N-OH glutamine derivatives and their preparation methods and applications

Abstract

The present invention relates to the field of N-OH amino acid derivatives, and discloses an N-OH glutamine derivative and its preparation method and application. The N-OH glutamine has a structure shown in formula (I), wherein R 1 is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, or substituted benzyl; R 2 is hydrogen, C1-C20 alkyl, aryl, or substituted aryl; R 3 is hydrogen, alkyl-substituted silicon, benzyl, substituted benzyl, allyl, allyloxycarbonyl, or tert-butyloxycarbonyl, wherein the substituent of the benzyl group is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro, and halogen; R 1 、R 2 、R 3 are not hydrogen at the same time; the stereo configuration of the chiral carbon of the compound is R or S. According to the present invention, a polar N-OH amino acid derivative and an efficient and universal preparation method and application of the N-OH amino acid derivative can be provided. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of N-OH amino acid derivatives, and in particular to N-OH glutamine derivatives and preparation methods and applications thereof. Background Art

[0002] N-OH amino acid fragments are widely present in the structures of natural products. The introduction of N-OH groups into the molecular structure can enhance the hydrogen bonding interaction between the target molecule and the target protein, improve the stability of certain proteases (Bianco, A. et al., J. Pept. Sci. 1998, 4, 471-478; Marastoni, M. et al., Bioorg. Med. Chem., 2001, 9, 939-945), and enhance the chelation effect with metals (Ye Y. et al., Biopolymers, 2003, 71, 489-515; Ye Y. et al., Biopolymers, 2006, 84, 472-489). In addition, peptide chains containing N-OH groups can act as T cell receptor antagonists (Hin, S. et al., J. Immunol. 1999, 163, 2363-2367) and have a certain improvement in biological activity (Maffioli, S.I. et al., Cell 2017,169,1240.). In recent years, natural product molecules containing one N-OH amino acid fragment have been reported, including (+)-Azinothricin, (+)-A83586C, (+)-kettapeptin, (+)-Citropeptin, (+)-GE3, (+)-Kettapeptin (Hale, KJ et al., J. Chem. Commun. 2010, 46, 4021.), L-156373 (Elbatrawi, YM et al., Org. Lett. 2018, 20, 2707.), natural products Aurantimycin A and B containing two N-OH amino acid fragments (Grigoriev, P. et al., Bioelectrochemistry and Bioenergetics 1995, 36, 57-59.), and Pseudouridinmycin with a nucleoside peptide structure (Maffioli, SI et al., Cell 2017, 169, 1240.). The instability and easy deterioration of N-OH amino acids have hindered the research on the synthesis of N-OH amino acids and N-OH peptides. Currently reported N-OH amino acid derivatives and synthesis methods are very limited, and are limited to the synthesis of non-polar N-OH amino acid derivatives. Summary of the Invention

[0003] The purpose of the present invention is to overcome the above-mentioned problems existing in the prior art and to provide a polar N-OH amino acid derivative and an efficient and highly universal preparation method and application of the N-OH amino acid derivative.

[0004] Therefore, in order to achieve the above-mentioned object, the first aspect of the present invention provides an N-OH amino acid derivative, wherein the N-OH derivative is a compound having a structure represented by formula (I);

[0005]

[0006] In formula (I), R 1 is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, or substituted benzyl, wherein the substituents of the aryl and benzyl groups are selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro, and halogen;

[0007] R 2 is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, diphenylmethyl, triphenylmethyl, wherein the substituent of the aryl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;

[0008] R 3 is hydrogen, an alkyl-substituted silicon group, benzyl, a substituted benzyl group, an allyl group, an allyloxycarbonyl group, or a tert-butyloxycarbonyl group, wherein the substituent of the benzyl group is selected from one of a C1-C6 alkoxy group, a C1-C6 alkyl group, a hydroxyl group, a nitro group, and a halogen group;

[0009] R 1 、R 2 、R 3 Not simultaneously hydrogen;

[0010] The stereo configuration of the chiral carbon of the compound is R or S.

[0011] Preferably, R 1 is a C1-C5 alkyl group and / or a benzyl group.

[0012] Preferably, R 2 It is hydrogen, benzyl, diphenylmethyl, or triphenylmethyl.

[0013] Preferably, R 3 It is hydrogen, alkyl-substituted silicon, benzyl, substituted benzyl, allyl, allyloxycarbonyl, tert-butyloxycarbonyl, wherein the substituent of the benzyl group is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen.

[0014] Preferably, R 2 is hydrogen, diphenylmethyl, triphenylmethyl, R 3 It is hydrogen or alkyl substituted silicon.

[0015] Preferably, R 2 is trityl, R 3 For hydrogen.

[0016] Preferably, the stereo configuration of the chiral center of the compound is S.

[0017] Preferably, the structure of the N-OH glutamine is as shown in formula (II),

[0018]

[0019] A second aspect of the present invention provides a method for preparing an N-OH glutamine derivative, wherein the method comprises the following steps:

[0020] (1) contacting the compound represented by formula (III) with a deprotection agent to remove the protecting group R 4 , then under the action of halogenated hydrocarbon and base, a compound with the structure shown in formula (IV) is obtained;

[0021]

[0022] (2) contacting the compound represented by formula (IV) with an oxidant to oxidize the secondary amine to a nitrone, thereby obtaining a compound represented by formula (V);

[0023]

[0024] (3) reacting the compound of formula (V) with a hydroxylamine substrate to obtain a compound of formula (I),

[0025]

[0026] In formula (I), formula (III), formula (IV) and formula (V), R 1 、R 2 and R 3 The definition of R in the N-OH glutamine derivative of the first aspect of the present invention is the same as 1 、R 2 and R 3 The definition of R is the same as 4 It is an amine protecting group.

