N-methylation method of N-Boc-amino acid

Abstract

The invention relates to an N-methylation method of N-Boc-amino acid, belongs to the technical field of pharmaceutical compounds, and particularly relates to a method for synthesizing N-Me-Boc-amino acid through condensation of N-Boc-amino acid and paraformaldehyde, oxazolidinone and palladium-carbon catalytic hydrogenation reduction, which comprises the following steps: adding L-N-Boc-amino acid, solid acid, a first solvent and paraformaldehyde into a reactor; reacting at the temperature; filtering and post-processing to obtain an intermediate crude product, and recovering a filter cake; recrystallizing to obtain a purified intermediate; sequentially adding the purified intermediate, a second solvent and a palladium carbon catalyst into a reactor; vacuumizing and introducing hydrogen, replacing the system with hydrogen for multiple times, and reacting at the temperature; filtering and washing; collecting filtrate, and concentrating under reduced pressure to obtain a crude product; and recrystallizing to obtain the N-Me-Boc-amino acid. The N-methylation method of Boc-amino acid is simple and convenient to operate and low in synthesis cost, and has application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical compounds, and in particular relates to an N-methylation method of N-Boc-amino acid. Background Art

[0002] N-methyl amino acids are important building blocks of numerous bioactive peptides and are also raw materials for the synthesis and discovery of related chiral drugs. The introduction of N-methyl groups not only modifies and constrains the peptide backbone, reducing the number of isomers, but also alters molecular conformation, thereby affecting receptor interactions. Common methods for amino acid N-methylation include direct methylation, reductive amination, the oxazolidinone intermediate method, and the α-azido acid method. The most classic N-methylation method involves the introduction of a methyl group using iodomethane in the presence of a strong base. This method offers mild reaction conditions and is relatively immune to racemization of chiral centers. However, the reaction must be carried out in the dark. Furthermore, the raw material, iodomethane, is relatively expensive and highly toxic, requiring low temperatures. Therefore, this method is suitable for small-scale laboratory use.

[0003] The oxazolidinone intermediate method is a mild and versatile method for synthesizing N-methyl amino acids. It is mainly used to N-methylate acid-stable benzyloxycarbonyl (Cbz-) or fluorenylmethyloxycarbonyl (Fmoc-) protected amino acids. The amino acids are not easily racemized and the reaction yield is also high. However, triethylsilane and a large amount of trifluoroacetic acid are often used for the reduction reaction, resulting in high synthesis costs and environmental pollution. At the same time, given that tert-butyloxycarbonyl (Boc-) protected amino acids are unstable under acidic conditions and the Boc group is easily removed, it is difficult to convert N-Boc-amino acids into the corresponding N-Boc-oxazolidinones. Therefore, attempts to use the oxazolidinone intermediate method to efficiently prepare N-methyl-N-Boc amino acids are highly challenging. However, N-methyl-Boc-amino acids are in great demand in peptide research and drug development. Therefore, developing a new, efficient and economical method for synthesizing N-Boc-oxazolidinone and converting it into N-methyl-Boc-amino acid using catalytic hydrogenation reduction technology not only conforms to the principle of green synthesis, but more importantly, also has important industrial value and social benefits. Summary of the Invention

[0004] The present invention provides an N-methylation method for N-Boc-amino acids, which is used to solve the technical bottleneck of the current N-Boc-oxazolidinone method for preparing N-methyl-N-Boc amino acids, and provides a green technical method with industrial value.

[0005] In view of this, the present invention provides a method for N-methylation of N-Boc-amino acids, which is a method for synthesizing N-Me-Boc-amino acids by condensing N-Boc-amino acids with paraformaldehyde, followed by oxazolidinone conversion, and palladium-carbon catalytic hydrogenation reduction, comprising the following steps:

[0006] S1: In a reactor, LN-Boc-amino acid, solid acid, first solvent and paraformaldehyde are added in sequence to obtain a mixed solution a;

[0007] S2: In a heating reflux apparatus, stirring the mixed solution a at a predetermined temperature to react to obtain a mixed solution b;

