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Rabeprazole correlate D synthesis method

A technology of rabeprazole and a synthetic method, which is applied in the field of medicine, can solve problems such as many side reactions, low yield, and difficult control of oxidation reaction, and achieve the effect of increasing yield and increasing yield

Active Publication Date: 2014-07-30
HYBIO PHARMA WUHAN CO LTD
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The main problems in the above synthesis route are: (1) the oxidation reaction in the second step is difficult to control, there are many side reactions, and the yield is low; (2) the molecular weight of the rabeprazole related product D is the same as that of the by-product B, and The polarity is almost the same, and it cannot be separated by HPLC, so it is impossible to obtain high-purity rabeprazole related substance D

Method used

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  • Rabeprazole correlate D synthesis method

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Experimental program
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Effect test

Embodiment 1

[0034] 1.1 Synthesis of thioether compound——2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]thio]benzimidazole

[0035] At room temperature, add 250 mL of analytically pure acetonitrile, 15.0 g (0.1 mol) of 2-mercaptobenzimidazole, and 13.3 g (0.05 mol) of 2-chloromethyl-3-methyl-4- (3-methoxypropoxy)pyridine hydrochloride and 13mL of triethylamine were stirred at room temperature for 24h. The reaction solution was rotary evaporated to dryness, and 50 mL of dichloromethane and 50 mL of water were added in sequence, and after shaking well, the layers were separated and the organic dichloromethane layer was taken. After rotary evaporation to dryness, 16.6 g of thioether compound was obtained, with a yield of 96.8%. [M+H + ]=344. 1 H NMR(400MHz,DMSO)δ12.61(s,1H),8.23(d,J=5.6Hz,1H),7.46(d,J=51.5Hz,2H),7.12(dd,J=6.0,3.1Hz ,2H),6.95(d,J=5.7Hz,1H),4.69(s,2H),4.10(t,J=6.2Hz,2H),3.49(t,J=6.2Hz,2H),3.25(d ,J=0.5Hz,3H),2.21(s,3H),1.99(dd,J=12.4,6.2Hz,2H).

[0036] 1.2 Synthesis...

Embodiment 2

[0039] 2.1 Oxide C——2-[[[4-(3-methoxypropoxy)-3-methyl-1-oxopyridin-2-yl]methyl]sulfonyl]benzimidazole—— Synthesis

[0040] Under the condition of an acetone dry ice bath, add 50 mL of dichloromethane, 5.0 g (0.015 mol) of the thioether compound prepared in step 1 and 15.5 g (0.09 mol) of 3-chlorobenzoic acid into the three-necked flask. Stir at room temperature for 24h. Add excess saturated aqueous sodium bicarbonate solution, shake well, let stand to separate the layers, take the dichloromethane layer, and spin dry. After purification by HPLC chromatography, 3.9 g of oxide C was obtained with a yield of 66%. [M+H + ]=392.

[0041] 2.2 Oxide C——2-[[[4-(3-methoxypropoxy)-3-methyl-1-oxopyridin-2-yl]methyl]sulfonyl]benzimidazole—— Synthesis

[0042] Oxide C was prepared as above, except that the solvent used was 50 mL of 1,4-dioxane. 3.8 g of oxide C were obtained with a yield of 64%.

Embodiment 3

[0044] 3.1 Rabeprazole related product D——2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfonyl]benzimidazole—— synthesis

[0045] Add 3.92g (0.01mol) of oxide C prepared in Example 2, 6.5g of reduced zinc powder, 6g of glacial acetic acid and 50mL of water into the three-necked flask, and stir at 95°C for 24h to obtain rabeprazole Related material D crude. After purification by HPLC chromatography, 3.56 g of rabeprazole related product D (purity: 99.5%) can be obtained with a yield of 94.9%. [M+H + ]=376. 1H NMR(400MHz,DMSO)δ13.74(s,1H),8.03(d,J=5.5Hz,1H),7.69(s,2H),7.39(dd,J=6.1,3.1Hz,2H),6.94 (d,J=5.6Hz,1H),5.06(s,2H),4.09(t,J=6.1Hz,2H),3.48(t,J=6.2Hz,2H),3.25(s,3H),2.18 (s, 2H), 2.02-1.93 (m, 2H).

[0046] 3.2 Rabeprazole related substance D——2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfonyl]benzimidazole—— synthesis

[0047] Rabeprazole related product D was prepared as above, except that the reducing agent used was 6 g of reduced iron powder. 3...

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Abstract

The present invention relates to a rabeprazole correlate D synthesis method, which comprises that: (1) in the presence of an excess oxidizing agent, a thioether compound 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]thio]benzimidazole is oxidized to produce an oxide C; and (2) in the presence of an acid and a reducing agent, the oxide C formed in the step (1) is reduced so as to form the rabeprazole correlate D.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a new method for synthesizing a related substance D of rabeprazole. Background technique [0002] Rabeprazole related D (CAS No.117976-47-3; 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfonyl ] Benzimidazole) is an impurity in the drug rabeprazole sodium for the treatment of peptic ulcer. It is usually used as a known impurity in the mass analysis of rabeprazole sodium, to clarify the position of the impurity in the sample, to investigate the separation between the impurity and the sample, and to make the analysis method more accurate. The synthetic method of the rabeprazole related substance D recorded in the Pharmacopoeia is as follows, the first step: 2-mercaptobenzimidazole and 3-chloromethyl-3-methyl-4-(3-methylpropoxy) Pyridine undergoes SN1 reaction to generate a thioether compound, the second step: the thioether compound generates rabeprazole related substance D and by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 刘斌李国弢袁慧星向闯南马亚平袁建成
Owner HYBIO PHARMA WUHAN CO LTD
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