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Method for preparing BCR-ABL inhibitor intermediate

A technology of solvents and halogenated reagents, applied in the field of medicinal chemical intermediates, can solve problems such as lower conversion rates, and achieve mild reaction conditions and simple post-treatment effects

Active Publication Date: 2015-04-08
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

4-Nitro-2-trifluoromethyltoluene (compound 1) is prone to monobrominated or polybrominated under the conditions of N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) Substitution reaction, polybromination reaction is difficult to react with N-methylpiperazine, resulting in lower conversion rate

Method used

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  • Method for preparing BCR-ABL inhibitor intermediate
  • Method for preparing BCR-ABL inhibitor intermediate
  • Method for preparing BCR-ABL inhibitor intermediate

Examples

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Embodiment 1

[0030] Example 1 Preparation of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine

[0031] Step 1) At room temperature (about 30°C), 4-nitro-2-trifluoromethyltoluene (20.00 g) was dissolved in CH 2 Cl 2 (250g), add H 2 O (250g), hydrobromic acid (40wt%, 78.89g), followed by H 2 o2 (30wt%, 44.20g) was added dropwise to the reaction mixture. After the dropwise addition, the mixture was reacted at room temperature for 36h, and the reaction was detected by HPLC. The raw material 4-nitro-2-trifluoromethyltoluene was 4.63%. 1-bromomethyl-4-nitro-2-(trifluoromethyl)benzene is 70.35%, 1-dibromomethyl-4-nitro-2-(trifluoromethyl)benzene (dibrominated product ) is 24.93%. After the reaction, the reaction mixture was washed with saturated NaHCO 3 solution (500mL) for washing, separation to obtain CH 2 Cl 2 Organic layer, CH 2 Cl 2 Layers were sequentially washed with saturated NaHCO 3 solution (200mL), saturated Na 2 SO 3 solution (200 mL), the resulting CH 2 Cl 2 The...

Embodiment 2

[0033] Preparation of Example 21-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine

[0034] Step 1) At room temperature (about 23 °C), 4-nitro-2-trifluoromethyltoluene (compound 1) (2 g) was dissolved in CH 2 Cl 2 (25g), NaBr (3.51g) was dissolved in H 2 O (25g) was added to the reaction mixture, the reaction mixture was stirred at room temperature, H 2 SO 4 (3.35g) was added dropwise in the reaction mixture, H 2 o 2 (30wt%, 3.87g) was added dropwise to the reaction mixture, and the reaction mixture was reacted at 30°C for 48h to separate CH 2 Cl 2 phase, water phase with CH 2 Cl 2 Extraction, combined organic phase, organic phase with saturated NaHCO 3 solution (100mL) for washing, separation to obtain CH 2 Cl 2 layer, then saturate Na 2 SO 3 Washing, separating the obtained CH 2 Cl 2 The organic layer was directly used in the next reaction. , in the reaction mixture, the raw material 4-nitro-2-trifluoromethyltoluene was detected by HPLC as 3.39%, 1-bromo...

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Abstract

The invention discloses a method for preparing a BCR-ABL inhibitor intermediate. A method for preparing N-methyl-4-(4-nitro-2-(trifluoromethyl) phenyl) piperazine (compound 4) as shown in the description comprises the following steps: 1), in a solvent, implementing halogenating reaction on a compound 1 and a halogenations reagent as shown in the description; 2), in a solvent, implementing reaction on the product obtained in the step 1) and N-methyl piperazine in the presence of alkali and phosphite ester, thereby obtaining the compound 4. By adopting the method disclosed by the invention, the conversion rate of 4-nitro-2-trifluoromethyl methylbenzene (compound 1) as a raw material for preparing 4-nitro-2-trifluoromethyl phenyl benzyl halogen (compound 2a) through halogenations is greater than 95%, and the yield of synthesizing the compound 4 from two steps is greater than 80% on the basis of the raw material 4-nitro-2-trifluoromethyl methylbenzene (compound 1).

Description

technical field [0001] The invention relates to medicinal chemical intermediates, in particular to a method for preparing BCR-ABL inhibitor intermediates. Background technique [0002] PCT application WO 2007075869 discloses a class of novel alkyne heteroaryl compounds and their preparation methods and their use in the treatment of cancer, bone disease, metabolic disease, inflammatory disease and other diseases, wherein 3-(imidazo[1 , 2-b] pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)-methyl)-3-(trifluoromethyl ) phenyl) benzamide (compound Ia) or a pharmaceutically acceptable salt thereof, is an orally effective multi-target kinase inhibitor, which is the most potent BCR-ABL inhibitor disclosed so far and capable of inhibiting target The first pan-BCR-ABL inhibitor of all known mutant forms of the drug, including the currently untreatable T315I mutant that is resistant to other drugs, [0003] [0004] PCT application WO 2011053938 discloses a pharmace...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/073
CPCC07B2200/13C07D295/073C07D487/04
Inventor 肖毅寇景平孙腾飞严辉贾玲玲
Owner SUNSHINE LAKE PHARM CO LTD