[0008] S3: Filter the mixed solution b, post-process it to obtain the intermediate crude product, and recover the filter cake for reuse;

[0009] S4: Recrystallizing the crude intermediate product to obtain a purified intermediate;

[0010] S5: In another reactor, sequentially add the purified intermediate, the second solvent, and the palladium-carbon catalyst, mix them evenly, and obtain a mixed solution c;

[0011] S6: Evacuate the reactor, introduce hydrogen, replace the system with hydrogen multiple times, and stir the reaction at a predetermined temperature to obtain a mixed solution d;

[0012] S7: Filter the mixed solution d, wash the filter cake, and recover the palladium-carbon catalyst;

[0013] S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude N-Me-Boc-amino acid product;

[0014] S9: Recrystallize the crude N-Me-Boc-amino acid product to obtain N-Me-Boc-amino acid.

[0015] Furthermore, a method for N-methylation of an N-Boc-amino acid is provided, wherein the N-Boc-amino acid is condensed with paraformaldehyde, followed by oxazolidinone conversion and palladium-carbon catalyzed hydrogenation reduction to synthesize an N-Me-Boc-amino acid, comprising the following steps:

[0016] S1: In a reactor, LN-Boc-amino acid, solid acid, first solvent and paraformaldehyde are added in sequence to obtain a mixed solution a;

[0017] S2: In a heating reflux apparatus, stirring the mixed solution a at a predetermined temperature to react to obtain a mixed solution b;

[0018] S3: Filter the mixed solution b, wash the filter cake with the first solvent, collect the filtrate, and concentrate under reduced pressure to obtain a crude intermediate product, then recover the filter cake and reuse it;

[0019] S4: Recrystallizing the crude intermediate product to obtain a purified intermediate;

[0020] S5: In another reactor, sequentially add the purified intermediate, the second solvent, and the palladium-carbon catalyst, mix them evenly, and obtain a mixed solution c;

[0021] S6: Evacuate the reactor, introduce hydrogen to remove air from the reactor, replace the system with hydrogen 3-4 times, and stir the reaction at a predetermined temperature to obtain a mixed solution d, thereby completing the reductive N-methylation;

[0022] S7: filtering the mixed solution d, washing the filter cake with a second solvent, and recovering the palladium-carbon catalyst;

[0023] S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude N-Me-Boc-amino acid product;

[0024] S9: Recrystallizing the crude N-Me-Boc-amino acid product to obtain the N-Me-Boc-amino acid;

[0025] The solvent used for recrystallization is any one of an ethyl acetate / petroleum ether mixed solvent with a volume ratio of 1:(3-10), an ethyl acetate / hexane mixed solvent with a volume ratio of 1:2, and an ethanol / dichloromethane mixed solvent with a volume ratio of 1:(10-15).

[0026] Optionally, the LN-Boc-amino acid includes natural amino acids and non-natural amino acids, wherein the natural amino acids are the 20 L-amino acids that constitute proteins except proline and hydroxyproline, and the non-natural amino acids include D-configuration amino acids and L / D-phenylglycine, L / D-parahydroxyphenylglycine.

[0027] Optionally, the solid acid in step S1 is a Lewis acid, which is any one of sulfonic acid resin, weak acid resin, ferric chloride, aluminum chloride, zinc chloride, and tin chloride, and is mixed with acetic acid in a molar ratio of 1:1.

[0028] Optionally, the first solvent in step S1 is any one of toluene, 1,4-dioxane, tetrahydrofuran, and cyclohexane.

[0029] Optionally, the molar ratio of the LN-Boc-amino acid, Lewis acid and paraformaldehyde is 1:(0.15-0.25):(3-5).

[0030] Optionally, the predetermined temperature in step S2 is 80-90° C., and the reaction time is 6-8 h.

[0031] Optionally, the second solvent in step S5 is any one of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane and tetrahydrofuran.

[0032] Optionally, the palladium carbon catalyst in step S5 is any one of 3%, 5% and 10% palladium carbon.

[0033] Furthermore, the palladium-carbon catalyst in step S5 is 10% palladium-carbon.

