Method for synthesizing cyclic dipeptide

Abstract

The invention provides a method for synthesizing cyclic dipeptide, which comprises the following steps: (1) in the presence of a condensing agent, carrying out condensation reaction on amino acid of carbobenzoxy protected amino and amino acid methyl ester hydrochloride to generate chain dipeptide A retaining carbobenzoxy and methyl ester; and (2) in the presence of ammonium formate and palladium on carbon, removing protecting groups from amino acids and attacking ester bonds by amino groups to complete ring closing in one step, so as to obtain the cyclic dipeptide with the initial amino acid configuration reserved.

Description

Technical Field

[0001] The present invention relates to the chemical synthesis of cyclic dipeptides, and specifically provides a simple method for synthesizing cyclic dipeptides. Background Art

[0002] Cyclic dipeptides are piperazine dione compounds with a rigid structure and biological activity, formed by two amino acids connected end to end. Cyclic dipeptides have a variety of biological activities, including anti-tumor, antibacterial, participation in intercellular information transmission, antioxidant and hypoglycemic, regulation of appetite and energy metabolism, etc. Cyclic dipeptides are widely available and can be obtained by extraction from organisms such as bacteria, fungi, plants and animals, or by chemical synthesis or biosynthesis. Extraction or biosynthesis from organisms is mainly through solvent immersion or extraction of fermentation broth or resin adsorption, which currently has the problems of high cost and immature technology. The large-scale chemical synthesis method is mainly obtained by palladium-carbon hydrogenation of benzyloxycarbonyl protected amino dipeptide methyl ester (see Tao Zhaolin, Wang Youchu, Synthesis of cyclo(L-phenylpropyl-L-proline), Journal of Anhui Normal University, 1999, 22 (3), 216-218), or tert-butyloxycarbonyl protected amino dipeptide methyl ester high temperature and high pressure hydrothermal reaction (see Thajudeen H, Park K, Moon S, Hong I, An efficient green synthesis of proline-based cyclic dipeptides under water-mediated catalyst-free conditions, Tetrahedron Letters, 2010, 51, 1303-1305). These two chemical synthesis methods have high requirements for equipment and have certain operational safety risks. Hydrogenation involves the use of dangerous and explosive gases, the purchase and operation license of special equipment and other series of requirements; high temperature and high pressure hydrothermal reaction also involves the purchase and operation license of pressure-resistant equipment and other requirements. From the perspective of cost and safety, there are certain unsatisfactory aspects.

[0003] The applicant has now discovered a method for preparing a cyclic dipeptide with simple steps. Specifically, the applicant has discovered that amino acids with amino groups protected by benzyloxycarbonyl (Cbz) are condensed with amino acid methyl ester hydrochloride in a solution to generate a chain dipeptide A retaining the benzyloxycarbonyl and methyl ester, and then the dipeptide A is deprotected and ring-closed in one step through ammonium formate-palladium carbon to obtain a cyclic dipeptide retaining the configuration of the starting amino acid. The present invention eliminates the need for pressure-resistant equipment and the use of explosive gases, and completes production under very safe and peaceful conditions. Summary of the invention

[0004] In one aspect, the present invention provides a method for synthesizing a cyclic dipeptide, comprising the following steps:

[0005] (1) In the presence of a condensing agent, an amino acid with a benzyloxycarbonyl protected amino group undergoes a condensation reaction with an amino acid methyl ester hydrochloride to generate a chain dipeptide A retaining the benzyloxycarbonyl group and the methyl ester;

[0006] (2) In the presence of ammonium formate and palladium on carbon, the amino acid is deprotected and the amino group attacks the ester bond to complete the ring closure in one step, thereby obtaining a cyclic dipeptide that retains the configuration of the starting amino acid.

[0007] In a preferred embodiment, the amino acids used in the method of the present invention include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, hydroxyproline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.

[0008] In a preferred embodiment, the condensing agent is selected from: EDCI, DCC, DMAP, HOBT, HOAT, HATU, HBTU, PyBOP or a combination thereof.

[0009] In a preferred embodiment, step (1) is performed in a solution selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or a combination thereof.

[0010] In a preferred embodiment, step (2) is performed in a solution, and the solution is an alcohol, more preferably methanol, ethanol, isopropanol or a combination thereof.

[0011] In a preferred embodiment, the method of the present invention comprises the following steps:

[0012] (1) In the presence of a condensing agent, a compound of formula (I) reacts with a compound of formula (II) to generate a chain dipeptide A of formula (III) that retains a benzyloxycarbonyl group and a methyl ester;

[0013]

[0014] (2) In the presence of ammonium formate and palladium on carbon, the compound of formula (III) completes the deprotection of the amino acid and the amino group attacks the ester bond to complete the ring closure in one step, thereby obtaining a cyclic dipeptide of formula (IV) that retains the configuration of the starting amino acid.

