A process for the preparation of an amino acid-based lactam amide
By using the catalytic reaction of α-amino acids and α-hydroxy esters and subsequent purification steps, the problems of high raw material risk and difficult product purification in the synthesis of amino acid-based lactone amides have been solved, realizing a simple and efficient preparation method that can be used for biodegradable polyester amide materials.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-08
- Publication Date
- 2026-03-31
AI Technical Summary
Existing methods for preparing amino acid-based lactone amides involve high-risk raw materials, cumbersome processes, and difficult product purification, making it difficult to achieve efficient and simple synthesis.
α-amino acids and α-hydroxy esters are reacted under the action of a first catalyst to generate N-(hydroxyacyl)-amino acid esters, which are then further converted into amino acid lactone amides under the action of a second catalyst. By selecting appropriate catalysts and solvents and controlling the reaction conditions, the catalysts and solvents are removed and the product is purified by recrystallization.
This method eliminates the need for highly toxic raw materials, simplifies the synthesis process, reduces the difficulty of product purification, and the prepared amino acid-based lactone amide can be used in biodegradable polyester amide materials, thus solving the problem of plastic white pollution.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention relates to the field of compound synthesis technology, and in particular to a method for preparing an amino acid-based lactone amide. Background Technology
[0002] Polyesteramides contain both ester and amide bonds in their main chain, giving them both the biocompatibility of polyesters and the excellent thermal and mechanical properties of polyamides, making them widely applicable. Current methods for preparing polyesteramides mainly include condensation polymerization, multicomponent polymerization, and ring-opening polymerization. Compared to the first two methods, the ring-opening polymerization of lactone amides offers advantages such as fast reaction speed, mild conditions, controllable molecular weight and distribution, and good stereoregularity, making it the primary method for preparing polyesteramides.
[0003] Regarding the preparation of lactone amides, Chinese patent application CN102408389A and literature Macromolecules, 2020, 53, 10830 report methods for synthesizing lactone amides from amino acids and acyl halides. This method requires the use of highly hazardous acyl halides as raw materials and the addition of an equivalent amount of triethylamine as an acid-binding agent during the reaction to prepare an N-haloacyl-amino acid intermediate, which is then subjected to a cyclization reaction to obtain the lactone amide. However, the method for synthesizing lactone amides from amino acids and acyl halides uses highly hazardous acyl halides and requires the addition of an equivalent amount of triethylamine as an acid-binding agent during the reaction, generating a large amount of waste and significantly increasing the difficulty of operation and purification of the target product.
[0004] The literature Macromolecules, 2019, 52, 4260 reports a method for synthesizing lactone amides by reacting the cyano derivatives of amino acids with aldehydes via a Passerini-type reaction to obtain N-(α-hydroxyacyl)-α-amino acids or amino acid ester intermediates, followed by reflux in toluene. However, this method requires the amino acid raw materials to be pre-reacted to obtain amino acid cyano derivatives, and the lactone amides need to be synthesized at extremely low concentrations, which increases the number of reaction steps, raw material costs, and post-processing workload. Summary of the Invention
[0005] In view of this, the technical problem to be solved by the present invention is to provide a simple and efficient method for preparing amino acid-based lactone amides, which can solve the technical problems of high raw material risk, complicated process and difficult product purification in the existing lactone amide synthesis process.
[0006] This invention provides a method for preparing an amino acid-based lactone amide, comprising the following steps:
[0007] A) Under the action of the first catalyst, α-amino acids and α-hydroxy esters are reacted in the first solvent to obtain N-(hydroxyacyl)-amino acid esters;
[0008] B) Under the action of a second catalyst, N-(hydroxyacyl)-amino acid esters are reacted in a second solvent to obtain amino acid-based lactone amides;
[0009] The amino acid-based lactone amide has the structure shown in Formula I;
[0010]
[0011] In Formula I, R1 and R2 are independently selected from one of hydrogen, a straight-chain or branched aliphatic hydrocarbon group of C1 to C4, a substituted or unsubstituted aryl group of C6 to C30, an amino group with a protecting group, a carboxyl group with a protecting group, a hydroxyl group with a protecting group, and a mercapto group with a protecting group; the protecting group is one of alkoxycarbonyl, acyl, and alkyl.
[0012] Preferably, R1 and R2 are independently selected from one of hydrogen, methyl, isopropyl, phenyl, benzyl, methylthio, and -CH2CH2SCH3.
