KR101060670B1 - Method for preparing ramipril - Google Patents

Abstract

After separating the benzyl group from (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester, this was followed by N- [1 (S) -ethoxycarbonyl- A method for preparing ramipril by reacting with 3-phenylpropyl] -L-alanine-N-carboxy anhydride is disclosed. Since it does not use Pd / C (carbon-containing palladium catalyst) and hydrogen gas, it has advantages in that it is excellent in work safety and does not cause a problem of disposal of metal materials remaining after the reaction, and also has excellent production efficiency.

Ramipril, strong base, weak base, KOH, NaOH, TEA, methyl chloride

Description

Process for the Preparation of Ramipril

The present invention relates to a process for preparing ramipril. More specifically, the present invention relates to a method for producing ramipril without using Pd / C (carbon-containing palladium catalyst) and hydrogen gas.

Ramipril is an angiotesin converting enzyme (hereinafter referred to as “ACE”) exemption and is widely used for the treatment of cardiovascular diseases, especially hypertension, and is effective in congestive heart failure. In connection with hypertension, ramipril is known to reduce peripheral arterial resistance, thereby reducing blood pressure without compensating increase in pulse rate. It has also been reported to reduce mortality in patients with clinical signs of congestive renal failure after resuscitation in acute myocardial infarction. Ramipril is known to have long-term protective effects in organs such as, for example, the heart, kidneys and blood vessels.

As a method of manufacturing such ramipril, it is disclosed, for example in PCT application WO 2005-121084 A1. Looking at the PCT application, through the process of Scheme 1 to produce a ramipril.

 Scheme 1

In Scheme 1, (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester hydrochloride and N- [1 (S) -ethoxycarbonyl-3 Using -phenylpropyl] -L-alanine-N-carboxy anhydride as a starting material, ramipril is synthesized by adding Pd / C (carbon-containing palladium catalyst) and hydrogen gas. Specific ramipril synthesis process is shown in Scheme 2.

Scheme 2

Looking at the reaction scheme 2, since the use of a metallic material and a strong explosive hydrogen gas there is a high risk of explosion during mass production. In addition, in the second step of Scheme 2, benzyl groups are removed using Pd / c and hydrogen gas, which costs a lot of equipment equipment and safety management. In addition, since the reaction proceeds using a gas, the reaction time is long and it is difficult to elicit a quantitative reaction. In particular, the Pd / c metal is a fire or explosion risk when there is a lack of moisture, the waste treatment of Pd / c remaining after the reaction is accompanied with a lot of cost and risk.

Therefore, there is an urgent need for a method for preparing ramipril that can reduce reaction time while being more stable and less dangerous.

An object of one embodiment of the present invention is to provide a more stable and efficient method for preparing ramipril.

It is an object of another embodiment of the present invention to provide a method for preparing ramipril that does not cause a waste disposal problem of the metal material (eg, Pd / c) remaining after the reaction.

The present invention relates to a process for preparing ramipril, comprising: (i) separating a benzyl group from (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester; And (ii) (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid and N- [1 (S) -ethoxycarbonyl-3, wherein the benzyl group is separated. -Phenylpropyl] -L-alanine-N-carboxy anhydride provides a method for producing ramipril comprising the step of synthesizing ramipril.

Since the ramipril manufacturing method according to the present invention does not use hydrogen gas having a high explosion risk, it is excellent in work safety and does not cause a problem of disposal of metal material remaining after the reaction. In addition, the ramipril manufacturing method according to the present invention has the advantage of being capable of mass production at a low production cost.

Ramipril manufacturing method according to an embodiment of the present invention can be expressed as in Scheme 3:

Scheme 3

In Scheme 3, (i) removing the benzyl group from (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester; And (ii) (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid and N- [1 (S) -ethoxycarbonyl-3 from which the benzyl group has been removed. -Phenylpropyl] -L-alanine-N-carboxy anhydride is characterized in that it comprises the step of synthesizing ramipril.

In the conventional ramipril production method, a Pd / c (carbon-containing palladium) catalyst and hydrogen gas are used to remove the benzyl group. However, in comparison with the conventional method requiring the risk of explosion, the efficiency of the reaction and the waste treatment of Pd / c remaining after the reaction, the metal catalyst and the hydrogen gas are not used, so the operation safety is excellent and the The advantage is that it does not cause disposal problems.

In one embodiment, step (i) comprises the treatment of a strong base to separate the benzyl group from (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester. can do. This is to avoid side reactions from other functional groups. The strong base is not particularly limited, but KOH or NaOH may be preferably used.

In one embodiment, the step (ii) is the (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid and N- [1 (S) from which the benzyl group is removed. ) -Ethoxycarbonyl-3-phenylpropyl] -L-alanine-N-carboxy anhydride can be reacted by mixing with the weak base. The weak base is not particularly limited, but may be preferably TEA (Triethylamine).

