Preparation method and intermediate of rosuvastatin and its pharmaceutical salts

The technology of a medicinal salt and a new method is applied in the field of preparation and intermediates of rosuvastatin and medicinal salts thereof, and can solve the problems of long steps, high cost, low total yield and the like

Inactive Publication Date: 2006-04-26
四川抗菌素工业研究所有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method has long steps, l

Method used

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  • Preparation method and intermediate of rosuvastatin and its pharmaceutical salts
  • Preparation method and intermediate of rosuvastatin and its pharmaceutical salts
  • Preparation method and intermediate of rosuvastatin and its pharmaceutical salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Preparation of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidine]carbaldehyde (II).

[0028] Add 6g [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) to the suspension of 5.4gPCC in dichloromethane (25ml) -5-pyrimidine]methanol (I) in dichloromethane (37ml), stirred at room temperature for 2h, poured into a mixture of EA (200ml) and water (200ml), shaken and separated into layers, and the organic phase was washed twice with water. Wash with saturated sodium chloride solution once and concentrate under reduced pressure to obtain 5.5 g of gray crystals [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)- 5-pyrimidine) formaldehyde (II). 1 H-NMR(CDCl 3 , 400MHz): 9.97(S.1H), 7.64(m.2H), 7.26(m.2H), 4.02(m.1H), 3.64(s.3H), 3.56(s.3H), 1.33(d. 3H), 1.31 (d.3H).

Embodiment 2

[0029] Example 2 [4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-(1-propenylnitrile)]pyrimidine (III) Preparation

[0030] Add 25ml of toluene to 6g [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidine]formaldehyde (II) (17mol) After stirring at room temperature to dissolve, 5.8ml (18.6mol) of cyanomethyl diethyl phosphate and 0.2ml of Aliquat 336 (0.40mmol, 3% in (II)) were added. While stirring, 10ml of 5N sodium hydroxide solution was added dropwise for 2h. Stir for another 2h after dripping. Add water to terminate the reaction, separate the layers, wash the organic layer with water until it is neutral, and concentrate under reduced pressure to obtain 5.6 g of light yellow crystals [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N) -Methanesulfonylamino)-5-(1-propenylnitrile)]pyrimidine (III) (molar yield: 88%). 1 H-NMR(CDCl 3 , 400MHz): 7.58(m.2H), 7.52(d.1H), 7.19(m.2H), 5.30(d.1H), 3.60(s.3H), 3.53(s.3H), 3.30(m. 1H), 1.33(d.3H), ...

Embodiment 3

[0031] Example 3 [4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-(1-acrylaldehyde)]pyrimidine (IV) preparation

[0032] 4.5g [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-(1-propenylnitrile)]pyrimidine(III)( 12mol), dissolved in 50ml of toluene, cooled to about -50°C, dripped 24ml (24mmol, 2 times) of diisobutylaluminum hydrogen toluene solution (1M), dripped for more than 2h, and kept for 2h after dripping. Then add 0.8ml methanol and stir for 40min, then add 3.5ml 1N hydrochloric acid solution and stir for 1.5h. Separate the layers, wash with water, NaHCO3, and concentrate to obtain 4.0g of white crystals [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5 -(1-Acrolein)]pyrimidine (IV) (molar yield 88.2%).1 H-NMR(CDCl 3 , 400MHz): 9.62(d.1H), 7.71(m.2H), 7.58(m.2H), 7.59(dd.1H), 6.20(dd.1H), 3.60(s.3H), 3.52(s. 3H), 3.39(m.1H), 1.33(d.3H), 1.31(d.3H).

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Abstract

The present invention discloses new preparation process of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfothio) amino] pyrimidyl-5-radical] -(3R.5S)-3,5-dihydroxy heptyl-6-olefine acid (Rosuvastatin) and its medicinal salt, and new intermediate. The preparation process has short period, less reaction steps, high yield and low cost.

Description

Technical field [0001] The present invention relates to the preparation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R .5S)-3.5-Dihydroxyhept-6-enoic acid (Rosuvastatin) and its medicinal salt new method and new intermediate. Background technique [0002] US patent US5 260 440 provides a method for preparing (II), but this method uses expensive 4-methylmorpholine-N-oxide and tetrapropylammonium percalcic acid as oxidants, but the method has a reaction time Long, many impurities, low yield. [0003] The Chinese patent CN1340054A provides a method for connecting DPPO and BFA, and after further reaction, rosuvastatin is obtained. This method uses expensive BFA, and expensive ethyl diphenylphosphinate is used in the synthesis of DPPO. The method has long steps, low total yield and high cost. Summary of the invention [0004] The purpose of the present invention is to find a method with short reaction time, few reaction steps, high yield a...

Claims

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Application Information

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IPC IPC(8): C07D239/26
Inventor 丁洪沈瑾志杜伟宏
Owner 四川抗菌素工业研究所有限公司
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