Process for preparing vardenafil and intermediates thereof

A compound and hydrolysis reaction technology, applied in the direction of organic chemistry, can solve the problems of low reaction yield and unsuitable reaction conditions for industrial scale-up, and achieve the effects of easy control of reaction conditions, reduction of side reactions and impurities, and improvement of yield

Inactive Publication Date: 2013-11-13
TOPHARMAN SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Some of the above methods have low reaction yields, or the reaction conditions are not suitable for industrial amplification and other defects

Method used

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  • Process for preparing vardenafil and intermediates thereof
  • Process for preparing vardenafil and intermediates thereof
  • Process for preparing vardenafil and intermediates thereof

Examples

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preparation example Construction

[0060] The preparation of VI and IX involved in the invention can be prepared with reference to the method of patent WO9924433A1.

[0061] The compound shown in the structural formula IV in the invention can also be formed by the compound of the formula VII With the compound of formula VIII treated with hydrazine hydrate After the reaction, it can be treated with phosphorus oxychloride.

[0062] Another preparation method of the compound shown in the formula IV is: after the reaction of the compound shown in the formula VII and the compound shown in the formula VIII is completed, the solvent is evaporated, and POCl is added immediately 3 , PCl 3 , PCl 5 One or more of the reactions in the reaction, after the reaction is poured into crushed ice, extracted with an organic solvent.

[0063] The compound shown in VIII involved in the invention can be prepared by referring to the literature (J.Chem.Soc.Perkin Trans.1; EN; 1980; 1139-1146) by reacting o-ethoxybenzamidine and h...

Embodiment 1

[0068] Preparation 1: Preparation of 2-butyrylaminopropionic acid (X)

[0069] Add D, L-alanine (20.0g, 0.225mol) into a mixed solvent made of water (100mL) and acetone (50mL), and then add NaOH (22.5g, 0.225mol) to obtain a clear solution. , slowly added n-butyryl chloride (26.4 mL, 0.248 mol) dropwise. After the dropwise addition, keep the reaction below 5°C for 2 hours, remove the ice bath, distill off the acetone under reduced pressure, adjust the pH to 1.0 with 6mol / L hydrochloric acid, add butyl acetate (100mL×3), divide water and dry, evaporate Butyl acetate was removed to obtain a light yellow oil, and an appropriate amount of petroleum ether was added to precipitate a white solid, which was filtered with suction and dried to obtain product X (25.8 g), with a yield of 72%. 1 H NMR (CDCl 3 , 300MHz) δ: 0.94(3H, t), 1.44(3H, d), 1.65(2H, m), 2.22(2H, t), 4.57(2H, m), 6.37(1H, d), 6.62(1H , s).

[0070] Preparation 2: Preparation of 3-butyrylamino-2-oxo-butyric acid e...

Embodiment 2

[0083] Preparation 1: Preparation of 2-(2-ethoxyphenyl)-4-chloro-5-methyl-7-propylimidazol[5,1-f][1,2,4]-triazine (IV)

[0084] O-ethoxybenzamidine hydrochloride (VIII) (2.01g, 10mmol) was dissolved in ethanol (15mL), and 85% hydrazine hydrate (0.59mL, 10mmol) was slowly added dropwise under ice-cooling. After the addition was complete, React in an ice bath for 30 minutes, stir at room temperature for 1 hour, then add the ethanol (15 mL) solution of the product (2.58 g) prepared in Example 1, heat to reflux for 3 hours, filter, spin evaporate the solvent to obtain an oil, add POCl 3 (3mL), heated under reflux for 3 hours, TLC observed that the reaction was complete, evaporated the excess phosphorus oxychloride under reduced pressure, poured the residue into crushed ice slowly, extracted the product with dichloromethane (30mL) immediately, and washed the organic phase with saturated Wash with brine (20mL×2), dry over anhydrous sodium sulfate, distill off the solvent to an appro...

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Abstract

The invention provides a process for preparing vardenafil and its intermediates. The process is novel. The invention also provides new intermediates for preparing vardenafil and their preparations. The process for preparing vardenafil decreased side reactions in the methods of the prior art and other steps, improved yield and is easy operated, thus has excellent industrial applicability.

Description

technical field [0001] The invention relates to a preparation method of vardenafil and an intermediate thereof. Background technique [0002] Vardenafil (vardenafil, the API of levitra), the structural formula is The chemical name is 2-[2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]phenyl]-5-methyl-7-propyl-imidazo[5,1 -f][1,2,4]triazin-4-one is a selective PDE5 inhibitor developed by Bayer Company of Germany in 2001 and used clinically for the treatment of ED. [0003] The international patent application WO9924433A1 first disclosed the compound, its preparation method and its use for ED treatment; the international patent application WO200250076 further improved the preparation method of the above patent application, so that vardenafil can be prepared in large quantities. [0004] WO0250075 and US2006264624 have successively disclosed new intermediates and new preparation methods of vardenafil, literature (Journal of Organic Chemistry, 2005, 70 (18): 7331-7337), literatur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 田广辉沈敬山刘正郑金赵庆杰
Owner TOPHARMAN SHANGHAI
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