A one-pot method for the chemical / enzymatic cascade preparation of s-delta-substituted caprolactams

Abstract

The application discloses a kind of S-delta-substituted caprolactam chemical / enzyme series preparation method, and the specific preparation method is: 1-substituted high allyl amine occurs dynamic kinetic resolution reaction with acrylic ester compound under the catalysis of alkaline protease (special treatment) and generates S-acryl (1-substituted high allyl) amine, then the product occurs intramolecular olefin metathesis under the catalysis of Grubbs reagent and finally generates S-delta-substituted caprolactam shown in formula (1), wherein, substituent R is phenyl, halogenated phenyl or C2-C12 alkyl.The application has mild reaction condition, is conducive to reducing the equipment requirement of preparation process, improves synthesis safety and economy;Secondly, the reaction course of the method is simple, and single configuration S-delta-substituted caprolactam can be obtained by one-pot reaction, with very high atom economy.

Description

Technical Field

[0001] This invention belongs to the field of chiral lactam synthesis technology, specifically relating to a one-pot chemical / enzymatic tandem preparation method for S-δ-substituted caprolactam. Background Technology

[0002] Nitrogen-containing heterocyclic compounds, such as cyclic halides, lactams, and cyclic amines, have long been important skeletons for drugs and natural alkaloids. Chiral lactams, especially those containing one or two adjacent stereocenters with nitrogen atoms on adjacent rings, are structural features of many biologically active natural products and drugs, such as the proteasome inhibitor lactocytin, the antitumor drug marizzomib, the antidepressant leupram, and the antiepileptic drug buvasidan.

[0003] For decades, researchers both domestically and internationally have been dedicated to developing green and efficient asymmetric methods for the synthesis of δ-substituted chiral lactams. Generally, there are two main routes for the asymmetric synthesis of δ-substituted lactams: chemical and biological methods. Chemical methods are mostly based on asymmetric Michael addition reactions to construct the chirality of δ-substituted lactams. In addition, asymmetric hydrogenation is also an important method for synthesizing chiral lactams. For example, in 2018, Professor Xumu Zhang's group at Southern University of Science and Technology reported a method for preparing chiral lactams by asymmetric hydrogenation of α,β-unsaturated lactams catalyzed by rhodium (Rh) complexes; and in 2020, Professor Qin Yin's group at Southern University of Science and Technology also developed a method for preparing chiral lactams by intramolecular cyclization following non-reductive amination of keto acids / esters catalyzed by ruthenium (Ru) complexes.

[0004] Overall, the chemical method for preparing δ-substituted chiral lactams still has many limitations, including complex reaction steps, expensive transition metal catalysts, and a narrow substrate range. Therefore, biocatalysis, with its green and environmentally friendly nature and high stereoselectivity, is gradually replacing chemical methods as an important alternative for the synthesis of chiral lactams. Summary of the Invention

[0005] To address the aforementioned problems in the existing technology, the present invention aims to provide a one-pot chemical / enzymatic tandem preparation method for S-δ-substituted caprolactam.

[0006] To achieve the above objectives, the following technical solution is proposed:

[0007] A one-pot chemical / enzymatic tandem method for preparing S-δ-substituted caprolactam includes the following steps: 1-substituted homoallylamine compounds of formula (2) and acrylate compounds of formula (3) undergo dynamic kinetic resolution reactions in a reaction solvent under the synergistic catalysis of enzyme preparation and palladium (Pd / C or Pd / BaSO4) to obtain an intermediate product of formula (4). The intermediate product undergoes intramolecular olefin metathesis under the catalysis of Grubbs' reagent to finally generate S-δ-substituted caprolactam of formula (1). The reaction formula is as follows:

[0008]

[0009] In the formula, substituent R is phenyl, halophenyl or C2-C12 alkyl, and substituent R1 is C1-C3 alkyl.

[0010] Furthermore, the acrylate compound represented by formula (3) is methyl acrylate, ethyl acrylate or isopropyl acrylate.

[0011] Furthermore, the molar ratio of the 1-substituted allylamine compound shown in formula (2) to the acrylate compound shown in formula (3) is 1.1-1.5:1.0.