[0013] Preferably, the α-amino acid has the structure shown in Formula II;
[0014]
[0015] The α-hydroxy ester has the structure shown in Formula III;
[0016]
[0017] In Formula III, R4 is selected from methyl, ethyl, isopropyl, or butyl.
[0018] Preferably, in step A), the first catalyst is an organotin catalyst, preferably one or more of dibutyltin dilaurate, dibutyltin oxide, stannous octoate, di(dodecyl sulfide)dibutyltin and dibutyltin diacetate;
[0019] The molar ratio of the first catalyst, α-amino acid, and α-hydroxy ester is 1–20:100:100;
[0020] The first solvent includes m-aryl alcohols with 1-n carbon atoms, where n is selected from integers from 1 to 30 and m is selected from integers from 1 to 10.
[0021] Preferably, in step A), the reaction temperature is 40–100°C and the time is 3–48 h.
[0022] Preferably, in step A), after the reaction, the reaction further includes: removing the first catalyst and the first solvent;
[0023] After removing the first catalyst and the first solvent, the process further includes: vacuum distillation;
[0024] The vacuum distillation temperature is 45–55°C, and the vacuum degree is 95–105 Pa.
[0025] Preferably, in step B), the second catalyst is at least one of concentrated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, aluminum trichloride, titanium dioxide, and sulfonic acid type ion exchange resin.
[0026] The molar ratio of the second catalyst to the N-(hydroxyacyl)-amino acid ester is 1 to 35:100.
[0027] Preferably, in step B), the second solvent includes at least one of ethyl acetate, toluene, xylene, dioxane, dioxane, dichloromethane, and chloroform.
[0028] Preferably, in step B), the reaction temperature is 40–150°C and the time is 3–60 h.
[0029] Preferably, in step B), after the reaction, the process further includes: removing the second catalyst and the second solvent;
[0030] After removing the second catalyst and the second solvent, the process also includes: recrystallization;
[0031] The solvent for recrystallization is at least one selected from ethyl acetate, diethyl ether, acetonitrile, n-hexane, petroleum ether, and tetrahydrofuran.
[0032] This invention provides a method for preparing an amino acid-based lactone amide, comprising the following steps:
[0033] A) Under the action of the first catalyst, α-amino acids and α-hydroxy esters are reacted in the first solvent to obtain N-(hydroxyacyl)-amino acid esters;
[0034] B) Under the action of a second catalyst, N-(hydroxyacyl)-amino acid esters are reacted in a second solvent to obtain amino acid-based lactone amides;
[0035] The amino acid-based lactone amide has the structure shown in Formula I;
[0036]
[0037] In Formula I, R1 and R2 are independently selected from one of hydrogen, a straight-chain or branched aliphatic hydrocarbon group of C1 to C4, a substituted or unsubstituted aryl group of C6 to C30, an amino group with a protecting group, a carboxyl group with a protecting group, a hydroxyl group with a protecting group, and a mercapto group with a protecting group; the protecting group is one of alkoxycarbonyl, acyl, and alkyl.
[0038] The method for preparing amino acid-based lactone amides provided by this invention eliminates the need for highly toxic raw materials, thus solving the technical challenges of high-risk raw materials, cumbersome processes, and difficult product purification in existing lactone amide synthesis methods. Furthermore, the amino acid-based lactone amide prepared by this invention undergoes ring-opening polymerization to produce a biodegradable polyester amide material, which can address the problem of white pollution from plastics. Attached Figure Description
[0039] Figure 1 This is a flowchart illustrating the preparation process of the amino acid-based lactone amide in this invention.
[0040] Figure 2 The above is the 1H NMR spectrum of the amino acid-based lactone amide of Example 1 of this invention;
[0041] Figure 3 The image shows the 1H NMR spectrum of the amino acid-based lactone amide from Example 6 of this invention. Detailed Implementation
[0042] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.