[0015]

[0016] Where:

[0017] R1, R2, R3, R4 are independently selected from the group consisting of: hydrogen, -C1-C6-alkyl, -C1-C6-haloalkyl, -C1-C6-alkoxy, -C1-C6-haloalkoxy, -(C 1-4 alkylene)aryl, or aryl having 5 to 14 ring atoms; or

[0018] R1 and R2, or R3 and R4, together with their adjacent atoms, form a ring selected from the group consisting of a heterocyclic group having 3 to 11 atoms, or a carbocyclic group having 3 to 10 atoms.

[0019] In a preferred embodiment, R1, R2, R3, R4 are independently selected from: hydrogen, -C1-C4-alkyl, -C1-C4-haloalkyl, -C1-C4-alkoxy, -C1-C4-haloalkoxy, -(C 1-4 or R1 and R2, or R3 and R4 together with their adjacent atoms form a 5-6 membered monocyclic heterocyclic ring, wherein the heteroatoms are selected from one to up to three of O, N or S.

[0020] In a preferred embodiment, step (2) uses ammonium formate and 10% palladium carbon, wherein the weight ratio of ammonium formate to 10% palladium carbon is 10: 1. More preferably, step (2) is performed under heating reflux. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The cyclo-L-leucine-L-proline dipeptide prepared in Example 1 is shown. 1 HNMR spectrum.

[0023] Figure 2 The cyclo-L-leucine-L-proline dipeptide prepared in Example 1 is shown. 13 CNMR spectrum.

[0024] Figure 3 The results of EIMS (relative abundance) of the cyclo-L-leucine-L-proline dipeptide prepared in Example 1 are shown.

[0025] Figure 4 The cyclo-L-phenylalanine-L-proline dipeptide prepared in Example 2 is shown. 1 HNMR spectrum.

[0026] Figure 5 The cyclo-L-phenylalanine-L-proline dipeptide prepared in Example 2 is shown. 13 CNMR spectrum.

[0027] Figure 6The results of EIMS (relative abundance) of the cyclo-L-phenylalanine-L-proline dipeptide prepared in Example 2 are shown. DETAILED DESCRIPTION

[0028] In this specification, unless otherwise specified, the technical features of each preferred technical solution and the more preferred technical solution can be combined with each other to form a new technical solution. For the purpose of brevity, the applicant omits the specific description of these combinations in the specification. However, all the technical solutions after the combination of these technical features should be deemed to be clearly recorded in writing in this specification.

[0029] Unless otherwise specified, percentages are by weight. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0030] definition

[0031] As used herein, "alkyl" refers to a branched or straight-chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl and neopentyl. The alkyl group can be unsubstituted or substituted with one or more substituents. In some embodiments, the alkyl group contains 1-9 carbon atoms (e.g., 1-6 carbon atoms, 1-4 carbon atoms, or 1-2 carbon atoms).

[0032] As used herein, "alkenyl" refers to a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In various embodiments, alkenyl can be unsubstituted or substituted with one or more substituents. Typically, alkenyl contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0033] As used herein, "alkynyl" refers to a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, etc. In various embodiments, the alkynyl group can be unsubstituted or substituted with one or more substituents. Typically, the alkynyl group contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0034] As used herein, "alkylene" refers to a divalent branched or straight-chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, tert-pentylene, and neopentylene. Alkylene can be unsubstituted or substituted with one or more substituents. Alkylene can be saturated or unsaturated at one or more positions (e.g., containing -C=C- or -C≡C- subunits). In some embodiments, alkylene includes 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0035] As used herein, "alkenylene" refers to a divalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as vinylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene, 2-butenylene, etc. In various embodiments, alkenylene can be unsubstituted or substituted with one or more substituents. Typically, alkenylene groups contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms or 2 carbon atoms).

[0036] As used herein, "alkynylene" refers to a divalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynylene, 1-propynylene, 1-butynylene, 2-butynylene, etc. In various embodiments, the alkynylene group can be unsubstituted or substituted with one or more substituents. Typically, the alkynylene group contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0037] As used herein, "carbocyclyl" refers to a ring system containing only carbon atoms in the ring system skeleton, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl. Carbocyclyl can include multiple fused rings. Carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Carbocyclyl groups can be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups contain 3 to 10 carbon atoms, such as 3 to 6 carbon atoms.

