阅读说明：本技术 3,6-二氮杂环[3.1.1]庚烷-6-羧酸叔丁酯的气相检测法 (Gas phase detection method of 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester ) 是由 陆茜 付杨杰 于 2021-09-08 设计创作，主要内容包括：本发明提供了一种3,6-二氮杂环[3.1.1]庚烷-6-羧酸叔丁酯的气相检测法,属于分析检测领域。本发明提供的3,6-二氮杂环[3.1.1]庚烷-6-羧酸叔丁酯的气相检测法,气相色谱的条件为：色谱柱温度：起始温度60℃-90℃,维持1min-5min,以18℃/min-22℃/min的速率升至130℃-180℃,维持3min-8min,再以30℃/min-45℃/min的速率升至280℃-320℃,保持5min-20min,检测器温度：280℃-320℃,进样口温度：260℃-300℃,载气：氮气,柱流速：1mL/min-2mL/min,分流比：(18-22):1,氢气流速：20mL/min-40mL/min,空气流速：280mL/min-320mL/min,尾吹气流速：20mL/min-30mL/min。因为发明采用了特定的气相色谱条件,所以,本发明能够将目标产物3,6-二氮杂环[3.1.1]庚烷-6-羧酸叔丁酯和在合成该化合物过程中产生的杂质有效分离,从而能够更有效准确地监控反应以及鉴定产物纯度。(The invention provides a gas phase detection method of 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester, belonging to the field of analysis and detection. The gas phase detection method of 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention has the following conditions of gas chromatography: temperature of the column: the initial temperature is 60-90 ℃, the temperature is maintained for 1-5 min, the temperature is increased to 130-180 ℃ at the speed of 18-22 ℃/min, the temperature is maintained for 3-8 min, the temperature is increased to 280-320 ℃ at the speed of 30-45 ℃/min, the temperature is maintained for 5-20 min, and the temperature of a detector is as follows: 280-320 ℃, injection port temperature: 260 ℃ to 300 ℃, carrier gas: nitrogen, column flow rate: 1mL/min-2mL/min, split ratio: (18-22) 1, hydrogen flow rate: 20mL/min-40mL/min, air flow rate: 280mL/min-320mL/min, tail gas blowing flow rate: 20mL/min-30 mL/min. Because the invention adopts specific gas chromatography conditions, the invention can effectively separate the target product 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester from impurities generated in the process of synthesizing the compound, thereby more effectively and accurately monitoring the reaction and identifying the purity of the product.)

1. A gas-phase detection method of 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester is characterized in that the conditions of gas chromatography are as follows:

temperature of the column: the initial temperature is 60-90 ℃, the temperature is maintained for 1-5 min, the temperature is increased to 130-180 ℃ at the speed of 18-22 ℃/min, the temperature is maintained for 3-8 min, the temperature is increased to 280-320 ℃ at the speed of 30-45 ℃/min, and the temperature is maintained for 5-20 min; or

The initial temperature is 60-90 ℃, the temperature is maintained for 1-5 min, the temperature is increased to 130-180 ℃ at the speed of 18-22 ℃/min, the temperature is maintained for 2-5 min, the temperature is increased to 190-210 ℃ at the speed of 3-7 ℃/min, the temperature is maintained for 2-5 min, the temperature is increased to 280-320 ℃ at the speed of 30-45 ℃/min, the temperature is maintained for 5-20 min,

detector temperature: at the temperature of 280-320 ℃,

sample inlet temperature: the temperature of the mixture is 260-300 ℃,

carrier gas: the nitrogen gas is introduced into the reaction kettle,

column flow rate: 1mL/min-2mL/min,

the split ratio is as follows: (18-22):1,

hydrogen flow rate: 20mL/min-40mL/min,

air flow rate: 280mL/min-320mL/min,

tail gas blowing flow rate: 20mL/min-30 mL/min.

2. The gas-phase detection method of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate according to claim 1, characterized by:

wherein the gas chromatography conditions further comprise:

the sample concentration is 5mg/mL-20 mg/mL.

3. The gas-phase detection method of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate according to claim 1, characterized by:

wherein the gas chromatography conditions further comprise:

the diluent is any one or more of methanol, ethanol, dichloromethane, dimethyl sulfoxide, N-dimethylformamide or N-methylpyrrolidone.

4. The gas-phase detection method of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate according to claim 3, characterized in that:

wherein the diluent is dichloromethane.

5. The gas-phase detection method of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate according to claim 1, characterized by:

wherein the gas chromatography conditions further comprise:

the sample amount is 1-2 μ L.

6. The gas-phase detection method of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate according to claim 1,

wherein the gas chromatography conditions further comprise:

the column was Agilent HP-5,30 m.times.0.32 mm.times.0.25. mu.m.

