Process for the preparation of zidovudine azide intermediate

Abstract

The present application relates to a kind of preparation of zidovudine azide intermediate (compound of formula I) using tubular reactor method, comprising the following steps: preparation of premix solution: compound of formula II, sodium azide, organic acid is dissolved in DMSO solution, preheating, standby;(2) the premix solution prepared in step (1) is input into tubular reactor by peristaltic pump;(3) receiving bottle is placed at the outlet of tubular reactor, and the effluent received is the reaction mixture containing compound of formula I;(4) reaction mixture is pumped into water by peristaltic pump, stirred at room temperature, crystallized, filtered, and dried to obtain compound of formula I. Wherein, the tubular reactor is coiled by pipeline with a certain inner diameter. The preparation method uses equipment structure simple, easy to operate, on the one hand, reduce the risk of operation in the actual production process of azide, on the other hand, realize the reaction efficiency and the yield greatly, realize product yield not less than 92%, and product purity is higher than 95%.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis, specifically relating to a method for preparing a zidovudine azide intermediate. Background Technology

[0002] Zidovudine was the world's first FDA-approved anti-AIDS drug, and due to its proven efficacy, it became a fundamental component of "cocktail" therapy. Currently, zidovudine has effectively become a standard medication.

[0003] Currently, the method of synthesizing zidovudine from β-thymidine is an effective method, and there are two main synthetic routes.

[0004] Route 1: US5124442 reports the following synthetic route.

[0005]

[0006] Route 2: J. Chem. Research(s), 1993, 326-327 reports the following synthetic route:

[0007]

[0008] The route for synthesizing zidovudine from β-thymidine is currently the most important industrial route. This route involves first dehydrating the hydroxyl group at the 3' position of the ribose with the carbonyl group on the pyrimidine ring to form an oxygen-bridged ring structure, then using an azide reagent to open the ring, obtaining an azide intermediate in which the hydroxyl group at the 3' position of the ribose is replaced by an azide group, and finally removing the protecting group at the 5' position of the ribose to obtain the zidovudine compound.

[0009] The reaction between the formed oxygen-bridged ring intermediate and the azide reagent involves the use of highly explosive sodium azide reagent, and the reaction must be carried out at a high temperature of at least 150°C, increasing the danger and complexity of industrial-scale implementation of this step. Although this reaction has been widely implemented in industrial processes, continuous efforts to develop safer and simpler procedures remain a focus of pharmaceutical synthesis research. Summary of the Invention

[0010] To address the problems existing in the prior art, the present invention aims to provide a method for preparing zidovudine azide intermediates using a tubular reactor. The tubular reactor used has a simple structure, low equipment cost, and simple operation. The tubular reaction process for preparing azide intermediates has high operational safety, stable reaction, high yield, and product quality that meets requirements.

[0011] In one aspect, the present invention provides a method for preparing a zidovudine azide intermediate (compound of formula I) using a tubular reactor, characterized by comprising the following steps:

[0012]

[0013] (1) Preparation of premixed solution: Dissolve compound II, sodium azide and organic acid in DMSO solution, preheat and set aside;

[0014] (2) The premixed solution prepared in step (1) is fed into the tubular reactor by a peristaltic pump;

[0015] (3) The receiving bottle is placed at the outlet of the tubular reactor, and the effluent received is the reaction mixture containing compound I.

[0016] (4) The reaction mixture is pumped into water by a peristaltic pump, stirred at room temperature, crystallized, filtered, and dried to obtain compound I.

[0017] The tubular reactor is formed by coiling a pipe with a certain inner diameter.

[0018] In another preferred embodiment, the organic acid in step (1) is selected from one or more of concentrated sulfuric acid, acetic acid, propionic acid, n-butyric acid, methanesulfonic acid, polyphosphoric acid, and phosphoric acid; preferably one or two of acetic acid or phosphoric acid; more preferably phosphoric acid.

[0019] In another preferred embodiment, the phosphoric acid is an 85% phosphoric acid solution.

[0020] In another preferred embodiment, the preheating temperature of the premixed liquid in step (1) is 80-100°C; preferably 80-90°C.

