Preparation method of diclazuril impurity A

A technology for diclazuril and impurities, applied in the field of chemistry or medicinal chemistry, can solve problems such as not finding diclazuril impurity A, and achieve the effects of easy availability of starting materials, easy operation and mild reaction conditions

Inactive Publication Date: 2020-08-11
CHANGZHOU YABANG QH PHARMACHEM +2
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0009] To carry out the detection method development and quality research of nitrosamine impurity, it is necessary to provide a reference substance of nitrosamine impurity A. At present, there is no literature on the preparation of diclazuril impurity A in my country.

Method used

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  • Preparation method of diclazuril impurity A
  • Preparation method of diclazuril impurity A
  • Preparation method of diclazuril impurity A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] (1) Condensation: Add 20 g (66 mmol) of (3-butoxycarbonylamino-3-oxopropionyl)-butyl carbamate, 140 g of dioxane, and 13.6 g of formic acid into a 250 mL four-necked flask, and heat up to 30 ℃, after stirring to dissolve, add the prepared solution of 18.1g sodium nitrite (262mmol) / 36.2g water, and stir and react at 30℃ for 15 hours.

[0028] (2) Decolorization and crystallization: Add 1.0 g of activated carbon to the condensation reaction solution in the previous step, stir for 0.5 hours to decolorize, and then filter with suction. After filtration, the wet product was dried at 50° C. for 16 hours to obtain 18.3 g of off-white diclazuril impurity A dry product with a yield of 83.5%. The content detected by HPLC was 99.6%.

[0029] [M+1]=332.15 (see figure 1 )

[0030] 1 HNMR(DMSO)δ: 0.96(t,6H),1.28-1.38(m,4H),1.50-1.59(m,4H),4.04-4.11(t,4H),10.32(S,1H),11.45,12.72 (S,2H). (See figure 2 )

Embodiment 2

[0032] (1) Condensation: Add 20 g (66 mmol) of (3-butoxycarbonylamino-3-oxopropionyl)-butyl carbamate, 100 g of dimethyl sulfoxide, and 8.0 g of sulfuric acid into a 250 mL four-necked flask, and heat to 35 ℃, after stirring to dissolve, add the prepared solution of 13.7g sodium nitrite (198mmol) / 36.2g water, and stir and react at 35℃ for 20 hours;

[0033] (2) Decolorization and crystallization: add 1.5 g of activated carbon to the condensation reaction solution in the previous step, stir for 1 hour to decolorize, filter with suction, transfer the filtrate to a 500 mL four-neck flask, add 250 g of methanol dropwise at 35°C, and add dropwise for 1 hour. After suction filtration, the wet product was dried at 80° C. for 12 hours to obtain 18.8 g of off-white diclazuril impurity A dry product with a yield of 85.8%. The content detected by HPLC was 99.7%.

Embodiment 3

[0035] (1) Condensation: Add 20 g (66 mmol) of (3-butoxycarbonylamino-3-oxopropionyl)-butyl carbamate, 100 g of dimethyl sulfoxide, and 4.0 g of acetic acid into a 250 mL four-necked flask, and heat to 40°C, stir to dissolve, then add the prepared 17.5g sodium nitrite (254mmol) / 36.2g water solution, stir and react at 40°C for 10 hours;

[0036] (2) Decolorization and crystallization: Add 1.5 g of activated carbon to the condensation reaction solution in the previous step, stir for 1 hour for decolorization, and filter with suction. After filtration, the wet product was dried at 60° C. for 14 hours to obtain 18.5 g of off-white diclazuril impurity A dry product with a yield of 84.4%. The content detected by HPLC was 99.8%.

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Abstract

The invention discloses a preparation method of a diclazuril impurity A. The diclazuril impurity A is obtained through the procedures of condensation reaction of a diclazuril intermediate (3-butyloxycarbonylamino-3-oxopropionyl)-butyl carbamate or (3-ethoxycarbonylamino-3-oxopropionyl)-ethyl carbamate (compound I) used as a starting material with sodium nitrite in a polar solvent and under acid catalysis, decoloration, crystallization and drying. The synthesis route is short, the starting material is easy to obtain, reaction conditions are mild, operation is easy and convenient, the impurity can be obtained without column chromatography, the purity of the prepared impurity can reach 99.5% or above, and the impurity can serve as a reference substance to be used for quality research.

Description

technical field [0001] The invention belongs to the field of chemistry or medicinal chemistry, and in particular relates to a method for preparing diclazuril impurity A. Background technique [0002] Diclazuril (CAS: 101831-37-2) was first developed by the Belgian Janssen company as a non-ionic anticoccidial drug. It was first put on the European market in 1992. Its code name is R-64433 and its chemical name is 2, 6-Dichloro-2-(4-chlorobenzene)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenylacetonitrile , the English name is 2,6-dichloro-alpha-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3h)-yl)benzeneacetonitrile, It belongs to triazine benzyl nitrile compound, which is a new type, high efficiency and low toxicity anticoccidial drug, widely used in chicken coccidiosis. [0003] Recently, there is a risk of detecting trace amounts of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in the marketed valsartan API. According to th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/64C07C269/08
CPCC07C269/06C07C269/08
Inventor 苏文杰王学成张峥张建峰刘祥宜
Owner CHANGZHOU YABANG QH PHARMACHEM
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