Synthesis process of anti-tumor drug Sapanisertib

An anti-tumor drug and a synthesis process technology, which is applied in the field of synthesis technology, can solve the problems of difficulty in scale-up preparation, long synthesis route and the like, and achieve the effects of good economic benefits, low production cost and cheap raw materials

Inactive Publication Date: 2020-09-01
YAOPU SHANGHAI PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method has a total of 10 steps of reaction, the synthetic route is long, and involves nitration reaction and hydrogenation reduction reaction, which is not easy to scale up and prepare, as shown in the following formula:

Method used

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  • Synthesis process of anti-tumor drug Sapanisertib
  • Synthesis process of anti-tumor drug Sapanisertib
  • Synthesis process of anti-tumor drug Sapanisertib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1: Preparation of 4-methoxy-3-nitrobenzoyl chloride

[0073] At room temperature, 4-methoxy-3-nitrobenzoic acid (compound I) (98.6g, 0.50mols, 1.0eq), N,N-dimethylformamide (0.914g, 0.0125mols, 0.025eq) and Dichloromethane (600ml, ~6V) was added into a 1L three-necked reaction flask, and the stirring was started. Cool down in an ice-water bath, and add dropwise oxalyl chloride (95.2 g, 0.75 mols, 1.5 eq) at a controlled temperature of 20 degrees Celsius. After the addition was complete, the mixture was naturally raised to room temperature and stirred for 20 hours. The reaction solution was concentrated under reduced pressure at 45 degrees Celsius to remove dichloromethane to obtain 4-methoxy-3-nitrobenzoyl chloride as a yellow oil (108.2g, 0.502mols), with a yield of 100.4%, which was directly used in the following One step reaction.

Embodiment 2

[0074] Embodiment two: the preparation of 2-(methoxy (4-methoxy-3-nitrophenyl) methylene) malononitrile

[0075] At room temperature, 4-methoxy-3-nitrobenzoyl chloride (compound II) (108.2g, 0.50mols, 1.0eq), malononitrile (33.0g, 0.50mols, 1.0eq) and tetrahydrofuran (1100ml, ~ 10V) was added into a 2L three-necked reaction flask, and the stirring was started. Under the protection of nitrogen, the temperature was cooled in an ice-water bath, and N,N-diisopropylethylamine (193.9 g, 1.50 mols, 3.0 eq) was added dropwise at a controlled temperature of 25 degrees Celsius, and the mixture was naturally raised to room temperature and stirred for 3 hours. At room temperature, dimethyl sulfate (157.7g, 1.25mols, 2.5eq), the reaction system was heated to 75 degrees Celsius, and stirred for 22 hours.

[0076] The reaction solution was cooled to room temperature, poured into ice-water mixture (1100ml), and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (...

Embodiment 3

[0077] Example 3: Preparation of 5-amino-1-isopropyl-3-(4-methoxy-3-nitrophenyl)-1H-pyrazole-4-carbonitrile

[0078]At room temperature, 2-(methoxy(4-methoxy-3-nitrophenyl)methylene)malononitrile (compound III) (77.77g, 0.3mols, 1.0eq), isopropylhydrazine salt Add salt (compound IV) (33.18g, 0.3mols, 1.0eq) and absolute ethanol (650ml, ~8V) into a 1L three-necked reaction flask, start stirring, add triethylamine (33.4g, 0.33mols, 1.1 eq). The reaction system was heated to 60° C. and stirred for 3 hours.

[0079] The reaction solution was concentrated under reduced pressure at 50°C to 2-3 times the volume, water (400ml, ~5V) and methanol (80ml, ~1V) were added, and stirred at room temperature for 2 hours. Filter, rinse the filter cake with a methanol / water mixed solvent (1 / 2, 140ml, ~2V), and dry to obtain 5-amino-1-isopropyl-3-(4-methoxy-3-nitrophenyl )-1H-pyrazole-4-carbonitrile was a yellow solid (86.1 g, 0.286 mols), yield 95.3%.

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Abstract

The invention discloses a synthesis process of anti-tumor drug Sapanisertib. The synthesis process comprises the following steps: step 1, carrying out carboxyl halogenation reaction on a compound I and a halogenating reagent in a proper solvent to obtain a compound II; 2, reacting the compound II with a methylation reagent in a proper solvent under the action of an alkali to obtain a compound III;3, reacting the compound III with a compound IV in a proper solvent to obtain a compound V; 4, reacting the compound IV with a cyclization reagent in a proper solvent to obtain a compound VI; 5, reacting the compound VI with an acid or Lewis acid to obtain a compound VII; 6, performing reduction reaction on the compound VII to obtain a compound VIII; and step 7, reacting the compound VIII with cyanogen bromide in a solvent to obtain the Sapanisertib. The synthetic process preparation method has the advantages of cheap and easily available raw materials, simple operation, stable process, easycontrol, convenient post-treatment, safety, environmental friendliness, high yield, low production cost and the like, has the commercial production potential of the Sapanisertib bulk drug, and generates good economic benefits.

Description

technical field [0001] The invention relates to a synthesis process, in particular to a synthesis process of the antineoplastic drug Sapanisertib. Background technique [0002] The chemical name of Sapanisertib is 3-(2-amino-5-benzoxazolyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, Its structural formula is shown in the following formula. [0003] [0004] Sapanisertib, also known as TAK-228, MLN0128, and INK128, is a small-molecule anti-tumor inhibitor targeting mammalian target of rapamycin (mTOR) in phase II clinical development of Takeda Pharmaceutical. The current clinical trial results show that the anti-tumor effect on a variety of solid tumors, lymphoma, and multiple myeloma is relatively good. [0005] The currently reported synthetic methods of Sapanisertib include the following two. [0006] 1. As reported in the patent WO2013 / 23184, compound 1: 2-amino-4-bromophenol was used as the starting material, and compound 2 was obtained by cyclization r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00
CPCA61P35/00C07D487/04
Inventor 蒋文斌雷培海柳惠李彬刘亚丽孙自德
Owner YAOPU SHANGHAI PHARMA TECH CO LTD
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