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A kind of preparation method of 6-fluoro-1h-indole-4-carboxylic acid methyl ester

A technology of methyl formate and methyl nitrobenzoate, which is applied in the field of medicine, can solve the problems of low safety, high price, and difficult industrialization, and achieve the effects of high safety, low cost, and short reaction steps

Active Publication Date: 2019-04-19
山东轩德医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] 6-Fluoro-1H-indole-4-carboxylic acid methyl ester is a key intermediate for the preparation of Rucaparib, Organic Process Research and Development; vol.16; nb.12; (2012) introduces the preparation method of Rucaparib and its intermediates , comprehensively discussed the existing technology, and proposed a synthetic route, but for the preparation of the key intermediate 6-fluoro-1H-indole-4-carboxylic acid methyl ester, the synthesis method has harsh conditions, and the method of catalytic reduction is adopted, which is safe. Low, using metal platinum catalyst, expensive, not easy to industrialize

Method used

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  • A kind of preparation method of 6-fluoro-1h-indole-4-carboxylic acid methyl ester
  • A kind of preparation method of 6-fluoro-1h-indole-4-carboxylic acid methyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 Preparation of 6-fluoro-1H-indole-4-carboxylhydrazide

[0020]

[0021] In the reaction flask, add DMF (5L), 5-fluoro-2-methyl-3-nitrobenzoic acid methyl ester (1kg, 4.7mol), N,N-dimethylformamide dimethyl acetal ( 3kg, 25.2mol), triethylamine (250g, 2.47mol), after the addition, the temperature was raised to 100 degrees Celsius, the reaction was completed, the temperature was lowered, and rotary steaming was added, methanol (5 liters), 50% hydrazine hydrate (1.4kg, 14.1mol) were added , heated to 60 degrees Celsius, the reaction was completed, and filtered to obtain a white solid, 6-fluoro-1H-indole-4-carboxylhydrazide, 843g, yield: 93.1%.

Embodiment 2

[0022] Example 2 Preparation of 6-fluoro-1H-indole-4-carboxylic acid methyl ester

[0023]

[0024] Add 6-fluoro-1H-indole-4-carboxylhydrazide (843g, 4.37mol) into the reaction flask, add methanol (1 liter), dichloromethane (5 liters), 2-iodobenzoic acid (1.47kg , 5.25mol), warming up to 40 degrees Celsius, stirring, the reaction is complete, adding 10% sodium sulfite aqueous solution, liquid separation, drying the organic layer, evaporating to dryness, recrystallizing with ethyl acetate and n-heptane to obtain the product 6-fluoro-1H- Indole-4-carboxylic acid methyl ester, 658g, yield: 78%.

[0025] 1H NMR (400MHz, 25°C, DMSO-d6):

[0026] 3.87(s,3H),6.9(dd,1H,J=0.8,3.1Hz),7.43-7.49(m,2H),7.51(d,1H,J=3.1Hz),11.47(s,br,1H) .

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Abstract

The invention relates to a preparation method of 6-fluoro-1H-indazole-4-methyl formate. The method has the advantages of simple and convenient reaction process, high safety, high yield and mass production capacity.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of methyl 6-fluoro-1H-indole-4-carboxylate. 2. Background technology [0002] Rucaparib, an ovarian cancer treatment drug, was granted FDA breakthrough drug designation in 2015 and is suitable for its third-line application in ovarian cancer. The spread of certain genetic mutations occurs. The FDA granted Breakthrough Therapy Designation to rucaparib for the treatment of patients with BRCA-mutated advanced ovarian cancer who had previously failed second-line therapy. In May 2016, a new drug listing application was submitted in the United States for the study of Rucaparib for the treatment of ovarian cancer. [0003] 6-Fluoro-1H-indole-4-carboxylic acid methyl ester is a key intermediate for the preparation of Rucaparib, Organic Process Research and Development; vol.16; nb.12; (2012) introduces the preparation method of Rucaparib and its intermediates , c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 董岩岩
Owner 山东轩德医药科技有限公司
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