[0043] This invention provides a method for preparing an amino acid-based lactone amide, comprising the following steps:
[0044] A) Under the action of the first catalyst, α-amino acids and α-hydroxy esters are reacted in the first solvent to obtain N-(hydroxyacyl)-amino acid esters;
[0045] B) Under the action of a second catalyst, N-(hydroxyacyl)-amino acid esters are reacted in a second solvent to obtain amino acid-based lactone amides;
[0046] The amino acid-based lactone amide has the structure shown in Formula I;
[0047]
[0048] In Formula I, R1 and R2 are independently selected from one of hydrogen, a straight-chain or branched aliphatic hydrocarbon group of C1 to C4, a substituted or unsubstituted aryl group of C6 to C30, an amino group with a protecting group, a carboxyl group with a protecting group, a hydroxyl group with a protecting group, and a mercapto group with a protecting group; the protecting group is one of alkoxycarbonyl, acyl, and alkyl.
[0049] In some embodiments of the present invention, R1 and R2 are independently selected from one of hydrogen, methyl, isopropyl, phenyl, benzyl, methylthio, and -CH2CH2SCH3.
[0050] In step A):
[0051] In the presence of a first catalyst, α-amino acids and α-hydroxy esters are reacted in a first solvent to obtain N-(hydroxyacyl)-amino acid esters.
[0052] Specifically, α-amino acids, α-hydroxy acid esters, a first solvent, and a first catalyst are mixed and reacted to obtain N-(hydroxyacyl)-amino acid esters.
[0053] In some embodiments of the present invention, the α-amino acid has the structure shown in Formula II;
[0054]
[0055] In Formula II, the selection of R1 is the same as above, and will not be repeated here. Specifically, the α-amino acid is alanine.
[0056] In some embodiments of the present invention, the α-hydroxy ester has the structure shown in Formula III;
[0057]
[0058] In Equation III, the selection of R2 is the same as above, and will not be repeated here;
[0059] R4 is selected from methyl, ethyl, isopropyl, or butyl. Specifically, the α-hydroxy ester is methyl glycolate.
[0060] In some embodiments of the present invention, the first catalyst is an organotin catalyst, preferably one or more of dibutyltin dilaurate, dibutyltin oxide, stannous octanoate, di(dodecyl sulfide)dibutyltin, and dibutyltin diacetate. The molar ratio of the first catalyst, α-amino acid, and α-hydroxy ester is 1 to 20:100:100, for example, 2:100:100, 12:100:100, 8:100:100, or 20:100:100.
[0061] In some embodiments of the present invention, the first solvent comprises m-type alcohols with 1-n carbon atoms, wherein n is selected from integers from 1 to 30 and m is selected from integers from 1 to 10; the concentration of α-amino acids in the mixed solution is 0.1-1 mol / L, for example 0.5 mol / L or 0.1 mol / L.
[0062] In some embodiments of the present invention, the first solvent has the structure shown in Formula IV;
[0063] R3OH, Formula IV;
[0064] In Formula IV, R3 is selected from methyl, ethyl, butyl, or tert-butyl. Specifically, the first solvent is n-butanol.
[0065] In some embodiments of the present invention, the reaction temperature is 40–100°C, for example 50°C; and the time is 3–48 h, for example 3 h. The reaction is a stirred reaction.
[0066] In some embodiments of the present invention, the reaction is followed by: removing the first catalyst and the first solvent. Specifically, this includes: removing the first catalyst by filtration and then drying the filtrate by rotary evaporation.
[0067] In some embodiments of the present invention, after removing the first catalyst and the first solvent, the process further includes vacuum distillation. The vacuum distillation is performed at a temperature of 45–55°C, for example, 50°C, and under a vacuum of 95–105 Pa, for example, 100 Pa. After evaporating the filtrate, a mixture of N-(hydroxyacyl)-alanine n-butyl ester and unreacted methyl glycolate is obtained. The unreacted methyl glycolate is removed by vacuum distillation.
[0068] In step B):
[0069] In the presence of a second catalyst, N-(hydroxyacyl)-amino acid esters are reacted in a second solvent to yield amino acid-based lactone amides.
[0070] In some embodiments of the present invention, the second catalyst is at least one selected from concentrated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, aluminum trichloride, titanium dioxide, and a sulfonic acid-type ion exchange resin; wherein the sulfonic acid-type ion exchange resin is Amberlyst 15 resin. The molar ratio of the second catalyst to N-(hydroxyacyl)-amino acid ester is 1–35:100; wherein, when the second catalyst is a sulfonic acid-type ion exchange resin, the sulfonic acid-type ion exchange resin is loaded with H... - The molar ratio of the content to N-(hydroxyacyl)-amino acid ester is 1 to 35:100; for example, 20:100, 25:100, 24:100, 30:100, 31.25:100, 18:100, 22:100, 22.5:100, 27.5:100.
