Alfacalcidol chiral selection reaction endpoint determination method and device

Abstract

The invention belongs to the technical field of drug synthesis, and discloses a method and a device for judging an alfacalcidol chiral selection reaction endpoint. The end point judgment method comprises the following steps: (1) adding raw materials such as intermediate alfacalcidol and the like in prescription dosage into a reaction container according to a preset process; (2) inserting an optical rotation determination test tube into the reaction liquid through a hose, arranging a peristaltic pump on the hose, and placing the optical rotation determination test tube in a polarimeter; and (3) starting the peristaltic pump and the polarimeter, continuously measuring the optical rotation of the reaction liquid through the polarimeter, measuring each point for N times (N is greater than or equal to 3), taking an average value, recording average change values, and judging that the reaction endpoint is generated when the average value of the three average change values is less than 2. According to the method, the reaction device is creatively and directly combined with the polarimeter, the optical rotation change condition of the reaction liquid is measured in real time through the polarimeter, whether the synthetic reaction reaches the end point or not is indirectly judged accordingly, and the measuring method is accurate, high in efficiency and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and relates to a method for synthesizing alfacalcidol, and in particular to a method and a device for determining the end point of a chiral selective reaction of alfacalcidol. Background Art

[0002] Alfacalcidol, chemically named 9,10-secocholesteryl-5Z,7E,10(19)-triene-1a,3b-diol, is a fat-soluble sterol in vitamin D compounds. It is a substance involved in the internal environment stability of calcium and phosphorus and the mineralization process of bones, and is a relatively important active metabolite of vitamin D3. It has the effects of treating osteoporosis in postmenopausal women and middle-aged and elderly people, hypoparathyroidism, vitamin D3-dependent rickets, renal osteodystrophy, and renal rickets, renal bone lesions, hypoparathyroidism caused by various kidney diseases such as renal failure.

[0003] At present, the synthesis of alfacalcidol generally adopts the following method: weigh the prescribed amount of alfacalcidol and dichloromethane, add them to the reaction bottle, and then add ethyl acetate solvent to dissolve; then add the prescribed amount of maleic anhydride, insert a condenser, connect the top of the condenser to an argon balloon device, pass argon protection, stir the reaction, and use HPLC to detect the reaction end point. The existing endpoint determination method of the alfacalcidol synthesis reaction adopts HPLC detection, which is inefficient, complicated to operate, and not suitable for automated production. Summary of the invention

[0004] The present invention solves the above technical problems existing in the existing HPLC detection and determination method and proposes a method for determining the endpoint of the chiral selective reaction of alfacalcidol with high determination efficiency and suitable for industrial production.

[0005] To achieve the above object, the present invention adopts the following technical solutions:

[0006] The first aspect of the present invention is to provide a method for determining the endpoint of the chiral selective reaction of alfacalcidol, comprising the following steps:

[0007] (1) The inlet and outlet of the optical rotation test tube at both ends are inserted into the reaction container through a hose, a peristaltic pump is arranged on the hose pipeline, and the optical rotation test tube is placed in the polarimeter;

[0008] (2) adding the intermediate alfacalcidol, dichloromethane, ethyl acetate and maleic anhydride in the prescribed amount into the reaction vessel according to the preset process to carry out a synthesis reaction, and inserting the hose of step (1) into the reaction solution;

[0009] (3) Turn on the peristaltic pump and the polarimeter, and continuously measure the optical rotation of the reaction solution using the polarimeter. Measure each point N times (N ≥ 3) and take the average value. Record the average change value. When the average of the three average change values ​​is less than 2, it can be determined as the reaction endpoint.

[0010] Preferably, in step (1), the left and right ends of the optical rotation measuring tube are coaxially arranged between the light source and the probe of the polarimeter.

[0011] Preferably, in step (2), the reaction formula of the synthesis reaction is as follows:

[0012]

[0013] Preferably, in step (2), after adding maleic anhydride to the reaction vessel, a condenser is inserted, argon gas is introduced for protection, and the optical rotation value is measured after stirring the reaction for about 5 hours.

[0014] In step (3), the measurement time node is to measure N times (N≥3) every 15 minutes to take the average value, and record the average change value of the optical rotation. When the average of the three average change values ​​is less than 1, it can be determined as the reaction endpoint.

[0015] The second aspect of the present invention is to provide an end point determination device for the chiral selective reaction of alfacalcidol used in the above method, comprising a reaction device, a detection device and a peristaltic pump, wherein:

[0016] The detection device comprises an optical rotation test tube and a polarimeter, wherein the optical rotation test tube is placed between a light source and a probe of the polarimeter;

[0017] The inlets and outlets at both ends of the optical rotation measuring test tube are respectively inserted into the reaction liquid in the reaction device through flexible pipes, and the peristaltic pump is arranged on the pipeline of the flexible pipe.