In one embodiment, when the strong base is NaOH, the weak base is TEA, the synthesis process of ramipril according to the present invention is shown in Scheme 4.

Scheme 4

In another embodiment, after separating the benzyl group removed in step (i), without the separate process of removing the separated benzyl group, step (ii) can be carried out. When the benzyl group is separated from (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester hydrochloride, the separated benzyl group is removed and the reaction proceeds. This is because unintended side reactions may occur. In addition, in the course of the extraction and purification steps to be described later, when the reaction proceeds without removing the separated benzyl group, there is an advantage that a more stable reaction yield is obtained.

In addition, ramipril synthesized by the production method according to the present invention can be extracted or purified through the following work-up step.

In one embodiment, the method for preparing ramipril may further include (iii) extracting the synthesized ramipril using methyl chloride. For the reaction solution containing ramipril, the extraction step using methyl chloride has an effect of significantly improving the yield of ramipril.

In another embodiment, the method for preparing ramipril further includes the step of (iv) extracting the synthesized ramipril using methyl chloride, and then obtaining solid crystals using heptane or hexane. can do. This is because there is a fear that the reaction yield may be lowered unless a solid crystal is obtained using heptane or hexane after the completion of the reaction. In particular, when ethyl acetate, methyl chlorite, ethanol, methanol and the like are used, not only the reaction yield is lowered, but also the progress of the crystallization reaction is lowered, and there is a possibility that side reactions occur.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments of the present invention, but the following examples are provided to clarify the effects of the present invention, and the scope of the present invention is not limited thereto.

Example 1 Preparation of Ramipril

100 g of (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester hydrochloride (0.4076 mol) was dissolved in 500 ml Methanol. At room temperature, 150 ml of 4 N NaOH (45 g) was added dropwise to the reaction solution for 30 minutes, followed by a hydrolysis reaction with stirring for 24 hours. After 24 hours, color separation with ninhydrin using gas chromatography confirmed separation of the benzyl group.

Then, the reaction solution was neutralized by adjusting the pH to 6, and then crystallized by completely removing methanol and water. The NMR of the crystallized material was determined to be (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid hydrochloride. In addition, the weight of the material was measured to confirm that the reaction yield was 63% (63.3 g). The NMR measurement results are shown in FIG. 1.

¹ H NMR spectrum (300 MHz, CDCl3): δ 4.7 (2.5H), 3.5 (1H), 3.35 (0.5H), 2.5 (1H), 2.3 (1H), 1.8 (1H), 1.6 (3.5H), 1.4 (1H), 1.3 (0.5H)

After dissolving it in 50 ml of water, 250 ml of acetonitrile was added and stirred. After stirring for 30 minutes, 104 ml (2.5 eq) of TEA was added dropwise to the ice bath for 30 minutes. One equivalent of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine-N-carboxy anhydride was dissolved in 250 ml of Acetonnitril after dissolving 118 g (0.4078 mol) of (S, S, S) To 2-azabicyclo (3,3,0) -octane-3-carboxylic acid was added dropwise for 1 hour in ice. After the dropwise addition, the mixture was stirred at 20 to 25 ° C. for 4 hours. Then, the reaction was confirmed using gas chromatography.

The reaction solution was titrated to pH 4-5, extracted three times with 100 ml of methyl chloride, collected, and completely removed with MgSO ₄ and distilled under reduced pressure.

After distillation under reduced pressure, the solution was dissolved in 30 ml of ethyl acetate, and rapidly added dropwise to 180 ml of heptane, followed by stirring at 0 ° C. or lower for 8 hours. After stirring, the solid material was filtered off, 150 ml of ethyl acetate was added and completely dissolved. The reaction solution in which the solid material was dissolved was cooled for 8 hours at 0 ° C. or less to confirm that a white solid material was produced. The white solid material was filtered off and dried at 83 ° C. for 8 hours.

NMR of the dried material was measured and found to be ramipril. In addition, the ramipril prepared through the above process was at least 99.8% pure and 126.9 g (yield: 70%). The NMR measurement results for ramipril are shown in FIG. 2.

¹ H NMR spectrum (300 MHz, CDCl3): δ 7.29-7.15 m (5H), 5.8 bs (2H), 4.62 dd (5.6 Hz, 9.4 Hz) (0.5H), 4.43 m (0.2H), 4.21-4.1 m (3.5H), 3.72 q (6.6 Hz) (0.5H), 3.18 t (6.7 Hz) (0.5H), 2.80-1.40 m (12H), 1.39 d (6.9 Hz) 1.37 d (6.6 Hz) (2H ), 1.30 t (7.1 Hz) 1.28 t (7.1 Hz) 1.26 d (6.0 Hz) 1.22 t (7.1 Hz) (4H)

Example 2 Preparation of Ramipril

100 g of (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester hydrochloride (0.4076 mol) was added to 500 ml of toluene, followed by stirring. 200 ml of 4 N NaOH was added dropwise at 15 ° C. After completion of the dropwise addition, the hydrolysis reaction was carried out while stirring at room temperature for 24 hours. After 24 hours, the development of benzyl group was confirmed by color development with ninhydrin using gas chromatography.

