Search

CN-122011072-A - Preparation method of Ai Tuoge-column net intermediate

CN122011072ACN 122011072 ACN122011072 ACN 122011072ACN-122011072-A

Abstract

The invention relates to a preparation method of Ai Tuoge-column clean intermediate, which is used for obtaining a high-purity monohydroxy intermediate by selectively removing TMS protecting groups of 6-hydroxyl of Ai Tuoge-column clean intermediate. The method has the advantages of good selectivity, less impurities, high raw material conversion rate, simple method, mild condition, continuous operation and suitability for industrial production, and only removes the 6-hydroxyl protecting group.

Inventors

  • YAN PEISHENG
  • SUN YUNBEI
  • WANG CHUNCHAO
  • WANG LIANHUI
  • JIA YANXIA
  • ZHAO ZHENNAN
  • SHEN WENGUANG
  • ZHOU HUANRAN
  • YANG MINGBO

Assignees

  • 山东罗欣药业集团恒欣药业有限公司
  • 山东罗欣药业集团股份有限公司
  • 山东裕欣药业有限公司
  • 罗欣药业(上海)有限公司

Dates

Publication Date
20260512
Application Date
20260129

Claims (8)

  1. 1. A process for preparing Ai Tuoge columns of net intermediates, comprising the steps of: (1) The compound IV reacts with trimethylchlorosilane under the conditions of an organic solvent and alkali to obtain a compound V; (2) Adding a small amount of water and a certain amount of methanol into the step (1) for heating reaction, and preparing a compound VI after finishing the reaction and post-treatment; the synthetic route is as follows: 。
  2. 2. The process for preparing Ai Tuoge columns of clean intermediates according to claim 1, wherein the organic solvent in step (1) is dichloromethane and the base is imidazole.
  3. 3. The method for preparing Ai Tuoge column clean intermediates according to claim 1, wherein the molar ratio of the compound IV, the base and the trimethylchlorosilane in the step (1) is 1:5-8:5-8, preferably 1:6-6.5:6.
  4. 4. The method for preparing Ai Tuoge columns of clean intermediates according to claim 1, wherein the volume-mass ratio of the organic solvent to the compound IV in the step (1) is 8-10 ml/g.
  5. 5. The method for preparing Ai Tuoge columns of clean intermediates according to claim 1, wherein the volume ratio of methanol in step (2) to organic solvent in step (1) is 1:1-4, preferably 1:1-2.
  6. 6. The process for preparing Ai Tuoge columns of net intermediates according to claim 1, wherein the reaction temperature in step (2) is 30-43 ℃, preferably 40 ℃.
  7. 7. The process for the preparation of Ai Tuoge-column net intermediate according to claim 1, wherein the reaction time in step (2) is 4-8 h, preferably 6h.
  8. 8. The process for preparing Ai Tuoge columns of clean intermediates according to claim 1, wherein the post-treatment is cooling, adding water solution, adding anhydrous sodium sulfate and drying to obtain dichloromethane solution of compound VI.

Description

Preparation method of Ai Tuoge-column net intermediate Technical Field The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of Ai Tuoge-column clean intermediate. Background Diabetes is a chronic disease marked by hyperglycemia, initiated by absolute or relative inadequate insulin secretion and by disorders of utilization, of which diabetes type 2 diabetes is the most common form. In recent years Ai Tuoge columns of SGLT-2 inhibitors and the like provide a new thought for treating type 2 diabetes mellitus, and the SGLT-2 inhibitors can inhibit the reabsorption of glucose by kidneys and discharge excessive glucose from urine, so that the effect of reducing blood sugar is achieved. Ai Tuoge column of net (Ertugliflozin), chemical name (1S, 2S,3S,4R, 5S) -5- (4-chloro-3- (4-ethoxybenzyl) phenyl) -1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol and (2S) -5-pyrrolidone-2-carboxylic acid co-crystal compound, which was developed jointly by pyroxene and moxadong, obtained commercially at 7 and 30 days in 2020 under the trade name of minoxidil. The structural formula is as follows: 。 A plurality of routes for synthesizing Ai Tuoge columns of net are provided, but the main current synthetic route is to take 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone (formula II) and 5-bromo-2-chloro-4' -ethoxydiphenylmethane (formula III) as starting materials, couple under the action of n-butyllithium to obtain a compound IV, then use trimethylsilyl to protect hydroxyl to obtain the compound V, then selectively remove a 6-position protecting group from the compound V to obtain a compound VI, sequentially carry out Parikh-Doering oxidation, crossed Crossed-Cannizzaro reaction and acid catalyzed etherification cyclization reaction to obtain Ai Tuoge columns of net, and finally eutectic with L-pyroglutamic acid to obtain Ai Tuoge columns of net raw materials. The synthetic route is as follows: The route has the advantages of easily obtained starting materials, low price, simple reaction operation and suitability for industrial production, but the existing process has the problems of poor selectivity or more residual raw materials when the protecting group of the 6-hydroxyl is selectively removed from the compound V to the compound VI. In CN10214917B, 1% potassium carbonate in methanol is used for selective removal, and the method has the problem of multiple solvent conversion, and the dichloromethane solution of the compound V needs to be converted into methanol first, and after the reaction of adding potassium carbonate is completed, the dichloromethane solution needs to be converted again for the next reaction. When the batch is large, the operation time is prolonged, part of protecting groups are fallen off, and impurities become large, so that the product quality of the subsequent steps is affected. And the solvent is converted for multiple times, so that the cost is increased, the working hours are prolonged, and the method is not suitable for industrial production. The document org. Process res. Dev.2014, 18 (1), 57-65 uses a mixed aqueous solution of p-toluenesulfonic acid and pyridine (PPTs) for selective deprotection, the method does not need to convert solvents, has few impurities, but can leave 8% of compound V, the compound V is deprotected and converted into compound IV in the subsequent Process, and the compound V is removed by repeated recrystallization, so that the yield of the product is greatly affected. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a preparation method of Ai Tuoge columns of net intermediates. In order to achieve the above purpose, the present invention adopts the following technical scheme: (1) The compound IV reacts with trimethylchlorosilane under the conditions of an organic solvent and alkali to obtain a compound V; (2) Adding a small amount of water and a certain amount of methanol into the step (1) for heating reaction, and preparing a compound VI after finishing the reaction and post-treatment; the synthetic route is as follows: preferably, in the step (1), the organic solvent is dichloromethane, and the base is imidazole. Preferably, the molar ratio of the compound IV to the alkali to the trimethylchlorosilane in the step (1) is 1:5-8:5-8, and further preferably, the molar ratio of the compound IV to the alkali to the trimethylchlorosilane is 1:6-6.5:6. Preferably, in the step (1), the volume-mass ratio of the organic solvent to the compound IV is 8-10 ml/g. Preferably, the volume ratio of the methanol in the step (2) to the organic solvent in the step (1) is 1:1-4, and more preferably, 1:1-2. Preferably, the reaction temperature of the step (2) is 30-43 ℃, and further preferably, the reaction temperature is 40 ℃. Preferably, the reaction time of the step (2) is 4-8 h, and further preferably, the reaction time is 6h. Preferably, the post-treatment is cooling, adding