[0038] As used herein, "aryl" refers to a monocyclic, bicyclic, tricyclic or polycyclic group having only carbon atoms in the ring backbone, having 5-14 ring atoms, or 5, 6, 9 or 10 ring atoms; having 6, 10 or 14 π electrons in a cyclic array; and at least one ring in the system is aromatic. The aryl group may be unsubstituted or substituted with one or more substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, etc. In some embodiments, the aryl group is phenyl.

[0039] As used herein, "arylalkylene" refers to an aryl-alkylene-group in which the aryl and alkylene portions are as described above. In some embodiments, the arylalkylene contains C 1-4 Alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenylethyl.

[0040] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic or polycyclic group having 5-14 ring atoms, or 5, 6, 9 or 10 ring atoms; having a total of 6, 10 or 14 π electrons in a cyclic array; and at least one ring in the system contains one or more heteroatoms independently selected from N, O and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl , quinolyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, etc. In some embodiments, the heteroaryl group is selected from the group consisting of thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0041] As used herein, "haloalkyl" refers to a hydrocarbon substituent that is a straight chain, branched chain, alkyl, alkenyl, or alkynyl group substituted with one or more of chlorine, bromine, fluorine, or iodine atoms. In some embodiments, the haloalkyl is a fluoroalkyl group in which one or more hydrogen atoms have been replaced with fluorine. In some embodiments, the haloalkyl group is 1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length, or 1 carbon in length). The term "haloalkylene" refers to a diradical variant of a haloalkyl group, which can serve as a spacer between groups, other atoms or rings, and other functional groups.

[0042] As used herein, "heterocyclyl" refers to a non-aromatic ring system containing at least one heteroatom in the ring system backbone. The heterocyclyl may include multiple fused rings. The heterocyclyl may be unsubstituted or substituted with one or more substituents. In some embodiments, the heterocycle is 3-11 members. In a six-membered monocyclic heterocycle, the heteroatom is selected from one to up to three of O, N or S, wherein when the heterocycle is a five-membered ring, it may have one or two heteroatoms selected from O, N or S. Examples of heterocyclic groups include: azetidinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, oxazinyl, thiazinyl, sulfinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, etc. In some embodiments, the heterocyclic group is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[0043] As used herein, when indicating that two groups are "connected" or "combined" to form a "ring", it is understood that a bond is formed between the two groups, which may include replacing a hydrogen atom on one or both groups with a bond to form a carbocyclyl, heterocyclyl, aryl or heteroaryl ring. Those skilled in the art will appreciate that such rings can and are easily formed by conventional chemical reactions. In some embodiments, the ring has 3-7 members, for example, 5 or 6 members.

[0044] Synthesis method

[0045] The purpose of the present invention is to provide a method for preparing a cyclodipeptide with simple steps. Ammonium formate and palladium carbon are core reagents, ammonium formate is used as a hydrogen source, and palladium carbon is a catalyst. The advantage of the present application is that the desired cyclodipeptide can be prepared under highly safe conditions by one-time deprotection and ring closure without the need for hydrogen and high-pressure hydrothermal equipment.

[0046] The steps of the present invention include:

[0047] 1) The amino acid with benzyloxycarbonyl (Cbz) protected amino group is condensed with amino acid methyl ester hydrochloride in a solution (including dichloromethane, chloroform, 1,2-dichloroethane, etc.) by a condensation agent (including EDCI, DCC, DMAP, HOBT, HOAT, HATU, HBTU, PyBOP, etc.) to generate a chain dipeptide A retaining the benzyloxycarbonyl and methyl ester.

[0048]

[0049] Step 1

[0050] 2) dissolving the dipeptide A obtained in step 1) in alcohol (methanol or ethanol or isopropanol, at a ratio of 3-30 ml of alcohol per gram of dipeptide), adding 2-6 equivalents of ammonium formate and 10% palladium carbon in an amount of one tenth of the weight of ammonium formate, heating and reflux for 1-3 hours, cooling to room temperature, filtering to remove palladium carbon, introducing the filtrate into a separatory funnel, adding two volumes of ethyl acetate, washing with 2N hydrochloric acid, saturated brine and deionized water, respectively, concentrating the organic phase to a paste, recrystallizing with water and alcohol (methanol, ethanol or isopropanol can be used), filtering and collecting the crystals, and the product is a cyclic dipeptide retaining the initial amino acid configuration

[0051]

[0052] Step 2

[0053] In some embodiments, the DIPEA used in step 1 can be regarded as a catalyst for the reaction.

[0054] In a preferred embodiment, the amino acids of the present invention are selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.

[0055] In some embodiments, the amino acid of the present invention can be a modified amino acid, such as a hydroxy-modified amino acid. In a specific embodiment, the amino acid used in the present invention is hydroxyproline.