[0012] Furthermore, the protease is an alkaline protease or subtilisin, and the treatment process is as follows: 0.1M phosphate buffer at pH=7 is heated, then n-octyl-β-D-glucopyranoside and methyl-β-cyclodextrin are added, stirred and dissolved, and then the alkaline protease or subtilisin liquid extract is added. The mixture is then rapidly cooled under liquid nitrogen and freeze-dried.

[0013] Furthermore, the reaction solvent is a substituted benzene solvent, preferably toluene or ethylbenzene.

[0014] Furthermore, the reaction time for the dynamic kinetic separation reaction is 24-72 hours, and the reaction temperature is 40-60℃.

[0015] Furthermore, the Grubbs reagent is either a first-generation Grubbs catalyst or a second-generation Grubbs catalyst.

[0016] Furthermore, the amount of Grubbs reagent used is 5%-25% of the mass of the acrylate compound shown in formula (3), preferably 10%.

[0017] Furthermore, the optical purity of the prepared S-δ-substituted caprolactam is greater than 90%.

[0018] By employing the above-described technology, the beneficial effects of the present invention compared to the prior art are as follows:

[0019] 1) This invention proposes a novel one-pot synthetic route for S-δ-substituted caprolactam by combining enzymatic dynamic kinetic resolution reaction with intramolecular olefin metathesis reaction. This method uses a bio-based enzyme catalyst, avoiding the use of conventional and complex precious metal catalysts, thus greatly reducing the preparation cost and avoiding the environmental pollution caused by precious metals. Secondly, compared with traditional asymmetric catalysis, this method has milder reaction conditions, which helps to reduce the equipment requirements of the preparation process and improves the safety and economy of synthesis. Finally, the reaction process of this method is simple, and a single configuration of S-δ-substituted caprolactam can be obtained through a one-pot reaction, which has very high atom economy.

[0020] 2) Based on the advantages of both enzymatic dynamic kinetic resolution and olefin metathesis reaction, this invention uses racemic 1-substituted homoallylamine as the starting material to synthesize S-δ-substituted caprolactam in a one-pot method. The enantiomeric excess value (ee value) of the S-δ-substituted caprolactam obtained by the reaction is over 90%, and the yield is over 80%. Detailed Implementation

[0021] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0022] Example 1

[0023]

[0024] 1) In a 100 mL flask, add 50 mL of phosphate buffer (0.1 M, pH = 7) and heat to 60 °C. Then add 60 mg of n-octyl-β-D-glucopyranoside and 60 mg of methyl-β-cyclodextrin, stir and dissolve. Take 25 mL of the solution and add 500 mg of alkaline protease liquid extract. The mixture is rapidly cooled under liquid nitrogen and freeze-dried at -54 °C for 20 hours to obtain 822 mg of enzyme powder.

[0025] 2) Dissolve 0.11 mmol of 1-phenylhomylated amine and 0.1 mmol of isopropyl acrylate in 5.0 mL of anhydrous toluene as a reaction solution. Then add Pd carbon (Pd / C) as a racemic reagent to the reaction solution (the amount added is 5% of the mass of 1-phenylhomylated amine). Add alkaline protease (treated in step 1) as an enzyme catalyst (the amount added is 20% of the mass of 1-phenylhomylated amine) to the dialysis bag, seal it, and add the reaction solution. The reaction solution is reacted at 40 °C for 24 h. Then add the second-generation Grubbs catalyst (the amount added is 10% of the mass of isopropyl acrylate) and continue the reaction for 48 h.

[0026] 3) After the reaction was completed, the reaction solution was filtered to remove the catalyst, and then the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography with petroleum ether: ethyl acetate = 3:1 (v / v) as the eluent to obtain the final product with a yield of 80% (based on 1-phenylhomylamine) and an ee value of 93%.

[0027]

[0028] S-δ-phenylcaprolactam (C 11 H 11 NO): 1 ¹H NMR (400MHz, CDCl₃) δ: 7.43–7.36 (m, 5H), 7.00–6.96 (m, 1H), 6.16–6.13 (m, 1H), 5.48–5.44 (m, 1H), 2.67–2.62 (m, 2H). (No peak was observed for the active hydrogen atom on the amino group.)

[0029] The ee value of the product was detected under the following conditions: a chiral column of Dassault AD-H, a mobile phase of n-hexane / isopropanol = 85 / 15, a flow rate of 0.1 mL / min, and a detection wavelength of 254 nm.

