Synthetic method of rosuvastatin calcium key intermediate

A technology for the synthesis of rosuvastatin calcium and its synthesis method, which is applied in the field of synthesis of key intermediates of rosuvastatin calcium, can solve the problems that do not conform to the development concept of green chemistry, are not conducive to the health of operators, and are not conducive to large-scale production. Achieve the effects of easy large-scale production, environmental protection, and mild reaction conditions

Active Publication Date: 2016-06-01
重庆瑞泊莱医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The process uses DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), which is extremely toxic, which is not conducive to the health of operators and does not conform to the development concept of green chemistry; Low rate, not conducive to large-scale production

Method used

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  • Synthetic method of rosuvastatin calcium key intermediate
  • Synthetic method of rosuvastatin calcium key intermediate
  • Synthetic method of rosuvastatin calcium key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Synthesis of 1-(4-fluorophenyl)-4-methylpentane-1,3-dione (compound IV)

[0035]

[0036] Add 150g of isopropanol to a 0.5L three-neck flask, then add 6.9g of sodium in batches, stir vigorously after the sodium is completely dissolved, add 13.81g (0.1mol) of p-fluoroacetophenone and 11.62g of ethyl isobutyrate dropwise (0.1mol) in 80g of isopropanol. The reaction solution was refluxed at 82° C. for 6 h, then cooled to room temperature, and stirred overnight. A large amount of product was precipitated, filtered to obtain an off-white product, and dried in a blast oven at 40°C to constant weight to obtain 18g, with a yield of 86%. NMR data (1HNMR, 500MHz, internal standard TMS, solvent CDCl3) is as follows: 1.30 (d, J=7.0Hz, 6H, CH 3 ), 2.61(m, 1H, CH), 4.15(s, 1H, CH 2 ), 7.18-7.12 (m, 2H, Ar-H), 7.93-7.87 (m, 2H, Ar-H).

Embodiment 2

[0037] Example 2: Synthesis of 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidin-2-amine (compound III)

[0038]

[0039] Add 10.4g (0.05mol) of compound IV, 6g (0.055mol) of methylguanidine hydrochloride, 8.4g (0.15mol) of potassium hydroxide, and 100ml of isopropanol into a 250ml three-necked flask, and heat up to reflux overnight. After the reaction was completed, the isopropanol was distilled off under reduced pressure, naturally cooled to 10°C, filtered, and a small amount of isopropanol was used to rinse the filter cake, and the resulting filter cake was dried in a vacuum oven at 50°C to constant weight. 11.4 g of off-white solid was obtained with a yield of 93%. NMR data (1HNMR, 500MHz, internal standard TMS, solvent DMSO) are as follows: 1.25(d, J=6.8Hz, 6H, CH 3 ), 2.98 (d, 3H, CH 3 ), 3.18(m, 1H, CH), 4.98(s, 1H, NH), 6.71(s, 1H, Ar-H), 7.16~7.10(m, 2H, Ar-H), 7.52~7.47(m, 2H, Ar-H).

Embodiment 3

[0040] Example 3: Synthesis of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine (Compound II)

[0041]

[0042]Under nitrogen protection, 9.8 g (0.04 mol) of compound III and 100 ml of dichloromethane were added to a 250 ml three-necked flask, and cooled to 5°C. , Add 12.1g (0.12mol) triethylamine, stir and react for half an hour. A solution of 5.5 g (0.048 mol) of methanesulfonyl chloride dissolved in 5 ml of dichloromethane was slowly added dropwise to the reaction solution, and the reaction was continued with stirring at 0-25° C. for 12 h. After the reaction was completed, 20ml of dichloromethane was added, 30ml of purification was added, concentrated hydrochloric acid was added to adjust the pH to 2-3, and the organic layer was obtained by separating the layers. The obtained organic layer was washed once with 50 ml of saturated brine, dried with 10 g of anhydrous sodium sulfate, and filtered. Dichloromethane was removed by desolvation unde...

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Abstract

The invention discloses a synthetic method of a rosuvastatin calcium key intermediate. The synthetic method particularly comprises the following steps: carrying out a condensation reaction between fluoroacetophenone and ethyl isobutyrate under the condition of using sodium as alkali by using isopropyl alcohol as a solvent to prepare 1-(4-fluorophenyl)-4-methyl amyl-1,3-diketone; then carrying out a ring closing reaction between the 1-(4-fluorophenyl)-4-methyl amyl-1,3-diketone and methylguanidine hydrochloride by using isopropanol as a solvent to obtain 4-(4-fluorophenyl)-6-isopropyl-N-methyl pyrimidine-2-amine; carrying out a substitution reaction between the 4-(4-fluorophenyl)-6-isopropyl-N-methyl pyrimidine-2-amine and methanesulfonyl chloride by using dichloromethane as a solvent to obtain 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl) amino] pyrimidine; finally, carrying out a Vilsmeier reaction between the 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl) amidogen] pyrimidine and DMF (Dimethyl Formamide) as well as phosphoryl chloride to obtain a target compound. The method disclosed by the invention has the advantages of being simple to operate, low in raw material price, high in availability of used raw materials, mild in reaction conditions, low in equipment requirements and production cost, easy for scale production and the like, and has significance industrial application value.

Description

technical field [0001] The invention relates to rosuvastatin calcium, in particular to a method for synthesizing a key intermediate of rosuvastatin calcium. Background technique [0002] Rosuvastatin Calcium, a new generation of statins with a fully synthesized single enantiomer, can reduce elevated low-density cholesterol, total cholesterol, triglyceride and apoprotein B concentrations, while increasing high-density cholesterol The concentration of cholesterol can be used for comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and belongs to HMG-CoA reductase inhibitors. [0003] 5-(formyl)-4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine is a synthetic rosuvastatin calcium Important intermediate, its structural formula is as follows (formula I): [0004] [0005] European patent EP521471 discloses a synthetic method of rosuvastatin calcium, which involves the preparatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
Inventor 钟齐昌陈琳高河勇冉勇
Owner 重庆瑞泊莱医药科技有限公司
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