[0021] In another preferred embodiment, the molar ratio of the compound of formula II to sodium azide in step (1) is 1.0:1.5 to 3.5; preferably 1.0:1.5 to 2.5.

[0022] In another preferred embodiment, the mass ratio of the compound of formula II to the organic acid in step (1) is 1.0:0.01 to 0.20; preferably 1.0:0.05 to 0.15, more preferably 1.0:0.05 to 0.1.

[0023] In another preferred embodiment, the volume ratio of the compound of formula II to DMSO in step (1) is 1.0:2.0 to 5.0; preferably 1.0:2.5 to 3.5.

[0024] In another preferred embodiment, the pumping rate of the peristaltic pump in step (2) is 1.0 ml / min to 5.0 ml / min, preferably 2.0 ml / min to 3.5 ml / min.

[0025] In another preferred embodiment, the tubular reactor described in step (2) needs to be placed in a heating medium, which includes, but is not limited to, steam and dimethyl silicone oil; the temperature of the heating medium is 110-170°C, preferably 150-160°C.

[0026] In another preferred embodiment, the residence time of the premixed liquid in the tubular reactor in step (2) is 10 min to 20 min, preferably 10 min to 15 min.

[0027] In another preferred embodiment, the inner diameter of the tubular reactor is 1.0 mm to 10.0 mm, preferably 1.5 mm to 5.0 mm, and more preferably 1.5 mm to 3.0 mm.

[0028] In another preferred embodiment, the method for preparing the zidovudine azide intermediate specifically includes the following steps:

[0029] (a) Preparation of premixed solution: Dissolve compound II, sodium azide and organic acid in DMSO solution, preheat to 100-110℃, and set aside;

[0030] (b) The premixed solution prepared in step (a) is pumped out by a peristaltic pump, the pipeline is kept at 80-90°C, and fed into a tubular reactor. The tubular reactor is placed in an oil bath, the oil bath is kept at 150-155°C, and the material stays in the tubular reactor for 11.5 min.

[0031] (c) The receiving bottle is placed at the outlet of the tubular reactor, and the effluent received is the reaction mixture containing compound I.

[0032] (d) The received reaction mixture is pumped into water by a peristaltic pump, stirred at room temperature for 0.5 to 1 hour, filtered, and the filter cake is placed in a drying oven and dried at 40 to 45°C to constant weight to obtain compound I.

[0033] The diameter of the tubular reactor is 1.5 mm to 3.0 mm.

[0034] In another preferred embodiment, the tubular reactor is made of stainless steel or titanium; the tubular reactor is a horizontal tubular reactor.

[0035] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0036] Figure 1 The flowchart of the tubular reactor of the present invention is as follows. Detailed Implementation

[0037] Through long-term, extensive and in-depth research, this invention has discovered a method for preparing zidovudine azide intermediates (compound of formula I) using a tubular reactor. The equipment used is simple and easy to operate, and it simultaneously improves the reaction time and reaction yield.

[0038] A tubular reactor is a continuously operating reactor with a tubular shape and a large length-to-diameter ratio, belonging to the plug flow reactor category. The tubular reactor described in this patent method (e.g.) Figure 1 The device (shown) consists of four parts: a pre-reaction bottle, a peristaltic pump, a tubular reactor, and a receiving device. The tubular reactor is the main body of the reactor and is formed by coiling pipes of a certain material and diameter. The material of the tubular reactor can be stainless steel or titanium. The inner diameter of the tubular reactor is selected according to the matching reaction vessel and the scale of the reaction.

[0039] The tubular reactor can be a vertical reactor or a horizontal reactor. In a vertical reactor, the reaction system may generate water vapor or other gases, which can cause backmixing of the reaction liquid and lead to incomplete substrate conversion. A horizontal reactor can avoid backmixing, but it may still experience intermittent outflow of liquid and reduced volume utilization due to the generation of water vapor or other gases inside the tube.

