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Preparation process of halcinonide intermediate

A technology of hascinide and preparation process, applied in the field of chemical pharmacy, can solve the problems of long production cycle, difficult waste water treatment, increased environmental protection pressure, etc., and achieve the effects of simplifying production steps, shortening production cycle, and reducing consumption

Inactive Publication Date: 2017-05-31
HENAN LIHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above-mentioned preparation method has the following defects: one is to react from intermediate N4 to intermediate N-5 in acetone with a high proportion, and acetone is a precursor to poison and is controlled by the state; Consumption, cumbersome operation steps, long production cycle; third, DMF-containing wastewater is difficult to handle, increasing the pressure on environmental protection

Method used

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  • Preparation process of halcinonide intermediate
  • Preparation process of halcinonide intermediate
  • Preparation process of halcinonide intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of intermediate N-3

[0026] A: Preparation of intermediate N-1 from triene acetate;

[0027] Add 8.1g of potassium permanganate to 105ml of water, heat up to 40°C, stir to dissolve the potassium permanganate, add 300ml of acetone after dissolving, stir and cool down to -15-20°C, set aside. Add 9g of sodium sulfite to 75ml of water, stir to dissolve, and set aside.

[0028] Add 15g of triene acetate to 600ml of acetone, cool down to -5-0°C, add 5.4ml of formic acid, stir for 5min, add the prepared potassium permanganate solution, control the temperature at -5-0°C for 10min, add the prepared A good sodium sulfite solution was heated up to 40°C, filtered, the filtrate was concentrated under reduced pressure to free of acetone, cooled to below 10°C, centrifuged, and dried at 60°C for 12 hours to obtain intermediate N-1, 14.5g, chromatographic purity: 98.2 %, yield 96.7%;

[0029] B: Preparation of Intermediate N-2 from Intermediate N-1;

...

Embodiment 2

[0033] Embodiment 2: the preparation of intermediate N-5

[0034] Dissolve 130g of potassium carbonate in 400ml of water, stir to dissolve, and set aside. Add 50ml of hydrofluoric acid (70% HF) and 5ml of acetone into a 100ml plastic bottle, stir evenly, cool down to -40--30°C, control the temperature within -40--30°C, add 10g of the substrate within 1h Body N-3, after adding, react at temperature -35--30°C for 5 hours, return to -5-0°C, react for 10 minutes, slowly add the reaction solution into the prepared potassium carbonate solution, control the temperature at 10°C After that, the addition was completed within 1 hour, the pH value was adjusted to 7.0-7.5, the material was filtered out, and after drying, 10.35 g of the crude intermediate N-5 was obtained, with a chromatographic purity of 96.2%.

Embodiment 3

[0035] Embodiment 3: Preparation of Intermediate N-5

[0036] Dissolve 130g of potassium carbonate in 400ml of water, stir to dissolve, and set aside. Add 50ml of hydrofluoric acid (70% HF) and 10ml of acetone into a 100ml plastic bottle, stir evenly, cool down to -40--30°C, control the temperature within -40--30°C, add 10g of intermediates within 1 hour Substance N-3, after adding, react at temperature -35--30°C for 5 hours, return to -5-0°C, react for 10 minutes, slowly add the reaction solution into the prepared potassium carbonate solution, control the temperature at 10°C After that, the addition was completed within 1 hour, the pH value was adjusted to 7.0-7.5, the material was filtered out, and after drying, 10.41 g of intermediate N-5 crude product was obtained, and the chromatographic purity was 96.7%.

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Abstract

The invention provides a prepration process of a halcinonide intermediate. The preparation process comprises the steps: taking a hydrofluoric acid-acetone mixed solvent as a solvent, slowly adding an intermediate N-3 at subzero 40 DEG C to subzero 30 DEG C, carrying out reaction for 4 to 8 hours after material feeding is completed, enabling the temperature to return to subzero 5 DEG C to 0 DEG C, continuously carrying out reaction for 10 to 30 min, slowly adding reaction fluid into a potassium carbonate solution after the reaction is completed, adjusting the PH value to 7.0 to 7.5, filtering and discharging a product, and drying the product to obtain the halcinonide intermediate with the structure as shown in formula N-5. According to the preparation process, a one-pot method is adopted for production, so that the production steps are effectively simplified, and the production period is shortened; the preparation process is more environment-friendly.

Description

technical field [0001] The invention relates to the synthesis of chemical drugs, in particular to a preparation process of a halcinonide intermediate, which belongs to the technical field of chemical pharmacy. 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- Diketone, a high-efficiency fluorine and chlorine-containing corticosteroid, 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. Halcinonide intermediate N-5 is the raw material for making halcinonide, and its chemical structural formula is: [0003] [0004] Halcinonide intermediate N-5 uses intermediate N-3 as a substrate, uses hydrofluoric acid (70%HF)-DMF mixed solv...

Claims

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Application Information

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IPC IPC(8): C07J71/00
CPCC07J71/0031
Inventor 王海波王瑞玲
Owner HENAN LIHUA PHARMA
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