KR20140078366A - Manufacturing method of cyclic dipeptide - Google Patents

Abstract

The present invention relates to a manufacturing method of cyclic dipeptide and, more specifically, to a method for directly and simply manufacturing a cyclic dipeptide compound from a linear dipeptide compound under the presence of a catalyst by one pot reaction.

Description

Manufacturing method of cyclic dipeptide < RTI ID = 0.0 >

The present invention relates to a process for preparing a novel cyclic dipeptide compound, and more particularly to a process for easily producing a cyclic dipeptide compound from a linear dipeptide compound in the presence of a catalyst by one pot reaction will be.

Cyclic dipeptide compounds may be used in combination with anticancer agents (Merwe, E. Peptides 2008 , 29, 1305; Nicholson, B. et al. Anticancer Drugs 2006 , 17, 25), antifungal agents (Houston, DR et al. J. Med . Chem. 2004, 47, 5713 ), antibacterial agents (Fdhila, F. et al. J. Nat. Prod. 2003, 66, 1299) anti-viral agents (Sinha, S. et al. Nucleosides , Nucleotides Nucleic Acids 2004, 23, 1815) are known to have various biological functions. Particularly, a cyclic di-peptide compound having proline as a skeleton of an amino acid recognizes various receptors in vivo and not only regulates its activity but also acts as an inhibitor of various enzymes (Martins, MB, Carvalho, I. Tetrahedron 2007 , 63, 9923; Wang, H. et al J. Med. Chem 2000 , 43, 1577).

Various studies have also been made on a method for producing cyclic di-peptide compounds having various biological activities. Known general methods for producing cyclic di-peptide compounds are as follows. As shown in Reaction Scheme 1, a linear dipeptide compound represented by Formula 11, which is prepared by condensing an amino acid compound in which an amino group is protected with an alkoxycarbonyl group and an amino acid ester compound in which an alkyl group is bonded to a carboxyl group, is reacted with HCOOH for 2 hours at room temperature (12) was heated in a butanol / toluene solvent for 3 hours while continuously adding the butanol to be evaporated, and the cyclic diene represented by the formula (14) was added thereto while being continuously refluxed with the butanol being evaporated while the unrecovered HCOOH salt (Nitecki, D, E .; Halpern, B .; Westley, JWJ Org. Chem. 1968 , 33, 864). Alternatively, as shown in Scheme 1, the compound of formula (I) is allowed to stand in a dioxane solvent containing 4 N HCl at room temperature for 30 minutes, and the unsupported HCl salt (formula 13) obtained after the solvent is blown is reacted with N-methylmorpoline And the mixture is reacted in butanol containing 0.1 to 2 M of acetic acid at a temperature of 120 ° C for 3 hours to be cyclized. These reactions involve a two-step preparation process in which the nitrogen protecting group is first removed and then cyclized in another solvent. In contrast, the method of cyclizing linear dipeptides (Formula 11) in a short time by irradiating a microwave in a high-temperature sealed container has advantages in that the cyclization proceeds in a one-pot reaction. However, since this method uses water as a solvent, the reaction yield is lowered when it is not dissolved in water. In order to mass-produce it, it is necessary to additionally install a large microwave generator and it is difficult to use a large- There is a very low economical efficiency for industrial application. As another method, there is known a method in which water is used as a catalyst in a pressure vessel and heated at 130 ° C to induce a cyclization reaction. However, this method also requires a mixed organic solvent in the case of a material that is insoluble in water, In addition, in order to install a large amount of the cyclization reaction process, an additional pressure reactor should be installed.

[Reaction Scheme 1]

Unlike the above method, a method in which a benzyl group is removed from a linear peptide in which nitrogen is protected with a benzyl group by a hydrogenation reaction, is heated in methanol as a starting material, or is produced by using N-carboxy-Leuch anhydride Are reported.

As described above, the conventional preparation method is composed of a two-step preparation process in which the deprotection reaction for removing the amine protecting group and the intramolecular cyclization reaction are performed under different reaction conditions, Yield is also lowered. In case of using strong acid, racemization occurs and it is disadvantageous in that purification is difficult or purity of product is lowered. When microwave is irradiated, the reaction process seems to be advantageous in one step. However, since the glass enclosed vessel capable of withstanding high pressure is used, the manufacturing facility must be special. In order to increase the production scale of the object, A problem arises. In the case of cyclizing a linear di-peptide having a low solubility in water, the yield of the reaction product becomes very low due to low solubility of the substance in water and the purification process becomes difficult.

Therefore, there is a need for research on a method for producing a cyclic di-peptide compound of high purity at a high yield while being simple and capable of mass production.

Merwe, E. Peptides 2008, 29, 1305; Nicholson, B. et al. Anticancer Drugs 2006, 17, 25  Houston, D. R. et al. J. Med. Chem. 2004, 47, 5713 Fdhila, F. et al. J. Nat. Prod. 2003, 66, 1299 Sinha, S. et al. Nucleosides, Nucleotides Nucleic Acids 2004, 23, 1815 Martins, M. B., Carvalho, I. Tetrahedron 2007, 63, 9923 Wang, H. et al. J. Med. Chem. 2000, 43, 1577 Nitecki, D, E .; Halpern, B .; Westley, J. W. J. Org. Chem. 1968, 33, 864

The present invention relates to a method for producing a cyclic dipeptide compound by directly carrying out a deprotection reaction and a cyclization reaction in a single step reaction operation using acetic acid to a linear dipeptide compound in which nitrogen is protected with an alkoxycarbonyl And to provide an effective method.

