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Synthesis method of telmisartan intermediate

A synthetic method, telmisartan technology, applied in the field of synthesis of telmisartan intermediates, can solve the problems of high reaction temperature, high equipment requirements, long reaction time, etc.

Pending Publication Date: 2021-06-25
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction temperature is high, the reaction time is long, and the equipment requirements are high, which is not conducive to industrial production

Method used

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  • Synthesis method of telmisartan intermediate
  • Synthesis method of telmisartan intermediate
  • Synthesis method of telmisartan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of Compound (14)

[0038] Take a 500mL three-necked flask, add 53.92g (0.27mol) of compound (13) and 150mL of methanol in sequence, stir to dissolve, add 50g (0.23mol) of compound (12), reflux for 5h, add saturated sodium bisulfite solution, and then reflux for 1h, TLC detects that the raw material point disappears, and the heating is stopped. Suction filtration, washing with 30 mL of methanol, the filtrate was dried under reduced pressure, and the concentrate was recrystallized with 50% aqueous ethanol to obtain 67.37 g of off-white solid as compound (14), melting point 175.4-176.1°C, yield 92%.

[0039] 1 H NMR (400MHz, DMSO-d 6 )δ9.00(brs,1H),7.73(d,J=1.2Hz,1H),7.67–7.64(m,2H),7.61(d,J=7.8Hz,1H),7.42(d,J=8.2 Hz,1H),7.27(m,2H),3.89(s,3H),2.28(s,3H),1.27(s,9H).

[0040] 13 C NMR (150MHz, CDCl 3 )δ176.75, 153.58, 143.00, 137.53, 136.72, 131.76, 128.61, 127.73, 126.21, 122.78, 122.50, 122.07, 119.77, 109.69, 40.07, 31.84, 27.81, 17.69.

[0041] MS-ESI:...

Embodiment 2

[0043] Preparation of compound (1)

[0044] Take the microwave reaction flask, add 48.2g (0.15mol) compound (14), 24.3g (0.60mol) sodium hydroxide, 140mL 95% ethanol in sequence, reflux reaction for 5h, point the plate to monitor the reaction of raw materials, stop the reaction, and spin down under reduced pressure Dry to get the crude product. Recrystallized with 35% ethanol aqueous solution to obtain 33.8 g off-white solid powder as compound (1), with a measured melting point of 147.4-149.9°C and a yield of 95%.

[0045] 1 H NMR (400MHz, DMSO-d 6)δ7.59–7.57(m,1H),7.53–7.51(m,1H),7.46(s,1H),7.41(dd,J=8.4,1.6Hz,1H),7.24-7.15(m,2H) ,6.73(d,J=8.4Hz,1H),5.36(brs,2H),3.84(s,3H),2.14(s,3H).

[0046] MS-ESI: m / z 238.1[M+H] + .

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Abstract

The invention relates to a synthesis method of a telmisartan intermediate, wherein the telmisartan intermediate is 2-methyl-4-(1-methyl-1H-benzimidazol-2-yl)amine (1), and the synthesis method comprises the steps: taking N-(4-formyl-2-methylphenyl)trimethyl acetamide and N-methyl-1,2-phenylenediamine as raw materials to react to generate a compound (14); and taking a compound 14 as a reactant, and reacting to generate the telmisartan intermediate 2-methyl-4-(1-methyl-1H-benzimidazol-2-yl)amine (1). The chemical structural formula of the compound (14) is shown in the specification; the synthesis method of the telmisartan intermediate provided by the invention has the advantages of easily available raw materials, high safety, few side reactions, high product purity, relatively high total yield and easy operation and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a synthetic method of a telmisartan intermediate. Background technique [0002] Telmisartan is an antihypertensive drug that has been approved by the FDA in the sartan class. It belongs to angiotensin Ⅱ receptor antagonist and has the advantages of maintaining the normal regulatory function of the cardiovascular system and reducing organ damage caused by high blood pressure. Compared with other antihypertensive drugs, telmisartan has the best efficacy and lower toxicity, and can be used to control blood pressure balance. Various reports indicated that efficient synthesis of 2-methyl-4-(1-methyl-1H-benzimidazol-2-yl)amine (1) is the key to the production of telmisartan. [0003] The first synthesis of telmisartan was described by Ries U.J. et al. Its synthetic route is as follows, [0004] [0005] Starting from 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/18
CPCC07D235/18
Inventor 赵建宏熊仪成徐小丽吴炜婷杨帆
Owner EAST CHINA UNIV OF SCI & TECH