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Propacetamol crystal form and preparation method thereof

A technology of propatamole and crystal form, applied in the field of chemical organic synthesis, can solve the problems of increased cost, difficulty in the purification of the next step, unqualified detection items such as clarity and color, etc., so as to prevent excessive or excessive use of hydrochloric acid. less effect

Pending Publication Date: 2020-04-21
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are no reports on the crystal form patents of propadamole at home and abroad. The related literature propadamole is an oily substance without purification. It is directly carried out in the next step reaction, which brings difficulties to the purification of the next step reaction and leads to the clarification of related substances and solutions of the product. The inspection items such as degree and color are unqualified, the yield is reduced, and the cost is increased

Method used

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  • Propacetamol crystal form and preparation method thereof
  • Propacetamol crystal form and preparation method thereof
  • Propacetamol crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 100.0g (0.6615mol, 1eq) of acetaminophen, 1L of acetone, and 110.4g (0.8000mol, 1.2eq) of anhydrous potassium carbonate into a three-necked flask, mechanically stir and slowly add chlorine in an ice bath at 0-5°C Acetyl chloride 63mL (0.8000mol, 1.2eq), continue to react under ice bath for 0.5h after dropping, and react at room temperature for 6h. After the reaction was completed, 5.5 g (0.0662 mol, 0.1 eq) of potassium iodide was added to the reaction solution, and 105.5 g (1.4424 mol, 2.18 eq) of diethylamine was added at 40° C., reacted for 2 hours, filtered, and 5 g of activated carbon was added to the filtrate, refluxed for decolorization, and filtered. Evaporated to dryness under reduced pressure, dissolved in 200 mL of ethyl acetate, slowly added dropwise 600 mL of n-heptane to crystallize, filtered, and dried under reduced pressure at 30°C to obtain 119.8 g of off-white solid with a yield of 68.5% and a purity of 99.1%.

Embodiment 2

[0034] Add 100.0g (0.66mol, 1eq) of paracetamol, 1L of acetone, and 63.3g (0.80mol, 1.2eq) of pyridine into a three-neck flask, mechanically stir and slowly add 63mL of chloroacetyl chloride in an ice bath at 0-5°C (0.80mol, 1.2eq), continue to react in ice bath for 0.5h after dropping, and react at room temperature for 6h. After the reaction was completed, 5.5 g (0.07 mol, 0.1 eq) of potassium iodide was added to the reaction solution, and 105.5 g (1.44 mol, 2.18 eq) of diethylamine was added at 40° C., reacted for 2 hours, filtered, and 5 g of activated carbon was added to the filtrate, refluxed for decolorization, and filtered. Evaporate to dryness under reduced pressure, dissolve in 200 mL of ethyl acetate, slowly add 600 mL of n-heptane to crystallize, filter, and dry under reduced pressure at 30°C to obtain 105.8 g of off-white solid with a yield of 60.5% and a purity of 98.1%.

Embodiment 3

[0036] Add 100.0g (0.66mol, 1eq) of acetaminophen, 1L of acetone, and 110.4g (0.80mol, 1.2eq) of anhydrous potassium carbonate into a three-neck flask, mechanically stir and slowly add chlorine dropwise under an ice bath at 0-5°C Acetyl chloride 69mL (1.00mol, 1.5eq), continue to react in ice bath for 0.5h after dropping, and react at room temperature for 6h. After the reaction was completed, 5.5 g (0.07 mol, 0.1 eq) of potassium iodide was added to the reaction solution, and 105.5 g (1.44 mol, 2.18 eq) of diethylamine was added at 40° C., reacted for 2 h, filtered, and 7 g of activated carbon was added to the filtrate, refluxed for decolorization, and filtered. Evaporated to dryness under reduced pressure, dissolved in 200 mL of ethyl acetate, slowly added dropwise 600 mL of n-hexane to crystallize, filtered, and dried under reduced pressure at 30°C to obtain 121.4 g of off-white solid with a yield of 69.4% and a purity of 98.6%.

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Abstract

The invention discloses a propacetamol crystal form and a preparation method thereof, and relates to the technical field of chemical organic synthesis. Acetaminophen and chloroacetyl chloride are usedas starting materials, the propacetamol crystal form is prepared through a chloroacetylation reaction and an ammoniation reaction, and the propacetamol crystal form is not reported in the prior art Propacetamol solid is prepared by utilizing the preparation method, and therefore, the feeding amount can be accurately controlled when the propacetamol hydrochloride is prepared through a subsequent salt forming reaction, the situation that the dosage of hydrochloric acid is too large or too small is avoided, and the problem that in the prior art, the yield and purity of the product propacetamol hydrochloride are seriously affected when the propacetamol hydrochloride is prepared through a propacetamol oily matter is solved.

Description

Technical field: [0001] The invention relates to the technical field of chemical organic synthesis, in particular to a crystal form of propadamole and a preparation method thereof. Background technique: [0002] Propatamol was synthesized in the mid-to-late 1970s. In the next ten years, few researchers got involved in its research. Until the mid-to-late 1980s, with the clinical application of paracetamol in antipyretic and analgesic Due to the wide application of paracetamol and the weaknesses exposed in the application of paracetamol, people have turned their attention to the prodrug of paracetamol, so propatamol has begun to receive attention and attention in clinical practice, especially in recent years. There are many reports on research and clinical application. Propatamol is mainly used clinically for the symptomatic treatment of pain, especially postoperative pain and cancer pain, and can also be used for the symptomatic treatment of fever, such as fever in infectiou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C233/25
CPCC07C231/12C07C233/25C07B2200/13
Inventor 高永好何勇杨士伟任何夏伦洋于艳英方宗华
Owner HEFEI HUAFANG PHARMA SCI & TECH
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