The present invention relates to a process for producing a cyclic dipeptide compound, which is a cyclic dipeptide compound, by reacting a linear dipeptide compound represented by the following formula 2, in which an amino group is protected and a carboxylic acid group is protected, There is provided a method for producing a cyclic dipeptide compound represented by the formula (1).

[Chemical Formula 1]

(2)

[In the above formula (1) or (2)

The carbon atom represented by * constitutes the chiral center;

R ₁ or R ₄ independently of one another are hydrogen, hydroxy, amino, carbamoyl, carboxylic acid, guanidino, mercapto, (C 1 -C 10) alkyl, (C 6 -C 20) C6-C20) aryl or (C3-C20) heteroaryl;

R ₂ or R ₃ independently from each other are hydrogen or (C 1 -C 10) alkyl, or R ₂ and R ₃ are (C2-C10) alkylene or (C2-C10) alkenylene to form an alicyclic or aromatic ring;

X is a (C1-C10) alkoxycarbonyl group;

Y is a (C1-C10) alkyl group;

The alkyl, aryl, aralkyl and heteroaryl of R ₁ or R ₄ , or the alkyl, alkylene, alkenylene, alicyclic and aromatic ring of R ₂ or R ₃ may be substituted by hydroxy, amino, cyano, (C6-C20) aryl, (C3-C20) heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, mercapto, (C1-C10) alkyl, Can be.]

The substituents comprising " alkyl ", " alkoxy " and other " alkyl " moieties described in this invention encompass both linear and branched forms. The term " aryl " in the present invention means an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and may be a single or fused ring containing 4 to 7, preferably 5 or 6 ring atoms, A ring system, and a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like. "Heteroaryl" in the present invention includes 1 to 4 heteroatoms selected from B, N, O, S, P (= O), Si and P as aromatic ring skeletal atoms and the remaining aromatic ring skeletal atoms are carbon Means a 5 to 6 membered monocyclic heteroaryl and a polycyclic heteroaryl condensed with at least one benzene ring and may be partially saturated. The heteroaryl in the present invention also includes a form in which one or more heteroaryl is connected to a single bond.

According to one embodiment of the present invention, R ₁ or R ₄ may be, independently of each other, hydrogen, (C 1 -C 10) alkyl or (C 6 -C 20) aryl (C 1 -C 10) alkyl.

More preferably, R ₁ or R ₄ independently represents hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert- Hydroxyethyl group, 2-hydroxyethyl group, thiomethyl group, 2-thioethyl group, methylthioethyl group, phenyl group, 4-hydroxyethyl group, A hydroxyphenyl group, a benzyl group, a 4-hydroxybenzyl group, a phenylethyl group, an imidazol-4-ylmethyl group or an indol-3-ylmethyl group;

R ₂ and R ₃ may be independently hydrogen, methyl or ethyl, or (C 2 -C 10) alkylene to form an alicyclic ring.

More preferably, the formula (1) may be selected from the following compounds, but is not limited thereto.

The linear dipeptide compound represented by Formula 2 according to an embodiment of the present invention is a compound prepared by condensation reaction of a common amino acid compound containing an amine group and a carboxyl group. In the present invention, there is no particular restriction on the choice of the amino acid constituting the linear dipeptide compound represented by the general formula (2), and both natural and synthetic materials are included. Also, as for the form of the carbon chain connecting the amine group and the carboxyl group There is no restriction.

The catalyst according to an embodiment of the present invention is characterized by being an aqueous solution of acetic acid or acetic acid.

More specifically, the method of the present invention for producing a cyclic di-peptide can be carried out by using an aqueous solution of acetic acid in an amount of 2 to 50% as a solvent or using acetic acid as a catalyst And the mixture is heated while maintaining the reaction temperature at 100 to 130 캜, preferably 100 to 125 캜, and more preferably 110 to 125 캜, so that the solvent inside the reactor can be refluxed, 2, the deprotection reaction for removing the amine protecting group and the intramolecular cyclization reaction are sequentially performed, thereby efficiently producing the cyclic dipeptide compound represented by the above formula (1).

If acetic acid is used alone in the linear dipeptide represented by the above formula (2), which is insoluble because of low solubility in an aqueous solution, the cyclization reaction can be facilitated. Even when there is no problem of solubility in an aqueous solution, desired compound can be obtained even by heating only with acetic acid instead of aqueous acetic acid.

Therefore, in the production method of the present invention, it is more preferable to use only acetic acid as a solvent and catalyst in terms of reaction efficiency.

The aqueous solution of acetic acid according to an embodiment of the present invention may contain 2 to 50% by weight, more preferably 2 to 20% by weight, of the linear dipeptide compound represented by Formula 2, And a range of 1 to 3 L of an aqueous acetic acid solution may be used.

More preferably, the cyclization reaction may be carried out at a temperature of from 110 ° C to 125 ° C for 2 hours to 7 hours, more preferably from 1 hour to 5 hours in terms of reaction efficiency.

After completion of the reaction, the acetic acid or acetic acid aqueous solution is removed under reduced pressure, and the obtained solid mixture is a cyclic dipeptide compound. Without purification, a cyclic dipeptide compound of high purity can be obtained, but it may be subjected to a purification process.

