KR100995755B1 - An improved process for the preparation of trityl candesartan cilexetil - Google Patents

Abstract

The present invention relates to 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1-trityl-1 H -tetrazol-5-) which is the main intermediate of candesartan cilexetil. Yl) -biphenyl-4-yl] methyl] 1 H -benzo [di] imidazole-7-carboxylate, ie trityl candesartan cilexetil.

The present invention uses 1-chloroethyl cyclohexyl carbonate represented by the following formula (4) to 1-iodoethyl cyclohexyl represented by the following formula (3) using 18-crown-6 as an alkali metal iodide and a catalyst in a polar aprotic solvent After synthesizing the carbonate, ethyl 2-ethoxy-1-[[2 '-(1-trityl-1 H -tetrazol-5-yl) -biphenyl represented by the following formula (2) under the same solvent condition: Trityl candesartan cilexetil represented by the formula (1) using -4-yl] methyl] -1 H -benzo [di] imidazole-7-carboxylic acid (trityl candesartan) and an inorganic basic compound It provides a method of manufacturing.

<Formula 1> <Formula 2>

<Formula 3> <Formula 4>

18-crown-6, polar aprotic solvent, 1-iodoethyl cyclohexyl carbonate, continuous reaction, trityl candesartan cilexetil

Description

An improved process for the preparation of trityl candesartan cilexetil}

The present invention relates to a process for preparing trityl candesartan cilexetil, which is the main intermediate of candesartan cilexetil. Candesartan cilexetil is an antagonist for angiotensin II receptors and is a useful drug for the treatment of cardiovascular diseases.

Candesartan cilexetil represented by the following formula (5) is a potent angiotensin II receptor antagonist, which is useful for the treatment of cardiovascular diseases such as the circulatory system, heart, and hypertension, and has a long-acting advantage. 5705517. In addition, trityl candesartan cilexetil represented by the following formula (1) can be prepared from trityl candesartan represented by the formula (2) as a major intermediate of candesartan cilexetil.

  <Formula 5>

<Formula 1> <Formula 2>

The method for preparing trityl candesartan cilexetil disclosed in the prior art can generally be represented by the following schemes.

 <Scheme 1>

Scheme 1 is described in US Pat. No. 5,705,517, which has the following disadvantages.

1) The yield is low at 47%, and it is not economical because column chromatography must be used in the purification process.

2) Dimethyl formamide (DMF), a solvent used in the reaction, is not suitable for industrial mass production because it is difficult to remove and toxic to humans.

3) In the case of 1-iodoethyl cyclohexyl carbonate used in the reaction, it is difficult to obtain commercially as an unstable substance, and it is known that it gradually deteriorates after 3 hours at room temperature. In addition, the refrigerated storage takes about one day, it was confirmed that the deterioration too. Therefore, the reaction using the material has problems such as an increase in impurities and a decrease in yield.

<Scheme 2>

1-iodoethyl cyclohexyl carbonate is generally known to be prepared by reacting 1-chloroethyl cyclohexyl carbonate with sodium iodide at 60 ° C. in acetonitrile or toluene solvent, as in Scheme 2, but yields range from 40% to 75%. It is only. (German Patent 102004060699 and Zhongguo Yiyao Gongye Zazhi 34 (9), 425-427, 2003)

   Japanese Patent No. 3138760 describes the preparation of 1-iodoethyl cyclohexyl carbonate in 92% yield by adding calcium chloride and reacting at 45 ° C., but separating such as washing with aqueous sodium thiosulfate solution to remove iodine. There is a disadvantage in industrial scale production, such as decomposition of the product, since the purification process involves a time delay of the manufacturing process.

   In addition, Japanese Patent Application Laid-Open No. 06072965 is characterized by using t-butyl ammonium bromide and toluene solvent, but there is an industrially disadvantageous problem such as using toluene which is difficult to remove by low yield and 85% yield.

<Scheme 3>

Meanwhile, methods for synthesizing trityl candesartan cilexetil using 1-chloroethyl cyclohexyl carbonate, which is a previous step like a reaction scheme, instead of unstable 1-iodoethyl cyclohexyl carbonate, were carried out in International Publication No. 2008012372. Example 3, International Publication No. 2007094015 Example 1, International Publication No. 2005037821 Example 2, and International Publication No. 2007074399 Example 1-a.

However, because these methods are less reactive with 1-chloroethyl cyclohexyl carbonate, they are difficult to remove or use toxic solvents such as dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO) and toluene. Or use THF solvents that present a risk of explosion. In addition, the yield is low, or the yield is high, but there are various problems such as the target is not separated into crystals or the solvent is not removed well, resulting in abnormally much higher yield than 100%. Not suitable for industrial mass production.