[0056] In the above formula (I), formula (II), formula (III) and formula (IV), R1, R2, R 3， R4 is a side chain of an amino acid. In a preferred embodiment, R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, -C1-C6-alkyl, -C1-C6-haloalkyl, -C1-C6-alkoxy, -C1-C6-haloalkoxy, -(C 1-4 In some embodiments, R1 and R2, or R3 and R4, can form a cyclic group. In a preferred embodiment, R1 and R2, or R3 and R4, together with their adjacent atoms, form a ring selected from the group consisting of a heterocyclic group having 3 to 11 atoms, or a carbocyclic group having 3 to 10 atoms.

[0057] The advantage of the present invention is that ammonium formate-palladium carbon is used to deprotect the amino group of the intermediate A, and heating reflux is performed simultaneously, and the amino group attacks the ester bond to complete the ring closure after the deprotection is completed in one step. The method for synthesizing cyclodipeptides of the present invention is simple to operate, low in cost, safer and more reliable than hydrogen hydrogenation debenzyloxycarbonylation, and has simple equipment requirements.

[0058] The present invention is further described in detail below in conjunction with specific embodiments. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages usually represent weight percentages. The protection scope of the present invention includes but is not limited to the following examples. Any modifications made to the details and forms of the technical solution of the present invention without departing from the meaning and scope of the present application fall within the protection scope of the present invention.

[0059] The following examples are intended to further illustrate the present invention but are not intended to limit the present invention in any way.

[0060] The reagents used in the examples were purchased from Adamas Reagent Company.

[0061] Abbreviations

[0062] Cbz: benzyloxycarbonyl

[0063] DCM: dichloromethane;

[0064] EDC: 1,2-dichloroethane;

[0065] TCM: chloroform;

[0066] DIPEA: diisopropylethylamine

[0067] EDCI: 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide

[0068] DCC: dicyclohexylcarbodiimide;

[0069] DMAP: 4-dimethylaminopyridine;

[0070] HOBT: 1-hydroxybenzotriazole;

[0071] HOAT: N-hydroxy-7-azabenzotriazole;

[0072] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxo

[0073] Hexafluorophosphate;

[0074] HBTU: N,N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate;

[0075] PyBOP: benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;

[0076] Example 1: Synthesis of Cyclic-L-Leucine-L-Proline Dipeptide

[0077] 10mmol Cbz-L-leucine, 10mmol L-proline methyl ester, 30mL DCM, add 3mL DIPEA, 2.45g EDCI, 80mg DMAP under ice bath to 0℃, keep ice bath, stir the reaction at 360 rpm for 18 hours. Add 30mL DCM, pour into a separatory funnel, wash with 20mL 2N HCl, 20mL brine, 20mL saturated sodium bicarbonate, 20mL water in sequence, and concentrate the organic phase to obtain a paste product.

[0078] Add 30mL of methanol to the paste product, add 0.3g of 10% palladium carbon, add 3g of ammonium formate, reflux at 80°C for 2 hours, cool, filter, add 60mL of ethyl acetate to the filtrate, pour into a separatory funnel, wash with 20mL of 2N hydrochloric acid, 20mL of saturated brine, and 20mL of deionized water in sequence. Concentrate the ethyl acetate phase, evaporate to dryness, add 30mL of methanol, 30mL of water, heat to reflux, cool to room temperature and filter after full dissolution to obtain 1.58g of the product cyclo-L-leucine-L-proline dipeptide, with a yield of 75% (based on the yield calculated according to the first step starting equivalent).

[0079] 1 HNMR(DMSO-d6,600M)δ:8.02(1H,s),4.19(1H,t,J=8.1Hz),4.02(1H,t,J=7.8Hz),3.35-3.41(2 H,m),2.12(1H,m),1.75-1.95(5H,m),1.35(1H,m),0.87(3H,d,J=6.6Hz),0.86(3H,d,J=6.6Hz).

[0080] 13 CNMR(DMSO-d6,150M)δ:170.8,167.0,58.9,53.0,45.3,38.2,27.9,24.5,23.3,22.9,22.4.

[0081] EIMS (relative abundance): 210 [M] + (1%), 154 (100%), 70 (99%)

[0082] [α] 25℃ -124 (MeOH, C = 0.30)

[0083] Example 2: Synthesis of Cyclic-L-Phenylalanine-L-Proline Dipeptide

[0084] 10mmol Cbz-L-phenylalanine, 10mmol L-proline methyl ester, 30mL DCM, add 3mL DIPEA, 2.45g EDCI, 80mg DMAP, keep ice bath, stir overnight at 360 rpm. Add 30mL DCM, pour into a separatory funnel, wash with 20mL 2N HCl, 20mL brine, 20mL saturated sodium bicarbonate, 20mL water, concentrate the organic phase to obtain a paste.

