Detection method for rapidly tracking synthetic reaction of 2, 3-dihydrobenzofuran

Abstract

The invention discloses a detection method for rapidly tracking a synthesis reaction of 2, 3-dihydrobenzofuran in the technical field of medical analysis, and the 2, 3-dihydrobenzofuran is detected by using a gas chromatography. According to the gas chromatography method, a dimethyl polysiloxane capillary chromatographic column is selected, and the method is suitable for detection of weak-polarity compounds. The gas chromatography method adopts an FID (Flame Ionization Detector). The method is high in response value, the 2, 3-dihydrobenzofuran product and impurities can be rapidly and effectively separated, the detection method is easy to operate, the stop time of the synthetic reaction can be fed back in time, over-reduced impurities are controlled at an extremely low level, the subsequent separation and purification operation is simple, high-purity products can be efficiently obtained, and the method is suitable for industrial production. And the applicability, specificity and sample introduction precision of the system all meet the requirements, and the problem of control of the synthetic reaction of the substance is solved.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical analysis, and in particular to a detection method for quickly tracking a 2,3-dihydrobenzofuran synthesis reaction. Background Art

[0002] A pharmaceutical intermediate, chemical name: 2,3-dihydrobenzofuran, CAS number: 496-16-2, structural formula is as follows:

[0003]

[0004] 2,3-Dihydrobenzofuran is a fine chemical raw material, widely used in the synthesis of tricyclic compounds, and is also an intermediate raw material for the synthesis of some important drugs discovered in recent years. 2,3-Dihydrobenzofuran is an intermediate raw material for the anti-tumor preparation benzofuran sulfonylurea compound I1, HIV protease inhibitor amino acid hydroxyethylaminosulfonyl, matrix metalloproteinase inhibitor aromatic sulfenamide isoxime hydroxy acid, etc.

[0005] As a raw material for the synthesis of high-quality APIs, the presence of impurities in this intermediate will directly affect the quality of the product, especially the content of certain specific impurities will have a significant impact on the purity of subsequent products. The existing synthesis methods mostly use catalytic hydrogenation. Due to the nature of the compound itself, the impurities produced by over-reduction are difficult to separate from the product. Therefore, it is necessary to strictly track and monitor the reaction and stop the reaction in time, so that the over-reduction impurities can be well controlled at an extremely low level, making the subsequent separation and purification operations simple and conducive to the efficient acquisition of high-purity products. The existing technology mostly uses high-performance liquid chromatography for analysis, and this method uses gas chromatography for analysis. Compared with liquid chromatography, it reduces the intermediate dilution and preparation links, is simpler and faster, shortens the analysis waiting time, avoids the problem of over-reaction, and has a good separation degree. The analytical method is verified by the analytical method. Summary of the invention

[0006] The purpose of the present invention is to develop a detection method for quickly tracking the synthesis reaction of 2,3-dihydrobenzofuran, which can quickly track and detect the synthesis reaction of 2,3-dihydrobenzofuran and can effectively detect and control impurities, and stop the reaction in time, so that over-reduction impurities can be well controlled at an extremely low level, making subsequent separation and purification operations simple and conducive to efficiently obtaining high-purity products.

[0007] The technical solution adopted by the present invention is as follows: a detection method for rapidly tracking the synthesis reaction of 2,3-dihydrobenzofuran, wherein the test sample is directly sampled, gas chromatography is used for detection, and impurities are effectively separated, wherein the specific impurity is 2,3-benzofuran and the over-reduced impurity is 4,7-dihydrobenzofuran;

[0008] The gas chromatography column is a dimethyl polysiloxane capillary column MEGA-1.

