S-fluoroalkyl substituted amino acid, polypeptide and preparation method of S-fluoroalkyl substituted amino acid and polypeptide

Abstract

The invention provides S-fluoroalkyl substituted amino acid, polypeptide and a preparation method of the S-fluoroalkyl substituted amino acid, and belongs to the technical field of fluorinated amino acid. The chemical structural formula of the compound is shown in the specification. Wherein Ar is 4-phenyl phenyl, 4-acetyl phenyl, 4-methoxycarbonyl phenyl, 4-acetoxyphenyl, 4-cyano phenyl, 4-(N, N-dicarboxamide) phenyl, 4-(N, N-dicarboxamide) phenyl, 4-(N, N-dicarboxamide) phenyl, 4-(N, N-dicarboxamide) phenyl, 4-(N, N- Ar'is phenyl, 4-iodophenyl, 4-bromophenyl, 3-methoxycarbonyl phenyl, 2-naphthyl or 3-thienyl, and R1 and R2 are methyl or H. According to the preparation method of the S-fluoroalkyl substituted amino acid and polypeptide, the adopted raw materials are low in cost, simple and easy to obtain, glassware cannot be corroded like other methods, and the tedious and functionalization steps are omitted in the preparation method.

Description

Technical Field

[0001] The present invention relates to the technical field of fluoroamino acids, and particularly relates to an S-fluoroalkyl-substituted amino acid, polypeptide and preparation method thereof. Background Art

[0002] With the wide application of more and more fluorine-containing compounds in the fields of pesticides, pharmaceuticals and material chemistry, organofluorine chemistry has achieved unprecedented development in the 19th century. Especially in recent decades, the synthetic methods for constructing bioactive molecules containing fluoroalkyl fragments have received extensive attention from scientists.

[0003] Fluoroamino acids are a very important class of unnatural amino acids. Due to the strong electron-withdrawing ability, high lipophilicity and large steric hindrance of the fluorine-containing group itself, fluoroamino acids exhibit some special physiological activities. Currently, many fluoroamino acids have been used as probes for tracking biochemical reactions.

[0004] In addition, due to the compact structure and strong lipophilicity of fluoroamino acids, introducing them into polypeptide drugs can significantly improve the biological activity of such drugs, making them not easily catalyzed and decomposed by enzymes in vivo, while enhancing their penetration ability in vivo, which is beneficial to the absorption of drugs in vivo. Therefore, it becomes very important and meaningful to develop a general, simple and efficient method for synthesizing amino acids and polypeptide compounds with diverse structures and different fluoro group substitutions. Summary of the Invention

[0005] The purpose of the present invention is to provide an S-fluoroalkyl-substituted amino acid, polypeptide and preparation method thereof, which eliminates the cumbersome functionalization steps, has low raw material costs and is simple and easily available.

[0006] The technical solution of the present invention is realized as follows:

[0007] The present invention provides an S-fluoroalkyl-substituted amino acid, and the chemical structural formula of the compound is shown in Formula I:

[0008]

[0009] Wherein, Ar is 4-phenylphenyl, 4-acetylphenyl, 4-methoxycarbonylphenyl, 4-acetoxyphenyl, 4-cyanophenyl, 4-(N,N-dimethylamide)phenyl; Ar' is phenyl, 4-iodophenyl, 4-bromophenyl, 3-methoxycarbonylphenyl, 2-naphthyl, 3-thienyl; R1, R2 are methyl or H.

[0010] The present invention further protects an S-fluoroalkyl-substituted polypeptide, which is prepared by removing the tert-butyl group from the above-mentioned S-fluoroalkyl-substituted amino acid and then condensing with other amino acids. The structural formula of the S-fluoroalkyl-substituted polypeptide is shown in Formula II:

[0011]

[0012] Among them, Ar is 4-phenylphenyl, 4-acetylphenyl, 4-methoxycarbonylphenyl, 4-acetoxyphenyl, 4-cyanophenyl, 4-(N,N-dimethylamide)phenyl; Ar' is phenyl, 4-iodophenyl, 4-bromophenyl, 3-methoxycarbonylphenyl, 2-naphthyl, 3-thienyl; R1 and R2 are H; R is methyl, isopropyl, tert-butyl.

[0013] The present invention further protects a preparation method of the above S-fluoroalkyl-substituted amino acid, comprising the following steps:

[0014] Under an inert gas atmosphere, trifluoromethyl olefin, benzyl bromide, manganese powder, nickel catalyst, ligand, and mercapto-containing amino acid are sequentially added to a solution to obtain a mixture;

[0015] Under an inert gas atmosphere, the mixture is reacted at 0 °C, and the S-fluoroalkyl-substituted amino acid is collected from the reaction product.

[0016] As a further improvement of the present invention, the molar ratio of the trifluoromethyl olefin, benzyl bromide, mercapto-containing amino acid / polypeptide, manganese powder, nickel catalyst, and ligand is 1:2-4:2-4:1-3:0.1-0.2:0.15-0.2.