[0071] In some embodiments of the present invention, the second solvent includes at least one selected from ethyl acetate, toluene, xylene, dioxane, dioxane, dichloromethane, and chloroform. The ratio of the N-(hydroxyacyl)-amino acid ester to the second solvent is 0.01–0.5 mol:1 L, for example, 0.1 mol:1 L or 0.08 mol:1 L.
[0072] In some embodiments of the present invention, the reaction temperature is 40–150°C, for example 60°C; and the time is 3–60 h, for example 3 h. The reaction is a reflux reaction.
[0073] In some embodiments of the present invention, the reaction is followed by: removing the second catalyst and the second solvent. Specifically, this includes: water extraction, collecting the organic phase, and rotary evaporation of the second solvent. The extraction may be performed three times.
[0074] In some embodiments of the present invention, after removing the second catalyst and the second solvent, the process further includes recrystallization. The solvent for recrystallization is at least one selected from ethyl acetate, diethyl ether, acetonitrile, n-hexane, petroleum ether, and tetrahydrofuran.
[0075] Figure 1 This is a flowchart illustrating the preparation process of the amino acid-based lactone amide in this invention.
[0076] The present invention does not impose any special restrictions on the source of the raw materials used above, and they can be commercially available.
[0077] To further illustrate the present invention, the following detailed description of a method for preparing an amino acid-based lactone amide provided by the present invention is provided in conjunction with embodiments, but it should not be construed as limiting the scope of protection of the present invention.
[0078] Example 1
[0079] Weigh 44.5 g (0.5 mol) alanine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L of n-butanol to dissolve them, then add 3.0 g (0.01 mol) dibutyltin oxide, heat and stir at 50 °C for 3 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-alanine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-alanine n-butyl ester (yield 56%).
[0080] 16.1 g (0.1 mol) of the obtained N-(hydroxyacyl)-alanine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of chloroform, and then 3.8 g (0.02 mol) of p-toluenesulfonic acid was added. The mixture was refluxed at 60 °C for 3 h, extracted three times with water, and the organic phase was collected. The chloroform was evaporated to dryness to obtain the crude amino acid-based lactone amide. The crude product was purified by recrystallization in ethyl acetate to obtain the amino acid-based lactone amide (yield 60%, purity 98.5%).
[0081] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 2 As shown, Figure 2 This is the 1H NMR spectrum of the amino acid-based lactone amide from Example 1 of the present invention. Wherein,1 ¹H NMR (DMSO, 300 MHz) δppm 8.53 (s, 1H, NH), 4.92-4.54 (q, 2H, OCH₂CO), 4.30 (q, 1H, NHCHCH₃CO), 1.33 (d, 3H, CHCH₃). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is a methyl group and R2 is hydrogen.
[0082] Example 2
[0083] Weigh 44.5 g (0.5 mol) alanine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L of n-butanol to dissolve them, then add 25 g (0.06 mol) stannous octoate, heat and stir at 80 °C for 8 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-alanine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-alanine n-butyl ester (yield 65%).
[0084] 16.1 g (0.1 mol) of the obtained N-(hydroxyacyl)-alanine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of dioxane, and then 3.8 g (0.02 mol) of p-toluenesulfonic acid was added. The mixture was refluxed at 100 °C for 5 h, extracted three times with water, and the organic phase was collected. The dioxane was evaporated to dryness to obtain a crude cyclic lactone amide product. The product was purified by recrystallization in ethyl acetate to obtain an amino acid-based lactone amide (yield approximately 65%, purity 98.3%).
[0085] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 2 As shown, where, 1 ¹H NMR (DMSO, 300 MHz) δppm 8.53 (s, 1H, NH), 4.92-4.54 (q, 2H, OCH₂CO), 4.30 (q, 1H, NHCHCH₃CO), 1.33 (d, 3H, CHCH₃). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is a methyl group and R2 is hydrogen.
[0086] Example 3
[0087] Weigh 44.5 g (0.5 mol) alanine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L of n-butanol to dissolve them, then add 25 g (0.04 mol) dibutyltin dilaurate, heat and stir at 80 °C for 9 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-alanine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-alanine methyl ester (yield 73%).