[0034] Optionally, the predetermined temperature in step S6 is 20-60° C., and the reaction time is 6-8 h.

[0035] Furthermore, the predetermined temperature in step S6 is 50-60° C., and the reaction time is 6-8 h.

[0036] Optionally, the yield of N-Me-Boc-amino acid in step S9 is above 85%.

[0037] It can be seen from the above technical solutions that the embodiments of the present invention have the following advantages:

[0038] 1. The method provided by the present invention is to generate N-Me-Boc-amino acids by solid acid catalysis, palladium-carbon catalyzed hydrogenation reduction ring-opening of Boc-amino acids via the corresponding N-Boc-oxazolidinone. The method has excellent selectivity, the reaction can be carried out under normal pressure and mild conditions, the synthesis yield is high, and the cost is low. It can also be applied to the N-methylation reaction of other natural / unnatural amino acids, and has industrial and green environmental value.

[0039] 2. The reducing agent palladium carbon in the present invention can be recycled and reused, which is environmentally friendly. DETAILED DESCRIPTION

[0040] In order to make those skilled in the art better understand the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. Unless otherwise specified, the various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or can be prepared by existing methods.

[0041] Example

[0042] Example 1

[0043] A synthesis of N-Me-Boc-alanine, which is prepared by the following method:

[0044] S1: In a reactor, 1.89 g of LN-Boc-alanine, 0.18 g of sulfonic acid resin, 0.06 g of acetic acid, 20 mL of 1,4-dioxane, and 1.24 g of paraformaldehyde were added in sequence to obtain a mixed solution a;

[0045] S2: In a heating reflux apparatus, the mixed solution a was stirred at 80°C for 8 h to obtain a mixed solution b;

[0046] S3: Filter the mixed solution b, wash the filter cake with 1,4-dioxane, collect the filtrate, and concentrate under reduced pressure to obtain a crude intermediate product, i.e., a crude product of tert-butyl (S)-4-methyl-5-oxooxazolidinone-3-carboxylate;

[0047] S4: The crude intermediate product was recrystallized with a mixed solvent of ethyl acetate and petroleum ether at a volume ratio of 1:10 to obtain 1.73 g of (S)-4-methyl-5-oxooxazolidinone-3-carboxylic acid tert-butyl ester with a yield of 86%. [α]D 25 =+99.8°;

[0048] S5: In another reactor, 1.00 g of tert-butyl (S)-4-methyl-5-oxooxazolidinone-3-carboxylate, 10 mL of isopropanol, and 0.27 g of a 10% palladium-carbon catalyst were added in sequence and mixed well to obtain a mixed solution c;

[0049] S6: Evacuate the reactor and introduce hydrogen to remove the air in the reactor. Replace the system with hydrogen four times and stir the reaction at 60°C for 6 hours to obtain a mixed solution d.

[0050] S7: Filter the mixed solution d, wash the filter cake with isopropyl alcohol, and recover the palladium-carbon catalyst;

[0051] S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude product of N-Me-Boc-alanine;

[0052] S9: The crude N-Me-Boc-alanine product was recrystallized using a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of 1:10 to obtain 0.88 g of N-Me-Boc-alanine with a yield of 87%. [α]D 25 =-37.2°.

[0053] Example 2

[0054] A synthesis of N-Me-Boc-valine, which is prepared by the following method:

[0055] S1: In a reactor, 2.18 g of LN-Boc-valine, 0.16 g of ferric chloride, 0.06 g of acetic acid, 20 mL of tetrahydrofuran, and 1.24 g of paraformaldehyde were added in sequence to obtain a mixed solution a;

[0056] S2: In a heating reflux apparatus, the mixed solution a was stirred at 80°C for 8 h to obtain a mixed solution b;

[0057] S3: Filter the mixed solution b, wash the filter cake with tetrahydrofuran, collect the filtrate, and concentrate under reduced pressure to obtain a crude intermediate product, i.e., a crude product of tert-butyl (S)-4-isopropyl-5-oxooxazolidinone-3-carboxylate;

