A kind of 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: 2018-01-16
重庆瑞泊莱医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of synthetic method of rosuvastatin calcium key intermediate
  • A kind of synthetic method of rosuvastatin calcium key intermediate
  • A kind of 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-methylpentan-1,3-dione (Compound IV)

[0035]

[0036] Add 150g of isopropanol to a 0.5L three-necked flask, then add 6.9g of sodium in batches, stir vigorously and after the sodium is completely dissolved, add 13.81g (0.1mol) of p-fluoroacetophenone and 11.62g of ethyl isobutyrate dropwise (0.1 mol) in 80 g of isopropanol. The reaction solution was refluxed at 82°C for 6 hours, then cooled to room temperature and stirred overnight. A large amount of product was precipitated, filtered to obtain off-white finished product, dried in a blast oven at 40° C. to constant weight, 18 g was obtained, and the yield was 86%. Nuclear magnetic data (1HNMR, 500MHz, internal standard TMS, solvent CDCl3) are 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] 10.4g (0.05mol) of compound IV, 6g (0.055mol) of methylguanidine hydrochloride, 8.4g (0.15mol) of potassium hydroxide and 100ml of isopropanol were added to a 250ml three-necked flask, and the reaction was carried out under reflux overnight. After the reaction was completed, the isopropanol was distilled off under reduced pressure, naturally cooled to 10° C., filtered, and the filter cake was rinsed with a small amount of isopropanol, and the obtained filter cake was dried in a vacuum oven at 50° C. to constant weight. 11.4 g of off-white solids were obtained with a yield of 93%. Nuclear magnetic 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-methanesulfonyl)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. , 12.1 g (0.12 mol) of triethylamine was added, and the reaction was stirred 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 to be stirred at 0 to 25° C. for 12 h. After the reaction was completed, 20 ml of dichloromethane and 30 ml of purification were added, the pH was adjusted to 2-3 with concentrated hydrochloric acid, and the organic layer was obtained by layering. The obtained organic layer was washed once with 50 ml of saturated brine, dried with 10 g of anhydrous sodium sulfate, and filtered. The dichloromethane was removed by pr...

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PUM

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Abstract

The invention discloses a synthesis method of rosuvastatin calcium intermediate formula I; the details are as follows: under the condition of using p-fluoroacetophenone and ethyl isobutyrate under the condition of sodium as base and isopropanol as solvent, after condensation The reaction produces 1-(4-fluorophenyl)-4-methylpentane-1,3-diketone; then with methylguanidine hydrochloride using isopropanol as a solvent, ring-closing reaction occurs to obtain 4-(4 ‑Fluorophenyl)‑6‑isopropyl‑N‑methylpyrimidine‑2‑amine; then with methanesulfonyl chloride using dichloromethane as a solvent, a substitution reaction occurs to obtain 4‑(4‑fluorophenyl)‑6‑ Isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine; finally Vilsmeier reaction with DMF and phosphorus oxychloride to obtain the target compound. The method of the invention has the advantages of simple operation, cheap and readily available raw materials, mild reaction conditions, low equipment requirements, low production cost, easy large-scale production, etc., and has significant 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 fully synthetic single-enantiomer, next-generation statin drug that reduces elevated LDL cholesterol, total cholesterol, triglycerides, and apoprotein B concentrations while increasing high density The concentration of cholesterol can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia. It belongs to HMG-CoA reductase inhibitor. [0003] 5-(Formyl)-4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methanesulfonyl)amino]pyrimidine is a synthetic rosuvastatin calcium Important intermediate, its structural formula is as follows (formula I): [0004] [0005] European patent EP521471 discloses a kind of synthetic method of rosuvastatin calcium, wherein just relates to the preparation me...

Claims

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Application Information

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Patent Type & Authority Patents(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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