阅读说明：本技术 一种parp抑制剂氟唑帕利中间体的合成工艺 (Synthesis process of PARP inhibitor fluxaparide intermediate ) 是由 孙鹏 石磊 吴保平 田贝贝 边奕澄 杨红侠 张欣 于 2020-06-28 设计创作，主要内容包括：本发明公开了适合放大制备2-三氟甲基[1,2,4]三唑并[1,5-a]吡嗪的工艺方法,属于药物中间体合成领域。以2-氨基吡嗪和三氟乙酸乙酯为原料,经过氨酯交换反应、取代反应和脱水反应得到2-三氟甲基[1,2,4]三唑并[1,5-a]吡嗪,本发明工艺选用便宜的三氟乙酸乙酯代替昂贵的三氟乙酸酐,其他有机溶剂代替一类溶剂二氯乙烷,TFFA代替很难后处理的PPA,大幅降低了现有生物、医药、化学中间体的生产成本,该工艺在公斤级规模进行了放大验证,收率和产品纯度与克级规模基本相当,有望作为工业化规模生产的工艺。(The invention discloses a process method suitable for preparing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine in an amplification way, belonging to the field of synthesis of pharmaceutical intermediates. The 2-aminopyrazine and ethyl trifluoroacetate are used as raw materials, and the 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine is obtained through urethane exchange reaction, substitution reaction and dehydration reaction.)

1. A preparation method of 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine is characterized in that the reaction formula is as follows:

the method comprises the following steps: 2-aminopyrazine and ethyl trifluoroacetate are taken as raw materials, and the 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine is obtained through amidation reaction, substitution reaction and dehydration cyclization reaction.

2. The preparation method of 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 1, which is characterized by comprising the following specific reaction steps:

step one, 2-aminopyrazine, organic alkali and ethyl trifluoroacetate react to generate 2,2, 2-trifluoro-N-pyrazin-2-yl acetamide;

secondly, reacting 2,2, 2-trifluoro-N-pyrazine-2-yl acetamide, phosphorus pentachloride and other chlorinated reagents in an organic solvent to generate 2,2, 2-trifluoro-N' -hydroxyl-N-pyrazine-2-yl ethylimine amide;

and thirdly, reacting the 2,2, 2-trifluoro-N' -hydroxy-N-pyrazin-2-ylethylimine amide, the 4-tosyl chloride and trifluoroacetic anhydride to generate the 2-trifluoromethyl [1,2,4] triazolo [1, 5-alpha ] pyrazine.

3. The process for producing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 2, characterized in that: in the first step, the organic base is selected from triethylamine, pyridine, 4-dimethylaminopyridine, 4-methylpyridine, N-dimethylaniline or N, N-diisopropylethylamine.

4. The process for producing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 2, characterized in that: in the first step, the molar ratio of the 2-aminopyrazine, the organic base and the ethyl trifluoroacetate is 1: 0.05-0.3: 1-3.

5. The process for producing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 2, characterized in that: in the second step, the chlorinating reagent is thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus trichloride.

6. The process for producing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 2, characterized in that: in the second step, the mol ratio of the chlorinated reagent to the phosphorus pentachloride is 1: 1-1.5.

7. The process for producing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 2, characterized in that: in the second step, the organic solvent is selected from chlorobenzene, acetonitrile or tetrahydrofuran.

8. The process for producing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 2, characterized in that: in the second step, the mol ratio of the 2,2, 2-trifluoro-N-pyrazine-2-yl acetamide, the phosphorus pentachloride and other chlorinated reagents is 1: 1-1.1: 1-1.1.

9. The process for producing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to claim 2, characterized in that: in the third step, the molar ratio of the 2,2, 2-trifluoro-N' -hydroxy-N-pyrazin-2-ylethylimine amide to the 4-toluenesulfonyl chloride to the trifluoroacetic anhydride is 1: 0.5-1.1: 2-5.

10. A process for the preparation of 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine according to any of claims 1 to 8 characterized in that: in the third step, the product is purified after being recrystallized by adopting an ethyl acetate/hexane mixed solvent.

Technical Field

The invention belongs to the field of synthesis of pharmaceutical intermediates, and particularly relates to a process method suitable for preparing 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine in an amplification manner.

Background

PARP refers to a polyadenylic diphosphribose polymerase, which plays a key role in the DNA repair pathway. PARP inhibitors are one of the cancer therapies targeting Poly ADP-ribose Polymerase (Poly ADP-ribose Polymerase) and are the first successful anticancer drugs to gain approval for clinical use using the Synthetic Lethality (SL) concept. The market for global PARP inhibitors is currently about $ 10 billion. The fluxaparide is the first new target medicine declared to be on the market in China, the project is a great special subsidized new medicine, and the 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine is a key intermediate of the fluxaparide.