[0040] In the preparation method of zidovudine sodium azide intermediate in this invention, since sodium azide is prone to explosion, traditional reactor feeding methods place stringent requirements on equipment and feeding operations. Using a tubular reactor, dissolving the sodium azide in a solvent and conducting a continuous reaction operation effectively avoids the explosive nature of sodium azide, making it easier to implement in industrial production. Furthermore, because zidovudine azide intermediates are easily degraded and destroyed under high-temperature conditions, the products generated in high-temperature azide reaction systems are partially destroyed, leading to low reaction yields and increased post-processing difficulties. Using a tubular reactor, the reaction residence time is shortened, and after the reaction conversion, the product flows out through a pipeline into a receiving bottle. The system temperature is individually controlled, avoiding degradation of the product due to prolonged high temperatures, significantly improving the reaction yield. Moreover, post-processing only requires simple water precipitation to meet quality requirements.

[0041] Advantages of this invention:

[0042] (1) The tubular reactor equipment used is simple and easy to operate, with low equipment cost, and is suitable for industrial promotion.

[0043] (2) Avoid the risk of explosion when using traditional reactors to feed sodium azide;

[0044] (3) The reaction products were separated in time, avoiding the by-products of high-temperature decomposition and improving the yield;

[0045] (4) The purity of the product is improved, and the post-processing only requires a simple water separation operation to obtain the azide intermediate that meets the quality requirements;

[0046] (5) By using a tubular reactor, the reaction proceeds continuously, resulting in a significant increase in reaction efficiency;

[0047] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, all experimental materials and reagents used in the following embodiments were obtained from commercially available sources.

[0048] Example 1

[0049] Add 75.0 g (1.0 eq) of compound II (prepared according to the preparation method in US5124442), 19.9 g (1.9 eq) of sodium azide, 150 ml of dimethyl sulfoxide solvent, and 7.5 g of 85% phosphoric acid solution to a pre-reaction flask. Heat the mixture to 100°C and stir for 10–15 min until most of the solid dissolves. Keep the system warm for later use.

[0050] The heating medium oil bath of the tubular reactor is heated to 155-160℃. The peristaltic pump is set to a flow rate of 1.5 ml / min. The pre-prepared reaction mixture is fed into the tubular reactor through the peristaltic pump. At the same time, the pump head and tubing of the peristaltic pump need to be kept at 90-100℃. After running for about 15 minutes, the effluent is collected in a receiving bottle. The effluent is the reaction solution containing compound I.

[0051] The reaction solution containing compound I was pumped into a reaction flask containing water, stirred for 0.5–1 hour, filtered, the filter cake was washed with water, and the filter cake was dried in a vacuum drying oven to constant weight, yielding 78.6 g of compound I (yield 96.3%, purity 96.7%).

[0052] Example 2

[0053] Add 75.0 g (1.0 eq) of compound II (prepared according to the preparation method in US5124442), 24.1 g (2.3 eq) of sodium azide, 225 ml of dimethyl sulfoxide solvent, and 7.5 g of 85% phosphoric acid solution to a pre-reaction flask. Heat the mixture to 100°C and stir for 10–15 min until most of the solid dissolves. Keep the system warm for later use.

[0054] The heating medium oil bath of the tubular reactor is heated to 155-160℃. The peristaltic pump is set to a flow rate of 2.5 ml / min. The pre-prepared reaction mixture is fed into the tubular reactor through the peristaltic pump. At the same time, the pump head and tubing of the peristaltic pump need to be kept at 90-100℃. After running for about 10 minutes, the effluent is collected in a receiving bottle. The effluent is the reaction solution containing compound I.

[0055] The reaction solution containing compound I was pumped into a reaction flask containing water, stirred for 0.5–1 hour, filtered, the filter cake was washed with water, and the filter cake was dried in a vacuum drying oven to constant weight, yielding 76.3 g of compound I (yield 93.6%, purity 95.3%).