[0030] Example 2

[0031]

[0032] 1) In a 100 mL flask, add 50 mL of phosphate buffer (0.1 M, pH = 7) and heat to 60 °C. Then add 60 mg of n-octyl-β-D-glucopyranoside and 60 mg of methyl-β-cyclodextrin, stir and dissolve. Take 25 mL of the solution and add 500 mg of Bacillus subtilis protease liquid extract. The mixture is rapidly cooled under liquid nitrogen and freeze-dried at -54 °C for 20 hours to obtain 822 mg of enzyme powder.

[0033] 2) 1-Heptylhomallylamine (0.15 mmol) and ethyl acrylate (0.1 mmol) were dissolved in 5.0 mL of anhydrous ethylbenzene to prepare the reaction solution. Then, palladium / barium sulfate (Pd / BaSO4, added at 10% of the mass of 1-heptylhomallylamine) and the enzyme catalyst (subtilisin treated in step 1, added at 15% of the mass of 1-heptylhomallylamine) were placed in a dialysis bag, sealed, and added to the reaction solution. The reaction was carried out at 50 °C for 48 h. Then, a first-generation Grubbs catalyst (added at 15% of the mass of ethyl acrylate) was added, and the reaction continued for another 48 h.

[0034] 3) After the reaction is complete, the reaction solution is filtered to remove the catalyst, and then the crude product is obtained by vacuum distillation. The crude product is purified by column chromatography with petroleum ether: ethyl acetate = 3:1 (v / v) as the eluent to obtain the final product with a yield of 85% (based on 1-heptylhomallylamine) and an ee value of 90%.

[0035]

[0036] S-δ-hepta-caprolactam (C 12 H 21 NO): 1 ¹H NMR (400MHz, CDCl₃) δ: 6.93–6.83 (m, 1H), 6.02 (m, 1H), 4.49–4.36 (m, 1H), 2.33 (m, 2H), 1.86–1.58 (m, 2H), 1.57–1.19 (m, 10H), 0.88 (m, 3H). (No peak was observed for the active hydrogen atom on the amino group.)

[0037] The ee value of the product was detected under the following conditions: a chiral column of Dassault AD-H, a mobile phase of n-hexane / isopropanol = 90 / 10, a flow rate of 0.1 mL / min, and a detection wavelength of 254 nm.

[0038] Example 3

[0039]

[0040] 1) In a 100 mL flask, add 50 mL of phosphate buffer (0.1 M, pH = 7) and heat to 60 °C. Then add 60 mg of n-octyl-β-D-glucopyranoside and 60 mg of methyl-β-cyclodextrin, stir and dissolve. Take 25 mL of the solution and add 500 mg of alkaline protease liquid extract. The mixture is rapidly cooled under liquid nitrogen and freeze-dried at -54 °C for 20 hours to obtain 822 mg of enzyme powder.

[0041] 2) Dissolve 0.13 mmol of 1-(4-chlorophenyl)polyallylamine and 0.1 mmol of methyl acrylate in 5.0 mL of anhydrous o-xylene. Then, place palladium / barium sulfate (Pd / BaSO4, added at 15% of the mass of 1-(4-chlorophenyl)polyallylamine) and alkaline protease (treated in step 1, added at 10% of the mass of 1-(4-chlorophenyl)polyallylamine) into a dialysis bag, seal it, and add the reaction solution. The reaction solution is reacted at 60 °C for 72 h. Then, the second-generation Grubbs catalyst (added at 25% of the mass of methyl acrylate) is added, and the reaction is continued for 48 h.

[0042] 3) After the reaction was completed, the reaction solution was filtered to remove the catalyst, and then the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography with petroleum ether: ethyl acetate = 3:1 (v / v) as the eluent to obtain the final product with a yield of 88% (based on 1-(4-chlorophenyl)homallylamine) and an ee value of 95%.

[0043]

[0044] S-δ-(4-chlorophenyl)caprolactam (C 11 H 10 ClNO): 1 ¹H NMR (400MHz, CDCl₃) δ: 7.50–7.37 (m, 4H), 7.02–7.01 (m, 1H), 6.20–6.16 (m, 1H), 5.50–5.47 (m, 1H), 2.74–2.54 (m, 2H). (No peak was observed for the active hydrogen atom on the amino group.)

