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Preparation method of Larotrectinib and intermediate of Larotrectinib

A system and compound technology, applied in the field of medicine and chemical industry, can solve the problems of low utilization of formula II compound, high industrialization cost, complicated purification operation, etc., and achieve the effects of shortening reaction time, reducing types and contents, and reducing reaction temperature

Active Publication Date: 2018-05-04
苏州东南药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this synthetic method, there are the following problems: 1) the preparation cost of the compound of formula II is relatively high, and after reacting with the compound of formula I, three-step reactions are needed to obtain Larotrectinib. Therefore, the utilization of the compound of formula II is relatively low, and the production cost is relatively low. Higher; 2) The reaction temperature between the compound of formula V and (S)-3-pyrrolidinol is 50°C, and the reaction time is as long as 19 hours, with many by-products, complicated purification operation and high industrialization cost

Method used

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  • Preparation method of Larotrectinib and intermediate of Larotrectinib
  • Preparation method of Larotrectinib and intermediate of Larotrectinib
  • Preparation method of Larotrectinib and intermediate of Larotrectinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the synthesis of formula 2 compound

[0036]

[0037] Add the compound of formula 1 (50g, 250mmol), ethanol (500mL), ammonium chloride (133g, 2.5mol) aqueous solution (500mL) and iron powder (140g, 2.5mol) into the reaction flask, heat, and reflux under nitrogen protection Under reaction 4-8 hours. After the reaction was completed, it was concentrated under reduced pressure, water and dichloromethane were added, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 40 g of the compound of formula 2 with a yield of 95.2%. δ=9.29(d,J=7.2Hz,1H),8.71(s,1H),8.16(d,J=7.2Hz,1H),5.92(s,2H); MS(m / z)[M+H ]+calcd for C 6 h 6 ClN 4 169.0, found 169.8.

Embodiment 2

[0038] Embodiment 2: the synthesis of formula 3 compound

[0039]

[0040] Add the compound of formula 2 (40g, 237mmol), N,N-diisopropylethylamine (36.8g, 284mmol) and methylene chloride (400mL) into the reaction flask at room temperature, drop to 0-10°C, slowly Add a dichloromethane solution of p-nitrophenyl chloroformate (50.2g, 249mmol) dropwise, keep the temperature not exceeding 10°C, and control in TLC. After the reaction is completed, wash with saturated brine, dry with anhydrous sodium sulfate, and Concentration under reduced pressure gave 74 g of the compound of formula 3 with a yield of 93.5%. 1H NMR (300MHz, d 6 DMSO)δ=10.2(s,1H),9.32(d,J=7.2Hz 1H),8.81(s,1H),7.4-8.6(m,5H); MS(m / z)[M+H]+ calcd for C 13 h 9 ClN 5 o 4 334.0, found 333.8.

Embodiment 3

[0041] Embodiment 3: the synthesis of formula 5 compounds

[0042]

[0043] Add the compound of formula 3 (70g, 210mmol), the compound of formula 4 (18g, 207mmol) and ethanol (300mL) into the reaction flask at room temperature, react at 25°C for 2-8 hours, control in TLC, after the reaction is completed, stir Methyl tert-butyl ether (800mL) was added under low temperature, and solids were precipitated. Continue stirring at this temperature for 30 minutes, filter, and drain to obtain 36g of the compound of formula 5. The mother liquor was recovered and purified by column chromatography to obtain 18g of the compound of formula 5. A total of 54g, the yield is 91%. 1H NMR (300MHz, d 6DMSO) δ=9.26(d,J=7.2Hz 1H),8.73(s,1H),8.78(s,1H),8.07(d,J=7.2Hz,1H),4.02(m,1H),3.62( m,2H),3.48(m,2H),2.36(m,2H); MS(m / z)[M+H]+calcd for C 11 h 13 ClN 5 o 2 282.1, found 281.9.

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Abstract

The invention relates to the field of pharmaceutical chemistry, and specifically relates to a preparation method of Larotrectinib and an intermediate of Larotrectinib. According to the method, 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine is taken as a raw material, a compound shown as the formula 5 in the description is obtained through a three-step reaction, a substitution reaction occurs between the compound shown as the formula 5 and a compound shown as the formula 6 in the description so as to obtain Larotrectinib. The method provides a new synthetic route of Larotrectinib, the consumption ofthe compound shown as the formula 6 is reduced, the production cost is reduced, and the reaction condition is mild, no column chromatography purification is needed, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of Larotrectinib and an intermediate thereof. Background technique [0002] Larotrectinib was developed by Loxo Oncology as a broad-spectrum tumor drug for all patients with tumors expressing tropomyosin receptor kinase (TRK), rather than targeting tumors at a certain anatomical location. TRK fusions are widespread in many cancers, affect all ages, and are independent of tumor genetics. The drug was granted breakthrough drug designation by the FDA on July 13, 2016, for unresectable or metastatic solid tumors in adults and children with positive TRK fusion gene mutations. Larotrectinib has been shown to be effective in a wide range of ages and tumor types Long-lasting antitumor activity and good tolerance in Trk fusion cancers. Larotrectinib will be the first treatment to be developed and approved in both adults and children, and the...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 吉民刘海东宗玺李锐万广朋王冬冬杨苏于文渊张影胡海燕
Owner 苏州东南药业股份有限公司
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