A kind of synthetic method of palo verde

Abstract

The present invention provides a new synthesis method of Parovide, a therapeutic drug for the new coronavirus. Wherein, the synthesis method of the intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride, the steps include nitrogen protection, reduction reaction, quenching, extraction, salification, and deprotection. The Parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride synthesized by this method has the characteristics of high yield, few impurities, safe reaction, simple operation, and no special requirements for equipment, thereby being more conducive to the synthesis of high-quality Parovide, a therapeutic drug for the new coronavirus.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and relates to a new synthesis method of the novel coronavirus therapeutic drug Paroverde, and in particular to a new synthesis method of the intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride. Background Art

[0002] Paxlovid is a new generation of effective drug developed by Pfizer for the treatment of new coronavirus. It is now available in the UK. Its structure is as follows:

[0003]

[0004] 6,6-Dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride is a key intermediate. It is primarily obtained by reduction of (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo [3.1.0] hexane. The reduction methods available in the prior art mainly include the following two methods:

[0005] Method 1: (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane is reduced using lithium aluminum tetrahydride. Lithium aluminum tetrahydride reacts violently with water, releasing hydrogen. There is a risk of explosion during large-scale production and it is difficult to control. In addition, lithium aluminum tetrahydride is expensive and not suitable for large-scale production.

[0006] Method 2: (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane is reduced using a combination of Lewis acid and borohydride. The Lewis acid used is aluminum chloride, nickel chloride, ferric bromide, etc., and the borohydride is sodium borohydride, potassium borohydride, lithium borohydride, etc. The disadvantages of this method are long reaction time, high impurities, and complex post-processing.

[0007] Therefore, it is necessary to develop a new method to synthesize 6,6-dimethyl-3-azabicyclo(3.2.0)hexane hydrochloride. Summary of the Invention

[0008] The main purpose of the present invention is to provide a new synthesis method of paloverde.

[0009] In the new synthetic method provided,

[0010] The present invention achieves the above-mentioned purpose through the following technology: a method for preparing a parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride, comprising the following steps:

[0011] (1) Reduction reaction: Add (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane, solvent, borane or borane complex into the reaction flask, heat to 20-90°C, and react for 1-3 hours until the reaction is complete;

[0012] (2) Quenching: add acid to quench the reaction under cooling, and then extract with extraction solution;

[0013] (3) Concentration: The extract is concentrated to remove the solvent and water to obtain a concentrated solution;

[0014] (4) Salt formation: Add an alcoholic solution of hydrochloric acid to the concentrated solution to form salt, cool and filter to obtain the intermediate of Paroverde, 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride.

[0015] Specifically, the mass ratio of the solvent in step (1) to (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane is 2-50:1.

[0016] Specifically, the solvent is selected from ethers such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, etc.; benzenes such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, etc.

[0017] Specifically, the borane or borane complex is selected from one of borane tetrahydrofuran complex, borane ether complex, borane dimethyl sulfide complex, borane N,N diethylaniline complex, and the like.

[0018] Specifically: The preparation method of 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride is characterized in that the molar ratio of the borane or borane complex to (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo [3.1.0] hexane is 2 to 10:1

[0019] Specifically: the acid used for quenching in step (2) is one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, etc.

[0020] Specifically: the extracting liquid in step (3) is selected from ethers such as tetrahydrofuran, methyltetrahydrofuran, ethyl ether, methyl tert-butyl ether, etc.; benzenes such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, etc.

[0021] Specifically: the alcohol hydrochloric acid solution in step (4) is ethanol hydrochloric acid solution, isopropanol hydrochloric acid solution, or methanol hydrochloric acid solution.

[0022] The preparation method of the paroverde intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride provided by the present invention can meet the requirements for the industrialization of the paroverde intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride. DETAILED DESCRIPTION

[0023] Below in conjunction with embodiment, the present invention is described in further detail:

[0024] Example 1:

[0025] (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane, 4 times the mass of tetrahydrofuran, and 4 times the molar number of borane were added to a reaction flask, the temperature was raised to 30°C, and the reaction was carried out for 2 hours until the reaction was complete; hydrochloric acid was slowly added while cooling to quench the reaction, and the pH was adjusted to neutral with aqueous sodium hydroxide solution; the organic phase was extracted twice with methyltetrahydrofuran; the organic phase was evaporated to remove the solvent and water; a small amount of isopropanol was added to dissolve the mixture, and a hydrochloric acid solution of isopropanol was slowly added under stirring to form a salt, cooled, filtered, and dried in vacuo to obtain 6,6-dimethyl-3-azabicyclo(3.2.0)hexane hydrochloride with a yield of 90% and a purity of 99%.

[0026] Example 2:

[0027] (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane, 5 times the mass of ether, and 5 times the molar number of borane dimethyl sulfide complex were added to a reaction flask, the temperature was raised to 20°C, and the reaction was carried out for 3 hours until the reaction was complete; hydrochloric acid was slowly added while cooling to quench the reaction, and the pH was adjusted to neutral with aqueous sodium hydroxide solution; the organic phase was extracted twice with methyl tert-butyl ether; the organic phase was evaporated to remove the solvent and water; a small amount of ethanol was added to dissolve the mixture, and a hydrochloric acid solution of isopropyl alcohol was slowly added with stirring to form a salt, and the mixture was cooled, filtered, and dried in vacuo to obtain 6,6-dimethyl-3-azabicyclo(3.2.0)hexane hydrochloride with a yield of 85% and a purity of 99.2%.

