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Diazepam-D8 and preparation method thereof

A technology of diazepam and compounds, applied in the field of preparation of deuterated diazepam standard product intermediates, can solve the problems such as the synthesis of diazepam-D8 that has not been reported

Active Publication Date: 2017-12-29
INST OF FORENSIC SCI OF MIN OF PUBLIC SECURITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The literature has not yet reported the synthesis of diazepam-D8, and diazepam-D8 can be used as a deuterated standard

Method used

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  • Diazepam-D8 and preparation method thereof
  • Diazepam-D8 and preparation method thereof
  • Diazepam-D8 and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Step (1): 2-acetamide-5-chlorobenzophenone-2',3',4',5',6'-d 5 (Formula II compound) preparation

[0037]

[0038] Put 2.6g of Mg strips in a 250mL three-necked flask, add 50mL of anhydrous THF, then add 30mg of iodine particles, add a THF solution of deuterated bromobenzene dropwise under stirring (8.8g of deuterated bromobenzene is added to 40mL THF), and reflux the reaction After 1 hour, the Grignard reagent was prepared.

[0039]Put 10.0g of raw material 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (compound of formula I) in a 250mL single-necked bottle, then add 50mL of toluene, and cool down to below 0°C in an ice bath , Add the above-mentioned Grignard reagent dropwise, and the dropping time is greater than 45min. After the addition, stir at 0°C for 30 minutes, then raise the temperature to room temperature and stir overnight, then cool the reaction down to 0°C, add 100 mL of 6mol / L dilute hydrochloric acid, stir for 30 minutes, then separate the liquids, extrac...

Embodiment 2

[0055] Embodiment 2 (preparation method of formula V compound)

[0056] Steps (1), (2) are the same as in Example 1.

[0057] Step (3): 2-bromoacetamide-5-chlorobenzophenone-2',3',4',5',6'-d 5 (Formula IV compound) preparation:

[0058]

[0059] Put 7.08g of the compound of formula III in a 250mL round-bottomed flask, add 36mL of toluene to dissolve it, then add 4.74g of pyridine, cool down to 0°C in an ice bath, add dropwise a toluene solution of bromoacetyl bromide (3.9 mL of bromoacetyl bromide is added to 20 mL of chloroform Middle), after TLC monitors that the reaction is completed, add water to quench the reaction, extract the organic phase with toluene (30 mL each time, 3 times in total), combine the organic phases and wash with saturated sodium carbonate, dry and concentrate under reduced pressure to obtain an oily substance, which is The crude product of the compound of formula IV was directly used in the next reaction without purification.

[0060] Step (4): 7-...

Embodiment 3

[0065] The difference between this example and Example 1 is that the preparation method of step (5) is different: dissolve the compound of formula V (5.5g) in chloroform (30mL), cool down to -5°C in an ice-salt bath, add Na 2 CO 3 (2.12g) and continued to stir for 15 minutes, at this time, the system was light yellow and transparent. A chloroform solution of deuteroiodomethane (2.9 g of deuteroiodomethane dissolved in 25 mL of chloroform) was slowly added dropwise to the reaction system, and the reaction was carried out for 30 minutes after the dropwise addition was completed. Then slowly add saturated ammonium chloride to quench the reaction. After chloroform extraction, the combined organic phases were washed three times with water. ) to obtain deuterated diazepam (foamy white solid), recrystallized from methanol to obtain 3.6 g of white crystals, yield 62%, HPLC purity>99%.

[0066] White crystal; m.p.124.2-125.0℃; 1 H NMR (300MHz, DMSO-d 6 )δ3.78(d, J=10.7Hz, 1H), 4.58...

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Abstract

The invention discloses diazepam-D8 and a preparation method thereof. The deuterated diazepam D8 is prepared by reacting 6-chloro-2-methyl-4H-3,1-benzoxazine-4-one (a compound shown as a formula I) serving as a raw material with a deuterated bromobenzene Grignard reagent, and performing hydrolysis, acylation, cyclization, methylation, separation and purification. The process disclosed by the invention has the advantages of mild reaction conditions, simple operation and the like. The deuterated diazepam D8 standard prepared by the method has high chemical purity, good product quality and good stability, and can be conveniently used for the preparation of analytical standards. The preparation method disclosed by the invention can be used for producing a deuterated internal standard substance during analysis and direction of diazepam.

Description

technical field [0001] The invention relates to the field of chemical analysis and detection, in particular to a method for preparing a deuterated diazepam standard product intermediate in the field of forensic science. Background technique [0002] Diazepam (compound VIa) is a benzodiazepine central nervous system depressant, which can cause inhibition of different parts of the central nervous system. As the dosage increases, the clinical manifestations can range from mild sedation to hypnosis or even coma. In recent years, criminal cases such as poisoning, suicide, and misuse caused by such drugs have occurred from time to time. This requires the public security judicial appraisal department to test the samples of samples involving such drugs. In order to ensure the preparation and reliability of the detection method, the internal standard is added during the detection, and the corresponding deuterium is the best internal standard. Since its use is non-civilian and has pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/24
CPCC07B2200/05C07D243/24Y02P20/55
Inventor 杜鸿雁徐小英于忠山宋歌魏春明
Owner INST OF FORENSIC SCI OF MIN OF PUBLIC SECURITY
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