[0088] 16.1 g (0.1 mol) of the obtained N-(hydroxyacyl)-alanine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of chloroform, and then 3.8 g (0.018 mol) was added to the resin-loaded H... - The product was reacted with Amberlyst 15 resin (by content) at 80°C for 60 h under reflux. The resin was filtered, and chloroform was evaporated to obtain a crude cyclic lactone amide. The product was then purified by recrystallization in ethyl acetate to obtain an amino acid-based lactone amide (yield 68%, purity 98.4%).
[0089] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 2 As shown, where, 1 ¹H NMR (DMSO, 300 MHz) δppm 8.53 (s, 1H, NH), 4.92-4.54 (q, 2H, OCH₂CO), 4.30 (q, 1H, NHCHCH₃CO), 1.33 (d, 3H, CHCH₃). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is a methyl group and R2 is hydrogen.
[0090] Example 4
[0091] Weigh 44.5 g (0.5 mol) alanine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L of n-butanol to dissolve them, then add 25 g (0.1 mol) dibutyltin oxide, heat and stir at 80 °C for 48 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-alanine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-alanine methyl ester (yield 80%).
[0092] 16.1 g (0.1 mol) of the obtained N-(hydroxyacyl)-alanine n-butyl ester was placed in a 2 L round-bottom flask, 1 L of dioxane was added to dissolve it, and then 4.5 g (0.024 mol) of p-toluenesulfonic acid was added. The mixture was refluxed at 100 °C for 48 h. After filtering through the resin, the dioxane was evaporated to dryness to obtain a crude cyclic amino acid-based lactone amide. The crude product was purified by recrystallization in ethyl acetate to obtain an amino acid-based lactone amide (yield 76%, purity 98.2%).
[0093] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 2 As shown, where, 1 ¹H NMR (DMSO, 300 MHz) δppm 8.53 (s, 1H, NH), 4.92-4.54 (q, 2H, OCH₂CO), 4.30 (q, 1H, NHCHCH₃CO), 1.33 (d, 3H, CHCH₃). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is a methyl group and R2 is hydrogen.
[0094] Example 5
[0095] Weigh 44.5 g (0.5 mol) alanine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.1 mol) dibutyltin oxide, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-alanine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-alanine n-butyl ester (yield 85%).
[0096] 16.1 g (0.1 mol) of the obtained N-(hydroxyacyl)-alanine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of dioxane, and then 4.5 g (0.022 mol) of H2O was added to the resin-loaded H2O. - (Based on content) Amberlyst 15 resin, refluxed at 100℃ for 48h, filtered through resin, and dioxane was evaporated to obtain crude amino acid-based lactone amide. It was then purified by recrystallization in ethyl acetate to obtain amino acid-based lactone amide (yield 82%, purity 98.6%).
[0097] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 2 As shown, where, 1¹H NMR (DMSO, 300 MHz) δppm 8.53 (s, 1H, NH), 4.92-4.54 (q, 2H, OCH₂CO), 4.30 (q, 1H, NHCHCH₃CO), 1.33 (d, 3H, CHCH₃). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is a methyl group and R2 is hydrogen.
[0098] Example 6
[0099] Weigh 58.5 g (0.5 mol) valine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.1 mol) dibutyltin oxide, heat and stir at 70 °C for 12 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-valine n-butyl ester (yield 63%).
[0100] 16.1 g (0.08 mol) of the obtained N-(hydroxyacyl)-valine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of ethyl acetate, and then 3.8 g (0.02 mol) of p-toluenesulfonic acid was added. The mixture was refluxed at 110 °C for 24 h. The mixture was extracted three times with water, and the organic phase was collected. The chloroform was evaporated to dryness to obtain the crude amino acid-based lactone amide. The crude product was purified by recrystallization in a mixed solution of ethyl acetate and n-hexane to obtain the amino acid-based lactone amide (yield 60%, purity 98.4%).
[0101] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 3 As shown, Figure 3 The image shows the 1H NMR spectrum of the amino acid-based lactone amide from Example 6 of this invention. 1 ¹H NMR (DMSO, 300 MHz) δppm 8.62 (s, 1H, NH), 4.74 (q, 2H, OCH₂CO), 3.97 (q, 1H, NHCHCO), 2.18 (m, 1H, CH(CH₃)₂), 0.96 (q, 6H, CH(CH₃)₂). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is isopropyl and R2 is hydrogen.
[0102] Example 7
[0103] Weigh 58.5 g (0.5 mol) valine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.06 mol) stannous octoate, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-valine n-butyl ester (yield 72%).