[0017] As a further improvement of the present invention, the trifluoromethyl olefin is at least one of 4-phenyl-α-trifluoromethylstyrene, 4-acetyl-α-trifluoromethylstyrene, 4-methoxycarbonyl-α-trifluoromethylstyrene, 4-acetoxy-α-trifluoromethylstyrene, 4-cyano-α-trifluoromethylstyrene, and 4-(N,N-dimethylamide)-α-trifluoromethylstyrene.

[0018] As a further improvement of the present invention, the bromobenzyl derivative is at least one of 1-bromomethyl-4-iodobenzene, 1-bromomethyl-4-bromobenzene, methyl 3-bromomethylbenzoate, 2-bromomethylnaphthalene, and 3-bromomethylthiophene.

[0019] As a further improvement of the present invention, the nickel catalyst is NiBr2·DME, and the ligand is 6,6-dimethylbipyridine.

[0020] As a further improvement of the present invention, the amino acid is penicillamine or cysteine.

[0021] As a further improvement of the present invention, the solvent is dimethoxyethylene glycol, N,N-dimethylformamide, or a mixture of the two.

[0022] As a further improvement of the present invention, the reaction time is 24 - 48 hours.

[0023] The present invention has the following beneficial effects:

[0024] (1) In the preparation method of S-fluoroalkyl-substituted amino acids and polypeptides of the present invention, the raw materials used have low cost, are simple and easily available; and they will not corrode glassware like other methods.

[0025] (2) The preparation method of S-fluoroalkyl-substituted amino acids and polypeptides of the present invention eliminates the cumbersome functionalization steps. Description of the Drawings

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0027] Figure 1 1H NMR spectrum of Compound 1 prepared in Example 1;

[0028] Figure 2 13C NMR spectrum of Compound 1 prepared in Example 1;

[0029] Figure 3 19F NMR spectrum of Compound 1 prepared in Example 1;

[0030] Figure 4 1H NMR spectrum of Compound 2 prepared in Example 2;

[0031] Figure 5 13C NMR spectrum of Compound 2 prepared in Example 2;

[0032] Figure 6 1H NMR spectrum of Compound 3 prepared in Example 3. Detailed Embodiments

[0033] The following will clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0034] Example 1:

[0035] This example provides a preparation method of S-fluoroalkyl-substituted D-penicillamine, including the following steps:

[0036] (1) Under a nitrogen atmosphere, 0.2 mmol of 4-phenyl-α-trifluoromethylstyrene, 0.6 mmol of N-Boc penicillamine methyl ester, 0.6 mmol of benzyl bromide, 0.6 mmol of manganese powder, 0.01 mmol of NiBr2·DME, and 0.012 mmol of 6,6-dimethylbipyridine were successively added to 1.0 mL of 1,2-dimethoxyethane to obtain a mixture;

[0037] (2) Under a nitrogen atmosphere, the mixture was stirred at 0 °C for 24 h, and the S-fluoroalkyl-substituted D-penicillamine derivative was collected from the product. The product was purified by column chromatography to obtain a colorless oil, which was Compound 1, 72.2 mg (0.12 mmol, dr 1:1), with a yield of 60%.

[0038] As Figure 1 , 1 H NMR (400 MHz, CDCl3) δ 7.69 - 7.55 (m, 7H), 7.50 - 7.44 (m, 2H), 7.41 - 7.34 (m, 1H), 7.25 - 7.10 (m, 5H), 5.48 - 5.29 (m, 1H), 4.42 - 4.24 (m, 1H), 3.76(3.71)(s, 3H), 3.58 - 3.03 (m, 4H), 1.47(1.46)(s, 9H), 1.39 - 1.32 (m, 6H).

[0039] As Figure 2 , 13 C NMR (101 MHz, CDCl3) δ 171.5(171.4), 155.5(155.5), 140.8, 140.3(140.3), 135.2, 135.1, 131.1(131.0), 129.1(129.0), 129.0, 127.4(q, J = 282.0 Hz), 128.0, 127.7, 127.3, 127.2, 126.9(126.8), 80.4, 60.6, 60.5, 52.4(52.3)(q, J = 22.3 Hz), 47.8(47.8), 40.4(40.0), 30.0, 29.8(29.8), 28.4, 26.4(26.3), 25.5(25.3).

[0040] As Figure 3 , 19 F NMR (376 MHz, CDCl3) δ -67.36(-67.60)(s).

[0041] MS(EI, m / z): calcd for C 33 H 38 F3NO4S[M]+ : 624.2371, found: 624.2369.

[0042] Example 2:

[0043] This example provides a method for preparing S-fluoroalkyl-substituted L-cysteine, comprising the following steps:

[0044] (1) Under a nitrogen atmosphere, 0.2 mmol of 4-phenyl-α-trifluoromethylstyrene, 0.6 mmol of N-tert-butoxycarbonyl-L-cysteine methyl ester, 0.6 mmol of benzyl bromide, 0.6 mmol of manganese powder, 0.03 mmol of NiBr2·DME, and 0.036 mmol of 6,6-dimethylbipyridine were successively added to 1.0 mL of 1,2-dimethoxyethane to obtain a mixture;

[0045] (2) Under a nitrogen atmosphere, the mixture was stirred at 0 °C for 24 h, and S-fluoroalkyl-substituted L-cysteine derivatives were collected from the product. The product was purified by column chromatography to obtain a colorless oil, which was Compound 2, 55.0 mg (0.09 mmol, dr 1:1), with a yield of 48%.

