Synthesis method of (6S,7S)-9-t-butyloxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane

Abstract

The invention relates to a synthesis method of (6S,7S)-9-t-butyloxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane, aiming at mainly solving the technical problem that a suitable industrial synthesis method does not exist at present. The synthesis method is divided into six steps as follows: firstly, taking a compound 1 and oxalyl chloride to react to obtain a compound 2; then, hydrogenating by palladium on carbon to generate a compound 3; taking the compound 3 to react with BOC (Butyloxycarbonyl) acid anhydride under an alkaline condition to obtain a compound 4; taking the compound 4 and acrylonitrile to be subjected to alkylation reaction under the action of sodium ethoxide to obtain a compound 5; carrying out reduction and ring closure on the compound 5 under the action of Raney nickel to obtain a compound 6; reducing the compound 6 with borane-dimethylsulfide to obtain a final compound 7, wherein a reaction formula is shown in the description.

Description

technical field

[0001] The invention relates to a synthesis method of compound (6S, 7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane. Background technique

[0002] Compound (6S, 7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane (CAS: 1263178-03-5) and related derivatives It is widely used in medicinal chemistry and organic synthesis. At present, there is no report on the industrial synthesis of (6S,7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane. Therefore, it is necessary to develop a synthetic method that is easy to obtain raw materials, easy to operate, easy to control the reaction, suitable for overall yield, and suitable for industrial production. Contents of the invention

[0003] The purpose of the present invention is to develop a kind of (6S, 7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9 that has raw material that is easy to get, easy to operate, easy to control, and high yield. - Sy...

Examples

Embodiment 1

[0012] Example 1: Compound 1 (5 g, 0.022 mol) was dissolved in dichloromethane (50 mL), then oxalyl chloride (5.63 g, 0.044 mol) was added dropwise at 20°C, and stirred at room temperature for 1 hour. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0.7) shows that the reaction is complete. The reaction solution was concentrated to remove dichloromethane and oxalyl chloride. The concentrate was dissolved in dichloromethane (50 mL), then methanol (10 mL) was added dropwise at 0°C, and stirred at room temperature for 1 hour. The reaction solution was concentrated to remove dichloromethane and methanol to obtain compound 2 (5.3 g), yield: 100%.

[0013] Compound 2 (5.3g, 0.022mol) and concentrated hydrochloric acid (0.07g, 0.002mol) were added to the suspension of Pd / C (2g) / methanol (100mL), hydrogen gas was exchanged 3 times, 50 degrees Celsius, 50psi stirring reaction 16 hours. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0) shows that the reaction is...

Embodiment 2

[0020] Compound 1 (47g, 0.208mol) was dissolved in dichloromethane (500mL), then oxalyl chloride (52.9g, 0.416mol) was added dropwise at 20°C, and stirred at room temperature for 1 hour. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0.7) shows that the reaction is complete. The reaction solution was concentrated to remove dichloromethane and oxalyl chloride. The concentrate was dissolved in dichloromethane (200 mL), then methanol (50 mL) was added dropwise at 0°C, and stirred at room temperature for 1 hour. The reaction solution was concentrated to remove dichloromethane and methanol to obtain compound 2 (49.9 g), yield: 100%.

[0021] Compound 2 (49.9g, 0.208mol) and concentrated hydrochloric acid (0.75g, 0.02mol) were added to a suspension of Pd / C (20g) / methanol (1000mL), hydrogen gas was exchanged for 3 times, and the reaction was stirred at 50 degrees Celsius and 50psi 16 hours. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0) shows that the re...

technical field

[0001] The invention relates to a synthesis method of compound (6S, 7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane. Background technique

[0002] Compound (6S, 7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane (CAS: 1263178-03-5) and related derivatives It is widely used in medicinal chemistry and organic synthesis. At present, there is no report on the industrial synthesis of (6S,7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9-diazaspiro[5.5]undecane. Therefore, it is necessary to develop a synthetic method that is easy to obtain raw materials, easy to operate, easy to control the reaction, suitable for overall yield, and suitable for industrial production. Contents of the invention

[0003] The purpose of the present invention is to develop a kind of (6S, 7S)-9-tert-butoxycarbonyl-7-(trifluoromethyl)-2,9 that has raw material that is easy to get, easy to operate, easy to control, and high yield. - Sy...

Examples

Embodiment 1

[0012] Example 1: Compound 1 (5 g, 0.022 mol) was dissolved in dichloromethane (50 mL), then oxalyl chloride (5.63 g, 0.044 mol) was added dropwise at 20°C, and stirred at room temperature for 1 hour. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0.7) shows that the reaction is complete. The reaction solution was concentrated to remove dichloromethane and oxalyl chloride. The concentrate was dissolved in dichloromethane (50 mL), then methanol (10 mL) was added dropwise at 0°C, and stirred at room temperature for 1 hour. The reaction solution was concentrated to remove dichloromethane and methanol to obtain compound 2 (5.3 g), yield: 100%.

[0013] Compound 2 (5.3g, 0.022mol) and concentrated hydrochloric acid (0.07g, 0.002mol) were added to the suspension of Pd / C (2g) / methanol (100mL), hydrogen gas was exchanged 3 times, 50 degrees Celsius, 50psi stirring reaction 16 hours. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0) shows that the reaction is...

Embodiment 2

[0020] Compound 1 (47g, 0.208mol) was dissolved in dichloromethane (500mL), then oxalyl chloride (52.9g, 0.416mol) was added dropwise at 20°C, and stirred at room temperature for 1 hour. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0.7) shows that the reaction is complete. The reaction solution was concentrated to remove dichloromethane and oxalyl chloride. The concentrate was dissolved in dichloromethane (200 mL), then methanol (50 mL) was added dropwise at 0°C, and stirred at room temperature for 1 hour. The reaction solution was concentrated to remove dichloromethane and methanol to obtain compound 2 (49.9 g), yield: 100%.

[0021] Compound 2 (49.9g, 0.208mol) and concentrated hydrochloric acid (0.75g, 0.02mol) were added to a suspension of Pd / C (20g) / methanol (1000mL), hydrogen gas was exchanged for 3 times, and the reaction was stirred at 50 degrees Celsius and 50psi 16 hours. TLC (petroleum ether / ethyl acetate volume ratio=5 / 1, R f =0) shows that the re...

Images