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A kind of preparation method of tmc-435 important intermediate

A technology of TMC-435 and intermediates, which is applied in the field of preparation of important intermediates of TMC-435, and can solve problems such as high price, harsh reaction conditions, and complicated post-processing

Active Publication Date: 2017-01-04
辽宁惠风生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] Summarizing the above-mentioned synthetic route, there are following defects in the process of preparing intermediate A: (1) when preparing intermediate I, used expensive DPPA, boron trichloride; when preparing intermediate II, also used expensive (2) during the preparation of intermediate II, the aftertreatment of synthetic compound H from compound G is more complicated, and finally will be extracted with a large amount of organic solvent; in the process from compound H to intermediate II, The operation is complicated, the reaction conditions are harsh, and the impurity 4-isopropylthiazole is easily generated during the reaction. These defects limit the industrial production of intermediate A

Method used

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  • A kind of preparation method of tmc-435 important intermediate
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  • A kind of preparation method of tmc-435 important intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment 1: The preparation method of the important intermediate of the anti-hepatitis C drug TMC-435 adopts the following specific process steps.

[0090] (1) Synthesis of Compound C:

[0091]

[0092] Prepare 10wt% sodium hydroxide solution (sodium hydroxide 32.70g, 0.0817mol) and join in the reaction flask, add compound B (5.00g, 0.0327mol) and tetrabutylammonium bromide (0.53g, 0.0016mol) successively, After stirring for 0.5 h, dimethyl sulfate (10.30 g, 0.0817 mol) was slowly added dropwise, and after 1.0 h of reaction at room temperature, TLC confirmed that the reaction was complete. Stop the reaction, add sodium hydroxide solution, stir for 0.5 h, filter with suction, wash the filter cake with water (2×50 mL), dry, and decolorize with activated carbon to obtain 5.1 g of yellow solid; yield 93.5%, 1 H-NMR (500MHz, CDCl 3 )δ (ppm): 2.36 (3H, s), 3.89 (3H, s), 7.04 (1H, d), 7.26 (1H, t), 7.39 (1H, d).

[0093] (2) Synthesis of Compound D:

[0094]

[009...

Embodiment 2

[0121] Embodiment 2: The preparation method of the important intermediate of TMC-435 adopts the following specific process steps.

[0122] (1) Synthesis of Compound C:

[0123] Prepare 15% potassium hydroxide solution (36.62g, 0.0981mol) and add it to the reaction flask, add compound B (5.00g, 0.0327mol) and tetrabutylammonium bromide (1.06g, 0.0033mol) in turn, and stir for 0.5h Then, dimethyl sulfate (12.36 g, 0.0981 mol) was slowly added dropwise, the temperature was controlled at about 30° C., and TLC confirmed that the reaction was complete after reacting at room temperature for 1 h. Stop the reaction, add potassium hydroxide solution, stir for 0.5 h, filter with suction, wash the filter cake with water (2×50 mL), dry, and decolorize with activated carbon to obtain 4.97 g of yellow solid; yield 91.0%.

[0124] (2) Synthesis of Compound D:

[0125] Add 80 mL of anhydrous dichloromethane into the reaction flask, add compound C (10.00 g, 0.0600 mol) under stirring, cool do...

Embodiment 3

[0142] Embodiment 3: The preparation method of the important intermediate of TMC-435 adopts the following specific process steps.

[0143] (1) Synthesis of compound C:

[0144] Prepare 30% sodium carbonate solution (46.22g, 0.1308mol) and add it to the reaction flask, then add compound B (5.00g, 0.0327mol) and tetrabutylammonium bromide (3.16g, 0.0098mol) successively, stir slowly after 0.5h Dimethyl sulfate (16.48 g, 0.1308 mol) was added dropwise, and after 2 hours of reaction at room temperature, TLC confirmed that the reaction was complete. Stop the reaction, add sodium carbonate solution, stir for 0.5 h, filter with suction, wash the filter cake with water (2×50 mL), dry, and decolorize with activated carbon to obtain 4.97 g of yellow solid; yield 91.0%.

[0145] (2) Synthesis of compound D:

[0146] Add 80 mL of anhydrous nitromethane into the reaction flask, add compound C (10.00 g, 0.0600 mol) while stirring, cool down to 0 °C with stirring in an ice bath, and add an...

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Abstract

The invention discloses a preparation method of an important intermediate of TMC-435. The steps are as follows: 1. Compound B is reacted with dimethyl sulfate under alkaline conditions to obtain compound C through methylation; 2. Compound C is processed by Fu Ke Acylation reaction to obtain compound D; 3. Compound D is reduced to amino compound-intermediate I by iron powder; 4. Compound E is subjected to carbonyl α-position bromination reaction to obtain compound F; 5. Compound F is cyclized with thiourea to obtain compound G; 6. Compound G was subjected to diazotization reaction and nucleophilic substitution reaction to obtain compound H; 7. Compound H and cuprous cyanide reacted under high temperature conditions to obtain compound I and compound J; 8. Compound I and compound J were reacted in alkali 9. Compound K was obtained by reacting intermediate II with an acid chloride reagent, and compound L was obtained by N-acylation reaction between compound K and intermediate Ⅰ; 10. Compound L was cyclized under alkaline conditions to obtain Target compound A. The method has low production cost and equipment requirements and high process stability.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a preparation method of an important intermediate of TMC-435. Background technique [0002] Important intermediate of TMC-435, chemical name: 4-hydroxy-2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinoline, American Chemical Abstracts accession number CAS: 923289 -21-8, has formula A structural formula: [0003] [0004] Simeprevir (TMC-435) is a novel protease inhibitor jointly developed by Janssen and Medivir for the treatment of genotype-1 chronic hepatitis C patients with compensated liver disease. Simeprevir is thought to work by blocking the protease that allows HCV to survive and replicate in host cells. [0005] In September 2013, Simeprevir (trade name Sovriad) was approved by the Japanese Ministry of Labor, Health and Welfare for use in combination with pegylated interferon and ribavirin for patients with genotype-1 chronic hepatitis C virus (HCV) infection Th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04
Inventor 尚振华安辰红
Owner 辽宁惠风生物医药科技有限公司
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