[0056] Comparative Example 1

[0057] 75.0 g (1.0 eq) of compound II (prepared according to US5124442), 19.9 g (1.9 eq) of sodium azide, 150 ml of dimethyl sulfoxide solvent, and 7.5 g of 85% phosphoric acid solution were added to a pre-reaction flask. The mixture was stirred, and the system was heated to 150–155 °C and stirred for 0.5–1 hour. Then, the reaction system was rapidly cooled to about 70 °C, and the reaction solution was added dropwise to water. The mixture was stirred at room temperature for 1–2 hours, filtered, and the filter cake was washed with room temperature water. The filter cake was then dried in a vacuum drying oven to constant weight to obtain 67.6 g of compound I (yield 82.7%, purity 87.8%).

[0058] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing enumerations of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. An industrial method for preparing zidovudine azide intermediates, i.e., compounds of formula I, using a tubular reactor, characterized in that... It consists of the following steps: (1) Preparation of premixed solution: Dissolve compound II, sodium azide and organic acid in DMSO solution, preheat and set aside; (2) The premixed solution prepared in step (1) is fed into the tubular reactor by a peristaltic pump; (3) The receiving bottle is placed at the outlet of the tubular reactor, and the effluent received is the reaction mixture containing compound I. (4) The reaction mixture is pumped into water by a peristaltic pump, stirred at room temperature, crystallized, filtered, and dried to obtain compound I; The tubular reactor is formed by coiling a pipe with a certain inner diameter. The diameter of the tubular reactor is 1.5mm to 3.0mm, and the tubular reactor is made of stainless steel or titanium. The tubular reactor is a horizontal tubular reactor. The residence time of the premixed liquid in the tubular reactor in step (2) is 10 min-20 min; The organic acid is selected from one or more of acetic acid, methanesulfonic acid, and phosphoric acid; The molar ratio of the compound of formula II to sodium azide is 1.0:1.5 to 2.5; The mass ratio of compound II to acid is 1.0:0.01 to 0.20; The volume ratio of compound II to DMSO is 1.0:2.0 to 5.

0.

2. The method as described in claim 1, characterized in that, The organic acid mentioned in step (1) is phosphoric acid.

3. The method as described in claim 1, characterized in that, The preheating temperature of the premixed liquid in step (1) is 80-100℃.

4. The method as described in claim 1, characterized in that, In step (1), the mass ratio of compound II to organic acid is 1.0:0.05 to 0.15; the volume ratio of compound II to DMSO is 1.0:2.5 to 3.

5.

5. The method as described in claim 1, characterized in that, The pumping rate of the peristaltic pump in step (2) is 1.0 ml / min to 5.0 ml / min.

6. The method as described in claim 1, characterized in that, The tubular reactor described in step (2) needs to be placed in a heating medium with a temperature of 110 to 170°C.

7. The method as described in claim 1, characterized in that, The residence time of the premixed liquid in the tubular reactor in step (2) is 10 min to 15 min.

8. The method as described in claim 1, characterized in that, The method for preparing the zidovudine azide intermediate consists of the following steps: (a) Preparation of premixed solution: Dissolve compound II, sodium azide and organic acid in DMSO solution, preheat to 100-110℃, and set aside; (b) The premixed solution prepared in step (a) is pumped out by a peristaltic pump, the pipeline is kept at 80-90°C, and fed into a tubular reactor. The tubular reactor is placed in an oil bath, the oil bath is kept at 150-155°C, and the material stays in the tubular reactor for 11.5 min. (c) The receiving bottle is placed at the outlet of the tubular reactor, and the effluent received is the reaction mixture containing compound I. (d) The received reaction mixture is pumped into water by a peristaltic pump, stirred at room temperature for 0.5 to 1 hour, filtered, and the filter cake is placed in a drying oven and dried at 40 to 45°C to constant weight to obtain compound I. The tubular reactor has a diameter of 1.5mm to 3.0mm and is made of stainless steel or titanium. It is a horizontal tubular reactor. The residence time of the premixed liquid in the tubular reactor in step (2) is 10 min to 20 min; The organic acid is selected from one or more of acetic acid, methanesulfonic acid, and phosphoric acid; The molar ratio of the compound of formula II to sodium azide is 1.0:1.5 to 2.5; The mass ratio of the compound of formula II to the organic acid is 1.0:0.01 to 0.20; The volume ratio of compound II to DMSO is 1.0:2.0 to 5.0.

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