[0027] Preferably, in step (1), the deprotection reagent is one or more of piperidine, diethylamine, morpholine and N-methylmorpholine, preferably piperidine and / or diethylamine.

[0028] Preferably, in step (1), the halogenated hydrocarbon is one or more of chloroacetonitrile, bromoacetonitrile, CNCH2OMs and CNCH2OTs, more preferably chloroacetonitrile and bromoacetonitrile.

[0029] Preferably, in step (1), the base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, 2,6-lutidine and DIPEA, more preferably potassium carbonate and / or DIPEA.

[0030] Preferably, in step (1), the reaction temperature is 0-100°C, more preferably 50-70°C.

[0031] Preferably, in step (1), the reaction is carried out in the presence of a first solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane and ethyl acetate, more preferably DMF and / or acetonitrile, further preferably acetonitrile.

[0032] Preferably, in step (2), the reaction temperature is -50 to 50°C, more preferably -10 to 0°C.

[0033] Preferably, in step (2), the oxidant is one or more of Oxone, tert-butyl peroxide, hydrogen peroxide, peracetic acid, sodium hypochlorite and meta-chloroperbenzoic acid, preferably hydrogen peroxide and / or meta-chloroperbenzoic acid.

[0034] Preferably, in step (2), the reaction is carried out in the presence of a second solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane and ethyl acetate, more preferably DMF and / or dichloromethane, further preferably dichloromethane.

[0035] Preferably, in step (3), the hydroxylamine substrate is one or more of hydroxylamine hydrochloride, O-methylhydroxylamine, TBSONH2 and BnONH2, more preferably hydroxylamine hydrochloride.

[0036] Preferably, in step (3), the reaction temperature is -50 to 50°C, more preferably -10 to 0°C;

[0037] Preferably, the reaction is carried out in the presence of a third solvent, which is a protic solvent selected from one or more of methanol, ethanol, propanol, isopropanol, trifluoroethanol and hexafluoroisopropanol, more preferably methanol and / or ethanol.

[0038] The third aspect of the present invention provides use of the N-OH glutamine derivative described in the first aspect of the present invention in the synthesis of dipeptides, natural products and medicines containing N-OH glutamine fragments.

[0039] Preferably, the structure of the natural product is as shown in formula (VII),

[0040]

[0041] Preferably, the structure of the dipeptide is as shown in formula (VI),

[0042]

[0043] In formula (VI), R 1 、R 2 and R 3 has the same meaning as in claim 1 or 2;

[0044] R 5 is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH2CONH2, -CH2CH2CONH2, -CH2COOH, -CH2CH2COOH, -(CH2) 1-5 NH2, -(CH2) 1-5 NHC(NH)NH2;

[0045] R 6 It is hydrogen, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, or ethoxycarbonyl, and preferably tert-butoxycarbonyl or fluorenylmethoxycarbonyl.

[0046] Preferably, the drug is an antibacterial drug, an antiviral drug or an antitumor drug.

[0047] According to a fourth aspect of the present invention, a dipeptide is provided, wherein the structure of the dipeptide is as shown in formula (VI):

[0048]

[0049] In formula (VI), R 1 、R 2 and R 3 The definition of R in the N-OH glutamine derivative of the first aspect of the present invention is the same as 1 、R 2 and R 3 The same definition as;

[0050] R 5 is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH2CONH2, -CH2CH2CONH2, -CH2COOH, -CH2CH2COOH, -(CH2) 1-5 NH2, -(CH2) 1-5 NHC(NH)NH2;

[0051] R 6It is hydrogen, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, or ethoxycarbonyl, and preferably tert-butoxycarbonyl or fluorenylmethoxycarbonyl.

[0052] The fifth aspect of the present invention provides a method for preparing the dipeptide of the fourth aspect of the present invention, wherein the method comprises: condensing an acylating agent of the structure represented by formula (XI") and an N-OH glutamine derivative of the structure represented by formula (I) under alkaline conditions to obtain a compound of formula (VI);

[0053]

[0054] R 5 ' is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, -CH2OR 5” 、-CH2SR 5” 、-CH2CONHR 5” 、-CH2CH2CONHR 5” 、-CH2COOR 5” 、-CH2CH2COOR 5” 、-(CH2) 1-5 NHR 5” 、-(CH2) 1-5 NHC(NH)NHR 5” , where R 5” is tert-butyl, trityl, methyl or benzyl;

[0055] R 6 is hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl;

[0056] X is chlorine, bromine or iodine;

[0057] The stereo configuration of the chiral carbon of the compound is R or S.

[0058] Preferably, the base used is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.

[0059] Preferably, the solvent used is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0060] The sixth aspect of the present invention provides a method for preparing a compound represented by formula (XII'), wherein the method comprises the following steps:

[0061] (1) treating the dipeptide of the fourth aspect of the present invention with a demethylating agent to obtain a compound represented by formula (VIII);

[0062]

[0063] (2) condensing the compound represented by formula (VIII) with the amine of the compound represented by formula (IX) in the presence of a Lewis acid, a peptide coupling reagent, and a base to obtain a compound represented by formula (X);

[0064]

[0065] In formula (IX) and formula (X), R 7 and R 8 Each is independently C1-C5 alkyl, benzyl, substituted benzyl, C1-C5 acyl, propylidene, benzylidene, more preferably propylidene and / or benzylidene; R 9 and R 10 Each is independently methyl, ethyl, propyl, butyl, tert-butyl, pentyl, neopentyl, more preferably methyl and / or tert-butyl;

[0066] (3) reacting the compound represented by formula (X) with a deprotecting agent, and then reacting with a pyrazolecarboxamidine compound to obtain a compound represented by formula (XI);

[0067]

[0068] In formula (XI), R 11 and R 12 Each is independently hydrogen, methyl, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl;

[0069] (4) Removing the protecting group from the compound represented by formula (XI) under acidic conditions to obtain the compound represented by formula (XI').

