Alfacalcidol chiral selection reaction endpoint judgment device

Abstract

The utility model provides an alfacalcidol chiral selection reaction endpoint judgment device which comprises a reaction device, a detection device and a peristaltic pump, the detection device comprises an optical rotation measurement test tube and a polarimeter, and the optical rotation measurement test tube is arranged between a light source and a probe of the polarimeter; an inlet and an outlet at two ends of the optical rotation measuring test tube are respectively inserted into reaction liquid in the reaction device through hoses, and peristaltic pumps are arranged on pipelines of the hoses. According to the reaction endpoint judgment device disclosed by the utility model, the reaction device is creatively and directly combined with the polarimeter, the reaction liquid in the reaction is directly and circularly communicated to the polarimeter by utilizing the detection device, and the optical rotation change condition of the reaction liquid is measured in real time through the polarimeter, so that whether the synthetic reaction reaches the endpoint or not is indirectly judged; the determination method is accurate, high in efficiency and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The utility model belongs to the technical field of medicine synthesis, and relates to a synthetic method of alfacalcidol, in particular to a chiral selection reaction end point determination device of alfacalcidol. BACKGROUND

[0002] Alfacalcidol, chemical name 9,10- open loop cholesta-5Z,7E,10(19)- triene-1a,3b- diol, is a fat-soluble sterol in vitamin D compounds, which is a kind of substance participating in the internal environment stability of calcium and phosphorus and the mineralization process of bone, and it is a kind of relatively important active metabolite of vitamin D3. It has the effects of treating postmenopausal women and senile osteoporosis, hypoparathyroidism, vitamin D3 dependent rickets, renal osteodystrophy and the like caused by multiple kidney diseases such as renal failure, and hypoparathyroidism.

[0003] At present, the synthesis of alfacalcidol generally adopts the following method: the prescription amount of alfacalcidol and dichloromethane are weighed, added into a reaction bottle, and then dissolved in ethyl acetate solvent; then the prescription amount of maleic anhydride is added, a condenser tube is inserted, the top end of the condenser tube is connected with an argon ball device, argon is introduced for protection, stirring reaction is carried out, and HPLC detection is used to detect the reaction end point. The existing end point determination method of alfacalcidol synthesis reaction adopts HPLC detection, which is low in efficiency, complex in operation and not suitable for automatic production. UTILITY MODEL CONTENT

[0004] The utility model provides a kind of alfacalcidol chiral selection reaction end point determination method with high determination efficiency, suitable for industrial production to solve the above technical problems existing in the prior art using HPLC detection determination method.

[0005] To achieve the above object, the utility model adopts the following technical solutions:

[0006] The utility model provides a kind of alfacalcidol chiral selection reaction end point determination device, including reaction device, detection device and peristaltic pump, wherein:

[0007] The detection device includes optical rotation determination test tube and polarimeter, and the optical rotation determination test tube is arranged between the light source and probe of the polarimeter;

[0008] The inlet and outlet of the optical rotation determination test tube are respectively inserted into the reaction liquid in the reaction device through hose, and the pipeline of the hose is provided with the peristaltic pump.

[0009] Preferably, the reaction device is a reaction container, and round-bottom flask, three-necked flask, conical flask or distillation flask is used.

[0010] Preferably, the transverse horizontal arrangement of the left and right ends of the polarimetry test tube is between the light source and the probe.

[0011] Preferably, the polarimetry test tube is vertically arranged between the light source and the probe.

[0012] Preferably, the inlet and outlet on the polarimetry test tube are arranged on the same side.

[0013] Preferably, the inlet and outlet on the polarimetry test tube are diagonally arranged.

[0014] Preferably, the polarimetry test tube is made of transparent glass material.

[0015] Preferably, the polarimeter is a digital automatic polarimeter.

[0016] Preferably, the peristaltic pump is arranged on the hose line of the inlet of the polarimetry test tube.