[0018] Preferably, the reaction device is a reaction container, which is a round-bottom flask, a three-necked flask, a conical flask or a distillation flask.

[0019] Preferably, the left and right ends of the optical rotation measuring tube are horizontally arranged between the light source and the probe.

[0020] Preferably, the liquid inlet and the liquid outlet on the optical rotation measuring test tube are arranged on the same side or diagonally.

[0021] Preferably, the optical rotation measuring test tube is made of transparent glass.

[0022] The present invention adopts the above technical solution, and has the following technical effects compared with the prior art:

[0023] (1) The present invention creatively combines the reaction device directly with the polarimeter, and uses the detection device to directly circulate the reaction liquid in the reaction to the polarimeter, and uses the polarimeter to measure the change of the optical rotation of the reaction liquid in real time, and indirectly judges whether the synthesis reaction has reached the end point. The determination method is accurate, efficient, and suitable for industrial production applications;

[0024] (2) The detection device of the present invention consists of an optical rotation test tube and a polarimeter. The optical rotation test tube is placed between the light source and the probe of the polarimeter, and the inlet and outlet at both ends of the test tube are respectively inserted into the reaction device through hoses, and a peristaltic pump is arranged on the hose of the liquid inlet. The peristaltic pump is used to circulate the reaction liquid between the reaction device and the polarimeter to achieve the purpose of dynamic measurement. The determination device has a simple and novel structural design, is easy to install and disassemble, and is stable and reliable. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the reaction formula for the chiral selective reaction of alfacalcidol of the present invention;

[0026] Figure 2 The structural principle of the end point determination device for the chiral selective reaction of alfacalcidol of the present invention Figure 1 ;

[0027] Figure 3 The structural principle of the end point determination device for the chiral selective reaction of alfacalcidol of the present invention Figure 2 ;

[0028] Among them, the reference numerals of the figures are: 100 - reaction device; 200 - detection device, 210 - optical rotation measurement tube, 211 - liquid inlet, 212 - liquid outlet, 220 - light source, 230 - probe. DETAILED DESCRIPTION

[0029] First, the present invention provides a method for determining the endpoint of the chiral selective reaction of alfacalcidol, which specifically comprises the following steps:

[0030] (1) The inlet and outlet of the optical rotation test tube at both ends are inserted into the reaction container through a hose, a peristaltic pump is arranged on the hose pipeline, and the optical rotation test tube is placed in the polarimeter;

[0031] (2) adding the intermediate alfacalcidol, dichloromethane, ethyl acetate and maleic anhydride in the prescribed amount into the reaction vessel according to the preset process to carry out a synthesis reaction, and inserting the hose of step (1) into the reaction solution;

[0032] (3) Turn on the peristaltic pump and the polarimeter. During the reaction, the polarimeter is used to continuously measure the optical rotation of the dynamically circulating reaction solution. The optical rotation is measured N times (N ≥ 3) at each measurement time node, and the average value is taken. The average change value of the optical rotation is recorded. When the average value of the three average changes in optical rotation is less than 2, it can be determined that the reaction endpoint.

[0033] In step (1), after adding maleic anhydride into the reaction container, a condenser is inserted, argon gas is introduced for protection, and the reaction is stirred for about 5 hours before the optical rotation value of the reaction solution is measured.

[0034] In step (2), the reaction formula of the synthesis reaction is as follows:

[0035]

[0036] Intermediate 7 is a chiral isomer mixture generated by the previous step reaction. This reaction is to eliminate trans-alfacalcidol. As an impurity of the finished product, trans-alfacalcidol is difficult to remove in the subsequent refining steps. According to the finished product quality standard, this reaction needs to control trans-alfacalcidol below 1.5%, that is, the trans-alfacalcidol content is less than 1.5% as the reaction end point.

[0037] In step (2), the left and right ends of the optical rotation test tube are coaxially placed between the light source and the probe of the polarimeter. By placing the light source and the probe of the polarimeter at the left and right ends of the optical rotation test tube, the measurement range of the reaction solution can be maximized, and the accuracy of the measurement is guaranteed under the premise of the circulation of the reaction solution.

[0038] Of course, according to actual needs, the optical rotation measuring tube can also be placed vertically between the light source and the probe of the polarimeter, that is, the light source and the probe are located on the left and right sides of the outer circumference of the optical rotation measuring tube, so as to accurately measure the reaction liquid flowing in the optical rotation measuring tube per unit time, and the change of the optical rotation of the reaction liquid can be detected in real time.

[0039] In step (3), the measurement time node is to measure N times (N≥3) every 15 minutes, take the average value, and record the average change value of the optical rotation. When the average of the three average change values ​​is less than 1, it can be determined as the reaction endpoint.

