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A synthesis method and avanafil technology, applied in the field of small molecule chemical drug preparation, can solve the problems of difficult removal, low yield, difficult separation and purification of reaction products, etc., and achieve improved operating environment, strong process controllability, and improved product high purity effect
Active Publication Date: 2017-04-26
ARROMAX PHARMATECH
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[0012] (1) Route-1: LDA needs to be used, and the reaction is carried out at ultra-low temperature -78°C, and it will be difficult to scale up production;
[0013] (2) Route-2: The second step reaction requires the use of heavy metal Pd and organic phosphine as a catalyst, which is expensive
In addition, it is difficult to completely remove the toxic and precious metal Pd from the product
[0014] (3) Route-3: In the methyl sulfide oxidation step, the oxidation reaction is incomplete, resulting in a mixture of sulfoxide and sulfone, resulting in the S N The yield of the Ar reaction is low, and the side reaction of amine transesterification will occur at the same time, making the reaction product difficult to separate and purify
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Embodiment 1
[0051] Synthesis of compound 19
[0052]
[0053] Compound 13 (5g, 21.86mmol) and compound 18 (5.34g, 25.4mmol) were dissolved in 75ml of anhydrous DMF 1 and stirred for 10 minutes. After stirring for 10 minutes, the reaction system was placed in a mixture of ice and water, and triethyl ether was slowly added dropwise into the reaction flask. Amine (21.4 g, 0.217 mole), slowly warmed to room temperature, TLC showed the reaction was complete after 4 hours. Add dichloromethane, wash with water five times, dry and filter, concentrate by rotary evaporation and pass through the column (PE:EA=25:1). Compound 19 (7.3 g, yield 78%) was obtained as a white powder.
[0056] Compound 13 (5g, 21.86mmol) and compound 18 (5.34g, 25.4mmol) were dissolved in 75ml of anhydrous DMF 1 and stirred for 10 minutes. After stirring for 10 minutes, the reaction system was placed in a mixture of ice and water, and triethyl ether was slowly added dropwise into the reaction flask. Amine (21.4g, 0.217mole), slowly raised to 50°C, TLC showed the reaction was complete after 2 hours. Add dichloromethane, wash with water five times, dry and filter, concentrate by rotary evaporation and pass through the column (PE:EA=25:1). Compound 19 was obtained as a white powder (7.1 g, yield 75.9%).
Embodiment 3
[0058] Synthesis of compound 20
[0059]
[0060] At 0°C, add compound 18 (62.5g, 0.3mol), compound 3 (50g, 0.2mol), 1L of anhydrous DMF to the reaction flask, slowly add DIPEA (107.3g, 0.83mol) dropwise, and react overnight at room temperature , TLC monitored the completion of the reaction. Dichloromethane (500ml×2) was added, extracted five times with 500ml water, the organic phase was dried and filtered, concentrated by rotary evaporation to obtain compound 20 (75g, yield 70%).
[0061] LC-MS: M / Z, 356.1 (M+1).
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Abstract
The invention provides a synthesis method of avanafil. The synthesis method of avanafil comprises the following steps: carrying out nucleophilic substitution reaction with a compound (13) or a compound (3) by a compound (18), hydrolyzing to prepare a compound (21) or a compound (22), reacting the compound (21) or the compound (22) with sulfonic acidchloride or pivaloyl chloride to obtain mixed anhydride, reacting the mixed anhydride with a compound (23) to prepare a compound (24) or a compound (25), then oxidizing the compound (24), subsequently reacting the compound (24) with a compound (9) to prepare avanafil, or directly reacting the compound (25) with the compound (9) to prepare avanafil. The synthesis method is high in controllability, simple in step, high in yield and low in cost, and is suitable for industrial production. The reaction route is shown in the description.
Description
technical field [0001] The invention relates to the field of preparation of small molecule chemical medicines, and more particularly relates to a synthesis method of avanafil. Background technique [0002] Avanafil (avanafil) is a drug developed by Vivus Company of the United States authorized by Mitsubishi Tanabe Pharmaceutical Co., Ltd. of Japan for the treatment of male erectile dysfunction. Stendra. The drug is an oral rapid-acting highly selectivephosphodiesterase-5 (PDE-5) inhibitor. The Chinese chemical name of avanafil: (S)-4-(3-chloro-4-methoxybenzyloxy)-2-(2-hydroxymethyl-1-pyrrolidinyl)-N-(2 -pyrimidinemethyl)-5-pyrimidinecarboxamide. [0003] [0004] The current synthetic route of avanafil reported in the literature is as follows: [0005] (1) Use 2,4-dichloropyrimidine as the starting material, undergo LDA hydrogen extraction at a low temperature of -78°C, and then combine with CO 2 The reaction gives the corresponding carboxylic acid. Further esterif...
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