml), stirring reaction 12h, HPLC detect, and raw material reaction is complete, 20% aqueous ammonium chloride solution cancellation reaction is added at-78 DEG C, add water (200ml) and ethyl acetate (100ml), stir 10min, separatory, aqueous phase is extracted with ethyl acetate, merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, be concentrated into dry, compound 7 (3.2g) is obtained, yield 60%, purity 98% after recrystallization purifying.
Example ten: (compound
7synthesis)
In the there-necked flask of a 50ml, add compound
5(4.9g), compound
6(4.2g), after THF (90ml), HMPA (16ml) stirring and dissolving, be cooled to-78 DEG C, add sodium hydride (1.3g) in batches, stirring reaction 14h, HPLC detect, and raw material reaction is complete, 20% aqueous ammonium chloride solution cancellation reaction is added at-78 DEG C, add water (220ml) and ethyl acetate (100ml), stir 10min, separatory, aqueous phase is extracted with ethyl acetate, merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, be concentrated into dry, compound 7 (4.2g) is obtained, yield 64%, purity 95% after recrystallization purifying.
Example 11: (compound
7synthesis)
In the there-necked flask of a 50ml, add compound
5(4.9g), compound
6(4.2g), THF (90ml), after HMPA (16ml) stirring and dissolving, be cooled to-78 DEG C, dropwise add LDA (the THF solution of 2M, 15ml), stirring reaction 11h, HPLC detects, raw material reaction is complete, 20% aqueous ammonium chloride solution cancellation reaction is added at-78 DEG C, add water (280ml) and ethyl acetate (120ml), stir 10min, separatory, aqueous phase is extracted with ethyl acetate, merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, be concentrated into dry, compound 7 (3.6g) is obtained after recrystallization purifying, yield 55%, purity 97%.
More than show and describe ultimate principle of the present invention, principal character and advantage.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (10)
1. rochovastatin ethyl ester (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-pyrimidine-5-base vinyl]-2,2-dimethyl-1, the preparation technology of 3-dioxane-4-ethyl acetate, it is characterized in that, comprise the steps:
(1) with (4R-cis)-6-[(acetoxyl group) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is starting raw material, at ambient temperature, in the presence of base, react 3h in a solvent and obtain (4R-Cis)-6-methylol-2,2-dimethyl-1,3-dioxane-4-ethyl acetate;
(2) under 0-5 DEG C of condition, (4R-Cis)-6-methylol-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is under the existence of alkali and solvent, (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2 is generated with 4-Nitrobenzenesulfonyl chloride effect, 2-dimethyl-1,3-dioxane-4-ethyl acetate;
(3) (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate is under alkali and solvent exist, react with 2-mercaptobenzothiazole under the condition of 70-80 DEG C and generate (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate;
(4) (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2,2-dimethyl-1,3-dioxane-4-ethyl acetate generates (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2 with hydrogen peroxide oxidation make the condition of catalyzer at Ammonium Molybdate Tetrahydrate under, 2-dimethyl-1,3-dioxane-4-ethyl acetate;
(5) (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2; 2-dimethyl-1; 3-dioxane-4-ethyl acetate in the presence of a base with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-5-formyl radical-1-pyrimidine at-75 DEG C--react at 80 DEG C and generate (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(methyl-methylsulfonyl-amino)-pyrimidine-5-base vinyl]-2; 2-dimethyl-1,3-dioxane-4-ethyl acetate.
2. preparation technology according to claim 1, it is characterized in that, in step (5), (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2, 2-dimethyl-1, 3-dioxane-4-ethyl acetate is reacted with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-5-formyl radical-1-pyrimidine and is generated (4R-cis)-6-[4-(4-fluorophenyl)-6-sec.-propyl-2-(methyl-methylsulfonyl-amino)-pyrimidine-5-base vinyl]-2 under two-(trimethyl silicon based) Lithamide exists at-78 DEG C, 2-dimethyl-1, 3-dioxane-4-ethyl acetate.
3. preparation technology according to claim 1 and 2, is characterized in that, in step (2), the p-nitrophenyl alkylsulfonyl of 4-Nitrobenzenesulfonyl chloride replaces with p-toluenesulfonyl or benzenesulfonyl.
4. preparation technology according to claim 1, is characterized in that, in step (1)-(3), described alkali is salt of wormwood or triethylamine; Described solvent is methyl alcohol; In step (2), described alkali is triethylamine; Described solvent is toluene; In step (3), described alkali is salt of wormwood, and described solvent is DMF.
5. preparation technology according to claim 1, is characterized in that, in step (5), described alkali is two-(trimethyl silicon based) Lithamide, sodium hydride or LDA.
6. preparation technology according to claim 1, it is characterized in that, in step (1), (4R-cis)-6-[(acetoxyl group) methyl]-2, the mol ratio of 2-dimethyl-1,3-dioxane-4-ethyl acetate and alkali is 1:1-2:1.
7. preparation technology according to claim 1, it is characterized in that, in step (2), (4R-Cis)-6-methylol-2, the mol ratio of 2-dimethyl-1,3-dioxane-4-ethyl acetate, alkali and 4-Nitrobenzenesulfonyl chloride is 1:0.5:1-1:1:2.
8. preparation technology according to claim 1, it is characterized in that, in step (3), (4R-cis)-6-[(p-nitrophenyl sulfonyloxy) methyl]-2, the mol ratio of 2-dimethyl-1,3-dioxane-4-ethyl acetate and 2-mercaptobenzothiazole is 2:1-1:1.
9. preparation technology according to claim 1, it is characterized in that, in step (4), (4R-cis)-6-[(benzothiazolyl) thiomethyl]-2, the mol ratio of 2-dimethyl-1,3-dioxane-4-ethyl acetate and hydrogen peroxide is 2:1-1:1.
10. preparation technology according to claim 1; it is characterized in that; in step (5); (4R-cis)-6-[(benzothiazole alkylsulfonyl) methyl]-2; the mol ratio of 2-dimethyl-1,3-dioxane-4-ethyl acetate and 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamide base)-5-formyl radical-1-pyrimidine is 2:1-1:1.
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| WO2014203045A1 (en) * | 2013-06-20 | 2014-12-24 | Lupin Limited | A novel, green and cost effective process for synthesis of tert-butyl (3r,5s)-6-oxo-3,5-dihydroxy-3,5-o-isopropylidene-hexanoate |
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| CN112028881A (en) * | 2020-09-02 | 2020-12-04 | 能特科技有限公司 | Synthetic method of high-grade intermediate R-1 of rosuvastatin calcium |
| CN112028881B (en) * | 2020-09-02 | 2023-08-15 | 能特科技有限公司 | Synthesis method of rosuvastatin calcium higher intermediate R-1 |
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