Method for preparing (S)-1-(1-naphthyl)ethylamine by enzymatic resolution

Abstract

The invention relates to a method for preparing (S)-1-(1-naphthyl)ethylamine by an enzyme method. According to the method, Candida antarctica lipase B is adsorbed by macroporous resin, and cross-linking is carried out by using glutaraldehyde so as to obtain immobilized Candida antarctica lipase B. The immobilized lipase serves as a catalyst, toluene serves as a solvent, ethyl acetate serves as an acyl donor, (S)-1-(1-naphthyl)ethylketoxime is selectively esterified, (R)-1-(1-naphthyl)ethylamine is not esterified, and a racemation reaction is carried out in the presence of a racemation catalyst and hydrogen gas. According to the method, the immobilized Candida antarctica lipase B can be used for completely converting 1-(1-naphthyl)ethylketoxime into (S)-1-(1-naphthyl)ethylamine ethyl ester at a relatively high temperature, and the reaction has the characteristics of short reaction time, high product optical purity, and the like.

Description

technical field

[0001] The invention relates to a biological resolution method, in particular to an immobilized enzyme resolution preparation method of (S)-1-(1-naphthyl)ethylamine. Background technique

[0002] (S)-1-(1-naphthyl) ethylamine is a kind of important chiral medicine intermediate, the method for preparing (S)-1-(1-naphthyl) ethylamine mainly comprises following several classes at present (with raw material classification):

[0003] (1) Asymmetric synthesis of 1-(1-naphthyl)ethanone: as shown in the following formula, 1-(1-naphthyl)ethanone is first catalytically hydrogenated to (R)-α- Naphthalene ethanol, and then reduced to obtain (S)-α-naphthylethylamine (such as international patent document WO2004110976A2). The chiral rhodium catalyst used in this method has a complex structure, is difficult to prepare, and has high cost, so it is difficult to industrialize large-scale production.

[0004]

[0005] (2) 1-(1-naphthyl)ethylamine chemical resolution metho...

Examples

Embodiment 1

[0025] A method for enzymatic resolution and preparation of (S)-1-(1-naphthyl)ethylamine has the following steps:

[0026] ① First, prepare 50 mL of Candida antarctica lipase B (hereinafter referred to as CLAB) enzyme solution with a concentration of 1.0 mg / mL, add 150 mg of macroporous resin D3520 to the enzyme solution, stir at 25°C for 3 hours, and remove the resin from the enzyme solution Second, add CLAB-adsorbed resin to 50 mL of 0.5% glutaraldehyde solution, stir and cross-link at 25°C for 2 hours, finally, separate the resin from the glutaraldehyde solution, and wash with pH=7.0 buffer, Immobilized CLAB was obtained after vacuum drying.

[0027] ②In 5mL of toluene solvent, add 5mg of immobilized CLAB prepared in step ①, 2775mg of 1-(1-naphthyl)acetoxime racemate (1.5mmol, hereinafter referred to as racemate) and 264mg of Ethyl acetate (3.0 mmol), 1 g of CuY, and a hydrogen pressure of 0.1 MPa were reacted at a constant temperature of 80° C. for 18 h.

[0028] ③ After...

example 2～ example 5

[0032] The method of each example is basically the same as Example 1, and the differences are shown in Table 1.

[0033] Table 1

[0034]

[0035] As can be seen from Table 1, under other conditions being the same, the immobilized CLAB using adsorbent D151 (Example 3) is the best enzyme catalyst.

Embodiment 6～ Embodiment 17

[0037] Each example is basically the same as Example 3 (that is, the immobilized CLAB of Example 3 is used), and the differences are shown in Table 2.

[0038] Table 2

[0039]

[0040] As can be seen from Table 2, under the situation of adopting the same immobilized enzyme, embodiment 9 (under the temperature of 80 ℃, CuY is racemization catalyst and hydrogen pressure is 0.3MPa) and embodiment 10 resolution effect are the best . But the hydrogen pressure of embodiment 10 is greater than embodiment 9, and following control experiment adopts embodiment 9.

technical field

[0001] The invention relates to a biological resolution method, in particular to an immobilized enzyme resolution preparation method of (S)-1-(1-naphthyl)ethylamine. Background technique

[0002] (S)-1-(1-naphthyl) ethylamine is a kind of important chiral medicine intermediate, the method for preparing (S)-1-(1-naphthyl) ethylamine mainly comprises following several classes at present (with raw material classification):

[0003] (1) Asymmetric synthesis of 1-(1-naphthyl)ethanone: as shown in the following formula, 1-(1-naphthyl)ethanone is first catalytically hydrogenated to (R)-α- Naphthalene ethanol, and then reduced to obtain (S)-α-naphthylethylamine (such as international patent document WO2004110976A2). The chiral rhodium catalyst used in this method has a complex structure, is difficult to prepare, and has high cost, so it is difficult to industrialize large-scale production.

[0004]

[0005] (2) 1-(1-naphthyl)ethylamine chemical resolution metho...

Examples

Embodiment 1

[0025] A method for enzymatic resolution and preparation of (S)-1-(1-naphthyl)ethylamine has the following steps:

[0026] ① First, prepare 50 mL of Candida antarctica lipase B (hereinafter referred to as CLAB) enzyme solution with a concentration of 1.0 mg / mL, add 150 mg of macroporous resin D3520 to the enzyme solution, stir at 25°C for 3 hours, and remove the resin from the enzyme solution Second, add CLAB-adsorbed resin to 50 mL of 0.5% glutaraldehyde solution, stir and cross-link at 25°C for 2 hours, finally, separate the resin from the glutaraldehyde solution, and wash with pH=7.0 buffer, Immobilized CLAB was obtained after vacuum drying.

[0027] ②In 5mL of toluene solvent, add 5mg of immobilized CLAB prepared in step ①, 2775mg of 1-(1-naphthyl)acetoxime racemate (1.5mmol, hereinafter referred to as racemate) and 264mg of Ethyl acetate (3.0 mmol), 1 g of CuY, and a hydrogen pressure of 0.1 MPa were reacted at a constant temperature of 80° C. for 18 h.

[0028] ③ After...

example 2～ example 5

[0032] The method of each example is basically the same as Example 1, and the differences are shown in Table 1.

[0033] Table 1

[0034]

[0035] As can be seen from Table 1, under other conditions being the same, the immobilized CLAB using adsorbent D151 (Example 3) is the best enzyme catalyst.

Embodiment 6～ Embodiment 17

[0037] Each example is basically the same as Example 3 (that is, the immobilized CLAB of Example 3 is used), and the differences are shown in Table 2.

[0038] Table 2

[0039]

[0040] As can be seen from Table 2, under the situation of adopting the same immobilized enzyme, embodiment 9 (under the temperature of 80 ℃, CuY is racemization catalyst and hydrogen pressure is 0.3MPa) and embodiment 10 resolution effect are the best . But the hydrogen pressure of embodiment 10 is greater than embodiment 9, and following control experiment adopts embodiment 9.

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