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A kind of preparation method of tadalafil related substance i

A technology for tadalafil and related substances, which is applied in the field of preparation of tadalafil related substances I, can solve problems such as low yield and long reaction time, and achieve the effects of high product purity, simple operation, and easy availability of raw materials

Active Publication Date: 2022-06-03
ZEIN BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are only two documents on the preparation method of tadalafil-related substance I: CN109796461A reports that tadalafil is obtained through oxidative rearrangement in N-halogenated imide, glacial acetic acid, tetrahydrofuran, and water system The method of non-related substance I, the reaction time of this method is relatively long, and the post-treatment needs to use a large amount of sodium carbonate to neutralize glacial acetic acid, and the yield is low; paper (Qian Pengfei. "The synthesis of tadalafil and related substances Research [D], Soochow University, 2016) mentioned the method of preparing tadalafil related substance I after oxidation of D-tryptophan methyl ester hydrochloride, a total of 4 steps of reaction, the total yield is only 11.7%

Method used

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  • A kind of preparation method of tadalafil related substance i
  • A kind of preparation method of tadalafil related substance i
  • A kind of preparation method of tadalafil related substance i

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 10ml of dichloromethane, 390mg of tadalafil, and 224mg of 3-chloroperoxybenzoic acid were added to a 50ml three-necked flask, and the reaction was carried out at room temperature for 40min, monitored by TLC (dichloromethane / methanol, 10:1). After the reaction was completed, 1 ml of dimethyl sulfide was added dropwise to quench, and the organic layer was concentrated to dryness under reduced pressure to obtain a concentrate (the compound represented by formula II).

[0024] The concentrate was dissolved in 20 ml of 1M sodium methoxide / methanol solution, heated under reflux for 40 min, and monitored by TLC (dichloromethane / methanol, 10:1). After the reaction was completed, the methanol was removed by concentration under reduced pressure, water / ethyl acetate was added for extraction, and the organic layer was concentrated to dryness under reduced pressure to obtain the crude product of tadalafil related substance I.

[0025] The crude product was purified by silica gel col...

Embodiment 2

[0027] 10 ml of chloroform, 390 mg of tadalafil, and 193 mg of peroxybenzoic acid were added to a 50 ml three-necked bottle, and the reaction was carried out at room temperature for 60 min, and monitored by TLC (dichloromethane / methanol, 10:1). After the reaction was completed, 5% sodium thiosulfate was added dropwise at 0 to 5°C to quench, and the layers were separated. The organic layer was extracted and washed with 5 ml of saturated sodium bicarbonate, and the organic layer was concentrated to dryness under reduced pressure to obtain a concentrate (the compound shown in formula II). ).

[0028] The concentrate was dissolved in 20 ml of 1M sodium ethoxide / ethanol solution, heated under reflux for 60 min, and monitored by TLC (dichloromethane / methanol, 10:1). After the reaction was completed, the ethanol was removed by concentration under reduced pressure, water / ethyl acetate was added for extraction, and the organic layer was concentrated to dryness under reduced pressure to...

Embodiment 3

[0031] 10ml of tetrahydrofuran, 390mg of tadalafil and 336mg of peroxysulfuric acid were added to a 50ml three-necked flask, and the reaction was carried out at room temperature for 60min, monitored by TLC (dichloromethane / methanol, 10:1). After the reaction is completed, 5% sodium sulfite 5ml is added dropwise at 0~5°C to quench, the layers are separated, the organic layer is extracted and washed with 5ml of saturated sodium bicarbonate, and the organic layer is concentrated to dryness under reduced pressure to obtain a concentrate (compound represented by formula II).

[0032] The concentrate was dissolved in 20 ml of 1M sodium methoxide / methanol solution, heated under reflux for 40 min, and monitored by TLC (dichloromethane / methanol, 10:1). After the reaction was completed, the methanol was removed by concentration under reduced pressure, water / ethyl acetate was added for extraction, and the organic layer was concentrated to dryness under reduced pressure to obtain the crude...

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Abstract

The invention discloses a preparation method of tadalafil related substance I. The preparation method uses tadalafil as a starting material, undergoes an oxidation reaction with peroxyacid in an organic solvent, rearranges through alkali action, and purifies by column chromatography to obtain tadalafil related substance I.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of tadalafil related substance I. Background technique [0002] Tadalafil Chemical name: (6R,12aR)-6-(1,3-benzodioxolan-5-yl)-2-methyl-2,3,6,7,12, 12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, its structural formula is as follows: [0003] [0004] Tadalafil, a phosphodiesterase V (PDE-5) inhibitor, was launched in the United States in 2003 under the trade name Cialis for the treatment of male erectile dysfunction (ED for short). )medicine. Compared with other anti-ED drugs, tadalafil has a rapid onset of action and the longest duration of action. It is the only drug among the four anti-ED drugs that is not affected by high-fat diet and alcohol intake. In addition to ED indications, tadalafil was approved for pulmonary arterial hypertension (PAH) in May 2009 and benign prostatic hyperplasia (BPH) in October 2011. [...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/20
CPCC07D487/20
Inventor 崔波肖光林黄超民严紫薇邓祥林
Owner ZEIN BIOTECHNOLOGY CO LTD