Although the purification process is not limited, it may be dissolved in methanol, ethyl acetate, hexane or a mixture thereof in order to purify more effectively, and the solvent may be removed to obtain a cyclic diepeptide compound as a white solid. High purity products can be obtained without purification steps such as chromatography. However, if there is color, the concentrated reaction mixture is dissolved in methanol, the color is removed using activated charcoal, and concentrated to remove impurities using a solvent selected from methanol, ethyl acetate, hexane or a mixture thereof, Can be filtered to give a cyclic diep peptide compound as a white solid.

The process for producing the cyclic dipeptide of the present invention has the effect of simplifying the process by simultaneously performing the deprotection reaction and the cyclization reaction in one reactor.

In addition to utilizing acetic acid, the production method of the present invention can perform the deprotection reaction and the cyclization reaction smoothly even under the condition that no catalyst or organic solvent is used, so that the cost of the production process can be reduced and it is very economical.

In addition, the production method of the present invention can be applied to mass production without requiring a complicated apparatus, and a high purity cyclic dipeptide can be produced at a high yield by a simple purification method or without any additional purification.

Further, the production method of the present invention is very economical since the cyclic dipeptide is not obtained as a racemate but is obtained as almost one isomer, and no separate separation is required.

It is to be understood that the present invention is not limited to the disclosed embodiments, but is intended to be limited only by the scope of the appended claims.

The linear dipeptide compound represented by Formula 2 was prepared and used according to a known method (Zeng, Y. et al., Bioorg Med Chem. Lett. 2005, 15, 3034, Thajudeen, H. et 2007, 52, 1224, Donkor, IO et al., Bioorg. Med. Chem., 1979, 13, 609; Lett 2001, 11, 2647).

[Example 1] Preparation of Compound 7

Compound 7, a product obtained by reacting 5%, 10% and 100% by weight of acetic acid in the case of a cyclic diep peptide (compound 7) consisting of valine and alanine was analyzed by high pressure liquid chromatography, It can be seen that the purity of the product is all very high. The reaction conditions and reaction yields are shown in Table 1. It can be seen that the reaction yield was the highest when only acetic acid was used as the solvent and catalyst.

Compound No. Reaction conditions Reaction temperature (캜) Reaction yield (%) Melting point (℃) 5% by weight acetic acid 98 78 215-219 10% by weight acetic acid 101 75 214-215 Compound 7 20% by weight acetic acid 102 82 213-216  Acetic acid 117 85 216-221

[Examples 2 to 23] Preparation of compounds 2 to 7, compounds 10 to 12, compounds 15 to 19 and compounds 21 to 28

In a round flask, a linear dipeptide compound (compound shown in Table 2; 0.5 mol) was dissolved in 1.5 L of acetic acid as a solvent and a catalyst. The flask was equipped with a reflux condenser and agitated at 1200 rpm for 4 hours with an electric stirrer so that the external temperature was maintained at 120 ° C. The acetic acid and the resulting liquid were removed under reduced pressure at about 50 < 0 > C, and the resulting solid was filtered through a mixture of hexane and ethyl acetate or methanol. The title compound was thus obtained as a white solid.

Melting points and yields of the cyclic dipeptide compounds prepared are also shown in Table 2, and the IUPAC names are shown in Table 3.

[Examples 24 to 28] The compounds 8, 9, 13, 14, 20

In Examples 2 to 23, compounds 8, 9, 13 and 14 were obtained in the same manner as in Examples 2 to 23 except that the compounds shown in the following Table 2 were used as starting materials and acetic acid was used in an amount of 10 wt% , 20 were prepared. The melting points and yields of the cyclic dipeptide compound thus prepared are also shown in Table 2, and the IUPAC names of the compounds 1 to 28 are shown in Table 3.