[0104] 16.1 g (0.08 mol) of the obtained N-(hydroxyacyl)-valine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of toluene, and then 3.8 g (0.02 mol) of p-toluenesulfonic acid was added. The mixture was refluxed at 80 °C for 24 h. The mixture was extracted three times with water, and the organic phase was collected. The dioxane was evaporated to dryness to obtain a crude cyclic amino acid lactone amide. The crude product was purified by recrystallization in a mixed solution of ethyl acetate and n-hexane to obtain an amino acid lactone amide (yield 74%, purity 98.5%).
[0105] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 3 As shown, where, 1 ¹H NMR (DMSO, 300 MHz) δppm 8.62 (s, 1H, NH), 4.74 (q, 2H, OCH₂CO), 3.97 (q, 1H, NHCHCO), 2.18 (m, 1H, CH(CH₃)₂), 0.96 (q, 6H, CH(CH₃)₂). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is isopropyl and R2 is hydrogen.
[0106] Example 8
[0107] Weigh 58.5 g (0.5 mol) valine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.1 mol) dibutyltin oxide, heat and stir at 70 °C for 12 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-valine n-butyl ester (yield 78%).
[0108] 16.1 g (0.08 mol) of the obtained N-(hydroxyacyl)-valine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of chloroform, and then 3.8 g (0.018 mol) was added to the resin-loaded H... -(Based on content) Amberlyst 15 resin, refluxed at 80℃ for 48h, filtered through resin, and dioxane was evaporated to obtain crude cyclic lactone amide product, which was then purified by recrystallization in diethyl ether (yield 80%, purity 98.6%).
[0109] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 3 As shown, where, 1 ¹H NMR (DMSO, 300 MHz) δppm 8.62 (s, 1H, NH), 4.74 (q, 2H, OCH₂CO), 3.97 (q, 1H, NHCHCO), 2.18 (m, 1H, CH(CH₃)₂), 0.96 (q, 6H, CH(CH₃)₂). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is isopropyl and R2 is hydrogen.
[0110] Example 9
[0111] Weigh 58.5 g (0.5 mol) valine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.04 mol) dibutyltin dilaurate, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-valine n-butyl ester (yield 82%).
[0112] 16.1 g (0.08 mol) of the obtained N-(hydroxyacyl)-valine n-butyl ester was placed in a 2 L round-bottom flask, 1 L of dioxane was added to dissolve it, and then 4.5 g (0.024 mol) of p-toluenesulfonic acid was added. The mixture was refluxed at 130 °C for 48 h. After filtering through the resin, the dioxane was evaporated to dryness to obtain a crude cyclic lactone amide product. The product was then purified by recrystallization in diethyl ether to obtain an amino acid-based lactone amide (yield 85%, purity 98.7%).
[0113] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 3 As shown, where, 1 ¹H NMR (DMSO, 300 MHz) δppm 8.62 (s, 1H, NH), 4.74 (q, 2H, OCH₂CO), 3.97 (q, 1H, NHCHCO), 2.18 (m, 1H, CH(CH₃)₂), 0.96 (q, 6H, CH(CH₃)₂). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is isopropyl and R2 is hydrogen.
[0114] Example 10
[0115] Weigh 58.5 g (0.5 mol) valine and 45.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.1 mol) dibutyltin oxide, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-valine n-butyl ester (yield 90%).
[0116] 16.1 g (0.08 mol) of the obtained N-(hydroxyacyl)-valine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of dioxane, and then 4.5 g (0.022 mol) of H2O was added to the resin-loaded H2O. - (Based on content) Amberlyst 15 resin, refluxed at 130℃ for 48h, filtered through resin, and dioxane was evaporated to obtain crude cyclic lactone amide product. It was then purified by recrystallization in diethyl ether to obtain amino acid-based lactone amide (yield 85%, purity 98.8%).
[0117] The 1H NMR spectrum of the amino acid-based lactone amide is as follows: Figure 3 As shown, where, 1 ¹H NMR (DMSO, 300 MHz) δppm 8.62 (s, 1H, NH), 4.74 (q, 2H, OCH₂CO), 3.97 (q, 1H, NHCHCO), 2.18 (m, 1H, CH(CH₃)₂), 0.96 (q, 6H, CH(CH₃)₂). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is isopropyl and R2 is hydrogen.