The synthetic documents of 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine are not reported in many places, and the prior art comprises the following steps:

on the whole, the existing synthesis process has low yield, difficult purification and poor economic benefit, needs to improve the existing process amplification, adopts cheaper and easily obtained raw materials, and develops a process suitable for industrial amplification.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the preparation method which is simple, convenient and stable to operate, easy to separate products in each step, high in yield, environment-friendly, low in production cost and suitable for industrial large-scale production of the 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine.

The invention provides a preparation method of 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine suitable for industrial amplification, and the reaction equation is as follows:

the method comprises the following steps: 2-aminopyrazine and ethyl trifluoroacetate are taken as raw materials, and the 2-trifluoromethyl [1,2,4] triazolo [1,5-a ] pyrazine is obtained through amidation reaction, substitution reaction and dehydration cyclization reaction.

Further, in the above technical solution, the method specifically includes the following steps:

step one, 2-aminopyrazine, organic alkali and ethyl trifluoroacetate react to generate 2,2, 2-trifluoro-N-pyrazin-2-yl acetamide;

secondly, reacting 2,2, 2-trifluoro-N-pyrazine-2-yl acetamide, phosphorus pentachloride and other chlorinated reagents in an organic solvent to generate 2,2, 2-trifluoro-N' -hydroxyl-N-pyrazine-2-yl ethylimine amide;

and thirdly, reacting the 2,2, 2-trifluoro-N' -hydroxy-N-pyrazin-2-ylethylimine amide, the 4-tosyl chloride and trifluoroacetic anhydride to generate the 2-trifluoromethyl [1,2,4] triazolo [1, 5-alpha ] pyrazine.

Further, in the above technical solution, in the first step, the organic base is selected from triethylamine, pyridine, 4-dimethylaminopyridine, 4-methylpyridine, N-dimethylaniline or N, N-diisopropylethylamine.

Further, in the above technical solution, in the first step, the molar ratio of 2-aminopyrazine, organic base and ethyl trifluoroacetate is 1: 0.05-0.3: 1-3.

Further, in the above technical solution, in the second step, the chlorinating reagent is thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus trichloride.

Further, in the above technical solution, in the second step, the molar ratio of 2,2, 2-trifluoro-N-pyrazin-2-yl acetamide, phosphorus pentachloride and other chlorinated reagents is 1: 1-1.5: 1-1.1.

Further, in the above technical solution, in the second step, the organic solvent is selected from chlorobenzene, acetonitrile or tetrahydrofuran.

Further, in the above technical scheme, in the third step, the molar ratio of 2,2, 2-trifluoro-N' -hydroxy-N-pyrazin-2-ylethylimine amide, 4-tosyl chloride and trifluoroacetic anhydride is 1: 0.5-1.1: 2-5.

Further, in the above technical scheme, in the third step, the product is purified after being recrystallized by using an ethyl acetate/hexane mixed solvent.

The invention has the beneficial effects that:

compared with the prior synthesis method, the invention has the following beneficial effects:

1. the invention adopts the cheap trifluoroacetic acid ethyl ester to replace the expensive trifluoroacetic anhydride, optimizes the preparation process, reduces the environmental pollution and greatly reduces the production cost.

2. The invention selects other organic solvents to replace dichloroethane. Dichloroethane is a class of solvents, a class of solvents that is known to be carcinogenic and is strongly suspected of being harmful to humans and the environment, and the use of such solvents should be avoided where possible.

3. The invention is simple and convenient to operate. In the prior art, PPA is used as a dehydrating reagent, but when PPA is used, the system is sticky, the post-treatment difficulty is high, and TFAA is used as the dehydrating reagent, so that the post-treatment is simple, and the operation cost is reduced.

4. The invention has high total reaction yield. The total reaction yield is more than 37%, and compared with the 8.1% yield of the existing process, the yield is remarkably improved, and the production cost is greatly reduced.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.

The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally carried out under conventional conditions.

The starting materials or reagents used in the following examples of the present invention are commercially available unless otherwise specified.

The average room temperature described in the following examples of the present invention is 20-35 ℃. Unless otherwise indicated, the reagents are not specifically indicated and are all used without purification. All solvents were purchased from commercial suppliers, such as Aldrich (Aldrich), and used without treatment. The reaction was analyzed by TLC or by HPLC, and the termination of the reaction was judged by the consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) precoated with silica gel 60F 2540.25 mm plates, developed with UV light (254nm) or iodine on silica gel, or TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or cerium sulfate solution were heated together.