In preparing trityl candesartan cilexetil represented by the following general formula (1), which is a major intermediate for the preparation of candesartan cilexetil, it is easy to mass-produce industrially without decomposition of raw materials or products of the reaction, and toxic There is a need for development of new methods that can be economically prepared without the use of solvents or difficult to handle reagents.

The present inventors can easily produce trityl candesartan cilexetil in industrially high yields by overcoming the problems of the prior art, such as using solvents that are harmful to the human body and difficult to remove, or have low yield problems. We have done a lot of research to find a way.

As a result, 1-iodoethyl cyclohexyl carbonate, which is known to be unstable, is used in an acetonitrile or acetone solvent with an alkali metal iodide and 18-crown-6 catalyst for a short reaction time of about 1 to 2 hours even in a mild condition at room temperature. It has been found that it can be produced in high yield.

In addition, it was found that due to mild conditions, raw materials and products are not decomposed and thus manufactured in high purity, and the next process can be performed without a general separation and purification process such as a washing process.

The 1-iodoethyl cyclohexyl carbonate thus prepared is reacted with trityl candesartan to produce trityl candesartan cilexetil, wherein dimethyl formamide (DMF), which is difficult to remove in the prior art and is toxic to the human body, is produced. Although used, surprisingly, the inventors have found that the desired trityl candesartan cilexetil can be produced in a high yield of 92% using an inexpensive and relatively less toxic solvent, acetonitrile or acetone.

Furthermore, since the solvent used in the 1-iodoethyl cyclohexyl carbonate production step and the solvent used in the trityl candesartan cilexetil production step are the same, a high-temperature concentrated distillation process for exchanging a series of solvents is not required. Since it was maintained and the waiting time between the reactions was short, it was confirmed that the alteration of 1-iodoethyl cyclohexyl carbonate was minimized to obtain trityl candesartan cilexetil in high yield.

The present inventors were able to prepare 1-iodoethyl cyclohexyl carbonate in the present invention in a short time even under mild conditions using 18-crown-6 and alkali metal iodide, which are catalysts readily available in polar aprotic solvents. In addition, by continuously reacting with trityl candesartan using an inorganic basic compound in the same solvent without any separate purification process, it is possible to minimize the deterioration of 1-iodoethyl cyclohexyl carbonate and to increase the trityl candesartan cilcetil Yield was obtained.

Accordingly, the present invention provides a novel process for preparing 1-iodoethyl cyclohexyl carbonate.

In addition, the present invention provides a method for producing a high-purity target product in high yield by proceeding the production of 1-iodoethyl cyclohexyl carbonate and the production of trityl candesartan cilexetil through a continuous reaction process.

The present invention provides an improved process for the preparation of trityl candesartan cilexetil, the main intermediate of candesartan cilexetil. Accordingly, the present invention is advantageous for industrial production by using 1) solvents that are difficult to remove and reagents that are difficult to handle, and 2) environmentally friendly and economical due to low use of organic solvents, and 3) trityl candesartan cilexetil. It provides the effect of producing in high yield in a short time under mild conditions.

Preparation of trityl candesartan cilexetil consists of a two-step reaction as shown in Scheme 4 below.

 <Scheme 4>

(i)

(ii)

(i) Preparation of 1-iodoethyl cyclohexyl carbonate using 18-crown-6 as a catalyst with alkali metal iodide in 1-chloroethyl cyclohexyl carbonate in a polar aprotic solvent and used or required without separation purification According to the step of removing only the sodium chloride produced during the reaction.

(ii) preparing trityl candesartan cilexetil by adding a predetermined amount of the solvent used in (i), and then reacting with trityl candesartan using an inorganic basic compound.

The reaction temperature in the step (i) is 20 ~ 40 ℃, preferably 20 ~ 25 ℃.

The alkali metal iodide used in step (i) may be sodium iodide or potassium iodide, and preferably sodium iodide.

After synthesizing 1-iodoethyl cyclohexyl carbonate in step (i), preferably, only sodium chloride produced during the reaction is filtered off without separation purification, and then the next step (ii) is carried out.

As the polar aprotic solvent used in the continuous reaction of steps (i) and (ii), acetonitrile or acetone may be used, and a mixed solvent of acetonitrile and acetone or a mixed solvent thereof mainly and a small amount of other solvents such as ethanol It is also possible to use a mixture of the most preferably acetonitrile is used.

In the step (ii), the inorganic basic compound may be potassium carbonate, sodium carbonate or potassium hydrogen carbonate, sodium hydrogen carbonate or the like which is an alkali metal carbonate, preferably potassium carbonate.