[0009] The gas chromatography detector temperature is 260-280°C, the detector temperature is 280-300°C;

[0010] In constant pressure mode, the column pressure is 40-60 kPa, and the split ratio is 60:1-100:1; the programmed temperature rise mode is selected;

[0011] The injection volume for gas chromatography is 0.1-0.5 μl;

[0012] The gas chromatography method uses a non-polar gas chromatography column;

[0013] The gas chromatography method adopts a FID detector;

[0014] The detection steps of the gas chromatography are:

[0015] Set the gas chromatograph according to the chromatographic conditions until the baseline is stable and wait for injection;

[0016] Test solution: Take the test sample and inject it directly;

[0017] According to the above chromatographic conditions, the sample was automatically injected, the peak area was recorded, and the specific impurity content and the purity of 2,3-dihydrobenzofuran were calculated according to the area normalization method. The calculation formula is as follows:

[0018]

[0019]

[0020] Where:

[0021] A 2,3-苯并呋喃 —Peak area of ​​2,3-benzofuran in the test solution;

[0022] A 4,7-二氢苯并呋喃 —The peak area of ​​4,7-dihydrobenzofuran in the test solution;

[0023] A 2,3-二氢苯并呋喃 —The peak area of ​​2,3-dihydrobenzofuran in the test solution;

[0024] A 总 —The peak area of ​​all chromatographic peaks in the test solution after deducting the blank.

[0025] In the present invention, the structural formula of 2,3-dihydrobenzofuran is as follows:

[0026]

[0027] The structural formula of the specific impurity 2,3-benzofuran is as follows:

[0028]

[0029] The structural formula of the over-reduced impurity 4,7-dihydrobenzofuran is as follows:

[0030]

[0031] The chromatographic column is a MEGA-1 chromatographic column with a specification of 30m×0.25mm×0.5μm.

[0032] Furthermore, the gas chromatography column pressure is 40-60 kPa, including but not limited to 40 kPa, 50 kPa, and 60 kPa.

[0033] Furthermore, the heating program is as follows: initial temperature 60-80°C, hold for 0 min, heating to 160-180°C at 15°C / min, hold for 5 min, heating to 240-260°C at 30°C / min, hold for 5 min;

[0034] Beneficial effects: The instrument provided by the present invention has low operating cost, simple and convenient detection process, good repeatability, and can be used to evaluate product quality. The present invention has a high response value, can quickly and effectively separate 2,3-dihydrobenzofuran products and impurities, the detection method is simple to operate, can timely feedback the stop time of the synthesis reaction, control the over-reduction impurities at an extremely low level, and make the subsequent separation and purification operation simple, which is conducive to efficiently obtaining high-purity products, and the system applicability, specificity, and injection precision all meet the requirements, solving the control problem of the synthetic reaction of the substance. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the chromatogram of the 2,3-dihydrobenzofuran test solution.

[0036] Figure 2 This is the chromatogram of the 2,3-dihydrobenzofuran system suitability solution. DETAILED DESCRIPTION

[0037] The present invention is further described below in conjunction with embodiments and drawings, but the present invention is not limited to the following embodiments.

[0038] Gas Chromatographic Detection Method for 2,3-Dihydrobenzofuran

[0039] The instruments and chemical tests used in the examples include: gas chromatograph (Agilent 8860, Agilent); electronic balance (BS124S, Sartorius); MEGA-1 chromatographic column (30 m×0.25 mm×0.5 μm, Mega).

[0040] Example 1

[0041] 1. Gas chromatography analysis conditions:

[0042] Chromatographic column: MEGA-1 chromatographic column (30m×0.25mm×0.5μm, Mega)

[0043] The gas chromatography injection port temperature was 280°C; the detection temperature was 280°C;

[0044] The column pressure was 40 kPa and the split ratio was 100:1;

[0045] The heating program was as follows: initial temperature 60°C, hold for 0 min, heating to 160°C at 15°C / min, hold for 5 min, heating to 260°C at 30°C / min, hold for 5 min;

[0046] The injection volume for gas chromatography was 0.2 μl, and the sample was injected directly

[0047] 2. Determination

[0048] GC-FID was used for detection, and the detection conditions were as described above.

[0049] Take blank and test solution and inject them into liquid chromatograph, record the chromatogram, the injection sequence is as follows:

[0050] name Number of injection needles blank ≥2, until the two needles completely overlap without interference Test solution 1

[0051] 3. Results

[0052] The test results of the test product are shown in Figure 1 Using this method, the retention time of the main peak (2,3-dihydrobenzofuran) is 11.458 min, and the total acquisition time is 20 min. This detection method is simple and fast.