[0070]

[0071] Preferably, in step (1), the demethylation reagent is one or more of lithium iodide, sodium iodide, potassium iodide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide.

[0072] Preferably, in step (1), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0073] Preferably, in step (2), the Lewis acid is one or more of TMSCl, TESCl, TBSCl, copper chloride, zinc chloride, ferric chloride, chromium chloride, nickel chloride, palladium chloride, cobalt chloride, bismuth chloride, copper bromide, ferric bromide and zinc bromide.

[0074] Preferably, in step (2), the peptide coupling reagent is one or more of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 7-aza-benzotriazole-1-yl-oxytris-(dimethylamino)phosphonium hexafluorophosphate and (3H-1,2,3-triazolo[4,5-b]pyridine-3-oxy)tris-1-pyrrolidinophosphonium hexafluorophosphate.

[0075] Preferably, in step (2), the base is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.

[0076] Preferably, in step (2), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0077] Preferably, in step (3), the deprotection reagent is one or more of piperidine, diethylamine, triethylamine and DBU.

[0078] Preferably, in step (3), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0079] Preferably, in step (4), the acid used for deprotection is one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid and hexafluorophosphoric acid.

[0080] Preferably, the acid is mixed with a solvent, the volume mixing ratio of the acid to the solvent is 1:(1-10), and the solvent is one or more of water, dichloromethane, acetone and acetonitrile.

[0081] The N-OH glutamine derivative provided by the present invention has high application prospects in drug synthesis. It can serve as a key intermediate and play an important role in the preparation of N-OH peptides and the synthesis of compounds containing N-OH amino acids. DETAILED DESCRIPTION

[0082] The endpoints of the ranges and any values disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0083] In the present invention, those skilled in the art will understand that the “*” on a carbon represents a chiral carbon, which may be an R-type or S-type conformation.

[0084] In the present invention, specific examples of "C1-C20 alkyl" include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-eicosyl. Alkyl groups with a narrower range of carbon atoms can also be selected from these specific examples based on the limitation of the number of carbon atoms.

[0085] In the present invention, specific examples of "C1-C6 alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like. Alkyl groups with a narrower carbon atom range can also be selected from these specific examples based on the limitation on the number of carbon atoms.

[0086] In the present invention, specific examples of "C1-C6 alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and cyclohexyl. Alkyl groups with a narrower carbon atom range can also be selected from these specific examples based on the limitation of the number of carbon atoms.

[0087] The first aspect of the present invention provides an N-OH glutamine derivative, wherein the N-OH glutamine derivative has a structure represented by formula (I);

[0088]

[0089] In formula (I), R 1 is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, or substituted benzyl, wherein the substituents of the aryl and benzyl groups are selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro, and halogen;

[0090] R 2is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, diphenylmethyl, triphenylmethyl, wherein the substituents of the aryl and benzyl groups are selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;

[0091] R 3 is hydrogen, an alkyl-substituted silicon group, benzyl, a substituted benzyl group, an allyl group, an allyloxycarbonyl group, or a tert-butyloxycarbonyl group, wherein the substituent of the benzyl group is selected from one of a C1-C6 alkoxy group, a C1-C6 alkyl group, a hydroxyl group, a nitro group, and a halogen group;

[0092] R 1 、R 2 、R 3 Not simultaneously hydrogen;

[0093] The stereo configuration of the chiral carbon of the compound is R or S.

[0094] Preferably, R 1 is a C1-C5 alkyl group and / or a benzyl group.

[0095] Preferably, R 2 It is hydrogen, benzyl, diphenylmethyl, or triphenylmethyl.

[0096] Preferably, R 3 It is hydrogen, alkyl-substituted silicon, benzyl, substituted benzyl, allyl, allyloxycarbonyl, tert-butyloxycarbonyl, wherein the substituent of the benzyl group is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen.

[0097] Preferably, the stereo configuration of the chiral center of the compound is S.

[0098] According to some embodiments of the present invention, R 2 is hydrogen, diphenylmethyl, triphenylmethyl, R 3 It is hydrogen or alkyl substituted silicon.

[0099] According to some embodiments of the present invention, R 2 is trityl, R 3 For hydrogen.

[0100] According to some embodiments of the present invention, R 1 It is a methyl group.

[0101] According to some embodiments of the present invention, R 2 It is a trityl group.

[0102] According to some embodiments of the present invention, R 3 For hydrogen.

[0103] According to some embodiments of the present invention, the stereo configuration of the chiral carbon of the compound is R or S.

