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Synthetic method of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine

A technology of methyl trioctyl ammonium chloride and methyl tert-butyl ether, applied in the direction of organic chemistry, can solve the problems of low yield, long steps, difficult purification of intermediates, etc., and achieve simple post-processing and excellent reaction conditions mild effect

Inactive Publication Date: 2012-08-08
PHARMABLOCK SCIENCES (NANJING) INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It mainly solves the problem of low yield, long steps, difficult purification of intermediates and no large Technical issues such as scale preparation

Method used

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  • Synthetic method of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine
  • Synthetic method of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine
  • Synthetic method of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine

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Experimental program
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Embodiment 1

[0032] Synthesis of Compound IX:

[0033]

[0034] MTBE (3L), compound VIII (186g, 1.2mol, 1.0eq.), ammonium chloride (385g, 7.2mol, 6.0eq.), Aliquat-336 (13.2g, 2.5%), 28.4% sodium hydroxide Add the solution (3.5L) into the reaction flask, control the temperature of the system at 15°C to 20°C, add 7L of 10% sodium hypochlorite solution dropwise to the system, and stir at room temperature for 3 hours. LC-MS shows that the raw materials have been reacted. The reaction was quenched by adding saturated sodium sulfite solution, extracted with EA, dried, and spin-dried to obtain 228 g of a brown liquid with a yield of 97.5%, which was directly used in the next reaction.

[0035] Synthesis of Compound VII:

[0036]

[0037] Compound IX (169g, 1.0mol) and formamide (2L) were added to the reaction flask, and reacted at 165°C for 6 hours. LC-MS showed that the raw materials had been reacted. The system was cooled to room temperature, and the reaction solution was poured into ice...

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Abstract

The invention relates to the field of medicinal intermediate synthesis, and concretely relates to a synthetic method of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine. The synthetic method is characterized in that the synthetic method comprises the following steps: carrying out in-situ synthesis on a compound VIII which is used as a raw material with methyl trioctyl ammonium chloride (Aliquat336) as a catalyst to generate chloramine (NH2Cl), and carrying out an N-amination reaction to obtain a compound IX; carrying out a ring closure reaction under the action of formamide to obtain a compound VII; and reacting the compound VII with POCl3 with DIPEA as an acid binding agent and toluene as a solvent to obtain 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine. According to the method of the invention, reaction conditions are mild, the yield in each step is high, and the total yield can reach 72.1%, so the method is suitable for the large scale production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 4-chloro-5-methyl-1H pyrrolo[2,1-f][1,2,4]triazine. Background technique [0002] 4-Chloro-5-methyl-1H-pyrrolo[2,1-f][1,2,4]triazine is a key intermediate of a very useful tyrosine kinase inhibitor (TKI). Tyrosine kinase inhibitors (TKIs) are a class of compounds that inhibit the activity of tyrosine kinases. Tyrosine kinase is a kind of kinase that catalyzes the transfer of γ-phosphate on ATP to protein tyrosine residues. It can catalyze the phosphorylation of various substrate protein tyrosine residues. It plays a role in the growth, proliferation and differentiation of tumor cells. important role. In recent years, a variety of tyrosine kinase inhibitors (TKIs) have been approved for marketing for the treatment of tumors, and many tyrosine kinase inhibitors (TKIs) are in different stages of clinical trials. [0003] Compounds suc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 舒庆宁朱春瑞余洋吴希罕杨民民
Owner PHARMABLOCK SCIENCES (NANJING) INC
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