[0028] Example 3:

[0029] (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane, 6 times the mass of toluene, and 6 times the molar number of borane N,N-diethylaniline complex were added to a reaction flask, the temperature was raised to 50°C, and the reaction was carried out for 3 hours until the reaction was complete; dilute sulfuric acid was slowly added while cooling to quench the reaction, and the pH was adjusted to neutral with aqueous sodium hydroxide solution; the organic phase was extracted twice with toluene; the organic phase was evaporated under reduced pressure to remove the solvent and water; a small amount of ethanol was added to dissolve the mixture, and a hydrochloric acid solution of isopropyl alcohol was slowly added with stirring to form a salt, and the mixture was cooled, filtered, and dried in vacuo to obtain 6,6-dimethyl-3-azabicyclo(3.2.0)hexane hydrochloride with a yield of 85% and a purity of 99%.

[0030] Example 4:

[0031] (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane, 10 times the mass of dichloromethane, and 6 times the molar number of borane were added to a reaction flask, the temperature was raised to 30°C, and the reaction was carried out for 2 hours until the reaction was complete; hydrochloric acid was slowly added while cooling to quench the reaction, and the pH was adjusted to neutral with aqueous sodium hydroxide solution; the organic phase was extracted twice with dichloromethane; the organic phase was evaporated to remove the solvent and water; a small amount of ethanol was added to dissolve the mixture, and an ethanolic hydrochloric acid solution was slowly added with stirring to form a salt, cooled, filtered, and dried in vacuo to obtain 6,6-dimethyl-3-azabicyclo(3.2.0)hexane hydrochloride with a yield of 88% and a purity of 99.2%.

[0032] Embodiment 5:

[0033] (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane, 10 times the mass of tetrahydrofuran, and 6 times the molar number of borane tetrahydrofuran complex were added to a reaction flask, the temperature was raised to 30°C, and the reaction was carried out for 2 hours until the reaction was complete; hydrochloric acid was slowly added while cooling to quench the reaction, and the pH was adjusted to neutral with aqueous sodium hydroxide solution; the organic phase was extracted twice with benzene; the organic phase was evaporated to remove the solvent and water; a small amount of isopropanol was added to dissolve the mixture, and a hydrochloric acid solution of isopropanol was slowly added while stirring to form a salt, and the mixture was cooled, filtered, and dried in vacuo to obtain 6,6-dimethyl-3-azabicyclo(3.2.0)hexane hydrochloride with a yield of 92% and a purity of 99.3%.

Claims

1. A method for preparing a parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride, characterized in that: The preparation method of the intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride comprises the following steps: (1) Reduction reaction: Add (1R,5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane, solvent, borane or borane complex into a reaction kettle, raise the temperature to 20-50°C, and react for 1-3 hours until the reaction is complete; The borane complex is selected from one of a tetrahydrofuran complex of borane, a diethyl ether complex of borane, a dimethyl sulfide complex of borane, and a N,N-diethylaniline complex of borane; (2) Quenching: Add acid to quench the reaction under cooling, then adjust the pH to neutral with sodium hydroxide aqueous solution, and then extract with the extraction solution; (3) Concentration: The extract is concentrated to remove the solvent and water to obtain a concentrated solution; (4) Salt formation: add an alcoholic solution of hydrochloric acid to the concentrate to form salt, cool and filter to obtain the intermediate of Parovide, 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride.

2. The method for preparing the Parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride according to claim 1, characterized in that: The mass ratio of the solvent to (1R, 5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane in step (1) is 2 to 50:

1.

3. The preparation method of the Parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride according to claim 1, characterized in that: The solvent in step (1) is selected from tetrahydrofuran, methyltetrahydrofuran, ether, methyl tert-butyl ether, benzene, toluene, xylene, dichloromethane, chloroform, and dichloroethane.

4. The method for preparing the Parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride according to claim 1, characterized in that: The molar ratio of the borane or borane complex to (1R, 5S)-6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane is 2 to 10:

1.

5. The method for preparing the Parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride according to claim 1, characterized in that: The quenching acid in step (2) is one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid.

6. The method for preparing the Parovide intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride according to claim 1, characterized in that: The extract in step (3) is selected from tetrahydrofuran, methyltetrahydrofuran, ether, methyl tert-butyl ether, benzene, toluene, xylene, dichloromethane, chloroform, and dichloroethane.

7. The method for preparing the new intermediate 6,6-dimethyl-3-azabicyclo (3.2.0) hexane hydrochloride of Parovird according to claim 1, characterized in that: The alcohol hydrochloric acid solution in step (4) is ethanol hydrochloric acid solution, isopropanol hydrochloric acid solution, or methanol hydrochloric acid solution.

Images