[0104] According to some embodiments of the present invention, the compound is a compound having a structure represented by formula (II),

[0105]

[0106] A second aspect of the present invention provides a method for preparing an N-OH glutamine derivative, the method comprising the following steps:

[0107] (1) contacting the compound represented by formula (III) with a deprotection agent to remove the protecting group R 4 , then under the action of halogenated hydrocarbon and base, a compound with the structure shown in formula (IV) is obtained;

[0108]

[0109] (2) contacting the compound of formula (IV) with an oxidizing agent to oxidize the secondary amine to a nitrone to obtain a compound of formula (V);

[0110]

[0111] (3) reacting the compound represented by formula (V) with a hydroxylamine substrate to obtain a compound represented by formula (I);

[0112]

[0113] In formula (I), formula (III), formula (IV) and formula (V), R 1 、R 2 and R 3 The definitions of are the same as those in the first aspect above; R 4 It is an amine protecting group.

[0114] In the present invention, the compound represented by formula (III) can be obtained commercially or prepared. The preparation of the compound represented by formula (III) is not particularly limited and can be carried out according to conventional methods in the art (Sieber, P.; Riniker, B. Tetrahedron Letters 1991, 32, 739).

[0115] According to the present invention, preferably, the deprotecting agent used in the reaction in step (1) is one or more of piperidine, diethylamine, morpholine and N-methylmorpholine, more preferably piperidine and / or diethylamine.

[0116] According to the present invention, preferably, the halogenated hydrocarbon used in the reaction in step (1) is one or more of chloroacetonitrile, bromoacetonitrile, CNCH2OMs and CNCH2OTs, more preferably chloroacetonitrile and bromoacetonitrile.

[0117] According to the present invention, preferably, the base used in the reaction in step (1) is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, 2,6-lutidine and DIPEA, more preferably potassium carbonate and / or DIPEA;

[0118] According to the present invention, preferably, in step (1), the reaction temperature is 0-100°C, more preferably 50-70°C.

[0119] According to the present invention, preferably, in step (1), the reaction is carried out in the presence of a first solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane and ethyl acetate, more preferably DMF and / or acetonitrile, further preferably acetonitrile.

[0120] In the present invention, in step (1), the molar ratio of the compound represented by formula (III) to the deprotection reagent can be 1:(1-100), preferably 1:(1-50), and more preferably 1:(5-20).

[0121] In the present invention, in step (1), the molar ratio of the compound of formula (III) to the halogenated hydrocarbon can be 1:(1-100), preferably 1:(1-50), and more preferably 1:(1-3).

[0122] In the present invention, in step (1), the molar ratio of the compound represented by formula (III) to the base can be 1:(1-100), preferably 1:(1-60), and more preferably 1:(1-5).

[0123] According to the present invention, preferably, in step (2), the reaction temperature is -50 to 50°C, preferably -10 to 0°C;

[0124] According to the present invention, preferably, the oxidant is one or more of Oxone, tert-butyl peroxide, hydrogen peroxide, peracetic acid, sodium hypochlorite and meta-chloroperbenzoic acid, preferably hydrogen peroxide and / or meta-chloroperbenzoic acid;

[0125] According to the present invention, preferably, the reaction is carried out in the presence of a second solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane and ethyl acetate, more preferably DMF and / or dichloromethane, further preferably dichloromethane.

[0126] According to the present invention, the molar ratio of the compound represented by formula (IV) to the oxidant may be 1:(1-20), preferably 1:(1-10), and more preferably 1:(1-3).

[0127] According to the present invention, preferably, in step (3), the hydroxylamine substrate is one or more of hydroxylamine hydrochloride, methoxyhydroxylamine, TBSONH2 and BnONH2, more preferably hydroxylamine hydrochloride.

[0128] According to the present invention, preferably, in step (3), the reaction temperature is -50 to 50°C, more preferably -10 to 0°C.

[0129] According to the present invention, preferably, in step (3), the reaction is carried out in the presence of a third solvent, and the third solvent is a protic solvent selected from one or more of methanol, ethanol, propanol, isopropanol, trifluoroethanol and hexafluoroisopropanol, more preferably methanol and / or ethanol.

[0130] In the present invention, the molar ratio of the compound represented by formula (V) to the hydroxylamine substrate can be 1:(1-20), preferably 1:(1-10), and more preferably 1:(3-6).

[0131] In the present invention, there is no particular limitation on the post-treatment of steps (1), (2), and (3), and various purification methods commonly used in the art can be adopted as long as they can meet the requirements of the present invention.

[0132] The third aspect of the present invention provides use of the N-OH glutamine derivative described in the first aspect of the present invention in the synthesis of dipeptides, natural products and medicines containing N-OH glutamine fragments.

[0133] Preferably, the structure of the natural product is as shown in formula (VII),

[0134]

[0135] Preferably, the drug is an antibacterial drug, an antiviral drug or an antitumor drug.

[0136] The fourth aspect of the present invention provides a dipeptide, wherein the structure of the dipeptide is as shown in formula (VI),

[0137]

[0138] In formula (VI), R 1 、R 2 and R 3 The definition of R in the first aspect of the present invention is the same as 1 、R 2 and R 3 The same definition as;

[0139] R 5 is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH2CONH2, -CH2CH2CONH2, -CH2COOH, -CH2CH2COOH, -(CH2) 1-5 NH2, -(CH2) 1-5 NHC(NH)NH2;

[0140] R 6 It is hydrogen, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, or ethoxycarbonyl, and preferably tert-butoxycarbonyl or fluorenylmethoxycarbonyl.

[0141] The fifth aspect of the present invention provides a method for preparing the dipeptide according to the fourth aspect of the present invention, wherein the method comprises: condensing an acylating agent having a structure represented by formula (XI") and an N-OH glutamine derivative having a structure represented by formula (I) according to the first aspect of the present invention under alkaline conditions to obtain a compound of formula (VI).

