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Preparation process of trirasilil compound

A technology for tralaciride and preparation process is applied in the field of preparation of tralaciride compounds, which can solve the problems such as the preparation process of tralacilide compounds needs to be improved, and achieves improvement of total yield and industrial operability, simple reaction operation, and reaction conditions. mild effect

Active Publication Date: 2022-02-08
武汉九州钰民医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the preparation process related to treracilil compounds still needs to be improved

Method used

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  • Preparation process of trirasilil compound
  • Preparation process of trirasilil compound
  • Preparation process of trirasilil compound

Examples

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preparation example Construction

[0072] The preparation of compound Triracilil shown in embodiment 9 formula I

[0073] At room temperature, add the compound shown in formula 8 (29.08g, 0.1mol) to dioxane (300mL), stir, add the compound shown in formula 9 (21.15g, 0.11mol), tBuOK (16.83g, 0.15mol) ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 , 4.58g, 0.005mol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP, 6.23g, 0.01mol), after nitrogen replacement for three times, stir and heat up to 100°C for 2h, then The reaction mixture was kept at 20°C to 25°C and stirred for 18h, then ethyl acetate (300ml) was added to the reaction solution, stirred evenly, filtered with diatomaceous earth, the filter cake was washed with ethyl acetate, and the obtained filtrate was collected and decompressed Concentrate, the concentrate that obtains adopts the mixed solvent that the dichloromethane / methanol of volume ratio is 20:1 to carry out silica gel column chromatography purification, collects the filtrate that ob...

Embodiment 12

[0080] Example 12 is a comparative example. In this example, the inventor adjusted the compound shown in formula 6 and triethylamine and the compound shown in formula 4 to slowly raise the temperature to 50°C and continue to stir for 2.5h. In terms of technical effect, this implementation The product yield (63.5%) that example obtains is significantly lower than the product yield (72.7%) when compound shown in formula 6 described in embodiment 5 and triethylamine, formula 4 are slowly warming up to 60 ℃ and continue to stir for 2h. %).

[0081] At room temperature, the compound shown in formula 6 (10g, 0.0565mol), Et 3 N (6.86g, 0.0678mol) was added into THF (80mL), and kept at 20°C to 25°C, slowly added dropwise a mixture containing the compound shown in formula 4 (15.91g, 0.0593mol) and THF (40mL), and The reaction temperature of the mixed system is kept at 20°C to 25°C. After stirring for 0.5 hours, slowly raise the temperature to 50°C and continue to stir for 2.5 hours. T...

Embodiment 13

[0083] Embodiment 13 is a comparative example. In this embodiment, the inventor adjusted the compound shown in formula 8, the compound shown in formula 9, tBuOK, Pd 2 (dba) 3 , the mol ratio of BINAP is 1:1.4:4:0.015:0.2, and its technical effect, the product yield obtained is significantly lower than the compound shown in formula 8, the compound shown in formula 9, tBuOK, Pd 2 (dba) 3 , the product yield when the molar ratio of BINAP is 1:(1.0~1.25):(1.2~3):(0.02~0.1):(0.05~0.15), and the HPLC purity of the triracilide product obtained obviously reduces, Impurities in the product increase.

[0084] At room temperature, add the compound shown in formula 8 (29.08g, 0.1mol) to dioxane (300mL), stir, add the compound shown in formula 9 (26.92g, 0.14mol), tBuOK (44.88g, 0.4mol ), Pd 2 (dba) 3 (1.37g, 0.0015mol), BINAP (12.45g, 0.02mol), after nitrogen replacement three times, stirred and heated up to 100°C for 2h, then kept the reaction mixture at 20°C~25°C and stirred for 18...

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Abstract

The invention relates to a novel preparation process of a trirasilil compound. According to the method disclosed by the invention, uracil and bromoacetyl bromide which are commercially easy to obtain and low in price are adopted as starting raw materials, wherein the trirasilil is obtained through five steps of chemical reactions in total; wherein tBuOK, Pd2(dba)3 and BINAP are used for halogenation reaction in the step (5), so that the yield of the product can be effectively improved, and generation of by-products is avoided. The reaction conditions of the whole synthesis route of the preparation method are mild; the used raw materials and reagents are cheap and simple, and the reaction yield of each step is high. In addition, post-treatment of the reaction is simple, pulping purification is mostly adopted for purification, column chromatography purification is avoided as much as possible, and the total yield and industrial operability of the reaction are effectively improved.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a preparation process of treracilil compound. Background technique [0002] Trilaciclib is a "First-in-Class" small molecule short-acting CDK 4 / 6 inhibitor discovered and developed by G1 Therapeutics. It is a comprehensive bone marrow protective agent and has been granted priority by the FDA. Review eligibility and breakthrough therapy designation. On February 12, 2021, G1’s bone marrow protective agent Triaciclib (trade name: COSELA) was approved by the US FDA for the prevention of platinum / etoposide or topotecan regimens in adult patients with diffuse small cell lung cancer. Myelosuppression due to chemotherapy. The approval of treracilil means that it is the first and only new drug in the world that is administered prophylactically during chemotherapy to protect bone marrow and immune system functions. [0003] The chemical structure of triracillib is specifically as th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/20
CPCC07D487/20
Inventor 陈程范昭泽余艳平
Owner 武汉九州钰民医药科技有限公司
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