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Preparation method of stable isotope labeled oxazepam internal standard reagent

A stable isotope and labeling technology, which is applied in the preparation of organic compounds, isotope introduction of heterocyclic compounds, and isotope introduction into organic compounds, etc., can solve the strict requirements of stable isotope labeling reagent conditions, low total yield of final products, and technical difficulties. Large problems such as short synthesis steps, easy availability of raw materials, and high chemical purity of products are achieved.

Inactive Publication Date: 2021-10-26
谱同生物医药科技常州有限公司
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Problems solved by technology

This document is obtained from 2-amino-5-chlorobenzoic acid through 8-step reactions such as acetylation, Grignard reaction, hydrolysis, oxime formation, ring formation, hydrolysis, acetylation, and hydrolysis. The steps are long and stable isotopes are prepared. The conditions of labeling format reagents are demanding, the technology is difficult, and the total yield of the final product is not high

Method used

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  • Preparation method of stable isotope labeled oxazepam internal standard reagent
  • Preparation method of stable isotope labeled oxazepam internal standard reagent
  • Preparation method of stable isotope labeled oxazepam internal standard reagent

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Embodiment 1: 2-amino-5-chlorobenzophenone (phenyl-D 5 )preparation

[0049]

[0050] In a 500mL three-necked flask, add deuterated phenylboronic acid (12.7g, 0.1mol), 2-amino-5-chlorobenzophenone (7.63g, 0.05mol), catalyst tetrakis (triphenylphosphine) palladium (2.89g , 2.5mmol), ligand 4,4'-dimethyl-2,2'-bipyridine (920mg, 5mmol), additive trifluoroacetic acid (57g, 0.5mol) and tetrahydrofuran: water = 1:1 mixed solvent (250mL); reacted at 90°C for 24 hours; after TLC traced the reaction raw materials to complete the reaction, the reaction liquid was cooled to room temperature, 200mL of water was added, extracted with ethyl acetate (3×300mL), the combined organic phases were washed with saturated bicarbonate successively Washing with sodium solution, washing with saturated sodium chloride solution, adding anhydrous sodium sulfate to dry, distilling off the solvent under reduced pressure, and obtaining the stable isotope labeled 2-amino-5-chlorobenzophenone (pheny...

Embodiment 2

[0051] Example 2: 2-chloroacetamido-5-chlorobenzophenone (phenyl-D 5 ) preparation

[0052]

[0053] In a 100mL three-necked flask, add 2-amino-5-chlorobenzophenone (phenyl-D 5 ) (2.37g, 10mmol), chloroacetyl chloride (1.69g, 15mmol) and dry dioxane (20mL); filled with nitrogen, reacted for 12 hours at 20 ° C; Remove the solvent by distillation under pressure, add 20mL of water, extract with ethyl acetate (3×30mL), combine the organic phases, wash with saturated sodium bicarbonate solution and saturated sodium chloride solution successively, add anhydrous sodium sulfate to dry, and distill under reduced pressure Remove the solvent, and the residue obtains stable isotope labeling 2-chloroacetamido-5-chlorobenzophenone (phenyl-D 5 ) (2.97g, yield 95%). 1 H NMR (DMSO-D 6 , 600MHz): δ10.50(s, 1H), 7.70(d, 2H), 7.44(t, 1H), 4.06(s, 1H), see attached image 3 .

Embodiment 3

[0054] Example 3: 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine -2-keto (phenyl-D 5 ) preparation

[0055]

[0056] In a 50mL three-neck flask, add stable isotope labeled 2-chloroacetamido-5-chlorobenzophenone (phenyl-D 5 ) (3.13g, 10mmol), urotropine (2.80g, 20mmol), ammonium chloride (1.07g, 20mmol), methanol (20mL); under nitrogen protection, heated to reflux, and reacted at this temperature for 24 hours After TLC traces the reaction raw material to react completely, remove solvent by distillation under reduced pressure, add 20mL water, extract with ethyl acetate (3 * 30mL), combine organic phase, wash with saturated sodium bicarbonate solution successively, saturated sodium chloride solution washes, Add anhydrous sodium sulfate to dry, distill off the solvent under reduced pressure, and the residue is subjected to column chromatography to obtain stable isotope labeled 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine -2-keto (phenyl-D 5 ) (2.97g, yield 95%...

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Abstract

The invention relates to a preparation method of a stable isotope labeled oxazepam internal standard reagent for monitoring the blood concentration of clinical treatment drugs, and belongs to the field of research and development of standard substances for monitoring clinical treatment drugs. The stable isotope labeled oxazepam is obtained by taking stable isotope labeled phenylboronic acid as a raw material through catalytic addition, acylation, cyclization, acetylation, hydrolysis and final separation and purification. The process has the advantages that raw materials needed for synthesis are simple and easy to obtain, reaction conditions are mild, the chemical purity of the target product stable isotope labeled oxazepam can reach 98% or above, the isotope abundance can reach 98% or above, and the preparation method can meet the technical requirements of a stable isotope labeled internal standard reagent needed by a clinical drug monitoring liquid chromatography-tandem mass spectrometry method.

Description

technical field [0001] The invention relates to a preparation method of a stable isotope-labeled oxazepam internal standard reagent for monitoring blood drug concentration of clinical therapeutic drugs, and belongs to the field of research and development of standard substances for clinical therapeutic drug monitoring. Background technique [0002] Oxazepam is a new generation benzodiazepine Class II psychotropic drugs, a variety of benzodiazepines The active metabolites of similar drugs have excellent anti-anxiety, anti-depression, anti-insomnia, anti-epileptic and combined anti-schizophrenia effects. Due to its good clinical feedback, it has been widely used in China. However, excessive use of such drugs still has certain side effects: 1. Nausea and vomiting; 2. Loss of appetite; 3. Dizziness and fatigue; 4. Sexual dysfunction, etc. This makes it necessary to strictly control the blood drug concentration of patients when taking such drugs clinically. [0003] At prese...

Claims

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Application Information

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IPC IPC(8): C07D243/26C07D243/28C07B59/00C07C221/00C07C225/22C07C231/02C07C233/33
CPCC07D243/26C07D243/28C07B59/001C07B59/002C07C221/00C07C231/02C07B2200/05C07C225/22C07C233/33
Inventor 李珂珂王玮潘黎东
Owner 谱同生物医药科技常州有限公司
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