compound X Y R ^One R ² R ³ R ⁴ Melting point
(° C) yield
(%) One Boc CH ₃  H H H H 212-216 89 2 Boc CH ₃ (S) CH ₃ H H H 211-213 92 3 Boc CH _{3 (S) (CH 3) 2} CH H H H 251-256 90 4 Boc CH _{3 (S) (CH 3) 2} CHCH 2 H H H 241-243 85 5 Boc CH _{3 (S) CH 3 CH 2 CH} (CH 3) H H H 225-230 83 6 Boc CH ₃ (S) CH ₃ H H (S) CH ₃ 241-246 88 7 Boc CH _{3 (S) (CH 3) 2} CH H H (S) CH ₃ 216-221 85 8 Boc CH _{3 (S) (CH 3) 2} CHCH 2 H H (S) CH ₃ 219-223 91 9 Boc CH _{3 (S) CH 3 CH 2 CH} (CH 3) H H (S) CH ₃ 220-225 88 10 Boc CH _{3 (S) (CH 3) 2} CHCH 2 H H (S) HOCH ₂ 208-213 84 11 Boc CH ₃  H H H (S) HOCH ₂ 219-223 82 12 Boc CH ₃ (S) 4-HO-C 6 H 5 -CH 2 H H (S) CH ₃ 271-273 83 13 Boc CH ₃  H H H (S) indol-3-ylmethyl 280-284 91 14 Boc CH _{3 (S) (CH 3) 2} CHCH 2 H H (S) C ₆ H ₅ -CH ₂ 279-283 81 15 Boc CH _{3 (S) (CH 3) 2} CHCH 2 H H _{(S) CH 3 CH (OH} ) 245-248 75 16 Boc CH ₃  H - (CH ₂ ) ₃ - (S) H 152-157 78 17 Boc CH ₃ (S) CH ₃ - (CH ₂ ) ₃ - (S) H 175-178 81 18 Boc CH _{3 (S) (CH 3) 2} CH - (CH ₂ ) ₃ - (S) H 167-172 84 19 Boc CH _{3 (S) (CH 3) 2} CHCH 2 - (CH ₂ ) ₃ - (S) H 152-155 81 20 Boc CH _{3 (S) CH 3 CH 2 CH} (CH 3) - (CH ₂ ) ₃ - (S) H 103-105 75 21 Boc CH ₃ (S) HOCH ₂ - (CH ₂ ) ₃ - (S) H 153-156 88 22 Boc CH ₃ (S) C ₆ H ₅ -CH ₂ - (CH ₂ ) ₃ - (S) H 133-137 86 23 Boc CH ₃ (S) indol-3-ylmethyl - (CH ₂ ) ₃ - (S) H 174-176 84 24 Boc CH ₃ (S) 4-HO-C 6 H 5 -CH 2 - (CH ₂ ) ₃ - (S) H 148-152 89 25 Boc CH _{3 (S) CH 3 CH (OH} ) - (CH ₂ ) ₃ - (S) H 162-165 78 26 Boc CH ₃ (S) H ₂ N-CO-CH ₂ CH ₂ - (CH ₂ ) ₃ - (S) H 190-195 69 27 Boc CH ₃ (S) H ₂ N-CO-CH ₂ - (CH ₂ ) ₃ - (S) H 180-183 63 28 Boc CH _{3 (S) CH 3 SCH 2 CH} 2 - (CH ₂ ) ₃ - (S) H 212-215 83

compound IUPAC Name One piperazine-2,5-dione 2 (S) -3-methylpiperazine-2,5-dione 3 (S) -3-isopropylpiperazine-2,5-dione 4 (S) -3-isobutylpiperazine-2,5-dione 5 (S) -3-sec-butylpiperazine-2,5-dione 6 (3S, 6S) -3,6-dimethylpiperazine-2,5-dione 7 (3S, 6S) -3-isopropyl-6-methylpiperazine-2,5-dione 8 (3S, 6S) -3-isobutyl-6-methylpiperazine-2,5-dione 9 (3S, 6S) -3-sec-butyl-6-methylpiperazine-2,5-dione 10 (3S, 6S) -3- (hydroxymethyl) -6-isobutylpiperazine-2,5-dione 11 (S) -3- (hydroxymethyl) piperazine-2,5-dione 12 (3S, 6S) -3- (4-hydroxybenzyl) -6-methylpiperazine-2,5-dione 13 (S) -3 - ((1H-indol-3-yl) methyl) piperazine-2,5-dione 14 (3S, 6S) -3-benzyl-6-isobutylpiperazine-2,5-dione 15 (3S, 6S) -3-sec-butyl-6- (1-hydroxyethyl) piperazine-2,5-dione 16 (S) -hexahydropyrrolo [1,2-a] pyrazine-1,4-dione 17 (3S, 8aS) -hexahydro-3-methylpyrrolo [1,2-a] pyrazine-1,4-dione 18 (3S, 8aS) -hexahydro-3-isopropylpyrrolo [1,2-a] pyrazine-1,4-dione 19 (3S, 8aS) -hexahydro-3-isobutylpyrrolo [1,2-a] pyrazine-1,4-dione 20 (3S, 8aS) -3-sec-butyl-hexahydropyrrolo [1,2-a] pyrazine- 1,4-dione 21 (3S, 8aS) -hexahydro-3- (hydroxymethyl) pyrrolo [1,2-a] pyrazine-1,4-dione 22 (3S, 8aS) -3-benzyl-hexahydropyrrolo [1,2-a] pyrazine-1,4-dione 23 (3S, 8aS) -3 - ((1H-indol-3-yl) methyl) hexahydropyrrolo 1,2- a pyrazine- 24 (3S, 8aS) -3- (4-hydroxybenzyl) hexahydropyrrolo [1,2-a] pyrazine-1,4-dione 25 (3S, 8aS) -hexahydro-3- (1-hydroxyethyl) pyrrolo [1,2- a] pyrazine- 1,4-dione 26 3 - ((3S, 8aS) -octahydro-1,4-dioxopyrrolo [1,2-a] pyrazin-3- yl) propanamide 27 2 - ((3S, 8aS) -octahydro-1,4-dioxopyrrolo [1,2-a] pyrazin-3- yl) acetamide 28 (3S, 8aS) -hexahydro-3- (2- (methylthio) ethyl) pyrrolo [1,2- a] pyrazine- 1,4-dione

Compound 1 Cyclo (Gly-Gly): white solid; Melting point 212-216 占 폚 (dec); _{^{1 H NMR (DMSO- d 6,}} 400 MHz) δ 7.98 (2H, s), 3.68 (4H, s) ppm; _{^{13 C NMR (DMSO- d 6,}} 100 MHz) δ 166.7, 45.0 ppm.

Compound 2 Cyclo (Ala-Gly): white solid; Melting point 211-213 占 폚 (dec); _{^{1 H NMR (DMSO- d 6,}} 400 MHz) δ 8.14 (1H, s), 7.95 (1H, s), 3.81 (1H, q, J = 6.4 Hz), 3.72 (2H, br d), 1.21 (3H , d) ppm; _{^{13 C NMR (DMSO- d 6,}} 100 MHz) δ 169.6, 167.0, 50.4, 45.1, 19.3 ppm.

