Synthetic method of bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate and application thereof

Abstract

The invention discloses a synthetic method of bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate and an application thereof. The bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate is prepared through a methyl sulfonylation reaction, a hydrocarbylation reaction, a Grignard reaction and a Suzuki coupling reaction by taking cheap and easily available N-Boc-4-hydroxyl piperidine as a raw material. The synthetic method is simple, the process is easy to control, and the yield of the prepared bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate is 86.7%; bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate can be used as a standard substance to detect and monitor synthesis of crizotinib. The synthetic method disclosed by the invention is suitable for synthesizing bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate and the synthesized substance is used for detecting and monitoring synthesis of crizotinib.

Description

technical field

[0001] The invention belongs to the field of pharmacy, and relates to a synthesis method of pharmaceutical intermediate impurities, in particular to a synthesis method of bis-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester and a synthesis product of the corresponding synthesis application. Background technique

[0002] In the process of drug synthesis, it is usually accompanied by the generation of impurities, and the research on impurities directly or indirectly affects the quality of the drug. The adverse reactions of the drug in clinical use are not only related to the pharmacological activity of the drug itself, but sometimes related to the drug itself. The presence of impurities also has a great relationship. Most impurities in drugs have potential biological activity and cytotoxicity. Therefore, the content of impurities may affect the safety and effectiveness of drugs, and even cause toxicity. The control of drug impurities plays a k...

Examples

Embodiment 1

[0045] Example 1 The synthetic method of two-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0046] The present embodiment is a kind of synthetic method of bis-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester, which is carried out according to the following steps:

[0047] (11) Mesylation reaction

[0048] Take 1mol N-Boc-4-hydroxypiperidine and dissolve it in MTBE / triethylamine mixed solution with a volume ratio of 10:1 at -10°C, add 1.3mol methanesulfonyl chloride (the manufacturer of methanesulfonyl chloride) dropwise Zhengzhou Haorong Chemical Products Co., Ltd.), keep warm for 2 hours after the dropwise addition; add water to quench the reaction, separate the organic phase, add a mixed solution of petroleum ether / n-heptane with a volume ratio of 62:38, and crystallize to obtain compound 1 -Boc-4-methanesulfonyloxypiperidine, denoted as A1;

[0049] The NMR image of A1 is as follows figure 1 As shown, the specific NMR data are as follo...

Embodiment 2-5

[0066] Example 2-5 The synthetic method of two-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0067] Embodiment 2-5 is respectively a kind of synthetic method of bis-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester, and their synthetic method is similar to that of Example 1, the difference is only The reason is that the corresponding technical parameters are different during the synthesis process, see the table below for details.

[0068] Table 1 Technical parameter table

[0069]

Embodiment 6

[0070] Example 6 Suzuki coupling reaction condition screening test

[0071] In the process of preparing the target product, in the Suzuki coupling reaction process, the selection of solvent, reaction temperature, reaction time, alkali amount, and phase transfer catalyst dosage are important. In order to explore this condition, the following experiments were carried out in this embodiment:

[0072] Table 2-1 Suzuki coupling reaction condition parameter table

[0073]

[0074] Table 2-2 Parameter table of Suzuki coupling reaction conditions

[0075]

[0076] Table 2-3 Parameter table of Suzuki coupling reaction conditions

[0077]

[0078] Table 2-4 Parameter table of Suzuki coupling reaction conditions

[0079]

[0080] Table 2-5 Parameters of Suzuki coupling reaction conditions

[0081]

technical field

[0001] The invention belongs to the field of pharmacy, and relates to a synthesis method of pharmaceutical intermediate impurities, in particular to a synthesis method of bis-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester and a synthesis product of the corresponding synthesis application. Background technique

[0002] In the process of drug synthesis, it is usually accompanied by the generation of impurities, and the research on impurities directly or indirectly affects the quality of the drug. The adverse reactions of the drug in clinical use are not only related to the pharmacological activity of the drug itself, but sometimes related to the drug itself. The presence of impurities also has a great relationship. Most impurities in drugs have potential biological activity and cytotoxicity. Therefore, the content of impurities may affect the safety and effectiveness of drugs, and even cause toxicity. The control of drug impurities plays a k...

Examples

Embodiment 1

[0045] Example 1 The synthetic method of two-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0046] The present embodiment is a kind of synthetic method of bis-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester, which is carried out according to the following steps:

[0047] (11) Mesylation reaction

[0048] Take 1mol N-Boc-4-hydroxypiperidine and dissolve it in MTBE / triethylamine mixed solution with a volume ratio of 10:1 at -10°C, add 1.3mol methanesulfonyl chloride (the manufacturer of methanesulfonyl chloride) dropwise Zhengzhou Haorong Chemical Products Co., Ltd.), keep warm for 2 hours after the dropwise addition; add water to quench the reaction, separate the organic phase, add a mixed solution of petroleum ether / n-heptane with a volume ratio of 62:38, and crystallize to obtain compound 1 -Boc-4-methanesulfonyloxypiperidine, denoted as A1;

[0049] The NMR image of A1 is as follows figure 1 As shown, the specific NMR data are as follo...

Embodiment 2-5

[0066] Example 2-5 The synthetic method of two-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0067] Embodiment 2-5 is respectively a kind of synthetic method of bis-4-(1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester, and their synthetic method is similar to that of Example 1, the difference is only The reason is that the corresponding technical parameters are different during the synthesis process, see the table below for details.

[0068] Table 1 Technical parameter table

[0069]

Embodiment 6

[0070] Example 6 Suzuki coupling reaction condition screening test

[0071] In the process of preparing the target product, in the Suzuki coupling reaction process, the selection of solvent, reaction temperature, reaction time, alkali amount, and phase transfer catalyst dosage are important. In order to explore this condition, the following experiments were carried out in this embodiment:

[0072] Table 2-1 Suzuki coupling reaction condition parameter table

[0073]

[0074] Table 2-2 Parameter table of Suzuki coupling reaction conditions

[0075]

[0076] Table 2-3 Parameter table of Suzuki coupling reaction conditions

[0077]

[0078] Table 2-4 Parameter table of Suzuki coupling reaction conditions

[0079]

[0080] Table 2-5 Parameters of Suzuki coupling reaction conditions

[0081]

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