[0118] Example 11
[0119] Weigh 74.6 g (0.5 mol) of methionine and 45.0 g (0.5 mol) of methyl glycolate into a 2 L round-bottom flask, add 1 L of n-butanol to dissolve them, then add 25 g (0.1 mol) of dibutyltin oxide, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacyl)-methionine n-butyl ester (yield 85%).
[0120] 17.7 g (0.08 mol) of the obtained N-(hydroxyacyl)-methionine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of dioxane, and then 4.5 g (0.022 mol) of H2O was added to the resin-loaded H2O.- (Based on content) Amberlyst 15 resin, refluxed at 130℃ for 48h, filtered through resin, and dioxane was evaporated to obtain crude cyclic lactone amide product. It was then purified by recrystallization in diethyl ether to obtain amino acid-based lactone amide (yield 80%, purity 98.3%).
[0121] The 1H NMR spectrum of the amino acid-based lactone amide 1 ¹H NMR (DMSO, 300MHz) δppm 8.14 (s, 1H, NH), 4.72 (q, 2H, OCH₂CO), 4.34 (q, 1H, NHCHCO), 2.65-2.61 (m, 2H, CHCH₂CH₂), 2.25 (m, 2H, CH₂CH₂SCH₃), 2.04 (s, 3H, CH₂SCH₃). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is -CH₂CH₂SCH₃ and R2 is hydrogen.
[0122] Example 12
[0123] Weigh 44.5 g (0.5 mol) alanine and 52.0 g (0.5 mol) methyl lactate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.1 mol) dibutyltin oxide, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-alanine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacetyl)-alanine n-butyl ester (yield 85%).
[0124] 16.1 g (0.1 mol) of the obtained N-(hydroxyacetyl)-alanine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of dioxane, and then 4.5 g (0.022 mol) was added to the resin-loaded H... - (Based on content) Amberlyst 15 resin, refluxed at 100℃ for 48h, filtered through resin, and dioxane was evaporated to obtain crude amino acid-based lactone amide. It was then purified by recrystallization in ethyl acetate to obtain amino acid-based lactone amide (yield 82%, purity 98.6%).
[0125] The 1H NMR spectrum of the amino acid-based lactone amide 1¹H NMR (DMSO, 300MHz) δppm 8.26 (s, 1H, NH), 5.71 (q, 1H, OCHCO), 4.92 (q, 1H, NHCHCO), 1.63 (d, 3H, CHCH3(-O)), 1.53 (d, 3H, CHCH3(-NH)). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is methyl and R2 is methyl.
[0126] Example 13
[0127] Weigh 58.5 g (0.5 mol) valine and 52.0 g (0.5 mol) methyl glycolate into a 2 L round-bottom flask, add 1 L n-butanol to dissolve them, then add 25 g (0.1 mol) dibutyltin oxide, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacetyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacetyl)-valine n-butyl ester (yield 90%).
[0128] 23.0 g (0.1 mol) of the obtained N-(hydroxyacetyl)-valine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of dioxane, and then 4.5 g (0.022 mol) of H2O was added to the resin-loaded H2O. - (Based on content) Amberlyst 15 resin, refluxed at 130℃ for 48h, filtered through resin, and dioxane was evaporated to obtain crude cyclic lactone amide product. It was then purified by recrystallization in diethyl ether to obtain amino acid-based lactone amide (yield 85%, purity 98.3%).
[0129] The 1H NMR spectrum of the amino acid-based lactone amide 1 ¹H NMR (DMSO, 300MHz) δppm 8.26 (s, 1H, NH), 5.69 (q, 1H, OCHCO), 4.23 (q, 1H, NHCHCO), 2.22 (m, 1H, CH(CH3)2), 1.52 (d, 3H, CHCH3(-NH), 0.96 (q, 6H, CH(CH3)2). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, wherein R1 is isopropyl and R2 is methyl.
[0130] Example 14
[0131] Weigh 74.6 g (0.5 mol) of methionine and 52.0 g (0.5 mol) of methyl glycolate into a 2 L round-bottom flask, add 1 L of n-butanol to dissolve them, then add 25 g (0.1 mol) of dibutyltin oxide, heat and stir at 80 °C for 10 h, filter the catalyst, and evaporate the filtrate to obtain a mixture of N-(hydroxyacyl)-valine n-butyl ester and unreacted methyl glycolate. Distill the mixture under reduced pressure at 50 °C and a vacuum of 100 Pa to remove unreacted methyl glycolate, and the remaining product is N-(hydroxyacetyl)-methionine n-butyl ester (yield 85%).