Compound 3 Cyclo (Val-Gly): white solid; Melting point 251-256 (dec) 占 폚; ^{_{[α] 20 D +24.5 (c}} 0.5, H 2 O); _{^{1 H NMR (CD 3 OD,}} 400 MHz) δ 4.01 (1H, d, J = 18.4 Hz), 3.82 (1H, d, J = 18.4 Hz), 3.73 (1H, d, J = 4.0 Hz), 2.28 - 2.20 (1H, m), 1.03 (3H, d, J = 7.2 Hz), 0.96 (3H, d, J = 7.2 Hz); ¹³ C NMR (100 MHz, CD ₃ OD)? 170.4, 169.0, 61.8, 45.3, 34.5, 19.1, 17.3 ppm.

Compound 4 Cyclo (Leu-Gly): white solid; Melting point 241-243 DEG C; [?] ²⁰ _D +25.1 ( c 0.5, CH ₃ OH); _{^{1 H NMR (CD 3 OD,}} 400 MHz) δ 4.01 (1H, d, J = 18.4 Hz), 3.89 (1H, t, J = 6.8 Hz), 3.82 (1H, d, J = 18.4 Hz), 1.72 - 1.89 (1H, m), 1.66-1.70 (1H, m), 0.97 (6H, t, J = 7.2 Hz) ppm; ¹³ C NMR (100 MHz, CD ₃ OD)? 171.7, 169.0, 54.9, 45.4, 44.0, 25.7, 23.5, 22.3 ppm.

Compound 5 Cyclo (Ile-Gly): white solid; Melting point 225-230 占 폚 (dec); [?] ²⁰ _D +12.8 ( c 0.5, CH ₃ OH); _{^{1 H NMR (DMSO- d 6,}} 400 MHz) δ 8.39 (1H, s), 8.23 (1H, s), 4.03 (1H, d, J = 17.6 Hz), 3.87-3.80 (2H, overlapped), 2.07- 1.99 (1H, m), 1.70-1.60 (1H, m), 1.43-1.34 (1H, m), 1.12 (3H, d, J = 7.2 Hz), 1.08 (3H, t, J = 7.2 Hz) ppm; ¹³ C NMR (100 MHz, CD ₃ OD)? 167.6, 166.4, 59.4, 44.6, 39.5, 24.6, 15.4, 12.1 ppm.

Compound 6 Cyclo (Ala-Ala): white solid; Melting point 241-246 占 폚 (dec); _{^{1 H NMR (DMSO- d 6,}} 400 MHz) δ 8.07 (2H, s), 3.89 (2H, q, J = 6.8 Hz), 1.22 (6H, d, J = 6.8 Hz) ppm; _{^{13 C NMR (DMSO- d 6,}} 100 MHz) δ 169.8, 50.5, 19.2 ppm.

Compound 7 Cyclo (Val-Ala): white solid; Melting point 216-221 占 폚 (dec); [?] ²⁰ _D -48.6 ( c 0.5, CH ₃ OH); _{^{1 H NMR (DMSO- d 6,}} 400 MHz) δ 8.11 (1H, s), 8.00 (1H, s), 3.86 (1H, q, J = 6.8 Hz), 3.66 (1H, br s), 2.15-2.10 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 0.81 (3H, d, J = 6.8 Hz) ppm; ¹³ C NMR (CD ₃ OD, 100 MHz)? 169.1, 167.1 59.8, 50.1, 31.5, 20.5, 18.9, 17.3 ppm.

Compound 8 Cyclo (Leu-Ala): white solid; Melting point 219-223 DEG C; _{^{1 H NMR (CD 3 OD,}} 400 MHz) δ 4.00 (1H, q, J = 6.8 Hz), 3.94 (1H, dd, J = 6.8, 5.6 Hz), 1.88-1.80 (1H, m), 1.63 (1H dd, J = 14.0, 6.8 Hz), 1.61 (1H, dd, 14.0, 5.4 Hz), 1.44 (3H, d, J = 6.8 Hz), 0.96 (6H, t, J = 7.2 Hz); ¹³ C NMR (CD ₃ OD, 100 MHz)? 171.6, 171.0, 60.9, 53.2, 45.0, 23.9, 22.2, 22.1, 19.5, 18.5 ppm.

Compound 9 Cyclo (Ile-Ala): white solid; Melting point 220-225 占 폚 (dec); [?] ²⁰ _D -34.8 ( c 0.5, CH ₃ OH); _{^{1 H NMR (CD 3 OD,}} 400 MHz) δ 4.07 (1H, q, J = 1.6 Hz), 3.92 (1H, d, J = 2.0 Hz), 2.00-1.91 (1H, m), 1.56-1.47 (1H (m, 1H), 1.44 (3H, d, J = 7.2 Hz), 1.31-1.18 (1H, m), 1.01 (3H, d, J = 7.2 Hz), 0.95 (3H, t, J = 7.2 Hz); ¹³ C NMR (CD ₃ OD, 100 MHz)? 169.8, 167.7, 59.5, 50.2, 38.9, 24.2, 19.5, 14.1, 10.7 ppm.

