Preparation method of trans-(N-4-Boc-aminocyclohexane) acetic acid

Abstract

The invention discloses a preparation method of trans-(N-4-Boc-aminocyclohexane) acetic acid, and belongs to the technical field of organic synthesis. The preparation method comprises the following specific steps: reducing carboxyl of trans-4-Boc-aminocyclohexanecarboxylic acid to obtain trans-(N-Boc-4-aminocyclohexyl) methanol, and then reacting the trans-(N-Boc-4-aminocyclohexyl) methanol with carbon tetrabromide and triphenylphosphine in a dichloromethane solution to obtain trans-(N-4-Boc-aminocyclohexane) ethyl bromide; then, carbon dioxide is introduced through Grignard reagent exchange, and trans-(N-4-Boc-aminocyclohexane) acetic acid is obtained. The raw materials used in the method are cheap and easy to obtain, the yield is high, large-scale toxic cyanide is avoided, steps are reduced, the method is suitable for large-scale production, p-toluenesulfonate with genotoxicity is avoided, and the method can be widely applied to the field of pharmacy.

Description

technical field

[0001] The invention relates to a preparation method of trans-(N-4-Boc-aminocyclohexane)acetic acid, which belongs to the technical field of organic synthesis. Background technique

[0002] trans-(N-4-Boc-aminocyclohexane)acetic acid, CAS: 189153-10-4. Its preparation method usually uses a metal catalyst to use 4-nitrophenylacetonitrile as a raw material for catalytic hydrogenation, thereby obtaining 4-aminocyclohexaneacetic acid with a dominant trans content, and then reacting with Boc anhydride to obtain cis and trans Mixed 4-Boc-aminocyclohexaneacetic acids. The pure trans-4-Boc-aminocyclohexaneacetic acid is obtained by recrystallization by utilizing the different solubility of cis- and trans-4-Boc-aminocyclohexaneacetic acids in organic solvents. The fatal shortcoming of this method is that in order to obtain 4-Boc-aminocyclohexaneacetic acid with trans content dominant, expensive metal catalysts are used and multiple recrystallizations are required to...

Examples

Embodiment 1

[0024]

[0025] Add trans-(N-Boc-4-aminocyclohexyl) formic acid (24.3g, 0.1mol) into the reaction flask, dissolve in 100mL tetrahydrofuran and 100mL methanol, lower the temperature to -5°C, add boron chloride in batches Sodium 4.9g (0.13mol), reacted at this temperature for 3 hours. Add saturated ammonium chloride aqueous solution to quench, add MTBE to extract, wash with saturated sodium bicarbonate aqueous solution once, and the organic phase is concentrated to stagnant liquid to obtain trans-(N-Boc-4-aminocyclohexyl)methanol 21.55g, HPLC96.8%, yield 94%.

Embodiment 2

[0027]

[0028] Add trans-(N-Boc-4-aminocyclohexyl)acetic acid (24.3g, 0.1mol) into the reaction flask, dissolve it in 300mL tetrahydrofuran, lower the temperature to 0°C, add dropwise 1.0M / L borane tetrahydrofuran solution 150mL (0.15mol), react at this temperature for 3 hours. Add water to quench, add MTBE, wash twice with saturated aqueous sodium bicarbonate, and concentrate the organic phase to stagnant liquid to obtain trans-(N-Boc-4-aminocyclohexyl)methanol 21.1g, HPLC96%, yield 92%.

Embodiment 3

[0030]

[0031] Dissolve 22.9g (0.1mol, 1.0eq) of trans-(N-Boc-4-aminocyclohexyl)methanol in 250mL of DCM, add 50g (0.15mol, 1.5eq) of carbon tetrabromide and triphenylphosphine 39.3g (0.15mol, 1.5eq). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was triturated with methyl tert-butyl ether to remove triphenylphosphine oxide. The obtained methyl tert-butyl ether solution was concentrated in vacuo to obtain 23.7 g of trans-(N-4-Boc-aminocyclohexane) ethyl bromide as a white solid, HPLC 99.1%, yield 81%.

technical field

[0001] The invention relates to a preparation method of trans-(N-4-Boc-aminocyclohexane)acetic acid, which belongs to the technical field of organic synthesis. Background technique

[0002] trans-(N-4-Boc-aminocyclohexane)acetic acid, CAS: 189153-10-4. Its preparation method usually uses a metal catalyst to use 4-nitrophenylacetonitrile as a raw material for catalytic hydrogenation, thereby obtaining 4-aminocyclohexaneacetic acid with a dominant trans content, and then reacting with Boc anhydride to obtain cis and trans Mixed 4-Boc-aminocyclohexaneacetic acids. The pure trans-4-Boc-aminocyclohexaneacetic acid is obtained by recrystallization by utilizing the different solubility of cis- and trans-4-Boc-aminocyclohexaneacetic acids in organic solvents. The fatal shortcoming of this method is that in order to obtain 4-Boc-aminocyclohexaneacetic acid with trans content dominant, expensive metal catalysts are used and multiple recrystallizations are required to...

Examples

Embodiment 1

[0024]

[0025] Add trans-(N-Boc-4-aminocyclohexyl) formic acid (24.3g, 0.1mol) into the reaction flask, dissolve in 100mL tetrahydrofuran and 100mL methanol, lower the temperature to -5°C, add boron chloride in batches Sodium 4.9g (0.13mol), reacted at this temperature for 3 hours. Add saturated ammonium chloride aqueous solution to quench, add MTBE to extract, wash with saturated sodium bicarbonate aqueous solution once, and the organic phase is concentrated to stagnant liquid to obtain trans-(N-Boc-4-aminocyclohexyl)methanol 21.55g, HPLC96.8%, yield 94%.

Embodiment 2

[0027]

[0028] Add trans-(N-Boc-4-aminocyclohexyl)acetic acid (24.3g, 0.1mol) into the reaction flask, dissolve it in 300mL tetrahydrofuran, lower the temperature to 0°C, add dropwise 1.0M / L borane tetrahydrofuran solution 150mL (0.15mol), react at this temperature for 3 hours. Add water to quench, add MTBE, wash twice with saturated aqueous sodium bicarbonate, and concentrate the organic phase to stagnant liquid to obtain trans-(N-Boc-4-aminocyclohexyl)methanol 21.1g, HPLC96%, yield 92%.

Embodiment 3

[0030]

[0031] Dissolve 22.9g (0.1mol, 1.0eq) of trans-(N-Boc-4-aminocyclohexyl)methanol in 250mL of DCM, add 50g (0.15mol, 1.5eq) of carbon tetrabromide and triphenylphosphine 39.3g (0.15mol, 1.5eq). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was triturated with methyl tert-butyl ether to remove triphenylphosphine oxide. The obtained methyl tert-butyl ether solution was concentrated in vacuo to obtain 23.7 g of trans-(N-4-Boc-aminocyclohexane) ethyl bromide as a white solid, HPLC 99.1%, yield 81%.

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