The reaction temperature in step (ii) is 25 ~ 70 ℃, preferably 40 ~ 60 ℃.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1. Preparation of 1-iodoethyl cyclohexyl carbonate

23.6 g of 1-chloroethyl cyclohexyl carbonate, 18.8 g of sodium iodide and 3.0 g of 18-crown-6 are stirred at room temperature under 100 ml of acetonitrile for 2 hours. After confirming that the reaction was completed, it was filtered to remove sodium chloride generated during the reaction, and the solution was used for the next reaction. The amount of 1-iodoethyl cyclohexyl carbonate as a target in the reaction solution was found to be 32.3 g through gas chromatography analysis. (95% yield)

Example 2 Preparation of Trityl Candesartan Silecetyl

To the acetonitrile solution of 1-iodoethyl cyclohexyl carbonate obtained in Example 1 was added 65.0 g of trityl candesartan and 15.8 g of potassium carbonate, and 360 ml of acetonitrile were added. The temperature of the reaction is raised to 40 ~ 50 ^° C., the temperature is maintained and stirred for 1 night. The next day the reaction was confirmed to be complete and the solvent was removed under reduced pressure, then the residue was dissolved in 260 ml of dichloromethane and washed twice with 130 ml of water. The organic layer is then dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated. The residue was crystallized with 195 ml of acetonitrile, filtered, and dried under reduced pressure at 40 ^° C. to obtain 74.7 g of trityl candesartan cilexetil crystals. (Yield 92%)

Example 3 Preparation of Trityl Candesartan Silecetyl

10.0 g of 1-chloroethyl cyclohexyl carbonate, 8.0 g of sodium iodide and 1.3 g of 18-crown-6 are stirred at room temperature under 40 ml of acetone for 2 hours. It was confirmed that the reaction was completed, and used immediately for the next reaction. The amount of 1-iodoethyl cyclohexyl carbonate as a target in the reaction solution was found to be 13.1 g through gas chromatography analysis. (91% yield)

To the acetone solution of 1-iodoethyl cyclohexyl carbonate obtained above is added 26.3 g of trityl candesartan and 6.4 g of potassium carbonate and 145 ml of acetone. The temperature of the reaction is raised to 40 ~ 50 ^° C., the temperature is maintained and stirred for 1 night. The next day the reaction was confirmed to be complete and the solvent was removed under reduced pressure, then the residue was dissolved in 105 ml of dichloromethane and washed twice with 53 ml of water. The organic layer is then dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated. The residue was crystallized with 79 ml of acetonitrile, filtered and dried under reduced pressure at 40 ^° C. to obtain 27.6 g of trityl candesartan cilexetil crystals. (Yield 84%)

Example 4 Preparation of Trityl Candesartan Silecetyl

10.0 g of 1-chloroethyl cyclohexyl carbonate, 8.8 g of potassium iodide and 1.3 g of 18-crown-6 are stirred at room temperature under 30 ml of acetonitrile and 10 ml of acetone mixed solvent for 2 hours. It was confirmed that the reaction was completed, and used immediately for the next reaction. The amount of 1-iodoethyl cyclohexyl carbonate as a target in the reaction solution was found to be 13.3 g through gas chromatography analysis. (Yield 92%)

26.3 g of trityl candesartan, 4.9 g of sodium carbonate are added to the reaction solution of 1-iodoethyl cyclohexyl carbonate obtained above, and 110 ml of acetonitrile and 35 ml of acetone are added. The temperature of the reactant is raised to 40-50 ^° C., and the temperature is maintained for 1 night. The next day the reaction was confirmed to be complete and the solvent was removed under reduced pressure, then the residue was dissolved in 105 ml of dichloromethane and washed twice with 53 ml of water. The organic layer is then dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated. The residue was crystallized with 79 ml of acetonitrile, filtered and dried under reduced pressure at 40 ^° C. to obtain 28.6 g of trityl candesartan cilexetil crystals. (Yield 87%)

Claims (4)

A process for preparing 1-iodoethyl cyclohexyl carbonate using 1-chloroethyl cyclohexyl carbonate using an alkali metal iodide and 18-crown-6.

1-iodoethyl cyclohexyl carbonate was prepared by using 1-chloroethyl cyclohexyl carbonate in acetonitrile or acetone or a mixed solvent containing them using an alkali metal iodide and 18-crown-6 as a catalyst. A method for preparing trityl candesartan cilexetil by reacting with thylic candesartan and an inorganic basic compound.

The production method according to claim 2, wherein the inorganic basic compound is selected from potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate which are carbonates of alkali metal. The process according to any one of claims 1 to 3, wherein the alkali metal iodide is selected from sodium iodide or potassium iodide.