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CN-115368424-B - Preparation method of zidovudine azide intermediate

CN115368424BCN 115368424 BCN115368424 BCN 115368424BCN-115368424-B

Abstract

The invention relates to a method for preparing zidovudine azide intermediate (compound of formula I) by using a tubular reactor, which comprises the following steps: The preparation of the premix solution comprises the steps of dissolving a compound of a formula II, sodium azide and an organic acid in a DMSO solution, preheating for standby, inputting the premix solution prepared in the step (1) into a tubular reactor through a peristaltic pump, placing a receiving bottle at an outlet of the tubular reactor, and pumping the received effluent liquid into water through the peristaltic pump, stirring at normal temperature, crystallizing, filtering and drying to obtain the compound of the formula I. Wherein, the tubular reactor is coiled by a pipeline with a certain inner diameter. The preparation method has the advantages of simple structure of equipment and easy operation, reduces the operation risk in the actual azide production process, greatly improves the reaction efficiency and the yield, and realizes the product yield of not less than 92% and the product purity of higher than 95%.

Inventors

  • CHEN ZHENGCAI
  • WANG ZHIJUN
  • LIN DAOBING

Assignees

  • 上海迪赛诺化学制药有限公司
  • 上海迪赛诺药业股份有限公司

Dates

Publication Date
20260508
Application Date
20210520

Claims (8)

  1. 1. An industrial method for preparing a zidovudine azide intermediate, namely a compound of formula I by utilizing a tubular reactor, which is characterized by comprising the following steps: (1) Preparing a premix, namely dissolving a compound of the formula II, sodium azide and an organic acid in a DMSO solution, and preheating for later use; (2) Inputting the premixed solution prepared in the step (1) into a tubular reactor through a peristaltic pump; (3) The receiving bottle is arranged at the outlet of the tubular reactor, and the received effluent liquid is the reaction mixed liquid containing the compound of the formula I; (4) Pumping the reaction mixture into water through a peristaltic pump, stirring at normal temperature, crystallizing, filtering and drying to obtain a compound of the formula I; the tubular reactor is formed by coiling a pipeline with a certain inner diameter, the pipe diameter of the tubular reactor is 1.5 mm-3.0 mm, the tubular reactor is made of stainless steel or titanium, and the tubular reactor is a horizontal tubular reactor; The residence time of the premix liquid in the step (2) in the tubular reactor is 10min-20min; The organic acid is selected from one or more of acetic acid, methanesulfonic acid and phosphoric acid; the molar ratio of the compound of the formula II to the sodium azide is 1.0:1.5-2.5; the mass ratio of the compound of the formula II to the acid is 1.0:0.01-0.20; the volume ratio of the compound of the formula II to the DMSO is 1.0:2.0-5.0.
  2. 2. The method of claim 1, wherein the organic acid in step (1) is phosphoric acid.
  3. 3. The method of claim 1, wherein the pre-mix liquid in step (1) is preheated to a temperature of 80-100 ℃.
  4. 4. The method of claim 1, wherein the mass ratio of the compound of formula II to the organic acid in step (1) is 1.0:0.05-0.15, and the volume ratio of the compound of formula II to DMSO is 1.0:2.5-3.5.
  5. 5. The method of claim 1, wherein the peristaltic pump in step (2) has a pumping rate of 1.0ml/min to 5.0ml/min.
  6. 6. The method of claim 1, wherein the tubular reactor in step (2) is placed in a heating medium at a temperature of 110 ℃ to 170 ℃.
  7. 7. The method of claim 1, wherein the residence time of the premix in the tubular reactor in step (2) is 10min to 15min.
  8. 8. The method of claim 1, wherein the preparation of the zidovudine azide intermediate comprises the steps of: (a) Preparing a premix, namely dissolving a compound of the formula II, sodium azide and an organic acid in a DMSO solution, and preheating the mixture to 100-110 ℃ for later use; (b) Pumping the premixed solution prepared in the step (a) through a peristaltic pump, preserving heat at 80-90 ℃ through a pipeline, inputting the temperature into a tubular reactor, placing the tubular reactor into an oil bath, preserving heat at 150-155 ℃ through the oil bath, and keeping the material in the tubular reactor for 11.5min; (c) The receiving bottle is arranged at the outlet of the tubular reactor, and the received effluent liquid is the reaction mixed liquid containing the compound of the formula I; (d) Pumping the received reaction mixture into water through a peristaltic pump, stirring for 0.5-1 hour at normal temperature, filtering, and drying a filter cake in a drying oven at 40-45 ℃ to constant weight to obtain a compound of the formula I; the pipe diameter of the pipe reactor is 1.5 mm-3.0 mm, the pipe reactor is made of stainless steel or titanium, and the pipe reactor is a horizontal pipe reactor; The residence time of the premix liquid in the step (2) in the tubular reactor is 10-20 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 the formula II to the sodium azide is 1.0:1.5-2.5; the mass ratio of the compound of the formula II to the organic acid is 1.0:0.01-0.20; the volume ratio of the compound of the formula II to the DMSO is 1.0:2.0-5.0.