[0142]

[0143] R 5 ' is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, -CH2OR 5” 、-CH2SR 5” 、-CH2CONHR 5” 、-CH2CH2CONHR 5” 、-CH2COOR 5” 、-CH2CH2COOR 5” 、-(CH2) 1-5 NHR 5” 、-(CH2) 1-5 NHC(NH)NHR 5” , where R 5” is tert-butyl, trityl, methyl or benzyl;

[0144] R 6 is hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl;

[0145] X is chlorine, bromine or iodine;

[0146] The stereo configuration of the chiral carbon of the compound is R or S.

[0147] Preferably, the base used in the condensation is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate. Furthermore, the molar ratio of the base to the compound represented by formula (I) is (1-10):1.

[0148] Preferably, the solvent used in the condensation is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0149] Preferably, the molar ratio of the compound of the structure represented by formula (I) to the acylating agent of the structure represented by formula (XI") is 1:(1-10).

[0150] The sixth aspect of the present invention provides a method for preparing a compound having a structure represented by formula (XII), wherein the method comprises the following steps:

[0151] (1) treating the N-OH glutamine derivative described in the fourth aspect of the present invention with a demethylation reagent to obtain a compound having a structure represented by formula (VIII);

[0152]

[0153] (2) condensing the compound represented by formula (VIII) with the amine of the compound represented by formula (IX) in the presence of a Lewis acid, a peptide coupling reagent, and a base to obtain a compound represented by formula (X);

[0154]

[0155] In formula (IX) and formula (X), R 7 and R 8 Each is independently C1-C5 alkyl, benzyl, substituted benzyl, C1-C5 acyl, propylidene, benzylidene, more preferably propylidene and / or benzylidene; R 9 and R 10 Each is independently methyl, ethyl, propyl, butyl, tert-butyl, pentyl, neopentyl, more preferably methyl and / or tert-butyl;

[0156] (3) reacting the compound represented by formula (X) with a deprotecting agent, and then reacting with a pyrazolecarboxamidine compound to obtain a compound represented by formula (XI);

[0157]

[0158] In formula (XI), R 11 and R 12Each is independently hydrogen, methyl, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, or 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf).

[0159] (4) Removing the protecting group from the compound represented by formula (XI) under acidic conditions to obtain the compound represented by formula (XI').

[0160]

[0161] Preferably, in step (1), the demethylation reagent is one or more of lithium iodide, sodium iodide, potassium iodide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide.

[0162] Preferably, in step (1), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0163] Preferably, in step (1), the molar ratio of the compound represented by formula (VI) to the demethylation agent is 1:(1-20), more preferably 1:(5-12).

[0164] Preferably, in step (1), the temperature required for the reaction is 0-100°C, more preferably 50-100°C.

[0165] Preferably, in step (2), the Lewis acid is one or more of TMSCl, TESCl, TBSCl, copper chloride, zinc chloride, ferric chloride, chromium chloride, nickel chloride, palladium chloride, cobalt chloride, bismuth chloride, copper bromide, ferric bromide and zinc bromide.

[0166] Preferably, in step (2), the peptide coupling reagent is one or more of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 7-aza-benzotriazole-1-yl-oxytris-(dimethylamino)phosphonium hexafluorophosphate and (3H-1,2,3-triazolo[4,5-b]pyridine-3-oxy)tris-1-pyrrolidinophosphonium hexafluorophosphate.

[0167] Preferably, in step (2), the base is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.

[0168] Preferably, in step (2), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0169] Preferably, in step (2), the molar ratio of the compound represented by formula (VIII) to the Lewis acid is 1:(1-10), more preferably 1:(1-5), and even more preferably 1:(1-2).

[0170] Preferably, in step (2), the molar ratio of the compound represented by formula (VIII) to the peptide coupling reagent is 1:(1-10), more preferably 1:(1-4), and even more preferably 1:(1-2).

[0171] Preferably, in step (2), the molar ratio of the compound represented by formula (VIII) to the base is 1:(1-10), more preferably 1:(1-4).

[0172] Preferably, in step (2), the molar ratio of the compound represented by formula (VIII) to the compound represented by formula (IX) is 1:(1-10), more preferably 1:(1-3).

[0173] Preferably, in step (3), the deprotection reagent is one or more of piperidine, diethylamine, triethylamine and DBU.

[0174] Preferably, in step (3), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

[0175] Preferably, in step (3), the volume ratio of the solvent to the deprotection reagent is 1:(1-10), more preferably 1:(3-8).

[0176] Preferably, in step (3), the molar ratio of the compound represented by formula (X) to the pyrazolecarboxamidine compound is 1:(1-10), more preferably 1:(1-3).

[0177] Preferably, in step (4), the acid used for deprotection is one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid and hexafluorophosphoric acid.

[0178] Preferably, the acid is mixed with a solvent, the volume mixing ratio of the acid to the solvent is 1:(1-10), more preferably 1:(6-10), and the solvent is one or more of water, dichloromethane, acetone and acetonitrile.

[0179] Preferably, in step (4), the volume of the mixed acid and solvent required for 1 mmol of the compound represented by the structure of formula (XI) is 1-10 ml.

[0180] The present invention will be described in detail below through examples.

[0181] In the following preparation examples and embodiments, unless otherwise specified, all raw materials used were commercially available.

