The preparation method of everolimus intermediate
A technology for everolimus and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, and can solve the problem of low yield and purity of tert-butyldimethylhydroxyethoxysilane, the product of ethylene glycol mono-substitution, and ethylene glycol double-substitution. There are many by-products, etc., to achieve high yield, improve purity, and reduce degradation
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Embodiment 1）
[0016] The preparation method of the everolimus intermediate of the present embodiment has the following steps:
[0017] ①Add 13g of tert-butyldimethylchlorosilane to 26.1g of dichloromethane, stir until dissolved to obtain a dichloromethane solution of tert-butyldimethylsilyl chloride; Diol, 78.3g of dichloromethane and 36.7g of pyridine were cooled to -30°C, and the above dichloromethane solution of tert-butyldimethylsilyl chloride was added dropwise, and the reaction was continued for 30 minutes after the dropwise completion.
[0018] After the reaction is over, add a phosphoric acid-potassium dihydrogen phosphate buffer solution with a concentration of 10wt% to adjust the pH of the reaction system to 2, then adjust the pH of the reaction system to 6 with saturated saline, let it stand, collect the organic phase, add a desiccant to dry, and filter , concentrated to obtain 16.9g of 2-(tert-butyldimethylsilyloxy)ethanol, the weight yield was 130%, the content detected by GC w...
Embodiment 2～ Embodiment 6）
[0022] The method of each embodiment is basically the same as that of Example 1, except for step ①, see Table 1 for details.
[0023] Table 1
[0024] Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 organic base pyridine 2,6-Lutidine pyridine 2,6-Lutidine pyridine 2,6-Lutidine inert solvent Dichloromethane Dichloromethane benzene benzene Chloroform Chloroform temperature reflex -30℃ -35℃ -25℃ -30℃ -35℃ -25℃ 2-(tert-Butyldimethylsilyloxy)ethanol 16.9g 16.2g 17.1g 16.4g 15.6g 16.0g Mono-substituted product content 85.0% 84.5% 82.5% 83.0% 84.0% 83.5% molar yield 94.5% 90.0% 92.8% 89.5% 86.2% 87.9% Double substitution by-product content 3.45% 3.74% 3.60% 3.98% 4.25% 3.76%
Embodiment 7）
[0026] The method of this embodiment is basically the same as that of Embodiment 1, the difference lies in step ①:
[0027] Add 13g of tert-butyldimethylsilyl chloride to 26.1g of dichloromethane, stir until dissolved to obtain a dichloromethane solution of tert-butyldimethylsilyl chloride; add 52.2g of ethylene dichloride to the reaction device Alcohol, 78.3g of dichloromethane and 36.7g of pyridine were cooled to -30°C, and the above dichloromethane solution of tert-butyldimethylsilyl chloride was added dropwise, and the reaction was continued for 30 minutes after the dropwise completion.
[0028] After the reaction, directly adjust the pH of the reaction system to 6, let it stand, collect the organic phase, add a desiccant to dry, filter, and concentrate to obtain 16.5 g of 2-(tert-butyldimethylsiloxy)ethanol, the weight yield It was 127%, and the GC detection content was 81.5%, and the molar yield was 88.5%, and the GC detection double-substituted by-product content was 4....
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