Compound 10 Cyclo (Leu-Ser): white solid; Melting point 208-213 DEG C; [?] ²⁰ _D -28.3 (c 0.3, CH ₃ OH); _{^{1 H NMR (CD 3 OD,}} 400 MHz) δ 3.94-3.91 (2H, m), 3.90 (1H, t, J = 3.6 Hz), 3.67 (1H, dd, J = 12.8 and 4.4 Hz) 1.85 (1H, m), 1.82 (2H, m), 0.95 (3H, d, J = 6 Hz), 0.95 (3H, d) ppm; _{^{13 C NMR (CD 3 OD,}} 100 MHz); [delta] 170.2, 167.6, 62.7, 57.8, 53.4, 45.0, 23.8, 22.4, 20.6 ppm.

Compound 11 Cyclo (Ser-Gly): white solid; ¹ H-NMR (CD ₃ OD, 400 MHz); δ 4.03 (1H, d, J = 17.6 Hz), 3.96 (1H, dd, J = 11.2, 2.8 Hz), 3.89 (1H, t, J = 2.8 Hz), 3.79 (1H, d, J = 17.6 Hz) , 3.71 (1H, dd, J = 11.2, 2.8 Hz) ppm; _{^{13 C NMR (DMSO- d 6,}} 100 MHz) δ 169.9, 169.5, 65.1, 59.0, 45.6 ppm.

Compound 12 Cyclo (Tyr-Ala): white solid; Melting point 271-273 DEG C (dec); _{^{1 H NMR (DMSO- d 6,}} 400 MHz) δ 9.25 (1H, s), 8.04 (1H, s), 7.90 (1H, s), 6.91 (2H, d, J = 7.2 Hz), 6.65 (2H, d, J = 7.2 Hz), 4.05 (1H, br s), 3.60 (1H, q, J = 7.2 Hz)), 3.00 (1H, dd, J = 13.6, 3.6 Hz)), 2.71 (1H, dd, J = 13.6, 3.6 Hz), 0.54 (3H, d, J = 7.2 Hz) ppm; _{^{13 C NMR (DMSO- d 6,}} 100 MHz) δ 169.7, 165.5, 155.8, 130.3 (2C), 127.2, 116.1 (2C), 59.5, 56.2, 45.6, 36.2, 28.4, 22.9 ppm.

Compound 13 Cyclo (Gly-Trp): White solid; Melting point 280 - 284 ° C C (dec); _{^{1 H NMR (DMSO- d 6,}} 400 MHz) δ 10.92 (1H, s), 8.09 (1H, s), 7.75 (1H, s), 7.52 (1H, d, J = 7.6 Hz), 7.31 (1H, d, J = 7.6 Hz), 7.06 (2H, overlapped), 6.93 (1H, t, J = 7.2 Hz), 4.00 (1H, q, J = 3.2 Hz), 3.33 (1H, dd, J = 17.2, 2.8 (2H, dd, J = 14.4, 4.4 Hz), 2.97 (1H, dd, J = 14.4, 4.4 Hz), 2.76 (1H, dd, J = 17.2, 1.2Hz) ppm; ¹³ C NMR (DMSO- d ₆ , 100 MHz)? 168.6, 166.3, 136.6, 128.1, 125.2, 121.5, 119.3, 119.1, 111.8, 109.0, 56.1, 44.5, 29.8 ppm.

Compound 15 Cyclo (Leu-Thr): white crystalline solid; Melting point 245-248 DEG C; [?] ²⁰ _D -48.2 (c 0.5, CH ₃ OH); ¹ H-NMR (CD ₃ OD, 400 MHz); (1H, d, J = 6.8 Hz), 3.87 (1H, dd, J = 4.0 Hz, 9.0 Hz), 3.71 (1H, d, J = 2.4 Hz), 1.89-1.83 -1.75 (1H, m), 1.23 (3H, d, J = 6.8 Hz), 0.94 (6H, d, J = 6.4 Hz) ppm; ¹³ C NMR (CD ₃ OD, 100 MHz)? 170.4, 168.0, 67.3, 60.8, 53.2, 45.0, 23.6, 22.2, 20.2, 18.5 ppm.

Compound 16 Cyclo (Gly-Pro): white solid; Melting point 152-156 ° C; 4.01 (1H, s), 4.08 (1H, br, J = 6.8 Hz), [?] ²⁰ _D -136.8 (c 0.5, CH ₃ OH; ¹ H NMR (CDCl ₃ , 400 MHz) m), 2.08-1.98 (2H, m), 1.93-1.86 (1H, m), 3.82 (2H, dd, J = 16.8,4.8Hz), 3.65-3.50 ^{m) ppm; 13 C NMR (} CDCl 3, 100 MHz) δ 170.1, 163.5, 58.5, 46.6, 45.3, 28.4, 22.4 ppm.

Compound 17 Cyclo (Ala-Pro): white solid; Melting point 175-178 ° C; [?] ²⁰ _D -88.7 (c 0.3, CH ₃ OH); _{^{1 H NMR (CDCl 3, 400}} MHz) δ 6.44 (1H, s), 4.13 (1H, d, J = 11.2 Hz), 4.11 (1H, d, J = 11.2 Hz), 3.61-3.46 (2H, m) , 2.37-2.32 (1H, m), 2.13-2.07 (1H, m), 2.07-1.98 (1H, m), 1.95-1.82 (1H, m), 1.46 (3H, d, J = 6.8 Hz) ppm; ¹³ C NMR (CDCl3 _, 100 MHz) [delta] 170.3, 166.3, 59.3, 51.2, 45.4, 28.2, 22.8, 16.0 ppm.