[0017] The utility model discloses the above-mentioned technical scheme, compared with the prior art, has the following technical effects:

[0018] (1) the utility model discloses creatively the reaction device directly with polarimeter and is combined together, utilizes detection device to circulate and connects directly to polarimeter in the reaction of reaction liquid, and the polarimeter real-time determination reaction liquid's polarimetry change situation, and indirectly judges whether the synthesis reaction reaches the end point with this, this determination method is accurate, and the efficiency is high, and is suitable for industrialized production application;

[0019] (2) the utility model discloses detection device by polarimetry test tube and polarimeter, and the polarimetry test tube is placed between the light source and the probe of polarimeter, and the inlet and outlet of both ends are inserted respectively in the reaction device through the hose, and sets up peristaltic pump on the hose of inlet, and utilizes peristaltic pump to circulate and flow between the reaction device and polarimeter, realizes the purpose of dynamic determination, and the determination device structure design is simple, novel, and convenient to install and dismount, and stable and reliable. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The structure principle of the alpha calciferol chiral selection reaction end point determination device Figure 1 ;

[0021] Figure 2 The structure principle of the alpha calciferol chiral selection reaction end point determination device Figure 2 ;

[0022] Among them, each reference sign is:

[0023] 100 - reaction device; 200 - detection device, 210 - polarimetry test tube, 211 - inlet, 212 - outlet, 220 - light source, 230 - probe. DETAILED DESCRIPTION

[0024] The utility model provides a kind of alfacalcidol chiral selection reaction end point determination device, as shown in Figure 1 The end point determination device mainly includes reaction device 100, detection device 200 and peristaltic pump 300, which creatively combines the reaction device directly with a polarimeter, and uses the detection device to circulate the reaction liquid in the reaction to the polarimeter, and determines the change of the optical rotation of the reaction liquid in real time by the polarimeter.

[0025] Specifically, the reaction device 100 is a reaction vessel for the synthesis reaction of alfacalcidol intermediate GHC08, and uses a round-bottom flask, a three-necked flask, a conical flask or a distillation flask; preferably, the reaction device 100 uses a single-necked reaction flask. It is equipped with a magnetic stirring device for stirring and mixing.

[0026] As shown in Figure 2 The detection device 200 includes a polarimetry test tube 210 and a polarimeter, and the polarimeter includes a light source 220 and a probe 230. The polarimetry test tube 210 is placed between the light source 220 and the probe 230.

[0027] As shown in Figure 1 and Figure 2 The polarimetry test tube 210 is connected to the reaction device 100 by a hose. The inlet and outlet at both ends of the polarimetry test tube 210 are 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.

[0028] Figure 2 As shown in , the horizontal arrangement of the polarimetry test tube 210 at both ends is arranged between the light source 220 and the probe 230. The inlet 211 and the outlet 212 on the polarimetry test tube 210 are arranged on the same side or diagonally.

[0029] The polarimetry test tube 210 is made of transparent glass material, 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 subjected to optical rotation polarization effect by the polarimetry test tube 210, and is collected by the probe 230 as a polarizer at the rear end. Finally, the polarization light intensity and polarization angle are converted into voltage signals and the like, so as to achieve the purpose of identifying chiral isomers.

[0030] The optical activity instrument used in the detection device 200 is commercially available, such as WZZ-2S digital automatic optical activity instrument. The specific structural features and detection principle are not described here. The optical activity instrument can continuously determine the optical activity of the reaction solution during the reaction and record the data, and determine the change of optical activity through the computer program.

[0031] The use method of the alfacalcidol chiral selection reaction end point determination device is:

[0032] (1) The inlet and outlet at both ends of the optical activity determination test tube are inserted into the reaction container through the hose, a peristaltic pump is arranged on the hose pipeline, and the optical activity determination test tube is placed in the optical activity instrument;

[0033] (2) The prescribed amount of intermediate alfacalcidol, dichloromethane, ethyl acetate, and maleic anhydride are added to the reaction container according to the pre-set process for synthesis reaction, and the hose in step (1) is inserted into the reaction solution;

[0034] (3) Turn on the peristaltic pump and the optical activity instrument, and continuously determine the optical activity of the dynamically circulating reaction solution during the reaction through the optical activity instrument. The optical activity determination is to determine N times (N≥3) at each determination time node and take the average value, and record the average change value of the optical activity. When the average value of the average change value of the optical activity is less than 2, it is determined that the reaction end point is reached.

