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Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

A technology of methylphenyl and fluorophenyl, which is applied in the field of preparation of 2--5-[methyl]thiophene, can solve the problems of low product purity, low yield, and high cost, and achieve high purity and low content of by-products The effect of reducing and increasing the yield

Active Publication Date: 2020-05-29
CANGZHOU SENARY CHEM SCI TEC
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  • Abstract
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Problems solved by technology

[0007] For the existing synthesis process of canagliflozin key intermediate 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, 2-methyl- The reduction process of 5-bromophenyl-2-(4-fluorophenyl) thiophenemethanone needs to use expensive catalyst and needs to add substances that are easy to cause environmental pollution such as Lewis acid to carry out selective reduction, and the obtained target product For the problems of low purity and low yield, the invention provides a method for preparing 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

Method used

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  • Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

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Experimental program
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Effect test

Embodiment 1

[0034] Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

[0035] 1) Preparation of copper-supported nitrogen-doped carbon material (Cu-NC):

[0036] Weigh 0.15g of Cu(NO 3 ) 2 ·3H 2 O was dissolved in 50mL of deionized water, 13g of chitosan was added thereto, stirred and reacted at 70°C for 5h, then spin-dried to remove water, and the obtained solid was dried at 80°C for 4h to obtain a catalyst precursor. The body was heated in a tube furnace under an argon atmosphere at a rate of 10°C / min. When the temperature was raised to 750°C, it was kept for 1.5h, and then lowered to room temperature to obtain 6.51g of Cu-NC, which was analyzed by ICP. The Cu content is 0.42%.

[0037] 2) Preparation of 2-methyl-5-bromophenyl-2-(4-fluorophenyl)thiophenemethanone by Friedel-Crafts reaction:

[0038]Under nitrogen protection, 23.6 g (0.1 mol) of 2-methyl-5-bromobenzoyl chloride, 18 g (0.1 mol) of 2-(4-fluorophenyl) thiophene and dehydrated dichloro...

Embodiment 2

[0043] Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

[0044] 1) Preparation of cobalt-loaded nitrogen-doped carbon material (Co-NC):

[0045] Weigh 1.50g of Co(NO 3 ) 2 ·6H 2 O was dissolved in 50mL of deionized water, 13g of chitosan was added thereto, stirred and reacted at 65°C for 5.5h, then spin-dried to remove water, and the obtained solid was dried at 85°C for 5h to obtain a catalyst precursor. The precursor was heated in a tube furnace under an argon atmosphere at a rate of 12°C / min. When the temperature was raised to 800°C, it was kept for 2 hours, and then lowered to room temperature to obtain 6.73g of Co-NC, which was analyzed by ICP. The content of Co is 3.53%.

[0046] 2) Preparation of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene by hydrogenation reduction:

[0047] Add 1g of Co-NC, 34.5g of the 2-methyl-5-bromophenyl-2-(4-fluorophenyl) thiophenemethanone crude product in Example 1, and 300ml of isopr...

Embodiment 3

[0049] Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

[0050] 1) Preparation of nickel-supported nitrogen-doped carbon material (Ni-NC):

[0051] Weigh 0.05g of Ni(NO 3 ) 2 ·6H 2 O was dissolved in 50mL of deionized water, 13g of chitosan was added thereto, stirred and reacted at 75°C for 6h, then spin-dried to remove water, and the obtained solid was dried at 85°C for 6h to obtain a catalyst precursor. The body was heated in a tube furnace under an argon atmosphere at a rate of 15°C / min. When the temperature was raised to 850°C, it was kept for 2.5 hours, and then lowered to room temperature to obtain 6.48g of Ni-NC, which was analyzed by ICP. The Ni content is 0.11%.

[0052] 2) Preparation of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene by hydrogenation reduction:

[0053] Add 1g of Ni-NC, 34.5g of 2-methyl-5-bromophenyl-2-(4-fluorophenyl) thiophenemethanone crude product, 300ml of isopropanol in a 500ml autoclav...

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Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene. The preparation method comprises the following steps: by taking a nitrogen-doped carbon material loaded with transition metal as a catalyst, introducing hydrogen, and performing hydrogenation reduction on 2-methyl-5-bromophenyl-2-(4-fluorophenyl)thiophene ketone at 50-180 DEG C, thereby obtaining 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene. The preparation method provided by the invention has the characteristics of the high product yield, high purity, the low cost, no toxicity and no pollution, and overcomes the defects in the traditional preparation process of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene. Background technique [0002] Canagliflozin is the first approved SGLT-2 inhibitor hypoglycemic drug developed by Johnson & Johnson for the treatment of type 2 diabetes in adult patients. Canagliflozin can lower blood sugar by decomposing glucose and excreting it through the kidneys. It has broad prospects for the treatment of type 2 diabetes in adults. In addition to good blood sugar control, canagliflozin has a more significant weight loss effect. Compared with glimepiride, canagliflozin causes much fewer hypoglycemic events, and is known as an important drug in the type II diabetes treatment market. pound of dynamite. [0003] 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene is an intermediate of canagliflozin, and its various synthesis processes have been publicl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/12B01J27/24
CPCC07D333/12B01J27/24
Inventor 张少平李培申漆定超于淑玲张月成
Owner CANGZHOU SENARY CHEM SCI TEC
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