Preparation method of stable isotope labeled alprazolam and estazolam internal standard reagent

A stable isotope and alprazolam technology, applied in the direction of isotope introduction of heterocyclic compounds, isotope introduction of organic compounds, organic chemical methods, etc., can solve problems restricting the application of compounds, achieve short synthesis steps, mild reaction conditions, and total yield high rate effect

Inactive Publication Date: 2021-10-26
谱同生物医药科技常州有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, stable isotope-labeled alprazolam and estazolam are only provided by foreign standard product companies, which can only be solved by importing, which seriously restricts the application of this compound in domestic clinical therapeutic drug monitoring

Method used

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  • Preparation method of stable isotope labeled alprazolam and estazolam internal standard reagent
  • Preparation method of stable isotope labeled alprazolam and estazolam internal standard reagent
  • Preparation method of stable isotope labeled alprazolam and estazolam internal standard reagent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: 2-amino-5-chlorobenzophenone (phenyl-D 5 )preparation

[0059]

[0060] 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 stable isotope labeled 2-amino-5-chlorobenzophenone (phenyl-D ...

Embodiment 2

[0061] Example 2: 2-chloroacetamido-5-chlorobenzophenone (phenyl-D 5 ) preparation

[0062]

[0063] 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

[0064] Example 3: 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine -2-keto (phenyl-D 5 ) preparation

[0065]

[0066]In a 100mL 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 60°C, and reacted at this temperature for 24 Hours; after TLC traced the reaction raw materials to complete the reaction, the solvent was distilled off under reduced pressure, 20 mL of water was added, extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution successively , adding anhydrous sodium sulfate to dry, and distilling off the solvent under reduced pressure, the residue was subjected to column chromatography to obtain stable isotope labeled 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine -2-ket...

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Abstract

The invention relates to a preparation method of a stable isotope labeled alprazolam and estazolam internal standard reagent for monitoring the blood concentration of a clinical treatment drug, and belongs to a standard substance for monitoring the clinical treatment drug. The stable isotope labeled alprazolam or stable isotope labeled estazolam is obtained by taking stable isotope labeled phenylboronic acid as a raw material, performing catalytic addition, acylation, cyclization, sulfur-oxygen exchange and cyclization and finally conducting separating and purifying. 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 alprazolam and stable isotope labeled estazolam can reach 98% or above, and the isotope abundance can reach 98% or above. The preparation method can meet the technical requirements of a stable isotope labeling internal standard reagent required by a liquid chromatography-tandem mass spectrometry method for monitoring the blood concentration of a clinical treatment drug.

Description

technical field [0001] The invention relates to a preparation method of stable isotope-labeled alprazolam and estazolam internal standard reagents 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] Alprazolam is also known as Jiajing stability, and Estazolam is also known as Shulezi, both of which belong to benzodiazepines. drugs. Alprazolam and estazolam act on central nervous system benzodiazepines It can strengthen the binding of the central inhibitory neurotransmitter γ-aminobutyric acid to the γ-aminobutyric acid A receptor, promote the opening of chloride ion channels, hyperpolarize cells, and enhance the activity of γ-aminobutyric acid neurons. Mediated synaptic inhibition reduces the excitability of neurons, thereby exerting clinical effects. Alprazolam has sedative, hypnotic, muscle relaxation, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07B59/00
CPCC07D487/04C07B59/002C07B2200/05
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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