Preparation method of 2-(2-(tert-butyloxycarbonyl)-2-azaspiro [3.4] octane-5-yl) acetic acid

Abstract

The invention discloses a preparation method of 2-(2-(tert-butyloxycarbonyl)-2-azaspiro [3.4] octane-5-yl) acetic acid. The preparation method comprises the following steps: dissolving a compound 1 and a compound 2 in 2-methyl tetrahydrofuran, dropwise adding lithium bis (trimethylsilyl) amide, and reacting to obtain a compound 3; dissolving the compound 3 into acetone, and reacting with sodium iodide to obtain a compound 4; dissolving the compound 4 in 2-methyl tetrahydrofuran, dropwise adding n-butyllithium, and reacting to obtain a compound 5; dissolving the compound 5 into 2-methyl tetrahydrofuran, then adding a compound 6, alkali and 1, 8-diazabicyclo undecene-7-ene, and reacting at room temperature to obtain a compound 7; dissolving the compound 7 into ethyl acetate, adding a catalyst, and reacting in hydrogen to obtain a compound 8; dissolving the compound 8 into tetrahydrofuran and water, adding alkali for hydrolysis to obtain a final compound 9, and continuously optimizing thestructure of a spiro compound to obtain the synthesis method suitable for industrial production.

Description

technical field

[0001] The invention relates to a compound synthesis method, in particular to a compound 2-(2-(tert-butoxycarbonyl)-2-azaspiro[3.4]octane-5-yl)acetic acid preparation method. Background technique

[0002] Compared with foreign competitors, Chinese pharmaceutical companies are often plagued by technical and financial problems, unable to effectively carry out new drug research and development, and can only simply repeat the production or imitate foreign patent expired drugs. The products lack international competitiveness, and the domestic market also suffers. The serious threat of imported western medicines, and the discovery of lead compounds is the only way to discover innovative drugs. Due to the long cycle of new drug development (8-10 years) and high cost (800-100 million US dollars), most developed countries currently adopt the method of "many, fast, high, and low cost"—combinatorial chemical technology platform to speed up the development of small molec...

Examples

Embodiment 1

[0036] The reaction formula of embodiment 1 is as follows:

[0037]

[0038] This embodiment adopts the following steps:

[0039] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -70°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900mL), diluted with water (800mL), then extracted twice with methyl tert-butyl ether (600mL), and the organic phases were combined with 20% aqueous citric acid solution (1500mL) and saturated Each was washed once with saline (80...

Embodiment 2

[0047] The reaction formula of embodiment 2 is as follows:

[0048]

[0049] This embodiment adopts the following steps:

[0050] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -70°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900mL), diluted with water (800mL), then extracted twice with methyl tert-butyl ether (600mL), and the organic phases were combined with 20% aqueous citric acid solution (1500mL) and saturated Each was washed once with saline (80...

Embodiment 3

[0058] The reaction formula of embodiment 3 is as follows:

[0059]

[0060] This embodiment adopts the following steps:

[0061] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -70°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900mL), diluted with water (800mL), then extracted twice with methyl tert-butyl ether (600mL), and the organic phases were combined with 20% aqueous citric acid solution (1500mL) and saturated Each was washed once with saline (80...

technical field

[0001] The invention relates to a compound synthesis method, in particular to a compound 2-(2-(tert-butoxycarbonyl)-2-azaspiro[3.4]octane-5-yl)acetic acid preparation method. Background technique

[0002] Compared with foreign competitors, Chinese pharmaceutical companies are often plagued by technical and financial problems, unable to effectively carry out new drug research and development, and can only simply repeat the production or imitate foreign patent expired drugs. The products lack international competitiveness, and the domestic market also suffers. The serious threat of imported western medicines, and the discovery of lead compounds is the only way to discover innovative drugs. Due to the long cycle of new drug development (8-10 years) and high cost (800-100 million US dollars), most developed countries currently adopt the method of "many, fast, high, and low cost"—combinatorial chemical technology platform to speed up the development of small molec...

Examples

Embodiment 1

[0036] The reaction formula of embodiment 1 is as follows:

[0037]

[0038] This embodiment adopts the following steps:

[0039] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -70°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900mL), diluted with water (800mL), then extracted twice with methyl tert-butyl ether (600mL), and the organic phases were combined with 20% aqueous citric acid solution (1500mL) and saturated Each was washed once with saline (80...

Embodiment 2

[0047] The reaction formula of embodiment 2 is as follows:

[0048]

[0049] This embodiment adopts the following steps:

[0050] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -70°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900mL), diluted with water (800mL), then extracted twice with methyl tert-butyl ether (600mL), and the organic phases were combined with 20% aqueous citric acid solution (1500mL) and saturated Each was washed once with saline (80...

Embodiment 3

[0058] The reaction formula of embodiment 3 is as follows:

[0059]

[0060] This embodiment adopts the following steps:

[0061] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -70°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900mL), diluted with water (800mL), then extracted twice with methyl tert-butyl ether (600mL), and the organic phases were combined with 20% aqueous citric acid solution (1500mL) and saturated Each was washed once with saline (80...

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