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Method for preparing 1alpha-calciferol

A technology of calcidol and 1-OH-3, applied in the field of chemical drug synthesis, can solve the problems of high temperature requirements, long cycle, unfavorable industrial production, etc.

Pending Publication Date: 2022-06-28
HANGZHOU XIASHA BIOCHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method can obtain alfacalcidol with higher purity, in the preparation process, the temperature requirement is relatively high, and multiple purifications or purification with the preparation liquid phase are required, which requires high equipment investment and is not conducive to industrial production.
[0006] There are certain limitations in the existing synthesis and separation methods, resulting in low yields and long cycle times, and it is difficult to effectively obtain pure alfacalcidol. It is urgent to design a preparation method that is easy to control and conforms to industrial production

Method used

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  • Method for preparing 1alpha-calciferol
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  • Method for preparing 1alpha-calciferol

Examples

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Effect test

Embodiment 1

[0070] A method for preparing 1α-calcidol, comprising the following steps:

[0071] (1) Acylation reaction (I)

[0072] Under nitrogen protection, add 9.62g VD to 100mL n-hexane 3 (25.0 mmol) and 10.50 g of p-toluenesulfonyl chloride (55.1 mmol), and the reaction was stirred for 4 h; under ice bath conditions, washed with water 3 to 4 times, after standing for stratification, the n-hexane phase was taken and heated at 50 ° C under vacuum pressure ≤-0.05MPa concentrated under reduced pressure for desolvation to obtain 13.47g VD 3 -3-p-toluenesulfonate.

[0073] (2) Cyclization reaction

[0074] Under nitrogen protection, the VD obtained in step (1) was added to 250 mL of methanol 3 -3-p-toluenesulfonate (25.0 mmol) and 1.40 g of anhydrous sodium carbonate (13.2 mmol) were stirred and reacted for 6 h; then extracted with n-hexane for 2 to 3 times, the extracts were combined, and the extracts were combined at 50 ° C under vacuum pressure ≤- 0.05MPa was concentrated under red...

Embodiment 2

[0093] A method for preparing 1α-calcidol, comprising the following steps: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring restoration, separation and purification, saponification, and crystallization; wherein, removing the saponification In addition, other steps are controlled according to the process parameters of Example 1. The main changes of the saponification described in Example 2 are: change 8.98g potassium hydroxide (160.0mmol), and other things remain unchanged, and finally obtain 1α-OH-VD with a purity of 99.5% 3 , the yield is 59.6%.

[0094] Compared with Example 1, the addition amount of potassium hydroxide was increased in Example 2, the product purity was slightly decreased, and the yield was decreased accordingly.

Embodiment 3

[0096] A method for preparing 1α-calcidol, comprising the following steps: acylation reaction (I), cyclization reaction, oxidation reaction, acylation reaction (II), ring restoration, separation and purification, saponification, and crystallization; wherein, removing crystallization In addition, other steps are controlled according to the process parameters of Example 1. The main changes in the crystallization described in Example 3 are: change 8.98g potassium hydroxide (160.0mmol), and other things remain unchanged, and finally obtain 1α-OH-VD with a purity of 99.7% 3 , the yield was 64.4%.

[0097] Compared with Example 1, the main changes in Example 3 are: the crystallization temperature is reduced to 0-5° C., the crystallization time is shortened to 12 h, and the product yield is increased.

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Abstract

The invention discloses a method for preparing 1alpha-calciferol, which comprises the following steps: by taking VD3 as a raw material, preparing 1-OH-3, 5-cyclo-VD3 through acylation, cyclization and oxidation, and then obtaining high-purity 1alpha-calciferol through acylation, ring recovery, separation, purification, saponification and crystallization. The reaction in each step can be carried out at normal temperature, the requirement on equipment is not high, the operation is convenient, the thermal isomerization of the intermediate is avoided, the separation and purification steps are reduced, and the yield is improved; by adjusting reactants and a synthetic route, the production period is greatly shortened; the method has the advantages that raw materials are easy to obtain, operation is convenient, reaction conditions are mild, environment friendliness is achieved, instability of the intermediate is overcome, tedious steps such as intermediate separation and purification are reduced, and the method has the advantages of being single in product, high in yield and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, in particular to a method for preparing 1α-calcidol. Background technique [0002] 1α-Calcidol as Vitamin D 3 One of the more important active metabolites of calcitriol is a calcitriol analog whose molecular formula is C 27 H 44 O 2 , the structural formula is: [0003] [0004] 1α-calcidol (1α-OH-VD 3 ) only needs to be hydroxylated in the liver to become active 1α,25-(OH) 2 -VD 3 , has the effect of regulating the inorganic salts of bone. It is suitable for improving various symptoms of abnormal vitamin D metabolism in chronic renal insufficiency, hypoparathyroidism, anti-vitamin D rickets, and osteomalacia, such as hypocalcemia, tetany, bone pain, bone lesions and osteomalacia. Porosis, etc. [0005] There are many chiral centers in the molecular structure of 1α-calcidol, the number of stereoisomers is huge, and the properties are unstable. Therefore, the purity of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00
CPCC07C401/00C07C2601/14C07C2602/08C07C2602/18C07B2200/07Y02P20/55
Inventor 汪浩周政颖邵振宝王子强
Owner HANGZHOU XIASHA BIOCHEM TECH
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