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Synthesis method of 2,3-benzopyrrole compound NPS-1577

A technology of NPS-1577 and compounds, applied in the direction of organic chemistry, can solve the problems of high cost of preparation of reaction substrates, difficult control of reaction conditions, expensive raw materials and other problems, and achieve easy industrial scale-up production, cheap raw materials, and easy access to raw materials Effect

Inactive Publication Date: 2013-05-22
TONGJI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The raw materials used in the existing process are relatively expensive, and the cost of preparing the reaction substrate is also high; the reaction cycle is long, the reaction conditions are difficult to control and the operation is cumbersome, so it is difficult to apply to scale-up industrial synthesis

Method used

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  • Synthesis method of 2,3-benzopyrrole compound NPS-1577
  • Synthesis method of 2,3-benzopyrrole compound NPS-1577
  • Synthesis method of 2,3-benzopyrrole compound NPS-1577

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057]

[0058] Add 300ml of concentrated sulfuric acid to the reaction bottle, add 100g of p-fluorobenzoic acid in batches, cool in an ice bath to below 10°C, add 71.5ml of concentrated nitric acid dropwise to control the temperature at 0-5°C, and raise the temperature to 50-55°C for 2.5 hours after dropping. TLC monitors that the reaction of the raw materials is completed and cooled down. The reaction solution is poured into 810ml of ice water, stirred for 0.5h, suction-filtered, and air-dried at 40°C to obtain 120g of intermediate 2 as a pale yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.10(s, 1H), 8.83 (dd, J = 2 Hz, 1H), 8.42 (m, 1H), 7.46 (t, 1H).

[0059]

[0060]

[0061] Add 2000ml of methanol and 500g of intermediate 2 to the reaction bottle in sequence, cool in an ice bath to 0°C, add 800ml of thionyl chloride dropwise (the dropwise addition is completed within 1 hour), heat up to 65°C and reflux for 1 hour after dropping, TLC shows that the reaction of th...

Embodiment 2

[0072]

[0073] Add 300ml of concentrated sulfuric acid to the reaction bottle, add 100g of p-fluorobenzoic acid in batches, cool in an ice bath to below 10°C, add 71.5ml of concentrated nitric acid dropwise to control the temperature at 5-10°C, and raise the temperature to 25-30°C for 6 hours after dropping, TLC After monitoring the completion of the raw material reaction and cooling, the reaction solution was poured into 810ml of ice water, stirred for 0.5h, suction filtered, and air-dried at 40°C to obtain 118g of intermediate 2 as a pale yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.10(s, 1H), 8.83 (dd, J = 2 Hz, 1H), 8.42 (m, 1H), 7.46 (t, 1H).

[0074]

[0075]

[0076] Put 1600ml of methanol and 400g of intermediate 2 into the reaction bottle in sequence, cool in an ice bath to 0°C, add 80g of concentrated sulfuric acid dropwise (completely added within 1 hour), and heat up to 65°C for 1 hour under reflux after dropping. The solvent was evaporated to obtain 3...

Embodiment 3

[0087]

[0088] Add 600ml of concentrated sulfuric acid to the reaction flask, add 200g of p-fluorobenzoic acid in batches, cool in an ice bath to 0-5°C, add 143ml of concentrated nitric acid dropwise to control the temperature at 5-10°C, and raise the temperature to 55-65°C for 1 hour after dropping, TLC After monitoring the completion of the raw material reaction and cooling, the reaction liquid was poured into 1620ml of ice water, stirred for 1 hour, suction-filtered, and air-dried at 40°C to obtain 240g of intermediate 2 as a pale yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.10(s, 1H), 8.83 (dd, J = 2 Hz, 1H), 8.42 (m, 1H), 7.46 (t, 1H).

[0089]

[0090]

[0091]Put 1600ml of ethanol and 400g of intermediate 2 into the reaction bottle in sequence, cool in an ice bath to 0°C, add 80g of concentrated sulfuric acid dropwise (completely added within 1 hour), and raise the temperature to 78°C for 1 hour under reflux after dropping, TLC shows that the reaction of the...

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Abstract

The invention belongs to the technical field of pharmaceutical synthesis and particularly relates to a synthesis method of a 2,3-benzopyrrole compound NPS-1577. The method comprises the following steps of: (a) by taking 4-fluorobenzoic acid (2) as a raw material, nitrifying to prepare a compound; (b) carrying out esterification reaction by using thionyl chloride to obtain a compound 3; (c) reacting the compound 3 with 3-methylbenzylamine to a reaction to obtain an intermediate (4); (d) reducing the intermediate (4) by using hydrazine hydrate to obtain an intermediate (5); (e) carrying out aminolysis reaction on intermediate (5) and piperidine to obtain a compound (6); and (f) carrying out cyclization by virtue of acetic anhydride to obtain a final product (1). Compared with the existing synthesis method, the synthesis method provided by the invention is realized through six-step reactions and has the advantages of mild reaction condition for each-step reaction, high yield, cheap and available raw materials and short reaction period, and is simple and convenient to operate, so as to be very easy for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing an indolizine compound NPS-1577 (compound 1). Background technique [0002] NPS-1577 (Figure 1.13) is a new drug developed by Korea Neopharm for the treatment of inflammatory skin diseases. At present, as a raw material of cosmetics, it has passed the toxicity test of animals, and the safety verification has been completed. Now NPS-1577 is in clinical trials, and its data show that it has also played a positive role. [0003] Chinese chemical name: [0004] 2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone; [0005] English chemical name: (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone. [0006] The molecular structural formula is as follows: [0007] [0008] NPS-1577 [0009] As the largest organ in the human body, the skin performs important functions of protecting...

Claims

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Application Information

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IPC IPC(8): C07D235/08
Inventor 匡春香王卓
Owner TONGJI UNIV
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