[0035] In step (1), after adding maleic anhydride to the reaction container, a condenser tube is inserted, argon is introduced for protection, and the optical activity value of the reaction solution is determined after about 5 hours of stirring reaction.

[0036] In step (2), the reaction formula of the synthesis reaction is as follows:

[0037]

[0038] Intermediate 7 is a mixture of chiral isomers generated in the previous reaction. This reaction is to eliminate trans alfacalcidol. As an impurity in the finished product, trans alfacalcidol is difficult to remove in subsequent refining steps. According to the quality standard of the finished product, the reaction needs to control the trans alfacalcidol to be less than 1.5%, that is, the content of trans alfacalcidol is less than 1.5% to determine the reaction end point.

[0039] In step (2), the left and right ends of the optical activity determination test tube are coaxially arranged between the light source and the probe of the optical activity instrument. By arranging the light source and the probe of the optical activity instrument at the left and right ends of the optical activity determination test tube, the determination range of the reaction solution can be maximized, and the accuracy of the determination is guaranteed under the premise of circulating flow of the reaction solution.

[0040] Of course, according to actual needs, the light source and the probe of the polarimeter can be arranged on the left and right sides of the polarimeter in the vertical direction of the polarimetry test tube, that is, the light source and the probe are located on the left and right sides of the outer periphery of the polarimetry test tube, so as to accurately measure the reaction solution flowing in the polarimetry test tube per unit time, and the change of the optical rotation of the reaction solution can be detected in real time.

[0041] The reaction end point determination method directly circulates the reaction solution in the reaction to the polarimeter, the change of the optical rotation of the reaction solution is determined by the polarimeter in real time, and whether the synthesis reaction reaches the end point is indirectly determined, the determination method is accurate and efficient, and is suitable for industrial production application.

[0042] The specific embodiments of the utility model are described in detail above, but it is only as an example, the utility model is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modification and substitution to the utility model are also within the scope of the utility model. Therefore, equivalent transformation and modification made without departing from the spirit and scope of the utility model should be covered in the scope of the utility model.

Claims

1. A device for determining the endpoint of an alfacalcidol chiral selective reaction, characterized in that, The application relates to a reaction device (100), a detection device (200) and a peristaltic pump (300), wherein: The detection device (200) comprises an optical rotation measuring test tube (210) and an optical rotation instrument, the optical rotation measuring test tube (210) is arranged between a light source (220) and a probe (230) of the optical rotation instrument; Inlets and outlets at two ends of the optical rotation measuring test tube (210) are respectively inserted into reaction liquid in the reaction device (100) through hoses, and the hoses are provided with the peristaltic pump (300) on pipelines.

2. The alfacalcidol chiral selection reaction end point determination device according to claim 1, characterized by The reaction device (100) is a reaction container, and a round-bottom flask, a three-necked flask, a conical flask or a distillation flask is adopted.

3. The alfacalcidol chiral selection reaction endpoint determination device according to claim 1, characterized by, The optical rotation measuring test tube (210) is arranged horizontally at two ends of the optical rotation measuring test tube (210) and between the light source (220) and the probe (230).

4. The alfacalcidol chiral selection reaction endpoint determination device according to claim 1, characterized by The optical rotation measuring test tube (210) is arranged vertically between the light source (220) and the probe (230).

5. The alfacalcidol chiral selection reaction endpoint determination device according to claim 1, characterized by The liquid inlet (211) and the liquid outlet (212) on the optical rotation measuring test tube (210) are arranged on the same side.

6. The alfacalcidol chiral selection reaction endpoint determination device according to claim 1, characterized by The liquid inlet (211) and the liquid outlet (212) on the optical rotation measuring test tube (210) are diagonally arranged.

7. The alfacalcidol chiral selection reaction endpoint determination device according to claim 1, characterized by The optical rotation measuring test tube (210) is made of transparent glass.

8. The alfacalcidol chiral selection reaction endpoint determination device according to claim 1, characterized by The optical rotation instrument is a digital automatic optical rotation instrument.

9. The alfacalcidol chiral selection reaction endpoint determination device according to claim 1, characterized by The peristaltic pump (300) is arranged on the hose pipeline of the liquid inlet (211) of the optical rotation measuring test tube (210).

Images