Preparation method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-formate

Abstract

The invention relates to a preparation method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-formate, and mainly solves the technical problem that no proper industrial synthesis methodexists at present. The product is synthesized by six steps, and the preparation method comprises the steps: a first step, a compound 1 is subjected to Swern oxidation reaction to generate a compound 2; a second step, a compound 3 is obtained through a Horner-Wadsworth-Emmons reaction; a third step, a compound 4 is obtained through Michael addition; a fourth step, a compound 5 is obtained through reduction of the compound 4 with lithium tetrahydroaluminum; a fifth step, the compound 5 is dehydrated and retained with a ring to obtain a compound 6 under the action of sodium hydrogen; and a sixthstep, hydrogenation is preformed to remove a protective group, and then a protective group is added to obtain the target compound 7. The obtained compound is a useful intermediate or product for synthesis of many drugs.

Description

technical field

[0001] The present invention relates to a synthesis method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-carboxylate (CAS: 1357353-23-1). Background technique

[0002] Tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-carboxylate and related derivatives are widely used in medicinal chemistry and organic synthesis. At present, there are few synthetic reports about tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-carboxylate, and similar literature reactions have certain dangers and The route is long and the yield is low. Therefore, it is necessary to develop a synthetic method with easy-to-obtain raw materials, convenient operation, easy-to-control reaction and suitable overall yield. Contents of the invention

[0003] The purpose of the present invention is to develop a kind of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5] with raw materials easy to get, easy to operate, easy to control and high yield. Preparation ...

Examples

Embodiment 1

[0011] a. Add oxalyl chloride (10.6 g, 84 mmol) into a solution of dimethyl sulfoxide (6.5 g, 84 mmol) in dichloromethane (200 mL), control the reaction temperature at -78 ° C, keep stirring for 0.5 hours, and then A solution of compound 1 (10 g, 42 mmol) in 50 ml of dichloromethane was added dropwise at the same temperature. The reaction was kept stirring at -78°C for 1 hour. Triethylamine (42 g, 0.42 mol) was added to the reaction system. TLC (petroleum ether / ethyl acetate volume ratio = 1 / 1) showed that the reaction was complete. The reaction liquid was added dropwise into saturated ammonium chloride (150 mL) solution, the organic phase was washed four times with 30 mL, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound 2 as a yellow solid (9 g, yield 92%).

[0012] b. Add compound 9 (50 g, 0.221 mol) in tetrahydrofuran (50 mL) dropwise into a solution of sodium hydrogen (8.8 g, 0.221 mol) in tetrahydrofuran (200 mL), the reaction system was...

Embodiment 2

[0020] a. Add oxalyl chloride (106 g, 0.84 mol) into a solution of dimethyl sulfoxide (65.2 g, 0.84 mol) in dichloromethane (2L), control the reaction temperature at -78 ° C, keep stirring for 0.5 hours, and then A solution of compound 1 (100 g, 0.42 mol) in 0.5 liter of dichloromethane was added dropwise at the same temperature. The reaction was kept stirring at -78°C for 1 hour. Triethylamine (422 g, 4.2 mol) was added to the reaction system. TLC (petroleum ether / ethyl acetate volume ratio = 1 / 1) showed that the reaction was complete. The reaction liquid was added dropwise into saturated ammonium chloride (1.5 L) solution, the organic phase was washed four times with 300 mL, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound 2 as a yellow solid (96 g, yield 96%).

[0021] b. Add compound 9 (496 g, 2.21 mol) in tetrahydrofuran (500 mL) dropwise into a solution of sodium hydrogen (88.4 g, 2.21 mol) in tetrahydrofuran (2 L), the reaction system ...

technical field

[0001] The present invention relates to a synthesis method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-carboxylate (CAS: 1357353-23-1). Background technique

[0002] Tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-carboxylate and related derivatives are widely used in medicinal chemistry and organic synthesis. At present, there are few synthetic reports about tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-carboxylate, and similar literature reactions have certain dangers and The route is long and the yield is low. Therefore, it is necessary to develop a synthetic method with easy-to-obtain raw materials, convenient operation, easy-to-control reaction and suitable overall yield. Contents of the invention

[0003] The purpose of the present invention is to develop a kind of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5] with raw materials easy to get, easy to operate, easy to control and high yield. Preparation ...

Examples

Embodiment 1

[0011] a. Add oxalyl chloride (10.6 g, 84 mmol) into a solution of dimethyl sulfoxide (6.5 g, 84 mmol) in dichloromethane (200 mL), control the reaction temperature at -78 ° C, keep stirring for 0.5 hours, and then A solution of compound 1 (10 g, 42 mmol) in 50 ml of dichloromethane was added dropwise at the same temperature. The reaction was kept stirring at -78°C for 1 hour. Triethylamine (42 g, 0.42 mol) was added to the reaction system. TLC (petroleum ether / ethyl acetate volume ratio = 1 / 1) showed that the reaction was complete. The reaction liquid was added dropwise into saturated ammonium chloride (150 mL) solution, the organic phase was washed four times with 30 mL, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound 2 as a yellow solid (9 g, yield 92%).

[0012] b. Add compound 9 (50 g, 0.221 mol) in tetrahydrofuran (50 mL) dropwise into a solution of sodium hydrogen (8.8 g, 0.221 mol) in tetrahydrofuran (200 mL), the reaction system was...

Embodiment 2

[0020] a. Add oxalyl chloride (106 g, 0.84 mol) into a solution of dimethyl sulfoxide (65.2 g, 0.84 mol) in dichloromethane (2L), control the reaction temperature at -78 ° C, keep stirring for 0.5 hours, and then A solution of compound 1 (100 g, 0.42 mol) in 0.5 liter of dichloromethane was added dropwise at the same temperature. The reaction was kept stirring at -78°C for 1 hour. Triethylamine (422 g, 4.2 mol) was added to the reaction system. TLC (petroleum ether / ethyl acetate volume ratio = 1 / 1) showed that the reaction was complete. The reaction liquid was added dropwise into saturated ammonium chloride (1.5 L) solution, the organic phase was washed four times with 300 mL, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound 2 as a yellow solid (96 g, yield 96%).

[0021] b. Add compound 9 (496 g, 2.21 mol) in tetrahydrofuran (500 mL) dropwise into a solution of sodium hydrogen (88.4 g, 2.21 mol) in tetrahydrofuran (2 L), the reaction system ...

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