Preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone

A technology of gluconolactone and trimethylsilyl, applied in the field of preparation of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, which can solve the problem of cooling production equipment Strict efficiency requirements, unstable product quality and production, etc., to achieve the effect of lower cooling efficiency requirements, stable reproducibility, and easy operation of the synthesis process

Active Publication Date: 2020-06-05
SHANGHAI SYNCORES TECH INC +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] What the present invention is to solve is that there are strict requirements on the cooling efficiency of production equipment in the large-scale production of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, and the production quality of the product is not good. Stability and other issues, a special preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone is proposed, the preparation method adopts the following method:

Method used

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  • Preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone
  • Preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone
  • Preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone

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Experimental program
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Effect test

Embodiment 1

[0042] Add 400L tetrahydrofuran and 290kg (2.86kmol, 6.4eq) N-methylmorpholine to the reaction flask, cool down to -5~15°C, slowly add 250kg (2.3mol, 5.1eq) trimethylchlorosilane dropwise, control system -5~15°C, after dropping, add 80kg (449.4mol, 1.0eq) gluconolactone in batches, and control the temperature at -5~20°C; add 1.4kg (23mol, 0.05eq) DMAP after feeding, and then Raise the temperature to 30-35°C and react for 3-5 hours; add 400kg of toluene, cool down to 0-10°C, add dropwise 100L of aqueous solution to quench the temperature at 0-10°C, add 250L of water to dissolve the system, and remove the water phase. The aqueous phase was extracted with 100L of toluene and the organic phase was combined. The organic phase was washed with 540 kg of 7% sodium dihydrogen phosphate aqueous solution and 520 kg of saturated brine. 207.6 kg of yellow oil, yield 99.1%, GC purity 98.7%, impurity compound IV purity 0.11%.

Embodiment 2

[0044] Add 200ml tetrahydrofuran and 79.7g (787.5mmol, 7.0eq) N-methylmorpholine to the reaction flask, cool down to 15-30°C, slowly add 73.3g (675mmol, 6.0eq) trimethylchlorosilane dropwise, control system 15-30°C, after dropping, add 20g (112.5mmol, 1.0eq) gluconolactone in batches, and control the temperature at 20-40°C; add 0.27g (2.25mmol, 0.02eq) DMAP after the addition, and then raise the temperature React at 30-35°C for 3-5 hours; add 100g of toluene, cool down to 5-15°C, add dropwise 25ml of aqueous solution to quench the temperature at 5-15°C, add 62.5ml of water to dissolve the system, and remove the water phase. The aqueous phase was extracted with 25ml of toluene and the organic phase was combined. The organic phase was washed with 135g of 7% sodium dihydrogen phosphate aqueous solution and 130g of saturated brine. The oil was 52.15g, the yield was 99.5%, the GC purity was 98.3%, and the impurity compound IV had a purity of 0.16%.

Embodiment 3

[0046] Add 200ml tetrahydrofuran and 145g (1.43mol, 6.4eq) N-methylmorpholine to the reaction flask, cool down to 20-30°C, slowly add 125g (1.15mol, 5.1eq) trimethylchlorosilane dropwise, control system 25 ~40°C, after dropping, add half of 20g (112.6mmol, 0.5eq) gluconolactone in batches, control the temperature at 25-40°C and stir overnight, then add the other half of 10g (112.6mmol, 0.5eq) gluconolactone Esters; add 1.4g (11.5mmol, 0.05eq) DMAP after feeding, then heat up to 30-35°C and react for 3-5h; add 200g toluene, cool down to 5-15°C, add dropwise 50ml of aqueous solution to quench control 5 ~15°C, add 125ml of water to dissolve the system, separate the water phase, extract the water phase with 50ml of toluene and combine the organic phase, wash the organic phase with 270g of 7% sodium dihydrogen phosphate aqueous solution, and wash with 260g of saturated saline , the organic phase was overbasic with alumina and then concentrated under reduced pressure to obtain 104.3...

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Abstract

The present invention provides a preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone. The method comprises the following steps: dropwise adding trimethylchlorosilane into a system of tetrahydrofuran and N-methylmorpholine, adding glucolactone in batches after dropwise adding of the trimethylchlorosilane, and then adding 4-dimethyl pyridine for reaction so as to obtain the 2, 3,4, 6-tetra-O-trimethylsilyl-D-glucolactone. Compared with the prior art, the preparation method disclosed by the invention has the advantages that the requirements on the feeding temperature and the feeding time during reaction are wider, the quality controllable range is widened, the process repeatability is good, the requirement on the cooling of production equipment is reduced, and the preparation method has great advantages in the aspects of product purity and impurity compound IV control.

Description

technical field [0001] The invention relates to a preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, belonging to the technical field of organic chemistry. [0002] technical background [0003] The compound I involved in the present invention is 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, the compound CAS number is 32384-65-9, and the specific structural formula is as follows: [0004] [0005] The compound I is a key starting material for the preparation of SGLT-2 inhibitors for treating adult patients with type II diabetes, such as canagliflozin, dapagliflozin and empagliflozin, and is widely used. [0006] The preparation reaction formula of canagliflozin is as follows: [0007] [0008] The preparation reaction formula of dapagliflozin is as follows: [0009] [0010] The preparation reaction formula of Empagliflozin is as follows: [0011] [0012] Regarding the preparation of compound I, there are many patents and literature repo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/188C07B2200/07
Inventor 季翔尹凯王东刘丰豪石凯强樊海生郭效文黄鲁宁顾虹
Owner SHANGHAI SYNCORES TECH INC
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