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A method for synthesizing high-purity sartan side chain TTBB

A high-purity, side-chain technology, applied in the field of synthesis of sartan-like pharmaceutical intermediates, can solve problems such as increased production costs, difficulty in separating target products, and affecting the quality of target products, achieving cost reduction and economical synthetic processes

Active Publication Date: 2020-08-21
JIANGSU RENMING BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this synthetic method has the following disadvantages: the preparation process of compound 4 is always accompanied by raw materials (TTMB) and dibrominated by-products, which makes the reaction yield of the target product decrease, and the separation of the target product is very difficult, which greatly increases the production cost. and affect the quality of the target product

Method used

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  • A method for synthesizing high-purity sartan side chain TTBB
  • A method for synthesizing high-purity sartan side chain TTBB
  • A method for synthesizing high-purity sartan side chain TTBB

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Synthesis of 5-[2-(4'-methylbiphenyl)]tetrazole compound (compound 2)

[0024] Weigh 4-methyl-2-cyanobiphenyl 1 (200g) and add it to a four-necked flask, add DMF solvent (500mL) to the four-necked flask, and wait for 4-methyl-2-cyanobiphenyl to stir After dissolving, add Et with macroporous sulfonic acid resin as carrier to the clear solution of 4-methyl-2-cyanobiphenyl in DMF at room temperature 3 NHCl (285.3g), start heating, between 40-50°C, start to add sodium azide (134.7g) in batches, after the addition, start to gradually increase the temperature, until 115°C for 30h, HPLC detection (raw material reaction is not complete) , cooled to room temperature, first filter out the Lewis acid triethylamine hydrochloride with macroporous sulfonic acid resin as carrier, then add toluene (200mL), water (800mL) and 48wt% NaOH solution (120mL). The toluene layer was separated by stirring, and toluene was added several times to ensure that the aqueous layer was free of starting...

Embodiment 2

[0026] Synthesis of 5-[2-(4'-methylbiphenyl)]tetrazole compound (Compound 2)

[0027] Weigh 4-methyl-2-cyanobiphenyl 1 (20g) and add it to a four-necked flask, add DMF solvent (50mL) to the four-necked flask, and wait for 4-methyl-2-cyanobiphenyl to stir After dissolving, add Et with macroporous sulfonic acid resin as carrier to the clear solution of 4-methyl-2-cyanobiphenyl in DMF at room temperature 3 Add NHCl (28.5g), add sodium azide (13.4g), gradually heat up under microwave radiation after adding, until react at 65°C for 2h, check by HPLC and cool to room temperature, first filter out the macrocyclic sulfonic acid resin as the carrier Lewis acid Triethylamine hydrochloride, then toluene (20 mL), water (80 mL) and 48 wt% NaOH solution (12 mL) were added. The toluene layer was separated with stirring, and toluene was added several times to ensure that the aqueous layer was free of starting material (three times in total, 60 mL). TLC detection raw material extraction is c...

Embodiment 3

[0029] Synthesis of 5-[2-(4'-methylbiphenyl)]tetrazole compound (Compound 2)

[0030] Weigh 4-methyl-2 cyanobiphenyl 1 (10g) and add it to a four-necked flask; add DMF solvent (25mL) to the four-necked flask, and stir to dissolve 4-methyl-2 cyanobiphenyl Finally, Et with macroporous sulfonic acid resin as a carrier was added to the clear solution of 4-methyl-2-cyanobiphenyl in DMF at room temperature. 3 NHCl (15 g) was added with sodium azide (7 g), and after the addition was completed, the temperature was gradually raised under ultrasonic radiation until 35° C. for 3 h. HPLC detection After cooling to room temperature, first filter out Lewis acid triethylamine hydrochloride, then add toluene (20mL), water (60mL) and 48wt% NaOH solution (12mL). The toluene layer was separated with stirring, and toluene was added several times to ensure that the aqueous layer was free of starting material (total three times, 50 mL). TLC detection raw material extraction is complete. Add the ...

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Abstract

The invention discloses a method for synthesizing high-purity sartan side chain TTBB. The method comprises the following steps: taking 4-methyl-2-cyanobiphenyl as a starting material; under a catalytic action of lewis acid triethylamine hydrochloride, carrying out cyclization reaction on the 4-methyl-2-cyanobiphenyl and sodium azide to generate a 5-[2-(4'-methyldiphenyl)]tetrazole compound; reacting the 5-[2-(4'-methyldiphenyl)] tetrazole compound with triphenylchloromethane under an alkaline condition to generate an N-(triphenylmethyl)-5-(4'-methylbiphenyl-2-yl)tetrazole compound; reacting togenerate a mixture of a compound TTBB and a compound Br-TTBB under the action of bromine-containing substances; promoting the compound Br-TTBB to be converted into the compound TTBB under the actionof diethyl phosphite by the mixture, thus finally obtaining the high-purity sartan side chain TTBB. The synthetic process disclosed by the invention has the advantages of better economical property, environment friendliness, high efficiency, simplicity and convenience; the mode of improving the purity of a target product through recrystallization for multiple times by adopting a conventional method is avoided.

Description

technical field [0001] The invention belongs to the technical field of synthesis of sartan pharmaceutical intermediates, in particular to a method for synthesizing high-purity sartan side chain TTBB, in particular to synthesizing antihypertensive drug sartan intermediate N-(triphenylmethyl )-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium compound. Background technique [0002] Sartan drugs are antihypertensive drugs used clinically after Puli drugs, and are the mainstream varieties in the global cardiovascular market. Among all antihypertensive drugs, sartans have the best tolerance, their safety is similar to that of placebo, their adverse reactions are mild and short-lived, and hypotension and cough effects are rare, so they are favored by the majority of hypertensive patients . [0003] Since Losartan Potassium, the first sartan drug, was launched in Sweden in 1994, a variety of sartan drugs such as valsartan, condesartan, and irbesartan have been launched successively so f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D257/04
CPCC07D257/04
Inventor 赵贝贝毛琳琳雷颜生
Owner JIANGSU RENMING BIOLOGICAL TECH CO LTD