Compound 18 Cyclo (Val-Pro): white solid; Melting point 167-172 DEG C; [?] ²⁰ _D -125.2 (c 0.3, CH ₃ OH); ^{1 H NMR (400 MHz, CD} 3 OD); δ 4.19 (1H, br t, J = 8.0 Hz), 4.03 (1H, br s), 3.47-3.58 (2H, m), 2.55-2.42 (1H, m), 2.38-2.21 (1H, m), 2.03 -1.93 (1H, m), 1.89-2.04 (2H, m), 1.09 (3H, d, J = 7.2 Hz), 0.93 (3H, d, J = 7.2 Hz) ppm; ^{13 C NMR (100 MHz, CD} 3 OD); [delta] 171.4, 166.4, 60.3, 58.8, 45.0, 28.7, 28.3, 22.1, 17.6, 15.5 ppm.

Compound 19 Cyclo (Leu-Pro): white solid; Melting point 152-155 DEG C; [?] ²⁰ _D -101.1 ( c 0.5, CH ₃ OH); _{^{1 H NMR (400MHz, CD 3}} OD) δ 4.25 (1H, br t, J = 8.0 Hz), 4.10-4.18 (1H, m), 3.47-3.53 (2H, m), 2.25-2.34 (1H, m) , 2.02 (1H, m), 1.89-2.01 (2H, m), 1.89 (1H, m), 1.84 (1H, m), 0.96 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 6.8 Hz) ppm; ^{13 C NMR (100 MHz, CDCl} 3) δ 170.7, 166.5, 59.2, 53.6, 45.7, 38.7, 28.3, 24.8, 23.5, 22.9, 21.5 ppm.

Compound 20 Cyclo (Ile-Pro): white solid; Melting point 103-105 ° C; _{^{1 H NMR (CDCl 3, 400}} MHz) δ 6.68 (1H, s), 4.01 (1H, t, J = 7.6 Hz), 3.93 (1H, s), 3.64-3.49 (2H, m), 2.34-2.23 ( 2H, m), 2.01-1.94 (2H , m), 1.88-1.82 (1H, m), 1.40-1.34 (1H, m), 1.21-1.13 (1H, m), 1.02 (3H, d, J = 6.8 Hz), 0.88 (3H, t, J = 8.0 Hz); _{^{13 C NMR (CDCl 3, 100}} MHz) δ 170.4, 165.3, 60.7, 58.9, 45.3, 35.5, 28.7, 24.2, 22.5, 15.9, 12.3 ppm.

Compound 21 Cyclo (Ser-Pro): white solid; Melting point 153-156 ° C; _{^{1 H NMR (CDCl 3, 400}} MHz) δ 7.40 (1H, s), 4.10 (2H, t), 3.97 (2H, dd), 3.62-3.54 (2H, m), 2.36-2.39 (1H, m), 2.07-1.99 (2H, m), 1.90-1.84 (1H, m) ppm; _{^{13 C NMR (CDCl 3, 100}} MHz) δ 170.5, 165.2, 61.2, 59.2, 56.7, 45.5, 28.4, 22.7 ppm.

Compound 22 Cyclo (Phe-Pro): white solid; Melting point 133-137 DEG C; [?] ²⁰ _{D -98.0 (c 0.4, CH 3 OH} ); ^{1 H NMR (400 MHz, CD} 3 OD) δ 7.28-7.22 (2H, overlapped), 7.27-7.19 (3H, overlapped), 4.44 (1H, br t, J = 5.2 Hz), 4.05 (1H, dd, J M), 2.09-2.02 (1H, m), 1.25-1.17 (1 H, m), 3.13-3.10 (2H, m) ), 0.79-0.72 (2H, m) ppm; ¹³ C NMR (100 MHz, CD ₃ OD)? 171.6, 167.0, 137.4, 131.2, 129.6, 128.2, 60.2, 57.8, 46.1, 38.4, 29.5, 22.9 ppm.

Compound 23 Cyclo (Trp-Pro): white solid; _{^{[α] 20 D -70.3 ℃℃ c}} 0.3, MeOH); _{^{1 H NMR (CDCl 3, 400}} MHz) δ 7.05 (2H, d, J = 8.4 Hz), 6.77 (2H, d, J = 8.4 Hz), 5.72 (1H, s), 4.21 (1H, d, J = 6.4 Hz), 4.08 (1H, t, J = 6.8 Hz), 3.68-3.58 (1H, m), 3.59- 3.50 (1H, m), 3.44-3.36 (1H, m), 2.75 (1H, dd, J = 14.4, 10.0 Hz), 2.30-2.24 (1H, m), 2.04-1.95 (1H, m), 1.96-1.84 (2H, m) ppm; ¹³ C NMR (CDCl ₃ , 100 MHz)? 169.8, 165.3, 155.6, 130.5 (2C), 127.4, 116.3 (2C), 59.3, 56.4, 45.6, 36.1, 28.5, 22.7 ppm.

