Preparation method of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane [3,5] nonane-7-carboxylic ester

Abstract

The invention relates to a preparation method of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane [3,5] nonane-7-carboxylic ester and mainly solves the technical problem that no appropriate industrial synthesis method exists at present. The method comprises two steps as follows: firstly, a compound 1 and a compound 2 produce a compound 3 under the action of zinc powder and ammonium chloride, then the compound 3 reacts with iodine and sodium bicarbonate in acetonitrile, a compound 4 is obtained, and the equation is shown in the specification. The compound obtained with the method is a useful intermediate for synthesis of numerous drugs or product.

Description

technical field

[0001] The invention relates to a synthesis method of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane[3,5]nonane-7-carboxylate (CAS: 1160246-84-3). Background technique

[0002] tert-butyl 2-iodomethyl-1-oxa-7-azaspirane[3,5]nonane-7-carboxylate and related derivatives are widely used in medicinal chemistry and organic synthesis. At present, there are few syntheses about tert-butyl 2-iodomethyl-1-oxa-7-azaspirane[3,5]nonane-7-carboxylate, and similar literature reactions have certain dangers and routes long and the yield is low. Therefore, it is necessary to develop a synthetic method with readily available raw materials, convenient operation, easy control of the reaction, and suitable overall yield. Contents of the invention

[0003] The purpose of this invention is to develop a kind of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane [3,5] that has raw materials that are easy to get, easy to operate, easy to control and high in yield. Synthetic method of nonane-7...

Examples

Embodiment 1

[0010] Embodiment 1: a, compound 1 (50g, 0.25mol) and zinc powder (49.2g, 0.75mol) were suspended in a mixed solution of tetrahydrofuran and aqueous ammonium chloride (2 / 3, 500mL). Control the temperature at -10-10°C, add the compound dropwise to the reaction solution 2 (109.3 g, 0.90 mol). The temperature of the reaction is slowly raised to 15-40° C., and the reaction is continued for 2-5 hours. TLC (petroleum ether / ethyl acetate volume ratio=2 / 1) showed that the reaction was complete. Ethyl acetate (100mLx3) was used for the reaction solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated by vacuum distillation to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate volume ratio=30 / 1 to 10 / 1) to obtain a colorless oily compound 3 (60 g), yield 99.9%.

[0011] δ(CDCl 3 )=5.827-5.740,1H),5.151-5.067(m,2H),3.776-3.739(m,2H),3.137-3.061(m,2H),2.176-2.157(d, J =7.6,2H), 1.593-1....

Embodiment 2

[0014] Embodiment 2: a, compound 1 (500g, 2.5mol) and zinc powder (492g, 7.5mol) were suspended in a mixed solution of tetrahydrofuran and ammonium chloride aqueous solution (2 / 3, 5L). Control the temperature at -10-10°C, add the compound dropwise to the reaction solution 2 (1.1kg, 9.0mol). The temperature of the reaction is slowly raised to 15-40° C., and the reaction is continued for 2-5 hours. TLC (petroleum ether / ethyl acetate volume ratio=2 / 1) showed that the reaction was complete. Ethyl acetate (1Lx3) was used for the reaction solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated by vacuum distillation to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate volume ratio=30 / 1 to 10 / 1) to obtain a colorless oily compound 3 (600g), yield 99.9%.

[0015] δ(CDCl 3 )=5.827-5.740,1H),5.151-5.067(m,2H),3.776-3.739(m,2H),3.137-3.061(m,2H),2.176-2.157(d, J =7.6,2H), 1.593-1.485...

technical field

[0001] The invention relates to a synthesis method of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane[3,5]nonane-7-carboxylate (CAS: 1160246-84-3). Background technique

[0002] tert-butyl 2-iodomethyl-1-oxa-7-azaspirane[3,5]nonane-7-carboxylate and related derivatives are widely used in medicinal chemistry and organic synthesis. At present, there are few syntheses about tert-butyl 2-iodomethyl-1-oxa-7-azaspirane[3,5]nonane-7-carboxylate, and similar literature reactions have certain dangers and routes long and the yield is low. Therefore, it is necessary to develop a synthetic method with readily available raw materials, convenient operation, easy control of the reaction, and suitable overall yield. Contents of the invention

[0003] The purpose of this invention is to develop a kind of tert-butyl 2-iodomethyl-1-oxa-7-azaspirane [3,5] that has raw materials that are easy to get, easy to operate, easy to control and high in yield. Synthetic method of nonane-7...

Examples

Embodiment 1

[0010] Embodiment 1: a, compound 1 (50g, 0.25mol) and zinc powder (49.2g, 0.75mol) were suspended in a mixed solution of tetrahydrofuran and aqueous ammonium chloride (2 / 3, 500mL). Control the temperature at -10-10°C, add the compound dropwise to the reaction solution 2 (109.3 g, 0.90 mol). The temperature of the reaction is slowly raised to 15-40° C., and the reaction is continued for 2-5 hours. TLC (petroleum ether / ethyl acetate volume ratio=2 / 1) showed that the reaction was complete. Ethyl acetate (100mLx3) was used for the reaction solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated by vacuum distillation to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate volume ratio=30 / 1 to 10 / 1) to obtain a colorless oily compound 3 (60 g), yield 99.9%.

[0011] δ(CDCl 3 )=5.827-5.740,1H),5.151-5.067(m,2H),3.776-3.739(m,2H),3.137-3.061(m,2H),2.176-2.157(d, J =7.6,2H), 1.593-1....

Embodiment 2

[0014] Embodiment 2: a, compound 1 (500g, 2.5mol) and zinc powder (492g, 7.5mol) were suspended in a mixed solution of tetrahydrofuran and ammonium chloride aqueous solution (2 / 3, 5L). Control the temperature at -10-10°C, add the compound dropwise to the reaction solution 2 (1.1kg, 9.0mol). The temperature of the reaction is slowly raised to 15-40° C., and the reaction is continued for 2-5 hours. TLC (petroleum ether / ethyl acetate volume ratio=2 / 1) showed that the reaction was complete. Ethyl acetate (1Lx3) was used for the reaction solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated by vacuum distillation to obtain a crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate volume ratio=30 / 1 to 10 / 1) to obtain a colorless oily compound 3 (600g), yield 99.9%.

[0015] δ(CDCl 3 )=5.827-5.740,1H),5.151-5.067(m,2H),3.776-3.739(m,2H),3.137-3.061(m,2H),2.176-2.157(d, J =7.6,2H), 1.593-1.485...

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