Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amido) pyrimidine-5-formaldehyde

A technology of methanesulfonylamino and methanesulfonylamino, which is applied in the field of pharmaceutical compound preparation, can solve the problems of long synthesis route, high energy consumption, unfavorable industrial production and the like

Active Publication Date: 2008-12-17
滁州市庆云医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (1) The synthetic route is long and requires 8 steps of reaction;
[0010] (2) The reaction raw material DDQ (2,3-dichloro-5,6-dicyano-1,4 benzoquinone) is highly toxic, and the raw material 4-methylmorphine-N-oxide and TPAP (tetraruthenate perruthenate Propyl ammonium) and diisobutyl aluminum hydride are expensive;
[0011] (3) The reduction reaction requires a low temperature of -74°C, high energy consumption and large equipment investment, which is not conducive to industrial production;
[0012] (4) The total reaction yield is low

Method used

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  • Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amido) pyrimidine-5-formaldehyde
  • Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amido) pyrimidine-5-formaldehyde
  • Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amido) pyrimidine-5-formaldehyde

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] [Example 1] The preparation method of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone (formula 2)

[0108] Add 52.2g (0.47mol) isobutyrylacetonitrile, 58.3g (0.47mol) 4-fluorobenzaldehyde, 49.4g (0.82mol) urea, 0.53g (5.3 mmol) ketone chloride (I), 5.3 ml sulfuric acid and 600 ml methanol. The material in the flask was refluxed for 22 hours under stirring and heating, cooled to room temperature, a solid was produced, filtered, washed the filter cake with methanol, combined the filtrate and washings, and concentrated under reduced pressure to obtain 101.1g of 4-(4-fluorobenzene yl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone A solid product having the following properties. The yield was 83% (based on the amount of isobutyrylacetonitrile).

[0109] m.p.: 174°C-178°C

[0110] UVλmax (CH3CN, nm): 270

[0111] 1 H-NMR (CDCl3, δ(ppm)): 1.17-1.25 (6H, d, J=6.8Hz), 3.0-3.2 (1H, m), 5.15 (1H, m), 5.6 (1H, m), 7.0 -7.3(2H, m), 7.2-7.4(2H, m), 8.0(...

Embodiment 2

[0112] [Example 2] The preparation method of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone

[0113] Repeat the method of Example 1 just to replace 530mg (5.3mmol) ketone chloride (I) with 14.33g (53mmol) iron chloride (III). Hexahydrate, obtain 79.2g4-(4-fluorophenyl)-6- Isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone is a colorless crystalline product having the following properties. The yield was 65% (based on the amount of isobutyrylacetonitrile).

Embodiment 3

[0114] [Example 3] The preparation method of 4-(4-fluorophenyl)-2-hydroxyl-6-isopropyl-5-cyanopyrimidine (formula 3)

[0115] 120 ml (1.57 mol) of nitric acid (60-61%, sp.gr.: 1.38) were added to a 250 ml glass flask equipped with a stirrer and a thermometer. Slowly add 33 g (0.127 mol) of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2 prepared by the same method as in Example 1 to nitric acid below 10°C (1H)-Dihydropyrimidinone, the mixture was reacted at room temperature for 50 minutes. After the reaction was completed, the reaction mixture was neutralized by adding the mixture to 1500 ml of saturated aqueous sodium bicarbonate solution to produce a white solid, which was filtered, washed with water, and dried. 29.26 g of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine as a white solid product having the following properties were obtained. The yield was 89% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone).

[0116] m.p...

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Abstract

The invention provides a method for preparing a Rosuvastatin intermediate, 4-Fluorophenyl-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidinyl-5-formyl. The method uses isobutyryl acetonitrile, 4-Fluorobenzaldehyde and carbamide as raw materials and is obtained by steps of cyclization, oxidation, substitution and reduction etc. The method of the invention dose not need expensive raw materials and has the advantages of low technological cost, simple reaction, high product yield and being applicable to industrialized production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to an intermediate 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl) of the blood lipid-lowering drug rosuvastatin calcium The preparation method of amino) pyrimidine-5-carbaldehyde. Background technique [0002] Rosuvastatin calcium (rosuvastatin calcium) is a clinically used blood lipid-lowering drug, the chemical name is (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2 -(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-calcium heptenoate (2:1), the chemical structural formula is as follows: [0003] [0004] US Patent No. 5,260,440 discloses rosuvastatin and its synthesis method. The method comprises the following steps: (1), (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphinomethylenehexanoic acid methyl ester and 4-( 4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-carbaldehyde (referred to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D239/22C07D239/34
CPCC07D239/38C07D239/42C07D239/557
Inventor 黄庆云
Owner 滁州市庆云医药有限公司
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