Description

Preparation method of zidovudine azide intermediate Technical Field The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of an zidovudine azide intermediate. Background Zidovudine is the first anti-AIDS drug in the world to be approved by the FDA in the United states, and is the most basic combination component of "cocktail" therapy because of its definite therapeutic effect. Currently, zidovudine is actually a standard drug. The current method for synthesizing zidovudine by taking beta-thymidine as a raw material is an effective method, and the synthetic route mainly comprises the following two routes. Scheme 1 US5124442 reports the following synthetic scheme Scheme 2 J.chem.research(s), 1993,326-327 reports the following synthetic scheme: The method is characterized in that beta-thymidine is used as a raw material to synthesize zidovudine, wherein the routes are the most main industrial routes at present, wherein the routes all involve that hydroxyl of ribose 3' -position value and carbonyl on pyrimidine ring are dehydrated to form an oxygen bridge ring structure, then azide reagent is used for ring opening to obtain an azide intermediate with ribose 3' -position hydroxyl replaced by azide, and finally ribose 5' -position hydroxyl protecting group is removed to obtain the zidovudine compound. In the reaction step of the formed oxygen bridge ring intermediate structure and the azide reagent, on one hand, an explosive sodium azide reagent is used, and on the other hand, the reaction needs to be carried out at a high temperature of not lower than 150 ℃, so that the danger of industrial implementation of the process and the complexity of operation are increased. Although this reaction has been widely practiced in industrial processes, it is continually being carried out in a safer, simpler operation, and is still a direction of pharmaceutical synthesis. Disclosure of Invention Aiming at the problems existing in the prior art, the invention aims to provide a method for preparing a zidovudine azide intermediate by using a tubular reactor, wherein the tubular reactor has the advantages of simple structure, low equipment cost, simple operation, high operation safety, stable reaction, high yield and product quality meeting the requirements. In one aspect of the present invention, there is provided a process for preparing zidovudine azide intermediate (compound of formula I) using a tubular reactor, comprising the steps of: (1) Preparing a premix, namely dissolving a compound of the formula II, sodium azide and an organic acid in a DMSO solution, and preheating for later use; (2) Inputting the premixed solution prepared in the step (1) into a tubular reactor through a peristaltic pump; (3) The receiving bottle is arranged at the outlet of the tubular reactor, and the received effluent liquid is the reaction mixed liquid containing the compound of the formula I; (4) Pumping the reaction mixture into water through a peristaltic pump, stirring at normal temperature, crystallizing, filtering and drying to obtain the compound of the formula I. Wherein, the tubular reactor is coiled by a pipeline with a certain inner diameter. 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, phosphoric acid, preferably one or both of acetic acid and phosphoric acid, more preferably phosphoric acid. In another preferred embodiment, the phosphoric acid is an 85% phosphoric acid solution. In another preferred embodiment, the preheating temperature of the premix in the step (1) is 80-100 ℃, preferably 80-90 ℃. In another preferred embodiment, the molar ratio of the compound of formula II to sodium azide in step (1) is 1.0:1.5-3.5, preferably 1.0:1.5-2.5. In another preferred embodiment, the mass ratio of the compound of formula II to the organic acid in step (1) is 1.0:0.01-0.20, preferably 1.0:0.05-0.15, more preferably 1.0:0.05-0.1. In another preferred embodiment, the volume ratio of the compound of formula II to DMSO in step (1) is 1.0:2.0-5.0, preferably 1.0:2.5-3.5. In another preferred example, the pumping speed of the peristaltic pump in the step (2) is 1.0ml/min to 5.0ml/min, preferably 2.0ml/min to 3.5ml/min. In another preferred embodiment, the tubular reactor in step (2) is placed in a heating medium, wherein the heating medium includes but is not limited to steam and simethicone, and the temperature of the heating medium is 110-170 ℃, preferably 150-160 ℃. In another preferred example, the residence time of the premix in the step (2) in the tubular reactor is 10 min-20 min, preferably 10 min-15 min. In another preferred embodiment, the inner diameter of the tubular reactor is 1.0mm to 10.0mm, preferably 1.5mm to 5.0mm, more preferably 1.5mm to 3.0mm. In another preferred embodiment, the preparation meth