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Synthesis method of anti-cancer drug intermediate methyl 2-fluoro-3-aminobenzoate

A technology of methyl aminobenzoate and methyl nitrobenzoate is applied in the field of synthesis of new anticancer drug intermediate 2-fluoro-3-aminobenzoic acid methyl ester, and can solve the problems such as difficulty in obtaining raw materials, high environmental protection pressure, etc. problem, to achieve the effect of increased reaction continuity and convenient operation

Active Publication Date: 2020-06-23
浦拉司科技(上海)有限责任公司
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Problems solved by technology

[0009] In the above synthesis method, raw materials are not easy to obtain, or pentavalent chromium is used to oxidize in strong acid, and hydrazine hydrate or iron powder is used for reduction, so the pressure on environmental protection is great

Method used

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  • Synthesis method of anti-cancer drug intermediate methyl 2-fluoro-3-aminobenzoate
  • Synthesis method of anti-cancer drug intermediate methyl 2-fluoro-3-aminobenzoate
  • Synthesis method of anti-cancer drug intermediate methyl 2-fluoro-3-aminobenzoate

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Effect test

Embodiment 1

[0036] Under nitrogen protection, 100g (0.5235mol) of 2,6-dichlorobenzoic acid was added in batches to 223g (2.093mol, 4eq) of 92% concentrated sulfuric acid, and the pre-configured 68 Mixed acid of 72g of concentrated nitric acid and 55g of 92% concentrated sulfuric acid, after the dropwise addition, the temperature was raised to 30°C for 0.5-1 hour reaction, sampling HPLC was performed to detect that the raw material was 1 HNMR (400MHz, MeOH-d 4 ):δ=7.98(d,1H),7.66(d,1H).

Embodiment 2

[0038] Under the protection of nitrogen, mix 100g (0.5235mol, 1eq) of 2,6-dichlorobenzoic acid and 70g (0.657mol, 1.26eq) of 92% concentrated sulfuric acid, and add the pre-configured Mixed acid of 36g of 95% fuming nitric acid and 38g of 92% concentrated sulfuric acid, react at room temperature for 5 hours after the dropwise addition, sample HPLC to detect the raw material <0.2%, cool to 0-10°C, add 8 times the volume of dichloromethane each time to carry out Extraction, a total of two extractions, combined the organic phases, adding water at 0-10 ° C to wash until the pH of the aqueous phase = 2-3, and concentrating the organic phases under reduced pressure to stagnant liquid to obtain the intermediate 2,6-dichloro-3-nitrate Base benzoic acid 116.8g, HPLC detection chemical purity 98.3%, yield 94.5%.

[0039] The second step: the synthesis of methyl 2,6-dichloro-3-nitrobenzoate

Embodiment 3

[0041] Dissolve 117.7 g of 2,6-dichloro-3-nitrobenzoic acid in 259 g of methanol, add 7.6 g of concentrated sulfuric acid, heat up to reflux, and react for 5 hours, sample HPLC to detect that the raw material is 1 HNMR (400MHz, DMSO-d 6 ):8.28(s,1H),7.52(s,1H),3.89(s,3H).

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Abstract

The invention discloses a synthetic method of 2-fluoro-3-methyl aminobenzoate, and belongs to the technical field of synthesis of medical intermediates. According to the method, 2, 6-dichlorobenzoic acid is taken as a raw material, 2, 6-dichloro-3-nitrobenzoic acid is obtained through nitration reaction and high selectivity, then the 2, 6-dichloro-3-nitrobenzoic acid reacts with methanol under anacidic condition to form ester, then 2-fluoro-3-nitro-6-methyl chlorobenzoate is obtained through selective fluorination, and finally 2-fluoro-3-methyl aminobenzoate is obtained through catalytic hydrogenation. By adopting the process route provided by the invention, the initial raw materials are easy to obtain, common unit operation in fine chemical engineering is adopted in the process, the reaction continuity is increased, industrial operation is facilitated, and a basis is provided for large-scale application of downstream medicines.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to the synthesis of multiple novel anticancer drug intermediates, methyl 2-fluoro-3-aminobenzoate. [0002] technical background [0003] The new anticancer drug intermediate is methyl 2-fluoro-3-aminobenzoate, CAS: 1195768-18-3, and its structural formula is as follows: [0004] [0005] In the current prior art WO 2011059610A1 patent, 2-fluoro-3 bromo-benzoic acid is used as raw material to obtain the product through esterification and ammoniation, but the raw material cost is very high, and the route is as follows: [0006] [0007] In addition, the patent also reported that o-fluorotoluene was used as a raw material to obtain the product through nitration, oxidation, replacement, and reduction, but there were many by-products and difficult purification, high yield and low cost. The synthetic route is as follows: [0008] [0009] In the above synthesis method, raw mat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/04C07C229/60
CPCC07C201/08C07C201/12C07C227/04C07C205/58C07C229/60
Inventor 陆电云蔡伟兵娄凯
Owner 浦拉司科技(上海)有限责任公司
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