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Application of TBTU in preparation of anti-cancer drug

An anti-cancer drug and a technology for its use are applied in the field of preparation of the anti-cancer drug lorlatinib, can solve the problems of waste of condensing agent and alkali accelerator, difficulty in purification, high usage of condensing agent and alkali accelerator, etc. The effect of industrialized production, short reaction time and reduced usage

Active Publication Date: 2021-03-09
广东博卓医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In addition to the low yield of the product lorlatinib, the above-mentioned methods all have the problem of a large amount of condensing agent and alkali accelerator, which leads to low overall catalytic efficiency, resulting in a large amount of condensing agent and alkali accelerator. Waste is unfavorable from an economic point of view. In addition, the use of more condensation agents and alkali accelerators will inevitably lead to more complicated post-processing operations and difficult purification. From a long-term point of view, it is not conducive to industrial development.

Method used

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preparation example Construction

[0020] The invention provides a preparation method of anticancer drug lorlatinib, which is characterized in that it comprises the following steps: dissolving the compound of formula A in an organic solvent, and adding a condensation agent TBTU (O-benzotriazole-N,N , N', N'-tetramethyluronium tetrafluoroborate) and base accelerator DBU (1,8-diazabicyclo[5.4.0]-undec-7-ene), stirred until uniform, and The temperature of the system is raised to 40-60°C, and the reaction is kept for 2-3 hours. After the reaction is complete as detected by TLC, it is cooled to room temperature, and ammonium chloride solution is added to quench the reaction. After extraction and separation, lorlatinib is obtained; the compound of formula A The structural formula is

[0021] According to the preparation method of an anticancer drug lorlatinib of the present invention, the organic solvent is selected from DMF, DMSO, acetonitrile, toluene or xylene

[0022] According to the preparation method of an ...

Embodiment 1

[0029] Add 0.1mol of the compound of formula A to 200ml of DMF, add 0.1mol of condensing agent TBTU, 0.1mol of base accelerator DBU, stir slowly until the system is evenly mixed, then raise the temperature of the system to 50°C, keep it warm for 2 hours, and detect the reaction by TLC After the end, the system was slowly cooled to room temperature, quenched by adding 100ml of saturated ammonium chloride solution, continued to stir for 20min, stood still for 5min, added ethyl acetate for extraction (100ml×3), collected the organic layer, and decompressed the organic layer After distillation, the solvent was completely removed to obtain a solid crude product, which was washed with 200 ml of n-hexane and dried in vacuo to obtain the target product lorlatinib with a yield of 87.8% and a purity of 98.2%.

Embodiment 2

[0031] Add 0.1mol of compound of formula A to 200ml of DMF, add 0.15mol of condensing agent TBTU, 50mmol of base accelerator DBU, stir slowly until the system is evenly mixed, then raise the temperature of the system to 50°C, keep it warm for 3 hours, and the reaction has been detected by TLC , slowly cool the system to room temperature, add 100ml of saturated ammonium chloride solution to quench the reaction, continue stirring for 20min, let stand for 5min, add ethyl acetate for extraction (100ml×3), collect the organic layer, and distill the organic layer under reduced pressure, The solvent was completely removed to obtain a solid crude product, which was washed with 200 ml of n-hexane and dried in vacuo to obtain the target product lorlatinib with a yield of 89.4% and a purity of 97.4%.

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Abstract

The invention provides application of TBTU in preparation of an anticancer drug Lorlatinib, which is characterized by comprising the following steps: dissolving a compound of formula A in an organic solvent, adding a condensing agent TBTU and an alkali promoter DBU, stirring uniformly, heating the system to 40-60 DEG C, keeping the temperature to react for 23 hours, cooling to room temperature after the reaction is detected by TLC, and adding an ammonium chloride solution to quench the reaction, and performing extraction and separation to obtain the Lorlatinib. According to the invention, theTBTU is used as the condensing agent, DBU is used as the alkali promoter, and the TBTU and the DBU are combined for use, so compared with the prior art, the use amounts of the condensing agent and thealkali promoter used in the invention are obviously reduced, the reaction time is shorter, but the reaction yield is much higher than that in the prior art, and the method is very suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of an anticancer drug, and more specifically relates to a preparation method of an anticancer drug lorlatinib. Background technique [0002] Lorlatinib, Chinese chemical name: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro -2H-4,8-(methine bridge)pyrazolo[4,3-h][2,5,11]benzoxadiazetetradecylcyclo-3-carbonitrile, English chemical name (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-(metheno)pyrazolo[4,3- h][2,5,11]benzoxadiaza-cyclotetradecine-3-carbonitrile. Lorlatinib is owned by Pfizer Pharmaceuticals in the United States [0003] Ltd., and was approved by the US FDA on November 2, 2018. The trade name is Lorbrena. It is a third-generation new drug for the treatment of non-small cell lung cancer (NSCLC). c-ros proto-oncogene 1 (c-ros oncogene 1, ROS1) dual receptor tyrosine kinase (recepto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 李治泉
Owner 广东博卓医药科技有限公司