[0053] Example 2

[0054] 1. System suitability

[0055] 1.1 Solution preparation:

[0056] Blank: Methanol

[0057] System suitability solution: Take 10μl of methanol, 10μl of 2,3-benzofuran (specific impurity), and 10μl of 4,7-dihydrobenzofuran (over-reduced impurity) respectively and put them into the same 1ml volumetric flask, add 2,3-dihydrobenzofuran to dilute to the scale, shake well, and obtain.

[0058] Test solution: Take an appropriate amount of this product and inject it directly.

[0059] 1.2 Determination method

[0060] Take blank, system suitability solution, and test solution and inject them in the following order and record the chromatogram. Injection order:

[0061]

[0062]

[0063] 1.3 Results

[0064] Depend on Figure 2 It can be seen that there is no interference in the blank; the separation degrees of the main peak (2,3-dihydrobenzofuran), over-reduced impurity (4,7-dihydrobenzofuran) and specific impurity peak (2,3-benzofuran) in the system suitability solution and the adjacent components are all greater than 1.5.

[0065]

[0066] 2. Injection precision

[0067] 2.1 Solution preparation:

[0068] Take the test solution under 1.1 and inject 6 times continuously, and record the chromatogram.

[0069] 2.2 Results:

[0070]

[0071]

[0072] The above content is a further detailed description of the technical solution provided in combination with the preferred implementation mode of the present invention. It cannot be determined that the specific implementation of the present invention is limited to the above descriptions. For ordinary technicians in the technical field to which the present invention belongs, without departing from the concept of the present invention, some simple deductions or substitutions can be made, which should be considered as falling within the protection scope of the present invention as needed.

Claims

1. A detection method for rapidly tracking the synthesis reaction of 2,3-dihydrobenzofuran, characterized in that: The test sample was directly injected and tested by gas chromatography, and the impurities were effectively separated, among which the specific impurity was 2,3-benzofuran and the over-reduced impurity was 4,7-dihydrobenzofuran; The gas chromatography column is a dimethyl polysiloxane capillary column MEGA-1. The gas chromatography detector temperature is 260-280°C, the detector temperature is 280-300°C; In constant pressure mode, the column pressure is 40-60 kPa, and the split ratio is 60:1-100:1; the programmed temperature rise mode is selected; The injection volume for gas chromatography is 0.1-0.5 μl; The gas chromatography method uses a non-polar gas chromatography column; The gas chromatography method adopts a FID detector; The detection steps of the gas chromatography are: Set the gas chromatograph according to the chromatographic conditions until the baseline is stable and wait for injection; Test solution: Take the test sample and inject it directly; According to the above chromatographic conditions, the sample was automatically injected, the peak area was recorded, and the specific impurity content and the purity of 2,3-dihydrobenzofuran were calculated according to the area normalization method. The calculation formula is as follows: Where: A 2,3-苯并呋喃 —Peak area of ​​2,3-benzofuran in the test solution; A 4,7-二氢苯并呋喃 —The peak area of ​​4,7-dihydrobenzofuran in the test solution; A 2,3-二氢苯并呋喃 —The peak area of ​​2,3-dihydrobenzofuran in the test solution; A 总 —The peak area of ​​all chromatographic peaks in the test solution after deducting the blank.

2. A detection method for rapidly tracking the synthesis reaction of 2,3-dihydrobenzofuran according to claim 1, characterized in that: The test solution was directly injected, and the concentration of the impurity localization solution was about 10 μg / ml.

3. A detection method for rapidly tracking the synthesis reaction of 2,3-dihydrobenzofuran according to claim 1, characterized in that: The specifications of the chromatographic column are 30m×0.25mm×0.5μm.

4. A detection method for rapidly tracking the synthesis reaction of 2,3-dihydrobenzofuran according to claim 1, characterized in that: The heating program was as follows: initial temperature 60-80°C, hold for 0 min, heating to 160-180°C at 15°C / min, hold for 5 min, heating to 240-260°C at 30°C / min, hold for 5 min.

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