CN101712682A - Method for synthesizing tasosartan - Google Patents

Abstract

The invention discloses a novel method for preparing tasosartan, which is mainly characterized in that: 8-(4'-benzyl bromide)-2,4-dimethyl-5,6-dihydropyrido[2,3-d]pyrimidine-7-one serving as a raw material and 2-[N-(trityl)-tetrazole]borophenylic acid generate coupling reaction, and then a reaction product is subjected to deprotection to obtain the tasosartan. The method mainly avoids a step of forming tetrazole, and the reaction is more high-efficiency and safe.

Description

The synthetic method of Tasosartan

Technical field

It is synthetic to the invention belongs to medicine.Be specifically related to the new preparation process of Tasosartan (1), and intermediate 2,4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5, the preparation method of 6-dihydro pyrido [2,3-d] pyrimidin-7-ones (2).

Background technology

Angiotensin II (Ang II) acceptor inhibitor is a kind of medicine of important treatment cardiovascular disorder.After Angiotensin II (Ang II) acceptor inhibitor listing in 1994, the researchist is on the basis of its parent nucleus, to its compound structure addition, derive, modify, constantly strengthened its hypotensive curative effect, prolonged action time, reduce toxic side effect, further promoted the development process of this class medicine, thereby formed the serial chemicals that is referred to as " husky smooth class ".

Sartans is the medication of hypertension first-line treatment, has brand-new step-down mechanism, and step-down steadily, good effect, long action time, patient tolerability be good.There is research institution carrying out the clinical study of treatment diabetes and heart failure at present, attempts to increase how new indication, to obtain bigger benefit.

2,4-dimethyl-8-[[4-[2-(1H-tetrazole-5-yl) xenyl] methyl]-5, the common called after Tasosartan of 6-dihydro pyrido [2,3-d] pyrimidin-7-ones is a kind of of sartans.

Known Tasosartan is synthetic to mainly contain patent WO 9640684, document J Med Chem1998, and 41 (22), 4251. mainly is to be the synthetic Tasosartan of raw material with the biphenyl analog derivative.This class methods raw material is not easy to obtain, if be the reaction that initiator also will relate to cyano group and trinitride with biphenyl cyanogen, relatively more dangerous, reaction is difficult to control.It is synthetic that this patent has then been avoided this respect.

Summary of the invention

The invention provides a kind of method for preparing Tasosartan; mainly be 8-(4 '-bromobenzyl)-2; 4-dimethyl-5; 6-dihydro pyrido [2; 3-d] pyrimidin-7-ones is raw material and 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide obtains intermediate 2 through linked reaction, 4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2; 3-d] pyrimidin-7-ones and to its deprotection that carries out, thus obtain Tasosartan.Do not need directly is that raw material synthesizes with the biphenyl derivatives.Wherein sloughing on the tetrazole on the protecting group protecting group can be undertaken by hydrolysis under acidic conditions.

Below content of the present invention is further explained.

With 2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones (2) be raw material to bromobenzyl bromine (3), under alkaline condition, pass through alkylated reaction and obtain 8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones.Alkaline condition reaches by adding organic bases or mineral alkali.

According to the present invention, be coupled under the alkaline condition, catalyzer exists, by 8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones and 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide reacts and obtains intermediate 6.

The linked reaction condition must be an anhydrous and oxygen-free.Need not stop drum nitrogen in the reaction and remove deoxidation.Solvent is a tetrahydrofuran (THF), methylene dichloride, and toluene, dioxane, any one must be an anhydrous solvent in the ethyl acetate.Alkaline condition can be an Anhydrous potassium carbonate, and anhydrous sodium carbonate is a kind of in the anhydrous phosphoric acid potassium.

Catalyzer mainly is that the title complex by palladium provides, and the title complex of the used palladium of the present invention is by what palladium reaction of triphenyl phosphorus, generates the triphenyl phosphorus palladium and is used as catalyzer.

2; 4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5; 6-dihydro pyrido [2,3-d] pyrimidin-7-ones sloughs that blocking group can obtain Tasosartan on the tetrazole, and deprotection of the present invention mainly is to remove blocking group under acidic conditions.

The invention has the advantages that: the relatively crucial synthesis step of this patent with the SUZUKI linked reaction, the SUZUKI coupling is efficient with respect to have reaction with the synthetic biphenyl of Grignard reagent method, mild condition, series of advantages such as by product is few.

Embodiment

Embodiment 1.

Step is (4 '-bromobenzyl)-2 a.8-, 4-dimethyl-5, the preparation of 6-dihydro pyrido [2,3-d] pyrimidin-7-ones.

Drying tube is being housed, thermometer, dropping funnel and churned mechanically 1000ml four-hole boiling flask add 2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 1.8g, methylene dichloride, salt of wormwood 3g stirs.Add the dichloromethane solution of 2.5g to the bromobenzyl bromine; Finish, under 75 ℃, continue reaction 4 to 5 hours, TLC shows that raw material disappears substantially; The sodium bicarbonate aqueous solution washing of adding 5%, the saturated brine washing, methylene dichloride is sloughed in the organic phase decompression, obtains 8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 3.1g.Thick product need not to be further purified, and directly carries out next step:

Step b.2,4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5, the preparation of 6-dihydro pyrido [2,3-d] pyrimidin-7-ones.

0.5g triphenyl phosphorus is dissolved in the 100ml tetrahydrofuran (THF), 50ml water.Remove wherein oxygen by drum nitrogen.0.4g palladium joins above-mentioned solution, stirs 30min, ceaselessly rouses nitrogen in the whipping process and comes deoxygenation.8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 3g, 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide 4.5g, salt of wormwood 5g drops in the above-mentioned reaction solution, remove miscellaneous oxygen in the reaction solution, reflux 24 hours by drum nitrogen.Reaction finishes, and cold filtration adds methylene dichloride 200ml, and filtrate is washed with deionized water repeatedly.With the organic phase concentrating under reduced pressure, separate out solid.The gained solid is 2,4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 4.7g.