[0040] The reaction endpoint determination method creatively circulates the reaction liquid in the reaction directly to the polarimeter, measures the change in the optical rotation of the reaction liquid in real time through the polarimeter, and uses this to indirectly determine whether the synthesis reaction has reached the endpoint. The determination method is accurate, efficient, and suitable for industrial production applications.

[0041] Secondly, the present invention also provides a device for determining the endpoint of the chiral selective reaction of alfacalcidol used in the above method, such as Figure 2As shown, the endpoint determination device mainly includes a reaction device 100, a detection device 200 and a peristaltic pump 300, which creatively combines the reaction device directly with the polarimeter, and utilizes the detection device to circulate the reaction liquid in the reaction directly to the polarimeter, and the polarimeter is used to measure the change of the optical rotation of the reaction liquid in real time.

[0042] Specifically, the reaction device 100 is a reaction vessel for the synthesis reaction of the intermediate of alfacalcidol, and adopts a round-bottom flask, a three-necked flask, a conical flask or a distillation flask, depending on the needs; preferably, the reaction device 100 adopts a single-necked reaction flask. A magnetic stirring device is provided for stirring and mixing.

[0043] like Figure 3 As shown, the detection device 200 includes an optical rotation measuring tube 210 and a polarimeter, and the polarimeter includes a light source 220 and a probe 230. The optical rotation measuring tube 210 is placed between the light source 220 and the probe 230.

[0044] like Figure 2 and Figure 3 As shown, the optical rotation test tube 210 is circulated and connected to the reaction device 100 through a hose. The inlet and outlet at both ends of the optical rotation test tube 210 are respectively inserted into the reaction liquid in the reaction device 100 through the hose, and the peristaltic pump 300 is arranged on the pipeline of the hose to realize the circulation of the reaction liquid.

[0045] Figure 3 As shown, the left and right ends of the optical rotation measuring tube 210 are horizontally arranged between the light source 220 and the probe 230. The liquid inlet 211 and the liquid outlet 212 on the optical rotation measuring tube 210 are arranged on the same side or diagonally.

[0046] The optical rotation measuring tube 210 is made of transparent glass, which is convenient for the light emitted by the light source 220 to pass through. The plane polarized light emitted by the light source 220 is polarized by the optical rotation measuring tube 210, and is collected by the probe 230 at the rear end as a polarizer, and finally the polarized light intensity and polarization angle are converted into signals such as voltage, so as to achieve the purpose of identifying chiral isomers.

[0047] The polarimeter used in the detection device 200 is commercially available, and its specific structural features and detection principle are not described here. The polarimeter can continuously measure the optical rotation of the reaction solution during the reaction process and record the data, and determine the change of the optical rotation through the built-in computer program.

[0048] The present invention is described in detail and specifically by specific examples below to provide a better understanding of the present invention, but the following examples do not limit the scope of the present invention.

[0049] 1. The raw material formula for the chiral selective reaction of alfacalcidol is shown in Table 1 below.

[0050] Table 1 Feeding table

[0051]

[0052] 2. Operation process of chiral selective reaction of alfacalcidol

[0053] (1) Figure 2 and 3 As shown, both ends of the optical rotation measuring test tube 210 are inserted into the single-mouth reaction bottle as the reaction device 100 through a hose in advance, a peristaltic pump 300 is arranged on the hose pipeline of the liquid inlet 211, and the optical rotation measuring test tube 210 is placed in the polarimeter;

[0054] (2) Transfer the intermediate alfacalcidol into a single-necked reaction bottle with a prescribed amount of dichloromethane (calculated based on the weight of alfacalcidol), add the prescribed amount of ethyl acetate (calculated based on the weight of alfacalcidol), add a stir bar, turn on magnetic stirring, and stir until the intermediate alfacalcidol is dissolved;

[0055] (3) Weigh maleic anhydride (calculated based on the weight of alfacalcidol) and transfer it to a single-mouth reaction bottle containing the reaction solution, insert a condenser, connect the top of the condenser to an argon balloon device, introduce argon protection, stir the reaction, and start the peristaltic pump and polarimeter after 5 hours of reaction. Use HPLC to detect the content of trans-alfacalcidol and use the detection device 200 to continuously read the optical rotation data of the reaction solution. The measured data are shown in Table 2 below;

[0056] (4) The optical rotation was measured three times at intervals of 15 minutes and the average value was taken. The average change value was recorded. When the average of the three average changes was less than 2 and the content of trans-alfacalcidol was less than 1.5%, the reaction was determined to be at the end point (in this embodiment, the reaction was continued for 495 minutes according to the measurement requirements). The reaction was determined to be complete, the argon protection was turned off, and the reaction solution was added with the prescribed amount of triethylamine (calculated based on the weight of alfacalcidol) to quench the reaction; after stirring for 10 minutes, the reaction solution was concentrated under reduced pressure on a rotary evaporator (the water bath temperature was controlled at 30-45° C. and the vacuum degree was 0.08-0.1 MPa) to obtain an oily substance, which was the crude product.