Then, hydrochloric acid (HCl) was added dropwise to the reaction solution and acidified to pH 3-4, and 250 ml of acetone was added to the water layer and stirred. After stirring for 30 minutes, 104 ml (2.5 eq) of TEA was added dropwise to the ice bath for 30 minutes. And 1 equivalent of 118 g (0.4078 mol) of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine-N-carboxy anhydride was dissolved in 250 ml of acetone (S, S, S ) Was added dropwise over 1 hour with ice-bathing to azazacyclo (3,3,0) -octane-3-carboxylic acid. After the dropwise addition, the reaction solution was stirred at 20-25 ° C. for 4 hours. Whether the reaction was the result was confirmed using gas chromatography.

Then, after filtering the solid remaining in the reaction, the solvent pH was acidified to 4-5, after removing all acetone, the water layer was extracted with methyl chloride and concentrated. The concentrated material was dissolved in 30 ml of ethyl acetate and then added dropwise to 180 ml of heptane at 0 ^° C. or lower. Solids were filtered out of the reaction solution, and the organic solvent was completely removed. After drying at 83 ° C., the dried material was recrystallized from diethyl acetate. As a result, about 60% purity and 100.38 g of ramipril were obtained.

Example 3 Preparation of Ramipril

100 g of (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester hydrochloride (0.4076 mol) was dissolved in 500 ml ethanol and then 150 ml of 4 at room temperature. N KOH was added dropwise for 30 minutes, followed by a hydrolysis reaction with stirring for 24 hours. After 24 hours, color separation with ninhydrin using gas chromatography confirmed separation of the benzyl group.

Thereafter, the pH was neutralized to 6, crystallized by completely removing ethanol and water and weighed. As a result, it was confirmed that the yield was 63% (63.3 g).

After dissolving it in 50 ml of water, 250 ml of acetone was added thereto and stirred. After stirring for 30 minutes, 104 ml (2.5eq) of TEA was added dropwise to the ice bath for 30 minutes and 1 equivalent of N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine- 118 g (0.4078 mol) of N-carboxy anhydride was dissolved in 250 ml of acetonitrile, and then ice-cold in (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid. It was added dropwise for 1 hour. After the dropwise addition, the mixture was stirred at 20-25 ° C. for 4 hours. The result of the reaction was judged using gas chromatography.

Thereafter, the reaction solution was titrated to 4-5, extracted three times with 100 ml of methyl chloride, and the extracted material was completely removed using MgSo _4, and then distilled under reduced pressure.

After distillation under reduced pressure, the solution was dissolved in 30 ml of ethyl acetate, and rapidly added dropwise to 180 ml of heptane, followed by stirring at 0 ° C. or lower for 8 hours. After stirring, the solid material was filtered off, 150 ml of ethyl acetate was added and completely dissolved. The reaction solution in which the solid material was dissolved was cooled for 8 hours at 0 ° C. or less to confirm that a white solid material was produced. The white solid material was filtered off and dried at 83 ° C. for 8 hours. Ramipril prepared through the above process was more than 99.8% purity, 126.9 g (yield: 70%).

1 is (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxyl, an intermediate in which benzyl ester is removed during the preparation of ramipril according to an embodiment of the present invention. NMR measurement results for acid hydrochloride.

2 is an NMR measurement result for ramipril prepared according to an embodiment of the present invention.

Claims (8)

In the method for producing ramipril, (i) treating the (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid benzyl ester with KOH or NaOH to separate the benzyl group; And (ii) (S, S, S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid and N- [1 (S) -ethoxycarbonyl-3-, wherein the benzyl group was separated A phenylpropyl] -L-alanine-N-carboxy anhydride is mixed with triethylamine (triethylamine, TEA) to react to produce a ramipril comprising the step of synthesizing ramipril. delete delete delete delete The method of claim 1, After separating the benzyl group in the step (i), without the separate process of removing the separated benzyl group, (ii) a method for producing a ramipril characterized in that the step is carried out. The method of claim 1, (iii) extracting the synthesized ramipril using methyl chloride (metyl chloride). The method of claim 7, wherein (iv) extracting the synthesized ramipril using methyl chloride, and then obtaining solid crystals using heptane (heptan) or hexane (hexan).

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