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Preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein

A methanesulfonamide and fluorophenyl technology, which is applied in the field of organic chemical synthesis, can solve the problems of cumbersome post-processing, many by-products, and high cost, and achieve the effects of simple post-processing, reduced by-product formation, and low cost

Active Publication Date: 2015-07-01
弈柯莱生物科技(集团)股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] However, there are more or less problems in these processes such as high cost, many by-products, cumbersome post-treatment, low yield, etc., which are not conducive to the technology transformation of large-scale industrial production

Method used

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  • Preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein
  • Preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein
  • Preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] Dissolve dimethyl sulfide (8.8mL) and bromoacetonitrile (8.4mL) in 100mL of anhydrous tetrahydrofuran, stir at room temperature overnight, add sodium ethoxide (8.2g) after the reaction, filter, and distill the filtrate under reduced pressure to obtain dimethyl Cyanomethylenesulfur ylide reagent.

[0035] Disperse the above-mentioned dimethylcyanomethylenesulfide ylide reagent in tetrahydrofuran (170mL), add anhydrous potassium carbonate (18.2g), stir and mix at room temperature for 1h, then add compound of formula IV (35.1g), heat to reflux reaction 3h, TLC showed that the reaction was complete, the solid salt was removed by filtration, the filtrate was concentrated to remove the solvent, and the intermediate epoxide represented by formula III was obtained.

[0036] Dissolve the epoxide represented by formula III in toluene (200 mL), add 1.57 g of nano-gold catalyst and 2 mL of water, feed carbon monoxide to 6000-7000 tor in the autoclave, and heat to 100 ° ...

Embodiment 2

[0045]

[0046]Dissolve dimethyl sulfide (8.8 mL) and methyl bromoacetate (11.2 mL) in 100 mL of anhydrous tetrahydrofuran, stir at room temperature overnight, add sodium hydride (2.8 g) after the reaction, filter, and distill the filtrate under reduced pressure to obtain Dimethylmethoxycarbonylmethylenesulfur ylide reagent.

[0047] Disperse the above-mentioned dimethylmethoxycarbonylmethylenethio ylide reagent in tetrahydrofuran (150mL), add anhydrous sodium ethylate (8.2g), stir and mix at room temperature for 1h, then add the compound of formula IV (35.1g), and heat to The reaction was refluxed for 4 hours, TLC showed that the reaction was complete, the solid salt was removed by filtration, and the filtrate was concentrated to remove the solvent to obtain the intermediate epoxide represented by formula III.

[0048] Dissolve the epoxide represented by formula III in toluene (180 mL), add 1.26 g of nano-gold catalyst and 2 mL of water, feed carbon monoxide to 6000-7000 t...

Embodiment 3

[0057]

[0058] Dissolve phenylene sulfide (20.1 mL) and bromoacetaldehyde diethyl acetal (18.0 mL) in 100 mL of anhydrous tetrahydrofuran, stir at room temperature overnight, add sodium ethoxide (8.2 g) after the reaction, filter, and distill the filtrate under reduced pressure Diphenyldiethanol formal methylene sulfide ylide reagent was obtained.

[0059] Disperse the above-mentioned diphenyldiethanol formal methylene sulfide ylide reagent in tetrahydrofuran (150 mL), add anhydrous sodium ethylate (8.2 g), stir and mix at room temperature for 1 h, add formula IV compound (35.1 g), and heat to reflux After 4 hours of reaction, TLC showed that the reaction was complete, and the solid salt was removed by filtration, and the filtrate was concentrated to remove the solvent to obtain the intermediate epoxide represented by formula III.

[0060] Dissolve the epoxide represented by formula III in toluene (150 mL), add 0.99 g of nano-gold catalyst and 2.2 mL of water, feed carbon ...

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Abstract

The invention discloses a preparation method of (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl] acrolein which can be used as a rosuvastatin intermediate. The preparation method comprises the following steps: reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidine-5-yl-formaldehyde with a sulfur ylide reagent under an alkaline condition to generate an epoxide shown in the formula III; then, reducing in the presence of a metal catalyst to generate a compound shown in the formula II; and finally reacting the compound shown in the formula II to generate the target product. The preparation method is simple in process and low in cost; no expensive catalyst is used; the generation of byproducts is reduced effectively so that the post-treatment becomes simple and easy to operate; in addition, the reaction yield is improved greatly; and therefore, the preparation method is quite suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, in particular to (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl) which can be used as an intermediate of rosuvastatin calcium A preparation method of -N-methylsulfonamido) pyrimidin-5-yl] acrolein. Background technique [0002] (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)pyrimidin-5-yl]acrolein is a synthetic clinical An important intermediate of blood lipid drug rosuvastatin calcium. For this intermediate, various synthetic methods have been disclosed in the prior art. For example: [0003] Chinese patent CN100351240A discloses a preparation method utilizing a witting reaction, and the reaction formula is as follows: [0004] [0005] Chinese patent CN200710024034 discloses the following preparation process: [0006] [0007] The following synthetic route is disclosed in the international patent application WO2006100689A1: [0008] [0009] In...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 罗煜丁时澄瞿旭东孙传民
Owner 弈柯莱生物科技(集团)股份有限公司
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