[0045] The ee value of the product was detected under the following conditions: a chiral column of Dassault AD-H, a mobile phase of n-hexane / isopropanol = 85 / 15, a flow rate of 0.1 mL / min, and a detection wavelength of 254 nm.

[0046] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A kind S - In the formula, the substituent R is phenyl, halophenyl or C2-C12 alkyl, and the substituent R1 is C1-C3 alkyl. -A one-pot chemical / enzymatic tandem preparation method for substituted caprolactam, characterized by... The method comprises the following steps: 1-substituted homoallyl amine compound shown in formula (2) and acrylic ester compound shown in formula (3) are subjected to dynamic kinetic resolution reaction in a reaction solvent under the synergistic catalysis of an enzyme preparation and Pd / C or Pd / BaSO4, to obtain intermediate product shown in formula (4), the intermediate product is subjected to intramolecular olefin metathesis reaction under the catalysis of Grubbs reagent, and finally 1-substituted homoallyl amine compound shown in formula (1) is generated S - The enzyme preparation and Pd / C or Pd / BaSO4 are placed in a dialysis bag to perform a dynamic kinetic resolution reaction; - substituted caprolactam, and the reaction formula is as follows: ， The enzyme preparation is alkaline protease or subtilisin, and the treatment process is as follows: heating 0.1M phosphate buffer solution with pH=7, then adding n-octyl-beta-D-glucopyranoside and methyl-beta-cyclodextrin, stirring, dissolving, and adding alkaline protease or subtilisin liquid extract, rapidly cooling under liquid nitrogen cooling and freeze-drying. The acrylic ester compound shown in formula (3) is methyl acrylate, ethyl acrylate or isopropyl acrylate. The molar ratio of the 1-substituted homoallyl amine compound shown in formula (2) to the acrylic ester compound shown in formula (3) is 1.1-1.5:1.

0.

2. A method according to claim 1 wherein the compound is S The reaction solvent is a substituted benzene solvent. - One-pot preparation of substituted caprolactam by chemical / enzymatic cascade characterized in that The reaction solvent is toluene or ethylbenzene. ​ 3. A composition according to claim 1 or 2 S The reaction time of the dynamic kinetic resolution reaction is 24-72 hours, and the reaction temperature is 40-60℃. - one-pot process for the substituted caprolactam chemical / enzymatic cascade, characterized in that The reaction time is 48 hours, and the reaction temperature is 50℃. ​ 4. A method according to claim 1 wherein the compound is ###0001### S - The Grubbs reagent is a first-generation Grubbs catalyst or a second-generation Grubbs catalyst. - One-pot preparation of substituted caprolactam by chemical / enzymatic cascade characterized in that The amount of the Grubbs reagent is 5%-25% of the mass of the acrylic ester compound shown in formula (3).

5. A method according to claim 4, wherein the compound is ###0002### S - The amount of the Grubbs reagent is 10% of the mass of the acrylic ester compound shown in formula (3). - One-pot preparation of substituted caprolactam by chemical / enzymatic cascade, characterized in that, ​ 6. A method according to claim 1 wherein the compound is ###0002### S - ​ - One-pot preparation of substituted caprolactam by chemical / enzymatic cascade characterized in that ​ 7. A method according to claim 6 wherein the compound is ###0002### S - ​ - One-pot preparation of substituted caprolactam by chemical / enzymatic cascade characterized in that ​ 8. A method according to claim 1 wherein the compound is ###0002### S - ​ - One-pot preparation of substituted caprolactam by chemical / enzymatic cascade characterized in that ​ 9. A process according to claim 1 or 8 wherein the process is a process according to claim 8. S - ​ - One-pot process for the substituted caprolactam chemical / enzymatic cascade, characterized in that ​ 10. A method according to claim 9 wherein the compound is ###00010### S - ​ - One-pot preparation of substituted caprolactam chemically / enzymatically in series characterized in that ​ 11. A method according to claim 1 wherein the compound is ###0002### S - ​ - One-pot preparation of substituted caprolactam by chemical / enzymatic cascade characterized in that The prepared S - ​ - the optical purity of the substituted caprolactam is greater than 90%.

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