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Preparation method of rosuvastatin calcium key intermediate

A technology of rosuvastatin calcium and asana, which is applied in the field of rosuvastatin calcium, can solve the problems of energy consumption, high equipment and production costs, unfavorable industrialized sound field, and high toxicity of compounds, so as to facilitate large-scale production and protect the environment , the effect of simple operation

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

AI Technical Summary

Problems solved by technology

[0006] The main defect of this technique is: 1, need to use DDQ (2,3-dichloro-5,6-dicyano 1,4 benzoquinone) in the technique, this compound toxicity is very large; 2, the 4 that uses in the technique -Methylmorpholine-N-oxide, TPAP (tetrapropylammonium perruthenate) and DIBAL-H are all very expensive; 3, DIBAL-H reduction needs to be reacted at low temperature (-70~-40°C), and consumes Energy, equipment and production costs will be very large, which is not conducive to industrial sound field; 4. Low reaction yield

Method used

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  • Preparation method of rosuvastatin calcium key intermediate
  • Preparation method of rosuvastatin calcium key intermediate
  • Preparation method of rosuvastatin calcium key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Synthesis of 1-(4-fluorophenyl)-4-methylpentane-1,3-dione (compound IV)

[0028]

[0029] 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

[0030] Example 2: Synthesis of 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidin-2-amine (compound III)

[0031]

[0032] 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

[0033] Example 3: Synthesis of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine (Compound II)

[0034]

[0035] 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 und...

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Abstract

The invention discloses a preparation method of a rosuvastatin calcium key intermediate, i.e. a compound as shown in a formula I. The preparation method comprises the following steps: a, carrying out a reaction between fluoroacetophenone and ethyl isobutyrate to prepare a compound as shown in a formula IV; b, carrying out a reaction between the obtained compound IV and methylguanidine hydrochloride as well as potassium hydroxide to obtain a compound as shown in a formula III; c, carrying out a reaction between the compound III and triethylamine as well as methanesulfonyl chloride to prepare a compound as shown in a formula II; d, carrying out a reaction between the compound as shown in the formula II and N,N-dimethylformamide as well as phosphorus oxychloride to obtain the compound as shown in the formula I. A reaction route of the preparation method is as shown in the following: (referring to the specification). 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 preparation method of a key intermediate of rosuvastatin calcium. Background technique [0002] Rosuvastatin calcium, chemical name: (3R, 5S, 6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) )-5-pyrimidine]-3,5-dihydroxy-6-heptenoate calcium, is a new generation of statins with a fully synthesized single enantiomer, which belongs to HMG-CoA reductase inhibitors, can reduce elevated Low-density cholesterol, total cholesterol, triglyceride and apoprotein B concentration, while increasing the concentration of high-density cholesterol, can be used for primary hypercholesterolemia and mixed lipodystrophy and homozygous familial hyperlipidemia Comprehensive treatment of cholesterolemia. Its structural formula is as follows: [0003] [0004] The compound shown in formula I involved in the present invention is an important intermediate for preparing rosuvastatin c...

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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