Synthesis method of ramipril key intermediate

A synthesis method and technology for intermediates, which are applied in the field of synthesis of pharmaceutical and chemical intermediates, can solve problems such as unfavorable environmental protection, high production cost, and many reaction steps, and achieve the effects of being suitable for industrial production, avoiding pollution problems, and mild reaction conditions.

Active Publication Date: 2017-05-31
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is loaded down with trivial details, and productive rate is lower (Urbach.H.J.; Henning.R.; Winfried.H.[P].DE3431541A1.1986-03-06.); (2) take cyclopentanone as starting material, after Claisen ketoester condensation reaction to synthesize α-methylene cyclic ketone, and then Michael addition with the active methylene compound 2-acetamidomalonate dimethyl ester, followed by decarboxylation and ring closure reactions under acidic conditions, and finally Hydrogenation to get 2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride, total yield 33%
Although the total yield of this route is higher, the raw materials are more expensive, the atom economy is lower, and it is difficult to adapt to industrial production (Tang Aihua. [Master's Dissertation]. Shandong University, 2007.); (3) use Vilsmeier reagent to cyclopentane Chloroformylation of ketone followed by Erlenmeyer reaction with benzoylglycine followed by alcoholysis, hydrogenation, hydrolysis, cyclization

Method used

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  • Synthesis method of ramipril key intermediate
  • Synthesis method of ramipril key intermediate
  • Synthesis method of ramipril key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0042] (1) Preparation of 2-phenyloxazol-5-(4H)-one (III)

[0043] Add N-benzoylglycine (35.8g, 0.2mol), solvent ethyl acetate 100mL, and acetic anhydride 10mL into a 250mL three-necked flask equipped with mechanical stirring and a thermometer, heat to 65°C, react for 4 hours, and use anhydrous sulfuric acid Sodium drying, after filtration, the crude product was purified by methanol recrystallization to obtain 25.60 g of light yellow solid, the yield was 79.5%, and the product purity was 97.5%

[0044] (2) Preparation of N-benzoylserine (IV)

[0045] Add 2-phenyloxazol-5-(4H)-one (18.7g, 0.096mol), 56.0mL of 35% aqueous formaldehyde solution, and 3.8mL of pyridine into a 250mL three-necked flask equipped with mechanical stirring and a thermometer, and react at room temperature After 17h, it was concentrated to remove water and pyridine. Add sodium hydroxide solution to adjust the pH to 8-11, continue stirring at room temperature for 1 h, add 50 mL of ethyl acetate for extrac...

Embodiment 2

[0058] (1) Preparation of 2-phenyloxazol-5-(4H)-one (III)

[0059] Add N-benzoylglycine (35.8g, 0.2mol), solvent ethyl acetate 100mL, and acetic anhydride 12mL into a 250mL three-necked flask equipped with mechanical stirring and a thermometer, heat to 65°C, react for 4 hours, and use anhydrous sulfuric acid Sodium drying, after filtration, the crude product was purified by methanol recrystallization to obtain 28.8 g of light yellow solid, the yield was 86.5%, and the product purity was 98.2%. (2) Preparation of N-benzoylserine (IV)

[0060] Add 2-phenyloxazol-5-(4H)-one (18.7g, 0.096mol), 40.0mL of 35% aqueous formaldehyde solution, and 11.6mL of pyridine into a 250mL three-necked flask equipped with mechanical stirring and a thermometer, and react at room temperature After 15h, concentrate to remove water and pyridine. Add sodium hydroxide solution to adjust the pH to 8-11, continue stirring at room temperature for 4 h, add 50 mL of ethyl acetate for extraction, and adjust ...

Embodiment 3

[0070] (1) Preparation of 2-phenyloxazol-5-(4H)-one (III)

[0071] Add N-benzoylglycine (35.8g, 0.2mol), solvent ethyl acetate 100mL, and acetic anhydride 28mL into a 250mL three-neck flask equipped with mechanical stirring and a thermometer, heat to 65°C, react for 4 hours, and use anhydrous sulfuric acid After drying with sodium, the crude product was filtered and refined by methanol recrystallization to obtain 27.1 g of a light yellow solid with a yield of 85.2% and a product purity of 98.7%.

[0072] (2) Preparation of N-benzoylserine (IV)

[0073] Add 2-phenyloxazol-5-(4H)-one (18.7g, 0.096mol), 18.7mL of 35% aqueous formaldehyde solution, and 15.5mL of pyridine in a 250mL three-necked flask equipped with mechanical stirring and a thermometer, and react at room temperature After 10 h, it was concentrated to remove water and pyridine. Add sodium hydroxide solution to adjust the pH to 8-11, continue stirring at room temperature for 3 h, add 50 mL of ethyl acetate for extr...

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Abstract

The invention discloses a synthesis method of a ramipril key intermediate. The ramipril key intermediate is 2-azabicyalo [3.3.0] octane-3-carboxylic acid hydrochloride. The 2-azabicyalo [3.3.0] octane-3-carboxylic acid hydrochloride is obtained through sequential dehydration cyclization, formaldehyde condensation, hydrolysis, removal, Michael addition, cyclization and palladium-carbon catalytic hydrogenation reduction of N-benzoyl-glycine as a raw material. According to the synthesis method of the ramipril key intermediate, the required raw material and reagent are cheap and available, the yield is relatively high, the operation is simple, the cost is low and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical and chemical intermediates, in particular to a method for synthesizing 2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride, a key intermediate of ramipril. [0002] technical background [0003] Angiotensin-converting enzyme (ACE) inhibitors act on the renin-angiotensin system, inhibit the activity of angiotensin-converting enzyme, reduce the production of angiotensin II, and achieve the purpose of lowering blood pressure and anti-heart failure. At present, such drugs mainly include captopril, enalapril, ramipril, perindopril, etc. These drugs significantly lower blood pressure and have a large market demand. [0004] Ramipril (Ramipril) is a drug of choice for the treatment of mild and essential hypertension and moderate and malignant congestive heart failure developed by the German Hearst company. The medicine has the characteristics of fast onset of action, strong action, little tox...

Claims

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Application Information

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IPC IPC(8): C07D209/52
Inventor 李坚军苏为科陆海波刘文中
Owner ZHEJIANG UNIV OF TECH
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