[0058] S4: The crude intermediate product was recrystallized with a mixed solvent of ethyl acetate and petroleum ether at a volume ratio of 1:10 to obtain 1.95 g of (S)-tert-butyl 4-isopropyl-5-oxooxazolidinone-3-carboxylate with a yield of 85%. [α]D 25 =+101.1°;

[0059] S5: In another reactor, 1.14 g of (S)-tert-butyl 4-isopropyl-5-oxooxazolidinone-3-carboxylate, 10 mL of ethanol, and 0.27 g of a 10% palladium-carbon catalyst were added in sequence and mixed well to obtain a mixed solution c;

[0060] S6: Evacuate the reactor and introduce hydrogen to remove the air in the reactor. Replace the system with hydrogen four times and stir the reaction at 60°C for 6 hours to obtain a mixed solution d.

[0061] S7: Filter the mixed solution d, wash the filter cake with ethanol, and recover the palladium-carbon catalyst;

[0062] S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude product of N-Me-Boc-valine;

[0063] S9: The crude N-Me-Boc-valine product was recrystallized using a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of 1:10 to obtain 0.97 g of N-Me-Boc-valine with a yield of 85%. [α]D 25 =-80.1°.

[0064] Example 3

[0065] A synthesis of N-Me-Boc-leucine, which is prepared by the following method:

[0066] S1: In a reactor, 2.31 g of LN-Boc-leucine, 0.18 g of sulfonic acid resin, 0.06 g of acetic acid, 20 mL of 1,4-dioxane, and 1.24 g of paraformaldehyde were added in sequence to obtain a mixed solution a;

[0067] S2: In a heating reflux apparatus, the mixed solution a was stirred at 80°C for 8 h to obtain a mixed solution b;

[0068] S3: Filter the mixed solution b, wash the filter cake with 1,4-dioxane, collect the filtrate, and concentrate under reduced pressure to obtain a crude intermediate product, i.e., a crude product of tert-butyl (S)-4-isobutyl-5-oxooxazolidinone-3-carboxylate;

[0069] S4: The crude intermediate product was recrystallized with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain 2.09 g of (S)-4-isobutyl-5-oxooxazolidinone-3-carboxylic acid tert-butyl ester with a yield of 86%. [α]D 25 =+119.1°;

[0070] S5: In another reactor, 1.21 g of tert-butyl (S)-4-isobutyl-5-oxooxazolidinone-3-carboxylate, 10 mL of methanol, and 0.27 g of a 10% palladium-carbon catalyst were added in sequence and mixed well to obtain a mixed solution c;

[0071] S6: Evacuate the reactor and introduce hydrogen to remove the air in the reactor. Replace the system with hydrogen four times and stir the reaction at 60°C for 6 hours to obtain a mixed solution d.

[0072] S7: Filter the mixed solution d, wash the filter cake with methanol, and recover the palladium-carbon catalyst;

[0073] S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude N-Me-Boc-leucine product;

[0074] S9: The crude N-Me-Boc-leucine product was recrystallized using a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of 1:10 to obtain 1.03 g of N-Me-Boc-leucine with a yield of 84%. [α]D 25 =-38.2°.

[0075] Example 4

[0076] A synthesis of N-Me-Boc-phenylalanine, which is prepared by the following method:

[0077] S1: In a reactor, 2.65 g of LN-Boc-phenylalanine, 0.14 g of zinc chloride, 0.06 g of acetic acid, 25 mL of 1,4-dioxane, and 1.24 g of paraformaldehyde were added in sequence to obtain a mixed solution a;

[0078] S2: In a heating reflux apparatus, the mixed solution a was stirred at 80°C for 8 h to obtain a mixed solution b;

[0079] S3: Filter the mixed solution b, wash the filter cake with 1,4-dioxane, collect the filtrate, and concentrate under reduced pressure to obtain a crude intermediate product, i.e., a crude product of tert-butyl (S)-4-benzyl-5-oxooxazolidinone-3-carboxylate;