7. The gas-phase detection method of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate according to claim 1,

wherein the temperature of the chromatographic column is 80 ℃ at the beginning, the temperature is maintained for 2min, the temperature is increased to 140 ℃ at the rate of 20 ℃/min, the temperature is maintained for 5min, the temperature is increased to 300-320 ℃ at the rate of 40 ℃/min, and the temperature is maintained for 10 min.

8. The gas-phase detection method of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate according to claim 1,

wherein the temperature of the chromatographic column is 80 ℃ at the starting temperature, the temperature is maintained for 2min, the temperature is increased to 180 ℃ at the speed of 20 ℃/min, the temperature is maintained for 2min, the temperature is increased to 200 ℃ at the speed of 5 ℃/min, the temperature is maintained for 3min, the temperature is increased to 280 ℃ at the speed of 30 ℃/min, and the temperature is maintained for 5 min.

Technical Field

The invention relates to an analytical detection method, in particular to a gas phase detection method of 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester.

Background

The diazacyclo structure of 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester is a very common and useful drug fragment, and in the prior art, many drugs contain the structure, for example, American Gift corporation develops a drug for treating metastatic non-small cell lung cancer positive for transfection rearrangement gene fusion, which contains a diaza-ring structure, the drug is named Selpercatinib, and the structural formula is as follows:

according to the reports of the documents such as WO 2018071447A 1 and WO2020114494A1, the synthesis process of Selpercatinib requires the tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate as a reaction intermediate, which also puts certain requirements on the purity of the tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate.

In the prior art, constant synthesis of N³-and N ⁶-monoprotected 3,6-diazabicyclo[3.1.1]heptanes; useful intermediates for the preparation of novel branched bicyclic piperazines (Tetrahedron Letters,2012,53(47):6332-]The synthesis method of the heptane-6-carboxylic acid tert-butyl ester comprises the following steps:

applicants have developed an alternative route to 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester, the reaction equation being:

however, both of the above routes produce an impurity during the synthesis which, in the prior art, is difficult to separate from the main product peak by gas chromatography, which presents certain difficulties in monitoring the reaction and identifying the purity of the product.

Disclosure of Invention

The present invention has been made to solve the above problems, and an object of the present invention is to provide a gas phase detection method capable of rapidly and efficiently identifying the purity of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate.

The invention provides a gas phase detection method of 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester, which is characterized in that the conditions of gas chromatography are as follows: temperature of the column: the initial temperature is 60-90 ℃, the temperature is maintained for 1-5 min, the temperature is increased to 130-180 ℃ at the speed of 18-22 ℃/min, the temperature is maintained for 3-8 min, the temperature is increased to 280-320 ℃ at the speed of 30-45 ℃/min, and the temperature is maintained for 5-20 min; or the initial temperature is 60-90 ℃, the temperature is maintained for 1-5 min, the temperature is increased to 130-180 ℃ at the speed of 18-22 ℃/min, the temperature is maintained for 2-5 min, the temperature is increased to 190-210 ℃ at the speed of 3-7 ℃/min, the temperature is maintained for 2-5 min, the temperature is increased to 280-320 ℃ at the speed of 30-45 ℃/min, the temperature is maintained for 5-20 min, and the temperature of a detector: 280-320 ℃, injection port temperature: 260 ℃ to 300 ℃, carrier gas: nitrogen, column flow rate: 1mL/min-2mL/min, split ratio: (18-22) 1, hydrogen flow rate: 20mL/min-40mL/min, air flow rate: 280mL/min-320mL/min, tail gas blowing flow rate: 20mL/min-30 mL/min.

The gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention can also have the following characteristics: wherein, the gas chromatography conditions further comprise: the sample concentration is 5mg/mL-20 mg/mL.

The gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention can also have the following characteristics: wherein, the gas chromatography conditions further comprise: the diluent is any one or more of methanol, ethanol, dichloromethane, dimethyl sulfoxide, N-dimethylformamide or N-methylpyrrolidone.

The gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention can also have the following characteristics: wherein the diluent is dichloromethane.

The gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention can also have the following characteristics: wherein, the gas chromatography conditions further comprise: the sample amount is 1-2 μ L.

The gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention can also have the following characteristics: wherein, the gas chromatography conditions further comprise: the column was Agilent HP-5,30 m.times.0.32 mm.times.0.25. mu.m.

The gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention can also have the following characteristics: wherein the temperature of the chromatographic column is 80 ℃ at the starting temperature, the chromatographic column is maintained for 2min, the chromatographic column is heated to 140 ℃ at the speed of 20 ℃/min, the chromatographic column is maintained for 5min, and the chromatographic column is heated to 300-320 ℃ at the speed of 40 ℃/min and maintained for 10 min.

The gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester provided by the invention can also have the following characteristics: wherein the temperature of the chromatographic column is 80 deg.C at the initial temperature, and is maintained for 2min, and is increased to 180 deg.C at a rate of 20 deg.C/min, and is maintained for 2min, and is increased to 200 deg.C at a rate of 5 deg.C/min, and is maintained for 3min, and is increased to 280 deg.C at a rate of 30 deg.C/min, and is maintained for 5 min.

Action and Effect of the invention

According to the gas phase detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester, which is related by the invention, because a specific gas chromatography condition is adopted, the invention can effectively separate the target product of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester from impurities generated in the process of synthesizing the compound, thereby more effectively and accurately monitoring the reaction and identifying the purity of the product.

Drawings

FIG. 1 is a gas chromatogram of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate of example 1-1 according to the present invention;

FIG. 2 is a gas chromatogram of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate of example 1-2 according to the present invention;

FIG. 3 is a gas chromatogram of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate of example 2 according to the present invention;

FIG. 4 is a gas chromatogram of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate of example 3 according to the present invention;

FIG. 5 is a gas chromatogram of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate of example 4 according to the present invention;

FIG. 6 is a gas chromatogram of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate of comparative example 1 in accordance with the present invention;

FIG. 7 is a gas chromatogram of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate of comparative example 2 according to the present invention.

Detailed Description

In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the invention is specifically described below by combining the embodiment and the attached drawings.

In the following examples and comparative examples, the gas instrument used was an Agilent model 8860 gas chromatograph (Agilent8860 with FID detector) equipped with a flame ionization detector, manufactured by Agilent.

In the following examples and comparative examples, all columns used were commercial columns manufactured by Agilent.

In the following examples and comparative examples, samples tested were, unless otherwise stated, made in the reference paper, Circuit Synthesis of N³-and N⁶-monoprotected 3,6-diazabicyclo[3.1.1]heptanes; obtained by the optimum method described in the publication of novel branched bicyclic piperazines (Tetrahedron Letters,2012,53(47): 6332-6334) without further purification.

< examples 1 to 1>

This example provides a gas chromatography of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate under the conditions shown in Table 1:

table 1 example 1-1 table of gas chromatography conditions

As shown in fig. 1, the main product peak (RT ═ 8.995) and the impurity peak (RT ═ 10.158) were separated by 10.1 in gas chromatography, and the separation was good and the peak pattern was good.

< examples 1 and 2>

This example provides a gas chromatography method for detecting tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate, which is identical to that of example 1-1 except that the sample used in this example is further purified to remove impurities.

The gas chromatogram obtained in this example is shown in fig. 2, the baseline is smooth, and no peak is found at the position corresponding to the impurity peak, indicating that the impurity has been completely separated.

< example 2>

This example provides a gas chromatography of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate under the conditions shown in Table 2:

table 2 example 2 table of gas chromatography conditions

As shown in fig. 3, the gas chromatogram showed that the main product peak (RT ═ 8.125) and the impurity peak (RT ═ 8.604) could be separated, but the degree of separation was only 6.1 less than that of example 1-1.

< example 3>

This example provides a gas chromatography of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate under the conditions shown in Table 3:

table 3 example 3 table of gas chromatography conditions

As shown in fig. 4, the gas chromatogram showed that the main product peak (RT ═ 8.483) and the impurity peak (RT ═ 9.150) could be separated, but the degree of separation was 8.0 slightly better than in example 2 but lower than in example 1-1.

< example 4>

This example provides a gas chromatography of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate under the conditions shown in Table 4:

table 4 example 4 table of gas chromatography conditions

As shown in fig. 5, the gas chromatogram shows that the main product peak (RT ═ 7.915) and the impurity peak (RT ═ 8.321) can be separated, but the degrees of separation are poor.

< comparative example 1>

This comparative example provides a gas detection of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate under the gas chromatographic conditions shown in Table 5:

TABLE 5 gas chromatography Condition Table for comparative example 1

The gas chromatogram obtained in this comparative example is shown in fig. 6, and the peak pattern is poor, and the degree of separation of the main product peak from the impurity peak is poor.

< comparative example 2>

This comparative example provides a gas detection of tert-butyl 3, 6-diazacyclo [3.1.1] heptane-6-carboxylate under the gas chromatographic conditions shown in Table 6:

TABLE 6 gas chromatography Condition Table for comparative example 2

The gas chromatogram obtained in this comparative example is shown in fig. 7, and the peak pattern was poor, the baseline was uneven, and an impurity peak could not be detected.

Effects and effects of the embodiments

According to the gas detection method of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester related to the embodiment, because specific gas chromatographic conditions are adopted, in particular an AgilentHP-5 chromatographic column is adopted, the invention can effectively separate the target product of the 3, 6-diazacyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester from impurities generated in the process of synthesizing the compound, thereby more effectively and accurately monitoring the reaction and identifying the purity of the product.

The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.