[0182] Example 1

[0183] Synthesis of N-OH Glutamine Derivatives

[0184]

[0185] (1) VIII (1.0 g, 1.6 mmol) was dissolved in dichloromethane (10 mL) and placed in an ice-water bath. Diethylamine (5 mL) was then added and the temperature was slowly raised to room temperature to continue the reaction. The end point of the reaction was determined by TLC. After the starting material disappeared, the solvent and diethylamine were removed by concentration to obtain a crude product containing XII, which was directly used in the next step without further purification.

[0186] (2) Then, 10 mL of acetonitrile was added, and bromoacetonitrile (240 mg, 2 mmol) and DIPEA (430 mg, 3.34 mmol) were added to the acetonitrile solution. The temperature was raised to 60°C and the reaction was continued for 5 h until the starting material disappeared. The reaction endpoint was detected by TLC. After the reaction was completed, water (10 mL) was added and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over MgSO4, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the white solid product XIII (615 mg, 87%).

[0187] (3) To a solution of XIII (100 mg, 0.23 mmol) in dichloromethane (5 mL) was added m-CPBA (85%) (94 mg, 0.46 mmol) under ice-water bath conditions. The temperature was then gradually raised to room temperature and the reaction endpoint was monitored by TLC. The reaction was then quenched with Na2S2O3 solution, saturated NaHCO3 solution (5 mL) was added, and stirring was continued for 20 min. The mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous MgSO4, and concentrated to obtain a crude product containing XIV, which was used in the next step without further purification.

[0188] (4) Hydroxylamine hydrochloride (76.5 mg, 1.1 mmol) was added to a methanol solution (3.5 mL) of the above nitrone XIV. The mixture was reacted at 60°C until the starting material disappeared. The reaction endpoint was detected by TLC. After the reaction, the solvent was concentrated under vacuum and dissolved in dichloromethane. The solid was filtered off, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain product II (80.0 mg, 87%). 1 H NMR (500MHz, CDCl3) δ7.31–7.22(m,15H),6.71(s,1H),5.50(br,1H),3.74(s,3H),3.50(dd,J=8.5,5.3Hz,1H),2.43(m,1H),2.34(m,1H),2.07(m,2H)

[0189] Applications of N-OH glutamine derivatives

[0190] Example 1

[0191] Synthesis of dipeptides containing N-OH glutamine.

[0192]

[0193] To a suspension of II (500 mg, 1.2 mmol) in dichloromethane (10 mL) was added pyridine (189 mg, 2.4 mmol). Subsequently, a solution of Fmoc-Gly-Cl (379 mg, 1.2 mmol) in dichloromethane (1 mL) was added dropwise. The mixture was allowed to react for 10 minutes, and TLC indicated complete reaction of the starting material. The mixture was concentrated under vacuum, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous MgSO₄, filtered, and separated by column chromatography to afford XV (808 mg, 97%) as a white solid. 1 H NMR (500MHz, CDCl3) δ8.74(s,1H),7.69(d,J=7.6Hz,2H),7.58(d,J=7.5Hz,2H),7.32( t,J=7.5Hz,2H),7.24(t,J=7.5Hz,2H),7.22–7.14(m,15H),6.76(s,1H),5.48(s,1H), 4.89(dd,J=11.2,4.0Hz,1H),4.37–4.31(m,2H),4.20(t,J=7.2Hz,1H),4.11–4.04(m, 1H), 3.72 (dd, J = 18.6, 4.7Hz, 1H), 3.61 (s, 3H), 2.64 (m, 1H), 2.28 (m, 2H), 2.11 (m, 1H).

[0194] Example 2

[0195] To a solution of II (500 mg, 1.2 mmol) in DMF (10 mL) was added DIPEA (309 mg, 2.4 mmol). Subsequently, a solution of Fmoc-Gly-Cl (379 mg, 1.2 mmol) in dichloromethane (1 mL) was added dropwise. The mixture was allowed to react for 10 minutes, and TLC indicated complete reaction of the starting material. The mixture was concentrated under vacuum, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous MgSO₄, filtered, and separated by column chromatography to afford XV (749 mg, 90%) as a white solid.

[0196] Example 3

[0197] Synthesis of natural products containing N-OH glutamine.

[0198]

[0199] 200 mg of the compound represented by formula (XV) was dissolved in 5 mL of ethyl acetate, and 388 mg of anhydrous lithium iodide was added. The mixture was then heated to 80°C and refluxed for 24 hours. After the reaction, the mixture was cooled to room temperature, the pH was adjusted to 4 with 0.1N dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was then washed with saturated sodium thiosulfate, dried, concentrated, and separated by silica gel column chromatography to obtain 137 mg of a white solid (compound represented by formula (XVI)) in a yield of 73%.

[0200] 684 mg of the compound of structure shown in formula (XVI) was suspended in 10 mL of dichloromethane. 387 mg of DIPEA and 130 mg of TMSCl were added in an ice-water bath and reacted for 10 minutes. 456 mg of HATU and 395 mg of amine (IX) were added. The temperature was then slowly raised to room temperature and the reaction was continued for half an hour. The mixture was extracted twice with water and 10 mL of ethyl acetate. The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain 743 mg of a foamy solid (compound of structure shown in formula (XVII)) in a 70% yield.

[0201] At room temperature, 200 mg of the compound represented by formula (XVII) was dissolved in 5 mL of dichloromethane, followed by the addition of 5 mL of diethylamine. The reaction was allowed to proceed for 10 minutes. After complete reaction, the mixture was concentrated under vacuum, the solvent was removed by toluene, and the mixture was dissolved in 5 mL of DMF. 49 mg of DIPEA and N,N-di-tert-butyloxycarbonyl-1-hydrogen-pyrazole-1-carboximidamide were added, and the reaction endpoint was monitored by TLC. After the reaction, 15 mL of water was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain 153 mg of a foamy solid (compound represented by formula (XVIII)) with a yield of 75%.