[0080] S4: The crude intermediate product was recrystallized with a mixed solvent of ethanol and dichloromethane with a volume ratio of 1:15 to obtain 2.38 g of tert-butyl (S)-4-benzyl-5-oxooxazolidinone-3-carboxylate with a yield of 86%. [α]D 25 =+191.6°;

[0081] S5: In another reactor, 1.38 g of tert-butyl (S)-4-benzyl-5-oxooxazolidinone-3-carboxylate, 10 mL of methanol, and 0.27 g of a 10% palladium-carbon catalyst were added in sequence and mixed well to obtain a mixed solution c;

[0082] S6: Evacuate the reactor and introduce hydrogen to remove the air in the reactor. Replace the system with hydrogen four times and stir the reaction at 60°C for 6 hours to obtain a mixed solution d.

[0083] S7: Filter the mixed solution d, wash the filter cake with methanol, and recover the palladium-carbon catalyst;

[0084] S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude product of N-Me-Boc-phenylalanine;

[0085] S9: The crude N-Me-Boc-phenylalanine product was recrystallized using a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of 1:5 to obtain 1.16 g of N-Me-Boc-phenylalanine with a yield of 83%. [α]D 25 =-84.5°.

[0086] Example 5

[0087] A synthesis of N-Me-Boc-glycine, which is prepared by the following method:

[0088] S1: In a reactor, 1.75 g of LN-Boc-glycine, 0.18 g of p-toluenesulfonic acid, 0.06 g of acetic acid, 15 mL of 1,4-dioxane, and 1.24 g of paraformaldehyde were added in sequence to obtain a mixed solution a;

[0089] S2: In a heating reflux apparatus, the mixed solution a was stirred at 80°C for 8 h to obtain a mixed solution b;

[0090] S3: Filter the mixed solution b, wash the filter cake with 1,4-dioxane, collect the filtrate, and concentrate under reduced pressure to obtain a crude intermediate product, i.e., a crude product of tert-butyl 5-oxooxazolidinone-3-carboxylate;

[0091] S4: The crude intermediate product was recrystallized using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:3 to obtain 1.59 g of tert-butyl 5-oxooxazolidinone-3-carboxylate, with a yield of 85%;

[0092] S5: In another reactor, 0.93 g of tert-butyl 5-oxooxazolidinone-3-carboxylate, 10 mL of methanol, and 0.27 g of 10% palladium-carbon catalyst were added in sequence and mixed evenly to obtain a mixed solution c;

[0093] S6: Evacuate the reactor and introduce hydrogen to remove the air in the reactor. Replace the system with hydrogen four times and stir the reaction at 60°C for 6 hours to obtain a mixed solution d.

[0094] S7: Filter the mixed solution d, wash the filter cake with methanol, and recover the palladium-carbon catalyst;

[0095] S8: Collect the filtrate and concentrate under reduced pressure to obtain crude N-Me-Boc-glycine;

[0096] S9: The crude N-Me-Boc-glycine product was recrystallized using a mixed solvent of ethyl acetate and hexane in a volume ratio of 1:2 to obtain 0.76 g of N-Me-Boc-glycine with a yield of 80%.

[0097] Example 6

[0098] A synthesis of DN-Me-Boc-phenylglycine is prepared by the following method:

[0099] S1: In a reactor, 2.51 g of DN-Boc-phenylglycine, 0.18 g of p-toluenesulfonic acid, 0.06 g of acetic acid, 25 mL of 1,4-dioxane, and 1.24 g of paraformaldehyde were added in sequence to obtain a mixed solution a;

[0100] S2: In a heating reflux apparatus, the mixed solution a was stirred at 80°C for 8 h to obtain a mixed solution b;

[0101] S3: Filter the mixed solution b, wash the filter cake with 1,4-dioxane, collect the filtrate, and concentrate under reduced pressure to obtain a crude intermediate product, i.e., a crude product of tert-butyl (R)-5-oxo-4-phenyloxazolidinone-3-carboxylate;

