Preparation method of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl)triphenyl phosphonium salt

A technology of methylmethanesulfonamide and p-fluorophenyl, which is applied in the field of preparation of -5-pyridyl)methyl)triphenylphosphonium salt, can solve the problem of unsuitable large-scale production, high price of monomethylguanidine, etc. question

Active Publication Date: 2014-02-12
江西博雅欣和制药有限公司
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Problems solved by technology

[0009] This method prepares phosphonium salt relatively simple, but the raw material 4-p-fluorophenyl-5-methyl-6-isopropyl group-2-( N -Methylmethylsulfonamido)pyrimidine needs to be prepared using monomethylguanidine, which is expensive, has no industrial product supply, and is not suitable for large-scale production

Method used

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  • Preparation method of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl)triphenyl phosphonium salt
  • Preparation method of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl)triphenyl phosphonium salt
  • Preparation method of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl)triphenyl phosphonium salt

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Embodiment 1

[0037] Embodiment 1, 4-p-fluorophenyl-5-hydroxymethyl-6-isopropyl-2-( N Synthesis of -methylmethylsulfonamido)pyrimidine (III)

[0038] Under nitrogen protection, sodium borohydride (0.38 g), dry tetrahydrofuran (40 mL) and glass beads (10 mL) were placed in a dry reaction flask, and trimethylchlorosilane (2.1 g) was added dropwise with stirring at room temperature After the addition, the temperature was raised to 60°C and stirred for 3h, then 4-p-fluorophenyl 6-isopropyl-2-( N -Methylmethanesulfonamido) pyrimidine-5-carboxylic acid (1.83 g) suspension in tetrahydrofuran (5 mL), after the addition was complete, keep stirring for 24 hours. After the reaction is complete, cool the reaction liquid to 0~5°C, slowly add saturated ammonium chloride solution dropwise, after the addition is complete, stir for 15 min, extract with dichloromethane, wash with 10% sodium carbonate solution, dry over anhydrous sodium sulfate, and reduce pressure The solvent was recovered to dryness, and ...

Embodiment 2

[0039] Embodiment 2, 4-p-fluorophenyl-5-hydroxymethyl-6-isopropyl-2-( N Synthesis of -methylmethylsulfonamido)pyrimidine (III)

[0040] Under nitrogen protection, potassium borohydride (0.54 g), dry tetrahydrofuran (40 mL) and steel beads (10 mL) were placed in a dry reaction flask, and trimethylchlorosilane (1.1 g) was added dropwise with stirring at room temperature, After the addition is complete, heat to 65°C and stir at reflux for 3h, then add 4-p-fluorophenyl 6-isopropyl-2-( N -Methylmethanesulfonamido)pyrimidine-5-carboxylic acid (1.83 g) in tetrahydrofuran (5 mL) suspension, after addition, keep stirring for 30 h. After the reaction is complete, cool the reaction liquid to 0~5°C, slowly add saturated ammonium chloride solution dropwise, after the addition is complete, stir for 15 min, extract with dichloromethane, wash with 10% sodium carbonate solution, dry over anhydrous sodium sulfate, and reduce pressure The solvent was recovered to dryness, and a solid was preci...

Embodiment 3

[0041] Embodiment 3, ((4-p-fluorophenyl-6-isopropyl-2-( N -Synthetic (X=BF) of triphenylphosphonium fluoroborate (I) of -methylmethylsulfonyl amido)-5-pyridyl)methyl) 4 )

[0042] Dissolve III (0.88 g) and triphenylphosphonium fluoroborate (0.88 g) in acetonitrile (20 mL), heat to 81°C and stir under reflux for 24 hours. After the reaction is complete, concentrate to dryness under reduced pressure to obtain a white foamy solid I(X=BF 4 , 1.67 g, 97%), 1 H NMR (400MHz, CDCl 3 ): δ 7.74( t, J =7.8 Hz, 3H), 7.54 ( td, J =8, 3.2 Hz, 6H), 7.26( t, J =6.8 Hz, 2H), 7.17(dd, J =12.8, 7.8 Hz, 6H), 6.98( t, J =8.4 Hz, 2H), 5.17 ( d, J =12.4 Hz, 2H), 3.48 ( s, 3H), 3.43 ( s, 3H), 2.73( sept. , J =6.4 Hz, 1H), 0.88(br, 6H).

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Abstract

The invention belongs to the technical field of organic chemistry and particularly relates to a preparation method of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl) triphenyl phosphonium salt. According to the invention, 4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide) pyrimidine-5-carboxylic acid is reduced in an organic solvent under the existence of hydroboron, alkyl substituted chlorosilane and an auxiliary so as to obtain 4-p-fluorophenyl-5-hydroxymethyl-6-isopropyl-2-(N-methylmethanesulfonamide) pyrimidine (II); the compound II reacts with triphenyl phosphonium salt in the organic solvent to obtain the ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethanesulfonamide)-5-pyridyl) methyl) triphenyl phosphonium salt. The method disclosed by the invention has mild reaction conditions, is simple and convenient to operate and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, in particular to a ((4-p-fluorophenyl-6-isopropyl-2-( N -The preparation method of methylmethylsulfonamido)-5-pyridyl)methyl)triphenylphosphonium salt. Background technique [0002] ((4-p-fluorophenyl-6-isopropyl-2-( N -Methylsulfonylamido)-5-pyridyl)methyl)triphenylphosphonium salt (I) is an important intermediate for the synthesis of hypolipidemic drug rosuvastatin (Rosuvastatin), and its structural formula is as (I ) as shown in: [0003] . [0004] Chinese patent CN101376647 has reported a brominated ((4-p-fluorophenyl-6-isopropyl-2-( N -Methylmethanesulfonamido)-5-pyridyl)methyl)triphenylphosphonium salt preparation method, this method is 4-p-fluorophenyl 6-isopropyl-2-( N -Methylmethanesulfonamido)pyrimidine-5-carboxylate alkyl ester is reduced by diisobutylaluminum hydride, brominated with phosphorus tribromide, and then salted with triphenylphosphorus, and its synthetic r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6512
Inventor 陈芬儿熊方均黄夏韫李杰陈文学何秋琴
Owner 江西博雅欣和制药有限公司
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