[0202] The compound represented by Formula (XVIII) was dissolved in 10 mL of 70% acetic acid and the temperature was slowly raised to 50°C. After the reaction, the solvent was concentrated and dried with toluene. 10 mL of trifluoroacetic acid / dichloromethane (9:1) was then added. The reaction was complete after 5 minutes. After concentration and separation by C18 column chromatography, 205 mg of the product, the compound represented by Formula (XVII), was obtained in a 94% yield. 1 H NMR (500MHz, DMSO) δ11.11(s,1H),10.89(m,1H),9.86(s,1H),7.89(t,J=5.2Hz,1H),7.40(m,1H),7.32(s,1H),6.87(s,1H),4.78(m,1H),4.41(s, 1H),4.32–4.17(m,1H),4.14–4.10(m,1H),3.99(m,1H),3.72(s,2H),3.2 9–3.25(m,1H),3.18–3.16(m,1H),2.13–2.08(s,3H),2.01–1.96(m,2H).

[0203] Example 4

[0204] 200 mg of the compound represented by formula (XV) was dissolved in 5 mL of methanol, and 20 mg of sodium methoxide was added. The mixture was then heated to 80°C and refluxed for 24 hours. After the reaction, the mixture was cooled to room temperature, the pH was adjusted to 4 with 0.1N dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was then washed with saturated sodium thiosulfate, dried, concentrated, and separated by silica gel column chromatography to obtain 159 mg of a white solid (compound represented by formula (XVI)) in an 85% yield.

[0205] 684 mg of the compound represented by the structure of formula (XVI) was suspended in 10 mL of dichloromethane. 387 mg of triethylamine and 130 mg of cupric chloride were added under an ice-water bath and reacted for 10 minutes. 456 mg of HBTU and 395 mg of amine (IX) were then added. The mixture was then slowly warmed to room temperature and the reaction continued for half an hour. The mixture was extracted twice with water and 10 mL of ethyl acetate. The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain 743 mg of a foamy solid (compound represented by the structure of formula (XVII)) in a 70% yield.

[0206] At room temperature, 200 mg of the compound represented by formula (XVII) was dissolved in 5 mL of DMF, followed by the addition of 5 mL of triethylamine. The reaction was allowed to proceed for 10 minutes. After complete reaction, the mixture was concentrated under vacuum, the solvent was removed by toluene, and the mixture was dissolved in 5 mL of DMF. 49 mg of DIPEA and N,N-di-tert-butyloxycarbonyl-1-hydrogen-pyrazole-1-carboximidamide were added, and the reaction endpoint was monitored by TLC. After the reaction, 15 mL of water was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain 163 mg of a foamy solid (compound represented by formula (XVIII)) with a yield of 80%.

[0207] The compound represented by formula (XVIII) was dissolved in 10 mL of 50% acetic acid and the temperature was slowly raised to 100°C. After the reaction, the solvent was concentrated and dried with toluene. 10 mL of trifluoroacetic acid / dichloromethane (5:1) was then added. The reaction was complete after 5 minutes. The solution was concentrated and separated by C18 column chromatography to obtain 185 mg of the product represented by formula (XVII), with a yield of 85%.

[0208] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. An N-OH glutamine derivative, characterized in that The N-OH glutamine has a structure shown in formula (I), In formula (I), R 1 is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, or substituted benzyl, wherein the substituents of the aryl and benzyl groups are selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro, and halogen; R 2 is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, diphenylmethyl, triphenylmethyl, wherein the substituent of the aryl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen; R 3 is hydrogen, an alkyl-substituted silicon group, benzyl, a substituted benzyl group, an allyl group, an allyloxycarbonyl group, or a tert-butyloxycarbonyl group, wherein the substituent of the benzyl group is selected from one of a C1-C6 alkoxy group, a C1-C6 alkyl group, a hydroxyl group, a nitro group, and a halogen group; R 1 、R 2 、R 3 Not simultaneously hydrogen; The stereo configuration of the chiral carbon of the compound is R or S.

2. The derivative according to claim 1, wherein R 1 is a C1-C5 alkyl group and / or a benzyl group.

3. The derivative according to claim 1, wherein R 2 It is hydrogen, benzyl, diphenylmethyl, or triphenylmethyl.

4. The derivative according to claim 1, wherein R 3 It is hydrogen, alkyl-substituted silicon, benzyl, substituted benzyl, allyl, allyloxycarbonyl, tert-butyloxycarbonyl, wherein the substituent of the benzyl group is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen.

5. The derivative according to claim 1, wherein R 2 is hydrogen, diphenylmethyl, triphenylmethyl, R 3 It is hydrogen or alkyl substituted silicon.

6. The derivative according to claim 1, wherein R 2 is trityl, R 3 For hydrogen.

7. The derivative according to claim 1, wherein The stereo configuration of the chiral center of the compound is S.

8. The derivative according to claim 1 or 2, wherein The structure of the N-OH glutamine is shown in formula (II), 9. A method for preparing an N-OH glutamine derivative, characterized in that: The method comprises the following steps: (1) contacting the compound represented by formula (III) with a deprotection agent to remove the protecting group R 4 , then under the action of halogenated hydrocarbon and base, a compound with the structure shown in formula (IV) is obtained; (2) contacting the compound represented by formula (IV) with an oxidant to oxidize the secondary amine to a nitrone, thereby obtaining a compound represented by formula (V); (3) reacting the compound of formula (V) with a hydroxylamine substrate to obtain a compound of formula (I), In formula (I), formula (III), formula (IV) and formula (V), R 1 、R 2 and R 3 The definition is the same as that in claim 1 or 2; R 4 It is an amine protecting group.