[0102] S4: The crude intermediate product was recrystallized using a mixed solvent of ethanol and dichloromethane in a volume ratio of 1:10 to obtain 2.29 g of tert-butyl (R)-5-oxo-4-phenyloxazolidinone-3-carboxylate, with a yield of 87%;

[0103] S5: In another reactor, 1.32 g of tert-butyl (R)-5-oxo-4-phenyloxazolidinone-3-carboxylate, 15 mL of methanol, and 0.27 g of a 10% palladium-carbon catalyst were added in sequence and mixed well to obtain a mixed solution c;

[0104] S6: Evacuate the reactor and introduce hydrogen to remove the air in the reactor. Replace the system with hydrogen four times and stir the reaction at 60°C for 6 hours to obtain a mixed solution d.

[0105] S7: Filter the mixed solution d, wash the filter cake with methanol, and recover the palladium-carbon catalyst;

[0106] S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude product of DN-Me-Boc-phenylglycine;

[0107] S9: Using column chromatography, the crude DN-Me-Boc-phenylglycine product was separated and purified using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain 1.09 g of DN-Me-Boc-phenylglycine with a yield of 82%.

[0108] Example 7

[0109] A synthesis of N-Me-Boc-aspartic acid, which differs from Example 1 in that an equal amount of LN-Boc-alanine is replaced by LN-Boc-aspartic acid, an equal amount of 1,4-dioxane is replaced by toluene, and an equal amount of 10% palladium on carbon is replaced by 5% palladium on carbon. The experiment is repeated to obtain N-Me-Boc-aspartic acid with an overall yield of 68%.

[0110] Example 8

[0111] A synthesis of N-Me-Boc-glutamine was prepared, which differed from Example 2 in that an equal amount of LN-Boc-valine was replaced by LN-Boc-glutamine, an equal amount of tetrahydrofuran was replaced by 1,4-dioxane, and an equal amount of ethanol was replaced by methanol. Other conditions and operations were the same as those in Example 2, to obtain N-Me-Boc-glutamine with a total yield of 68%.

[0112] Example 9

[0113] A synthesis of N-Me-Boc-threonine was performed, which differed from Example 2 in that an equal amount of LN-Boc-valine was replaced by LN-Boc-threonine, an equal amount of ferric chloride was replaced by a weakly acidic resin, an equal amount of tetrahydrofuran was replaced by dichloromethane, and an equal amount of ethanol was replaced by isopropanol. Other conditions and operations were the same as those in Example 2, and N-Me-Boc-threonine was obtained in an overall yield of 67%.

[0114] Example 10

[0115] A synthesis of N-Me-Boc-lysine, which differs from Example 3 in that an equal amount of LN-Boc-leucine is replaced by LN-Boc-lysine, an equal amount of 1,4-dioxane is replaced by dichloromethane, an equal amount of methanol is replaced by isopropanol, and an equal amount of 10% palladium carbon is replaced by 3% palladium carbon. Recrystallization uses a mixed solvent of ethyl acetate / cyclohexane with a volume ratio of 1:1. Other conditions and operations are the same as those in Example 3, to obtain N-Me-Boc-lysine with a total yield of 64%.

[0116] Example 11

[0117] A synthesis of N-Me-Boc-histidine is disclosed, which differs from Example 4 in that an equal amount of LN-Boc-phenylalanine is replaced by LN-Boc-histidine, an equal amount of zinc chloride is replaced by a sulfonic acid resin, an equal amount of 1,4-dioxane is replaced by dichloromethane, an equal amount of methanol is replaced by ethanol, and an equal amount of 10% palladium on carbon is replaced by 5% palladium on carbon. Recrystallization is performed using a mixed solvent of ethyl acetate / cyclohexane in a volume ratio of 1:2. Other conditions and operations are the same as those in Example 4, to obtain N-Me-N-Boc-histidine with a total yield of 71%.

[0118] Example 12

[0119] A synthesis of N-Me-Boc-tryptophan was performed, which differed from Example 11 in that an equal amount of LN-Boc-histidine was replaced with LN-Boc-tryptophan. Other conditions and operations were the same as those in Example 11, yielding N-Me-N-Boc-tryptophan in a total yield of 65%.