[0057] Table 2 Optical rotation data

[0058]

[0059] Table 2 shows the sampling and measurement data of the same reaction (embodiment) at different time points (sampling and measurement started after 300 minutes of reaction, and measurement was performed every 15 minutes), which are respectively the content data of trans-alfacalcidol detected by HPLC and the optical rotation reading data of the reaction solution. According to the HPLC measurement data, the reaction can be determined as the end point at 405-420 minutes; the optical rotation measurement is to measure each point N times (N≥3) and take the average value, record the average change value, and when the average value of the average change value of the three optical rotations is less than 2, it can be determined as the end point of the reaction. According to the measured values ​​in the above table, the reaction can be determined as the end point of the reaction at 420 minutes.

[0060] As can be seen from the analysis of the measurement data in Table 2 above, the optical rotation measurement method of the present invention is simpler to operate than HPLC measurement, the results can be read online instantly, and there is no need to consume the reaction solution, which is more economical and efficient. In addition, the measured optical rotation data can be connected to a computer, and the algorithm can be updated later to make the reaction control more accurate and more suitable for intelligent manufacturing.

[0061] The specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.

Claims

1. A method for determining the endpoint of an alfacalcidol chiral selective reaction, characterized in that: The steps include: (1) The inlet and outlet of the optical rotation test tube at both ends are inserted into the reaction container through a hose, a peristaltic pump is arranged on the hose pipeline, and the optical rotation test tube is placed in the polarimeter; (2) adding the intermediate alfacalcidol, dichloromethane, ethyl acetate and maleic anhydride in the prescribed amount into the reaction vessel according to the preset process to carry out a synthesis reaction, and inserting the hose of step (1) into the reaction solution; (3) Turn on the peristaltic pump and the polarimeter, and continuously measure the optical rotation of the reaction solution using the polarimeter. Measure each point N times (N ≥ 3) and take the average value. Record the average change value. When the average of the three average change values ​​is less than 2, it can be determined as the reaction endpoint.

2. The method for determining the endpoint of the chiral selective reaction of alfacalcidol according to claim 1, characterized in that: In step (1), the left and right ends of the optical rotation measuring tube are coaxially arranged between the light source and the probe of the polarimeter.

3. The method for determining the endpoint of the chiral selective reaction of alfacalcidol according to claim 1, characterized in that: In step (2), the reaction formula of the synthesis reaction is as follows:

4. The method for determining the endpoint of the chiral selective reaction of alfacalcidol according to claim 1, characterized in that: In step (2), after adding maleic anhydride into the reaction container, a condenser is inserted, argon gas is introduced for protection, and the optical rotation value is measured after stirring the reaction for about 5 hours.

5. The method for determining the endpoint of the chiral selective reaction of alfacalcidol according to claim 1, characterized in that: In step (3), the measurement time node is measured every 15 minutes, N=3 times are measured and the average value is taken, and the average change value of the optical rotation is recorded. When the average of the three average change values ​​is less than 1, it can be determined as the reaction endpoint.

6. A device for determining the endpoint of the chiral selective reaction of alfacalcidol used in the method according to any one of claims 1 to 5, characterized in that: It comprises a reaction device (100), a detection device (200) and a peristaltic pump (300), wherein: The detection device (200) comprises an optical rotation measuring tube (210) and a polarimeter, wherein the optical rotation measuring tube (210) is placed between a light source (220) and a probe (230) of the polarimeter; The inlet and outlet ports at both ends of the optical rotation measuring test tube (210) are respectively inserted into the reaction liquid in the reaction device (100) through flexible pipes, and the peristaltic pump (300) is arranged on the pipeline of the flexible pipe.

7. The end point determination device for chiral selective reaction of alfacalcidol according to claim 6, characterized in that: The reaction device (100) is a reaction container, which is a round-bottom flask, a three-necked flask, a conical flask or a distillation flask.

8. The device for determining the endpoint of the chiral selective reaction of alfacalcidol according to claim 6, characterized in that: The left and right ends of the optical rotation measuring test tube (210) are horizontally arranged between the light source (220) and the probe (230).

9. The device for determining the endpoint of the chiral selective reaction of alfacalcidol according to claim 6, characterized in that: The liquid inlet (211) and the liquid outlet (212) on the optical rotation measuring test tube (210) are arranged on the same side or diagonally.

10. The end point determination device for chiral selective reaction of alfacalcidol according to claim 6, characterized in that: The optical rotation measuring test tube (210) is made of transparent glass.

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