[0132] 23.6 g (0.1 mol) of the obtained N-(hydroxyacetyl)-methionine n-butyl ester was placed in a 2 L round-bottom flask, dissolved in 1 L of dioxane, and then 4.5 g (0.022 mol) of H2O was added to the resin-loaded H2O. - (Based on content) Amberlyst 15 resin, refluxed at 130℃ for 48h, filtered through resin, and dioxane was evaporated to obtain crude cyclic lactone amide product. It was then purified by recrystallization in diethyl ether to obtain amino acid-based lactone amide (yield 80%, purity 98.6%).
[0133] The 1H NMR spectrum of the amino acid-based lactone amide 1 ¹H NMR (DMSO, 300MHz) δppm 8.11 (s, 1H, NH), 4.83 (q, 1H, OCHCO), 4.32 (q, 1H, NHCHCO), 2.73-2.58 (m, 2H, CHCH₂CH₂), 2.34 (m, 2H, CH₂CH₂SCH₃), 1.57 (s, 3H, CH₂SCH₃). Therefore, the amino acid-based lactone amide has the structure shown in Formula I, where R1 is -CH₂CH₂SCH₃ and R2 is a methyl group.
[0134] The descriptions of the above embodiments are merely illustrative of the methods and core ideas of the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims
1. A method for preparing an amino acid-based lactam, comprising the steps of: A) reacting an α-amino acid and an α-hydroxy acid ester in a first solvent in the presence of a first catalyst to obtain an N-(hydroxyacyl)-amino acid ester; the first catalyst being one or more of dibutyltin dilaurate, dibutyltin oxide and stannous octoate; the first solvent being n-butanol; B) reacting the N-(hydroxyacyl)-amino acid ester in a second solvent in the presence of a second catalyst to obtain the amino acid-based lactam; the second catalyst being at least one of concentrated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, triflic acid, trifluoroacetic acid, aluminum trichloride, titanium dioxide and a sulfonic acid type ion exchange resin; the amino acid-based lactam having a structure shown in Formula I; Formula I wherein R1 and R2 are independently selected from one of hydrogen, methyl, isopropyl, phenyl, benzyl, methylthio and -CH2CH2SCH3; the α-amino acid having a structure shown in Formula II; Formula II the α-hydroxy acid ester having a structure shown in Formula III; Formula III wherein R4 is selected from methyl, ethyl, isopropyl or butyl; in step A), the molar ratio of the first catalyst, the α-amino acid and the α-hydroxy acid ester is 1-20:100:100; in step A), the reaction temperature is 40-100°C and the reaction time is 3-48 h; in step A), after the reaction, the first catalyst and the first solvent are removed; after removing the first catalyst and the first solvent, the mixture is subjected to vacuum distillation; the vacuum distillation is carried out at a temperature of 45-55°C and a vacuum degree of 95-105 Pa; in step B), the second catalyst is at least one of concentrated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, triflic acid, trifluoroacetic acid, aluminum trichloride, titanium dioxide and a sulfonic acid type ion exchange resin; in step B), the molar ratio of the second catalyst to the N-(hydroxyacyl)-amino acid ester is 1-35:100; in step B), the second solvent includes at least one of ethyl acetate, toluene, xylene, dioxolane, dioxane, dichloromethane and chloroform; in step B), the reaction temperature is 40-150°C and the reaction time is 3-60 h; in step B), after the reaction, the second catalyst and the second solvent are removed; after removing the second catalyst and the second solvent, the mixture is subjected to recrystallization; the recrystallization solvent is at least one of ethyl acetate, diethyl ether, acetonitrile, n-hexane, petroleum ether and tetrahydrofuran. Formula I; 2. The production method according to claim 1, characterized by, Formula II; Formula III; 3. The preparation method according to claim 1, characterized in that, 4. The method of claim 1, wherein, 5. The preparation method according to claim 1, characterized in that, 6. The method of claim 1, wherein, 7. The preparation method according to claim 1, characterized in that, 8. The method of claim 1, wherein, 9. The method of claim 1, wherein,
Citation Information
Patent Citations
Lactic acid-glutamic acid morpholine dione and synthetic process method thereof
CN102408389A