Avanafil intermediate as well as preparation method and application thereof

Abstract

The invention discloses an avanafil intermediate as well as a preparation method and application thereof. The avanafil intermediate is a compound having a general formula as shown in the description, wherein R in the general formula is selected from C1-C4 alkyl. The preparation method of the intermediate comprises the steps a-d in the synthesis route as shown in the description. The invention also discloses an application of the intermediate. Each reaction step for preparing avanafil from the intermediate has the advantages of simple operation, mild reaction conditions, easily available reaction raw materials, high reaction yield and the like, the products are easy to separate and purify; the total yield of prepared avanafil is increased to 40% and the HPLC purity reaches up to 99.8%; the preparation cost of avanafil is greatly reduced, the quality of avanafil is ensured, and thus the intermediate is very much in line with industrial production requirements and has practical value.

Description

technical field

[0001] The invention relates to an avanafil intermediate, a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. Background technique

[0002] Avanafil, also known as Avanafil, its chemical structure is as follows:

[0003]

[0004] Avanafil (STENDRA) researches and develops a new drug for the treatment of erectile dysfunction for Japan Tanabe Pharmaceutical Co., Ltd. It belongs to the class of phosphodiesterase inhibitors type 5 (PDE5-I), which increases blood flow to the penis. Like other PDE5-Is, this drug should not be used in men who are also taking nitrates for chest pain because their combined use can cause a dramatic drop in blood pressure. The US FDA approved the new drug avanafil on April 27, 2012 for the treatment of erectile dysfunction (ED).

[0005] Patent document WO2001019802 discloses two synthetic methods of this compound, wherein the route of method one is as follows:

[0006] [0...

Examples

Embodiment 1

[0038] Embodiment 1: prepare the intermediate of the present invention

[0039] Step a: prepare the compound shown in formula II

[0040]

[0041] Add 12.9g proline methyl ester hydrochloride (compound shown in formula I), 17.2g oxymethylisourea sulfate and 65mL methanol in the 250mL there-necked flask that is equipped with reflux condenser, thermometer; Heat to reflux; Reflux After reacting for 16 hours, the reaction was terminated, and the temperature was lowered to 0° C. to prepare a methanol solution containing the compound represented by formula II for future use.

[0042] Step b: prepare the compound shown in formula III

[0043]

[0044] Add 18.9g sodium methoxide and 30mL methanol to the methanol solution containing the compound shown in formula II prepared in step a;

[0045] Control the reaction temperature below 10°C, add 21.6g of ethoxymethylene dropwise; after the dropwise addition, return to room temperature and react for 16 hours; after the reaction is c...

Embodiment 2

[0068] Embodiment 2: Application of the intermediate of the present invention to prepare avanafil

[0069] Step ①: prepare the compound shown in formula V

[0070]

[0071] Add 26.9g of the intermediate of the present invention prepared in Example 1 and 150mL of methanol to a 250mL three-necked flask equipped with a reflux condenser and a thermometer; 2.3g of sodium borohydride was added; after the addition, the temperature was slowly raised to room temperature and reacted for 3 hours; after the reaction was completed, the pH of the system was adjusted to neutrality with concentrated hydrochloric acid; 25 g of the compound represented by formula V was obtained as a white solid with a molar yield of 90% and an HPLC purity of 98%.

[0072] Step ②: prepare the compound shown in formula VI

[0073]

[0074] Add 25g of the compound shown in formula V and 100mL dimethyl sulfoxide to a 250mL three-necked flask equipped with a reflux condenser and a thermometer, and stir until...

technical field

[0001] The invention relates to an avanafil intermediate, a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. Background technique

[0002] Avanafil, also known as Avanafil, its chemical structure is as follows:

[0003]

[0004] Avanafil (STENDRA) researches and develops a new drug for the treatment of erectile dysfunction for Japan Tanabe Pharmaceutical Co., Ltd. It belongs to the class of phosphodiesterase inhibitors type 5 (PDE5-I), which increases blood flow to the penis. Like other PDE5-Is, this drug should not be used in men who are also taking nitrates for chest pain because their combined use can cause a dramatic drop in blood pressure. The US FDA approved the new drug avanafil on April 27, 2012 for the treatment of erectile dysfunction (ED).

[0005] Patent document WO2001019802 discloses two synthetic methods of this compound, wherein the route of method one is as follows:

[0006] [0...

Examples

Embodiment 1

[0038] Embodiment 1: prepare the intermediate of the present invention

[0039] Step a: prepare the compound shown in formula II

[0040]

[0041] Add 12.9g proline methyl ester hydrochloride (compound shown in formula I), 17.2g oxymethylisourea sulfate and 65mL methanol in the 250mL there-necked flask that is equipped with reflux condenser, thermometer; Heat to reflux; Reflux After reacting for 16 hours, the reaction was terminated, and the temperature was lowered to 0° C. to prepare a methanol solution containing the compound represented by formula II for future use.

[0042] Step b: prepare the compound shown in formula III

[0043]

[0044] Add 18.9g sodium methoxide and 30mL methanol to the methanol solution containing the compound shown in formula II prepared in step a;

[0045] Control the reaction temperature below 10°C, add 21.6g of ethoxymethylene dropwise; after the dropwise addition, return to room temperature and react for 16 hours; after the reaction is c...

Embodiment 2

[0068] Embodiment 2: Application of the intermediate of the present invention to prepare avanafil

[0069] Step ①: prepare the compound shown in formula V

[0070]

[0071] Add 26.9g of the intermediate of the present invention prepared in Example 1 and 150mL of methanol to a 250mL three-necked flask equipped with a reflux condenser and a thermometer; 2.3g of sodium borohydride was added; after the addition, the temperature was slowly raised to room temperature and reacted for 3 hours; after the reaction was completed, the pH of the system was adjusted to neutrality with concentrated hydrochloric acid; 25 g of the compound represented by formula V was obtained as a white solid with a molar yield of 90% and an HPLC purity of 98%.

[0072] Step ②: prepare the compound shown in formula VI

[0073]

[0074] Add 25g of the compound shown in formula V and 100mL dimethyl sulfoxide to a 250mL three-necked flask equipped with a reflux condenser and a thermometer, and stir until...

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