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Preparation method of a 25-hydroxy vitamin D3 intermediate

A technology for hydroxyvitamins and intermediates, which is applied in the field of preparation of 25-hydroxyvitamin D3 intermediates, which can solve the problems of high risk of lithium reagents, and achieve the effects of easy process operation, simple operation of the preparation process, and low cost

Pending Publication Date: 2020-04-10
肇庆巨元生化有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, lithium reagents are more dangerous in the production process.

Method used

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  • Preparation method of a 25-hydroxy vitamin D3 intermediate
  • Preparation method of a 25-hydroxy vitamin D3 intermediate
  • Preparation method of a 25-hydroxy vitamin D3 intermediate

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preparation example Construction

[0060] A form of 25-hydroxyvitamin D 3 Process for the preparation of intermediates, the 25-hydroxyvitamin D 3 The intermediate is 2-methyl-4-(phenylsulfonyl)-2-butanol, which is prepared from 3-methyl-3-butanol-1-p-toluenesulfonate, halide and sodium benzenesulfinate in Made in solvent.

[0061] That is, the application provides a novel 25-hydroxyvitamin D 3 Intermediate C 5 The fragment is an alcohol sulfone fragment, which has high safety. The preparation process is simple, easy to separate, and the raw material is easy to obtain. It is 25-hydroxyvitamin D 3 The synthesis of intermediates provides a new, more economical and safer way of thinking.

[0062] Specifically, the present invention provides a two-step and "one-pot" method for synthesizing 25-hydroxyvitamin D 3 Intermediates, wherein the two-step process comprises:

[0063] 1) Under the protection of an inert gas, react 1 mol of 3-methyl-3-butanol-1-p-toluenesulfonate with 1.0-2.5 mol of halide in the first or...

Embodiment 1

[0072] A form of 25-hydroxyvitamin D 3 The preparation method of intermediate comprises the following steps:

[0073] Step 1) Preparation of 4-bromo-2-methyl-2-butanol:

[0074] Under nitrogen protection, add 0.10mol 3-methyl-3-butanol-1-p-toluenesulfonate, 0.15mol sodium bromide and 20mL methanol to a 500mL reaction flask, stir magnetically and heat to reflux, then add 0.05mol DMF (moisture content 1.0%), continue to reflux reaction for 6.0h;

[0075] After the reaction was complete, methanol was recovered under reduced pressure, and 100 mL of water was added to dissolve the solid, extracted three times with dichloromethane, the organic phases were combined, the dichloromethane was recovered, drained, the concentrate was refined under reduced pressure, and the fractions were collected to obtain 16.19 g of a colorless liquid , GC content 82.41%, GC graph as shown in figure 1 As shown, the yield calculated based on 3-methyl-3-butanol-1-p-toluenesulfonate was 79.87%.

[0076...

Embodiment 2

[0080] A form of 25-hydroxyvitamin D 3 The preparation method of intermediate comprises the following steps:

[0081] Step 1) Preparation of 4-bromo-2-methyl-2-butanol:

[0082] Under nitrogen protection, add 0.05mol 3-methyl-3-butanol-1-p-toluenesulfonate, 0.08mol sodium bromide and 20mL acetone to a 500mL reaction flask, stir magnetically and heat to reflux, then add 0.05mol DMF (moisture content 2.5%), continue the reflux reaction for 7.0h;

[0083] After the reaction was completed, acetone was recovered under reduced pressure, and 60 mL of water was added to dissolve the solid, extracted three times with dichloromethane, the organic phases were combined, the dichloromethane was recovered, drained, the concentrate was refined under reduced pressure, and 8.10 g of colorless liquid was obtained by collecting fractions , the GC content is 86.86%, and the yield calculated by 3-methyl-3-butanol-1-p-toluenesulfonate is 85.28%.

[0084] Step 2) Preparation of 2-methyl-4-(phenyl...

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Abstract

The invention discloses a preparation method of a 25-hydroxy vitamin D3 intermediate, wherein the 25-hydroxy vitamin D3 intermediate is 2-methyl-4-(phenylsulfonyl)-2-butanol, and is prepared from 3-methyl-3-butanol-p-toluenesulfonate, a halide and sodium benzenesulfinate in a solvent. According to the invention, the synthesis route of the 25-hydroxyvitamin D3 intermediate is short, raw materials are easy to obtain, separation is simple, anhydrous conditions are not needed in synthesis operation, and a new and safe C5-fragment is provided for synthesis of 25-hydroxyvitamin D3.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a 25-hydroxyvitamin D 3 Methods of preparation of intermediates. Background technique [0002] 2-methyl-4-(phenylsulfonyl)-2-butanol, referred to as C 5 -Alcohol sulfone, a colorless transparent liquid, is a key intermediate in the synthesis of 25-hydroxyvitamin D3. 25-Hydroxyvitamin D 3 , that is, 25-hydroxycholate (solid) alcohol, also known as 25-hydroxycholecalciferol, calcium glycol, medically known as cholecalciferol, abbreviated as 25-OH-D 3 . 25-Hydroxyvitamin D 3 The potency of vitamin D 3 3-5 times that of vitamin D, the final biological activity expressed is vitamin D 3 20-40 times. 25-Hydroxyvitamin D 3 than vitamin D 3 Easier to absorb, higher biological activity. Direct 25-Hydroxyvitamin D Supplementation 3 , not only shortened vitamin D 3 In the body's metabolic process, it reduces the burden on the liver, and avoids the impact on absorption ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C315/00C07C317/18
CPCC07C29/62C07C315/00C07C31/36C07C317/18
Inventor 廖艳金方泽华姚伟平蒙美壮叶振兴
Owner 肇庆巨元生化有限公司
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