10. The method according to claim 9, wherein: In step (1), the deprotection reagent is one or more of piperidine, diethylamine, morpholine and N-methylmorpholine.

11. The method according to claim 10, wherein: In step (1), the deprotection reagent is piperidine and / or diethylamine.

12. The method according to claim 9, wherein In step (1), the halogenated hydrocarbon is one or more of chloroacetonitrile and bromoacetonitrile.

13. The method according to claim 12, wherein: In step (1), the halogenated hydrocarbons are chloroacetonitrile and bromoacetonitrile.

14. The method according to claim 9, wherein In step (1), the base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, 2,6-lutidine and DIPEA.

15. The method according to claim 14, wherein In step (1), the base is potassium carbonate and / or DIPEA.

16. The method according to claim 9, wherein In step (1), the reaction temperature is 0-100°C.

17. The method according to claim 16, wherein In step (1), the reaction temperature is 50-70°C.

18. The method according to claim 9, wherein In step (1), the reaction is carried out in the presence of a first solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, ether, dichloromethane and ethyl acetate.

19. The method according to claim 18, wherein In step (1), the first solvent is DMF and / or acetonitrile.

20. The method according to claim 19, wherein In step (1), the first solvent is acetonitrile.

21. The method according to claim 9, wherein In step (2), the reaction temperature is -50 to 50°C.

22. The method according to claim 21, wherein In step (2), the reaction temperature is -10 to 0°C.

23. The method according to claim 9, wherein In step (2), the oxidant is one or more of Oxone, tert-butyl peroxide, hydrogen peroxide, peracetic acid, sodium hypochlorite and m-chloroperbenzoic acid.

24. The method according to claim 23, wherein In step (2), the oxidant is hydrogen peroxide and / or m-chloroperbenzoic acid.

25. The method according to claim 9, wherein In step (2), the reaction is carried out in the presence of a second solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, ether, dichloromethane and ethyl acetate.

26. The method according to claim 25, wherein The second solvent is DMF and / or dichloromethane.

27. The method according to claim 26, wherein The second solvent is dichloromethane.

28. The method according to claim 9, wherein In step (3), the hydroxylamine substrate is one or more of hydroxylamine hydrochloride, O-methylhydroxylamine, TBSONH2, and BnONH2.

29. The method according to claim 28, wherein In step (3), the hydroxylamine substrate is hydroxylamine hydrochloride.

30. The method of claim 9, wherein: In step (3), the reaction temperature is -50 to 50°C.

31. The method according to claim 30, wherein In step (3), the reaction temperature is -10 to 0°C.

32. The method of claim 9, wherein: In step (3), the reaction is carried out in the presence of a third solvent, which is a protic solvent selected from one or more of methanol, ethanol, propanol, isopropanol, trifluoroethanol and hexafluoroisopropanol.

33. The method according to claim 32, wherein The third solvent is methanol and / or ethanol.

34. Use of the N-OH glutamine derivative according to any one of claims 1 to 8 in the synthesis of dipeptides and natural products containing N-OH glutamine fragments, in, The structure of the natural product is shown in formula (VII), The structure of the dipeptide is shown in formula (VI), In formula (VI), R 1 、R 2 and R 3 has the same meaning as in claim 1 or 2; R 5 is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH2CONH2, -CH2CH2CONH2, -CH2COOH, -CH2CH2COOH, -(CH2) 1-5 NH2, -(CH2) 1-5 NHC(NH)NH2; R 6 It is hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, or ethoxycarbonyl.

35. The use according to claim 34, wherein R 6 It is tert-butyloxycarbonyl and fluorenylmethoxycarbonyl.

36. A method for preparing a dipeptide, characterized in that: The method comprises: condensing an acylating agent having a structure represented by formula (XI") and an N-OH glutamine derivative having a structure represented by formula (I) according to any one of claims 1 to 8 under alkaline conditions to obtain a compound having formula (VI); R 5 ' is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, -CH2OR 5” 、-CH2SR 5” 、-CH2CONHR 5” 、-CH2CH2CONHR 5” 、-CH2COOR 5” 、-CH2CH2COOR 5” 、-(CH2) 1-5 NHR 5” 、-(CH2) 1-5 NHC(NH)NHR 5” , where R 5” is tert-butyl, trityl, methyl or benzyl; R 6 is hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl; X is chlorine, bromine or iodine; The stereo configuration of the chiral carbon of the compound is R or S, In formula (VI), R 1 、R 2 and R 3 The meaning is the same as in any one of claims 1 to 8; R 5 is hydrogen, C1-C5 alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH2CONH2, -CH2CH2CONH2, -CH2COOH, -CH2CH2COOH, -(CH2) 1-5 NH2, -(CH2) 1-5 NHC(NH)NH2; R 6 and R in formula (XI") 6 same.

37. The method according to claim 36, wherein R 6 It is tert-butyloxycarbonyl and fluorenylmethoxycarbonyl.

38. The method of claim 36, wherein: The base used is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.

39. The method according to claim 36, wherein The solvent used is one or more of dichloromethane, chloroform, tetrahydrofuran, ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.

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