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Preparation method of halcinonide and intermediate thereof

A compound, N-7 technology, applied in the field of preparation of halcyonide and its intermediates, can solve the problems of product quality and yield need to be improved, strong irritation, large energy consumption, etc., so as to shorten the production cycle and simplify the production Steps, the effect of reducing consumption

Pending Publication Date: 2021-10-12
HENAN LIHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above synthesis method, the N-3→N-4 fluoride reaction system is neutralized with ammonia water, thereby producing a large amount of high-ammonia-nitrogen waste water, causing environmental pressure; N-4→N-5 is reacted in acetone with a high proportion and triethylamine neutralization, after the reaction is complete, concentration requires a lot of energy consumption, the operation steps are cumbersome, and a large amount of high-ammonia nitrogen wastewater is produced at the same time; Methylsulfonyl chloride reaction, methylsulfonyl chloride is a highly irritating drug, and is highly irritating, causing serious environmental pollution; N-6→Halcinonide is reacted in the DMF system, and after the reaction, water analysis produces a large amount of high ammonia nitrogen Waste water, does not conform to the concept of clean production
In addition, the HPLC content of the product halcinonide obtained by the above method is about 98.5%, the impurity content is about 0.2%, and the yield is about 80%. The product quality and yield still need to be improved

Method used

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  • Preparation method of halcinonide and intermediate thereof
  • Preparation method of halcinonide and intermediate thereof
  • Preparation method of halcinonide and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The preparation of embodiment 1 intermediate N-3

[0049] This embodiment provides the preparation method of the compound of intermediate formula N-3, the steps are as follows:

[0050] Step A: Preparation of intermediate N-1 from triene acetate

[0051] Add 8.1g of potassium permanganate to 105ml of water, heat up to 40°C, stir to dissolve potassium permanganate, add 300ml of acetone after dissolving, stir and cool down to about -5°C to obtain potassium permanganate solution; set aside.

[0052] Add 9g of sodium sulfite into 75ml of water, stir and dissolve to obtain sodium sulfite solution; set aside.

[0053] Add 15g of triene acetate to 600ml of acetone, cool down to about -5°C, add 5.4ml of formic acid, stir for 5 minutes, add the potassium permanganate solution prepared above, control the temperature at -5°C for 10 minutes, add the prepared The sodium sulfite solution was heated to 40°C, filtered, and the filtrate was concentrated under reduced pressure to be fr...

Embodiment 2

[0059] The preparation of embodiment 2 halcinonide

[0060] This embodiment provides the preparation method of halcinonide, the steps are as follows:

[0061] Step A: Preparation of Intermediate N-7

[0062] Dissolve 60g of potassium hydroxide in 300ml of water, stir and dissolve to obtain potassium hydroxide solution; set aside.

[0063] Under the protection of nitrogen, add 160ml of chloroform, 20g of the compound of formula N-3 and 20g of p-toluenesulfonyl chloride into the reaction flask, cool down to about -5°C, add 25ml of diethylamine dropwise, drop it in 30 minutes, and then - React at about 5°C for 5 hours, TLC (dichloromethane: acetone = 6:1) detects almost no spots at Rf 0.35, add 2ml of methanol, heat up to about 30°C, keep warm for 10 hours, TLC (dichloromethane: acetone =6:1) There is almost no spot at Rf 0.65, washed twice with 100ml of drinking water, the organic layer is cooled to below 10°C, under the protection of nitrogen, add 1g of antioxidant BHT, conti...

Embodiment 3

[0068] The preparation of embodiment 3 halcinonide

[0069] This embodiment provides the preparation method of halcinonide, the steps are as follows:

[0070] Step A: Preparation of Intermediate N-7

[0071] Dissolve 60g of potassium hydroxide in 300ml of water, stir and dissolve to obtain potassium hydroxide solution; set aside.

[0072] Under the protection of nitrogen, add 160ml of dichloromethane, 20g of the compound of formula N-3 and 18g of p-toluenesulfonyl chloride into the reaction flask, cool down to about 0°C, add 25ml of triethylamine dropwise, drop it in 30 minutes, and put it at 0°C React for about 5 hours, TLC (dichloromethane: acetone = 6: 1) detects that there is almost no spot at Rf 0.35, add 2ml of methanol, heat up to about 35 ° C, keep the reaction for 10 hours, TLC (dichloromethane: acetone = 6: 1) There are almost no spots at Rf 0.65, wash twice with 100ml of drinking water, cool the organic layer to below 10°C, add 1g of antioxidant BHT under nitrogen...

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Abstract

The invention provides a preparation method of halcinonide and an intermediate thereof. The preparation method of the halcinonide intermediate (namely a compound of a formula N-7) comprises the following steps: carrying out a chlorination reaction on a compound of a formula N-3 and a chlorination reagent, and then carrying out a fluorination reaction with a fluorine-containing reagent, wherein the reaction formula is disclosed in the invention, the chlorination reagent is selected from sulfonyl chloride of aromatic hydrocarbon and is specifically selected from at least one of benzene sulfonyl chloride, p-toluenesulfonyl chloride and p-chlorobenzene sulfonyl chloride, and the fluorine-containing reagent is hydrofluoric acid. The preparation method is efficient, green and environmentally friendly, the production period is shortened, a large amount of wastewater is reduced, the yield is improved, the production cost is reduced, clean production is achieved, the HPLC content of the halcinonide product reaches 99.0% or above, the content of any impurity is smaller than 0.10%, and the yield reaches 100% or above.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, in particular to a preparation method of halcinonide and its intermediate. Background technique [0002] The chemical name of halcinonide is 16α,17-[(1-methylethylidene)bis(oxy)]-11β-hydroxy-21-chloro-9-fluoropregna-4-ene-3,20-di Ketone, the chemical structure formula is as follows. Halcinonide is a high-efficiency corticosteroid containing fluorine and chlorine, which has anti-inflammatory, anti-pruritic and vasoconstrictive effects. Cyclase increases the generation of cAMP, and inhibits phosphoethylesterase to reduce the destruction of cAMP. As a result, the annual concentration of cAMP in cells increases, and at the same time inhibits the release of histamine. [0003] [0004] The traditional synthetic method of halcinonide is to use triene acetate as a substrate, and it is prepared through processes such as dioxyhydroxide, bromo-hydroxyl reaction, epoxy hydrolysis, fluorine reacti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00C07J7/00
CPCC07J7/0085C07J71/0031
Inventor 王海波王瑞玲李合兴牛志刚
Owner HENAN LIHUA PHARMA
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