Compound 24 Cyclo (Tyr-Pro): white solid; Melting point 148-152 캜; [?] ²⁰ _D-1 (c 0.2, CH ₃ OH); ^{1 H NMR (400 MHz, CD} 3 OD); δ 7.02 (2H, d, J = 8.0 Hz), 6.68 (2H, d, J = 8.0 Hz), 4.35 (1H, t, J = 4.8 Hz), 4.03 (1H, dd, J = 10.8, 6.4 Hz) , 3.54 (1H, dt, J = 12.0, 8.4 Hz), 3.35 (1H, q, J = 6.4 Hz), 3.07 (1H, dd, J = 14.4, 5.2 Hz), 3.03 (1H, dd, J = 14.4 , 5.2 Hz), 2.08 (1H, sext, J = 5.4 Hz), 1.80 (2H, m), 1.21 (1H, quin, J = 10.5 Hz) ppm; ^{13 C NMR (100 MHz, CD} 3 OD); [delta] 169.6, 165.8, 156.5, 130.9, 126.4, 115.0, 58.9, 56.7, 44.7, 36.5, 28.2, 21.5 ppm.

Compound 25 Cyclo (Thr-Pro): white solid, ¹ H NMR (CDCl ₃ , 400 MHz)? 7.09 (1H, s), 4.27 (1H, dd), 4.01 (1H, m), 3.57-3.50 (1H, m), 3.47-3.41 (1H, m), 2.29-2.23 (1H, m), 2.04-1.90 d) ppm; _{^{13 C NMR (CDCl 3, 100}} MHz) δ 170.7, 165.5, 65.8, 59.6, 59.1, 45.5, 28.2, 22.8 ppm.

Compound 27 Cyclo (Asn-Pro): white solid, ¹ H NMR (DMSO- d ₆ , 400 MHz)? 7.96 (1H, s), 7.41 (1H, s), 6.90 t, J = 7.2 Hz), 4.18 (1H, t, J = 7.2 Hz), 3.42-3.33 (1H, m), 3.32-3.24 (1H, m), 2.70 (1H, dd, J = 16.0, 5.6 Hz ), 2.28 (1H, dd, J = 16.0, 6.4 Hz), 2.12-2.06 (1H, m), 1.90-1.77 (3H, m) ppm; _{^{13 C NMR (DMSO- d 6,}} 100 MHz) δ 172.1, 170.4, 166.2, 59.2, 52.1, 45.5, 35.3, 28.2, 23.0 ppm.

Compound 28 Cyclo (Met-Pro): white solid, _{^{1 H NMR (CDCl 3, 400}} MHz) δ 7.33 (1H, s), 4.20 (1H, t, J = 6.0 Hz), 4.10 (1H, t, J = 8.2 Hz), 3.60-3.49 (2H, m) , 2.69 (2H, t, J = 7.0 Hz), 2.40-2.29 (2H, m), 2.10 (3H, s), 2.05-1.94 (3H, m), 1.92-1.83 (1H, m) ppm.

Claims (8)

A method for producing a cyclic dipeptide compound represented by the following formula (1) by cyclizing a linear dipeptide compound represented by the following formula (2) in the presence of a catalyst.
[Chemical Formula 1]

(2)

[In the above formula (1) or (2)
The carbon atom represented by * constitutes the chiral center;
R ₁ or R ₄ independently of one another are hydrogen, hydroxy, amino, carbamoyl, carboxylic acid, guanidino, mercapto, (C 1 -C 10) alkyl, (C 6 -C 20) C6-C20) aryl or (C3-C20) heteroaryl;
R ₂ Or R ₃ is independently hydrogen or (C1-C10) alkyl each other, R ₂ And R < _{3 &} (C2-C10) alkylene or (C2-C10) alkenylene to form an alicyclic or aromatic ring;
X is a (C1-C10) alkoxycarbonyl group;
Y is a (C1-C10) alkyl group;
R ₁ Or R ₄ an alkyl, aryl, aralkyl and heteroaryl, or R ₂ Or the R ₃ alkyl, alkylene, alkenylene, alicyclic ring, an aromatic ring with hydroxy, amino, cyano, carbamoyl, carboxylic acid, guanidino, mercapto, (C1-C10) alkyl, (C6-C20 (C1-C10) alkyl, (C6-C20) aryl and (C3-C20) heteroaryl. The method according to claim 1,
Wherein R ₁ or R ₄ are, independently from each other, hydrogen, (C 1 -C 10) alkyl or (C 6 -C 20) aryl (C 1 -C 10) alkyl. The method according to claim 1,
Wherein R ₁ or R ₄ independently represent hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert- butyl group, a 5-aminopentyl group, a carbamoylmethyl group, a 2-carbamoylethyl group, , A 2-carboxylethyl group, a 3-guanidino propyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a thiomethyl group, a 2-thioethyl group, a methylthioethyl group, Benzyl group, 4-hydroxybenzyl group, phenylethyl group, imidazol-4-ylmethyl group or indol-3-ylmethyl group;
R ₂ and R ₃ are independently of each other hydrogen, methyl or ethyl, or (C 2 -C 10) alkylene to form an alicyclic ring. The method according to claim 1,
Wherein said formula (1) is selected from the following compounds.

The method according to claim 1,
Wherein the catalyst is an aqueous solution of acetic acid or acetic acid. 6. The method of claim 5,
Wherein the acetic acid aqueous solution contains 2 to 50% by weight of acetic acid. The method according to claim 1,
Wherein the cyclization reaction is carried out at a temperature of from 100 캜 to 130 캜. The method of claim 7,
Wherein the reaction is carried out at a temperature of from 110 DEG C to 125 DEG C for from 2 hours to 7 hours.