[0085] Add 30mL of methanol to the paste, add 0.3g of 10% palladium carbon, add 3g of ammonium formate, reflux at 80°C for 2 hours, cool, filter, add 60mL of ethyl acetate to the filtrate, pour into a separatory funnel, wash with 20mL of 2N hydrochloric acid, 20mL of saturated brine, and 20mL of deionized water in sequence. Concentrate the ethyl acetate phase, evaporate to dryness, add 30mL of methanol, 30mL of water, heat to reflux, cool to room temperature and filter after full dissolution to obtain 1.95g of the product cyclo-L-phenylalanine-L-proline dipeptide, with a yield of 80% (calculated according to the equivalent of the first step starting material).

[0086] 1 HNMR(DMSO-d6,600M)δ:8.01(1H,s),7.18-7.29(5H,m)4.36(1H,t,J=4.8Hz),4.07(1H,t ,J=7.6Hz),3.39(1H,m),3.28(1H,m),3.05(2H,m),2.01(1H,m),1.73(2H,m),1.42(1H,m)

[0087] 13 CNMR(DMSO-d6,150M)δ:169.5,165.5,137.7,130.3,128.4,126.8,58.8,56.2,45.0,35.8,28.2,22.4

[0088] EIMS (relative abundance): 244[M]+ (40%), 125 (100%), 70 (60%)

[0089] [α] 25℃ -99.7 (MeOH, C = 0.30)

[0090] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing a cyclic dipeptide, comprising the following steps: (1) In the presence of a condensing agent, an amino acid with a benzyloxycarbonyl protected amino group undergoes a condensation reaction with an amino acid methyl ester hydrochloride to generate a chain dipeptide A retaining the benzyloxycarbonyl group and the methyl ester; (2) In the presence of ammonium formate and palladium on carbon, the amino acid is deprotected and the amino group attacks the ester bond to complete the ring closure in one step, thereby obtaining a cyclic dipeptide that retains the configuration of the starting amino acid.

2. The method according to claim 1, characterized in that The amino acids are selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, hydroxyproline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.

3. The method according to claim 1, characterized in that The condensing agent is selected from: EDCI, DCC, DMAP, HOBT, HOAT, HATU, HBTU, PyBOP or a combination thereof.

4. The method according to claim 1, characterized in that Step (1) is completed in a solution selected from the group consisting of: dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or a combination thereof.

5. The method according to claim 1, characterized in that Step (2) is performed in a solution, and the solution is an alcohol.

6. The method according to claim 5, characterized in that The alcohol is selected from: methanol, ethanol, isopropanol or a combination thereof.

7. The method according to claim 1, characterized in that The method comprises the following steps: (1) In the presence of a condensing agent, a compound of formula (I) reacts with a compound of formula (II) to generate a chain dipeptide A of formula (III) that retains a benzyloxycarbonyl group and a methyl ester; (2) In the presence of ammonium formate and palladium on carbon, the compound of formula (III) completes the deprotection of the amino acid and the amino group attacks the ester bond to complete the ring closure in one step, thereby obtaining a cyclic dipeptide of formula (IV) that retains the configuration of the starting amino acid. Where: R1, R2, R3, R4 are independently selected from the group consisting of: hydrogen, -C1-C6-alkyl, -C1-C6-haloalkyl, -C1-C6-alkoxy, -C1-C6-haloalkoxy, -(C 1-4 alkylene)aryl, or aryl having 5 to 14 ring atoms; or R1 and R2, or R3 and R4, together with their adjacent atoms, form a ring selected from the group consisting of a heterocyclic group having 3 to 11 atoms, or a carbocyclic group having 3 to 10 atoms.

8. The method according to claim 7, characterized in that R1, R2, R3, R4 are independently selected from the group consisting of: hydrogen, -C1-C4-alkyl, -C1-C4-haloalkyl, -C1-C4-alkoxy, -C1-C4-haloalkoxy, -(C 1-4 or R1 and R2, or R3 and R4 together with their adjacent atoms form a 5-6 membered monocyclic heterocyclic ring, wherein the heteroatoms are selected from one to up to three of O, N or S.

9. The method according to claim 7, characterized in that Step (2) uses ammonium formate and 10% palladium carbon, wherein the weight ratio of ammonium formate to 10% palladium carbon is 10:

1.

10. The method according to claim 7, characterized in that Step (2) is carried out under heating reflux conditions.

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