[0120] Example 13

[0121] A synthesis of N-Me-Boc-DOPA was prepared, which differed from Example 11 in that an equal amount of LN-Boc-histidine was replaced with LN-Boc-DOPA. Other conditions and operations were the same as those in Example 11, yielding N-Me-N-Boc-DOPA in a total yield of 64%.

[0122] Example 14

[0123] A synthesis of N-Me-N-Boc-2-quinolinolane was prepared, which differed from Example 11 in that an equal amount of LN-Boc-histidine was replaced with N-Boc-2-quinolinolane. Other conditions and operations were the same as those in Example 11, yielding N-Me-N-Boc-2-quinolinolane in an overall yield of 68%.

[0124] Example 15

[0125] A synthesis of N-Me-N-Boc-2-naphthylalanine was prepared, which differed from Example 11 in that an equal amount of LN-Boc-histidine was replaced by N-Boc-2-naphthylalanine, and an equal amount of 5% palladium on carbon was replaced by 10% palladium on carbon. Other conditions and operations were the same as those in Example 11, yielding N-Me-N-Boc-2-naphthylalanine in a total yield of 72%.

[0126] As described above, the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments can still be modified, or some of the technical features thereof can be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for N-methylation of N-Boc-amino acids, characterized in that: The invention relates to a method for synthesizing N-Me-Boc-amino acid by condensing N-Boc-amino acid with paraformaldehyde, followed by oxazolidinone conversion and palladium-carbon catalytic hydrogenation reduction, comprising the following steps: S1: In a reactor, LN-Boc-amino acid, solid acid, first solvent and paraformaldehyde are added in sequence to obtain a mixed solution a; S2: In a heating reflux apparatus, stirring the mixed solution a at a predetermined temperature to react to obtain a mixed solution b; S3: Filter the mixed solution b, post-process it to obtain the intermediate crude product, and recover the filter cake for reuse; S4: Recrystallizing the crude intermediate product to obtain a purified intermediate; S5: In another reactor, sequentially add the purified intermediate, the second solvent, and the palladium-carbon catalyst, mix them evenly, and obtain a mixed solution c; S6: Evacuate the reactor, introduce hydrogen, replace the system with hydrogen multiple times, and stir the reaction at a predetermined temperature to obtain a mixed solution d; S7: Filter the mixed solution d, wash the filter cake, and recover the palladium-carbon catalyst; S8: Collect the filtrate and concentrate under reduced pressure to obtain the crude N-Me-Boc-amino acid product; S9: Recrystallize the crude N-Me-Boc-amino acid product to obtain N-Me-Boc-amino acid.

2. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The LN-Boc-amino acids include natural amino acids and non-natural amino acids. The natural amino acids are 20 L-amino acids constituting proteins except proline and hydroxyproline. The non-natural amino acids include D-configuration amino acids and L / D-phenylglycine and L / D-p-hydroxyphenylglycine.

3. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The solid acid in step S1 is a Lewis acid, which is any one of sulfonic acid resin, weak acid resin, ferric chloride, aluminum chloride, zinc chloride, and tin chloride, and is mixed with acetic acid in a molar ratio of 1:

1.

4. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The first solvent in step S1 is any one of toluene, 1,4-dioxane, tetrahydrofuran, and cyclohexane.

5. A method for N-methylation of an N-Boc-amino acid according to claim 3, characterized in that: The molar ratio of the LN-Boc-amino acid, Lewis acid and paraformaldehyde is 1:(0.15-0.25):(3-5).

6. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The predetermined temperature in step S2 is 80-90° C., and the reaction time is 6-8 h.

7. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The second solvent in step S5 is any one of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane and tetrahydrofuran.

8. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The palladium carbon catalyst in step S5 is any one of 3%, 5% and 10% palladium carbon.

9. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The predetermined temperature in step S6 is 20-60° C., and the reaction time is 6-8 hours.

10. A method for N-methylation of an N-Boc-amino acid according to claim 1, characterized in that: The yield of N-Me-Boc-amino acid in step S9 was 85% or more.