Step c 2,4-dimethyl-8-[[4-[2-(1H-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones.

Reflux condensing tube is being housed, and temperature is taken into account in the churned mechanically 1000ml there-necked flask, adds the product 4.7g of step b, and tetrahydrofuran (THF) (60ml) and hydrochloric acid (37%, 8ml), stirring and dissolving, the adularescent solid is separated out; Be heated to about 80 ℃, reacted 1 hour, be cooled to room temperature, regulate PH=6.9-7.0, concentrating under reduced pressure with the sodium hydroxide solution of 5mol/L.Residual solution is regulated PH=2-3 with the hydrochloric acid of 2mol/L, separates out solid.Filter, solid washes with water, and vacuum-drying obtains white solid.The gained solid is 2,4-dimethyl-8-[[4-[2-(1H-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 2.5g is Tasosartan.

Embodiment 2.

Step is (4 '-bromobenzyl)-2 a.8-, 4-dimethyl-5, the preparation of 6-dihydro pyrido [2,3-d] pyrimidin-7-ones.

Drying tube is being housed, thermometer, dropping funnel and churned mechanically 1000ml four-hole boiling flask add 5,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 3.5g, methylene dichloride, triethylamine 5ml stirs.Add the dichloromethane solution of 5.2g to the bromobenzyl bromine; Finish, under 75 ℃, continue reaction 4 to 5 hours, TLC shows that raw material disappears substantially; The sodium bicarbonate aqueous solution washing of adding 5%, the saturated brine washing, methylene dichloride is sloughed in the organic phase decompression, obtains 8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 6.5g.Thick product need not to be further purified, and directly carries out next step:

Step b..2,4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5, the preparation of 6-dihydro pyrido [2,3-d] pyrimidin-7-ones.

0.05g four triphenyl phosphorus palladiums are dissolved in the 100ml tetrahydrofuran (THF), 50ml water.Remove wherein oxygen by drum nitrogen.Stir 30min, ceaselessly rouse nitrogen in the whipping process and come deoxygenation.8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 6.5g, 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide 9.5g, salt of wormwood 5g drops in the above-mentioned reaction solution, remove miscellaneous oxygen in the reaction solution, reflux 24 hours by drum nitrogen.Reaction finishes, and cold filtration adds methylene dichloride 200ml, and filtrate is washed with deionized water repeatedly.With the organic phase concentrating under reduced pressure, separate out solid.The gained solid is 2,4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 10.0g.

Step c 2,4-dimethyl-8-[[4-[2-(1H-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones.

Reflux condensing tube is being housed, and temperature is taken into account in the churned mechanically 1000ml there-necked flask, adds the product 10g of step b, and tetrahydrofuran (THF) (100ml) and hydrochloric acid (37%, 12ml), stirring and dissolving, the adularescent solid is separated out; Be heated to about 80 ℃, reacted 1 hour, be cooled to room temperature, regulate PH=6.9-7.0, concentrating under reduced pressure with the sodium hydroxide solution of 5mol/L.Residual solution is regulated PH=2-3 with the hydrochloric acid of 2mol/L, separates out solid.Filter, solid washes with water, and vacuum-drying obtains white solid.The gained solid is 2,4-dimethyl-8-[[4-[2-(1H-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones 5.4g is Tasosartan.

Claims (7)

1. the preparation method of a Tasosartan (1) is characterized in that reactions steps is a reaction formula 1.

Reaction formula 1

In the described reaction formula 1, with 2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones (2) be raw material to bromobenzyl bromine (3), through alkylated reaction, obtain intermediate 8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones (4), again by intermediate 4 and 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide obtains 2 through linked reaction, 4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones (6).Intermediate 6 obtains Tasosartan (1) through steps such as deprotections again.

2. method according to claim 1, it is characterized in that: described that alkylated reaction is in the presence of alkali, by 2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones with to the bromobenzyl bromine in organic solvent, nucleo philic substitution reaction obtains intermediate 4, wherein temperature of reaction is at-20-80 ℃; Reaction times is in 1-24 hour.

3. method according to claim 2 is characterized in that: alkali can be that organic bases also can be mineral alkali in the described alkylated reaction; Organic bases: triethylamine or diisopropylethylamine, mineral alkali: yellow soda ash, salt of wormwood, sodium bicarbonate; Described flux is selected from tetrahydrofuran (THF), methylene dichloride, acetonitrile, toluene, dioxane methyl alcohol, in the ethanol any one.

4. according to the described method of claim 1, it is characterized in that: linked reaction is meant 8-(4 '-bromobenzyl)-2,4-dimethyl-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones (4) and 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide in the presence of catalyzer, obtain 2 through coupling, 4-dimethyl-8-[[4-[2-(N '-trityl-tetrazole-5-yl) xenyl] methyl]-5,6-dihydro pyrido [2,3-d] pyrimidin-7-ones (6).

5. according to the described method of claim 4, it is characterized in that: the linked reaction solvent can be a tetrahydrofuran (THF), methylene diethyl ether, methylene dichloride, toluene, in the dioxane any one; Catalyzer is a palladium, triphenyl phosphorus, and salt of wormwood combines.

6. according to the described method of claim 4, it is characterized in that: entire reaction need be carried out under the condition of anhydrous and oxygen-free, mainly comes deoxidation by drum nitrogen or argon gas.

7. according to the described method of claim 1, it is characterized in that: deprotection need carry out under acidity or condition, and acid is mineral acid or organic acid; Described mineral acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid; Organic acid comprises methylsulfonic acid, acetic acid.