[0046] As Figure 4 , 1 1H NMR (400 MHz, CDCl3) δ 7.69 - 7.59 (m, 4H), 7.59 - 7.51 (m, 2H), 7.50 - 7.41 (m, 2H), 7.40 - 7.33 (m, 1H), 7.26 - 7.21 (m, 3H), 7.19 - 7.09 (m, 1H), 5.340 (t, J = 8.0 Hz, 1H), 4.60 - 4.47 (m, 1H), 3.74 (s, 1.5H), 3.72 (s, 1.5H), 3.54 (dd, J = 14.1, 7.0 Hz, 1H), 3.41 (dd, J = 14.1, 7.2 Hz, 1H), 3.31 - 3.04 (m, 2H), 3.03 - 2.86 (m, 2H), 1.44 (s, 4.5H), 1.43 (s, 4.5H).

[0047] As Figure 5 , 1313C NMR (101 MHz, CDCl3) δ 171.47, 155.1, 140.9, 140.2, 135.2, 135.1 (135.0), 130.96 (130.91), 129.0, 129.0, 128.20, 127.7, 127.27 (127.24), 127.2, 127.0, 127.4 (q, J = 286.3 Hz), 80.4, 53.6 (53.4), 52.8, 52.7 (q, J = 22.8 Hz), 39.2 (39.1), 36.8 (36.7), 35.4 (35.3), 28.4.

[0048] 19 19F NMR (376 MHz, CDCl3) δ -69.02 (-69.07) (s).

[0049] HRMS (ESI, m / z): calcd for C 31 H 35 F3NO4S [M+H] + : 574.2239, found: 574.2209.

[0050] Example 3:

[0051] This example provides a method for preparing S-fluoroalkyl-substituted BocN-Val-Cys-OMe, comprising the following steps:

[0052] (1) Under a nitrogen atmosphere, 0.2 mmol of 4-phenyl-α-trifluoromethylstyrene, 0.3 mmol of BocN-Val-Cys-OMe, 0.3 mmol of benzyl bromide, 0.6 mmol of manganese powder, 0.03 mmol of NiBr2·DME, and 0.036 mmol of 6,6-dimethylbipyridine were successively added to 0.5 mL of 1,2-dimethoxyethane to obtain a mixture;

[0053] (2) Under a nitrogen atmosphere, the mixture was stirred at 0 °C for 2 h, and a 0.5 mL N,N-dimethylformamide solution of 0.3 mmol of BocN-Val-Cys-OMe and 0.3 mmol of benzyl bromide was added dropwise to the above mixture through a syringe. Then, the resulting mixture was continuously stirred at 0 °C for 46 h, and the S-fluoroalkyl-substituted L-cysteine derivative was collected from the product. The product was purified by high-performance liquid chromatography to obtain 54.0 mg (0.084 mmol, dr 1:1) of compound 3 as a white solid, with a yield of 42%.

[0054] As Figure 6 , 11H NMR (400 MHz, CDCl3) δ 7.66 - 7.58 (m, 4H), 7.58 - 7.50 (m, 2H), 7.49 - 7.42 (m, 2H), 7.40 - 7.34 (m, 1H), 7.26 - 7.17 (m, 3H), 7.16 - 7.05 (m, 2H), 6.92 - 6.79 (m, 1H), 5.20 - 5.05 (m, 1H), 4.80 (dt, J = 7.6, 5.2 Hz, 1H), 4.06 - 3.90 (m, 1H), 5.340 (t, J = 8.0 Hz, 1H), 4.60 - 4.47 (m, 1H), 3.74 (s, 1.5H), 3.72 (s, 1.5H), 3.519 (dd, J = 14.1, 7.7 Hz, 1H), 3.401 (dd, J = 14.0, 8.9 Hz, 1H), 3.27 - 2.87 (m, 3H), 2.24 - 2.08 (m, 1H), 1.43 (s, 4.5H), 1.42 (s, 4.5H), 1.10 - 0.89 (m, 6H).

[0055] HRMS (ESI, m / z): calcd for C 36 H 43 F3N2NaO5S [M + H] + : 695.2742, found: 695.2740.

[0056] Examples 4 - 8

[0057] Examples 4 - 8 have the same preparation steps as Example 2, except that the raw materials are different, as shown in Table 1 below.

[0058] Table 1

[0059]

[0060]

[0061] Examples 9 - 12:

[0062] Examples 9 - 12 have the same preparation steps as Example 3, except that the raw materials are different, as shown in Table 2 below.

[0063] Table 2

[0064]

[0065] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. An S-fluoroalkyl-substituted amino acid, characterized in that, The chemical structural formula of the said compound is shown as Formula I: Wherein, Ar is 4-phenylphenyl, 4-acetylphenyl, 4-methoxycarbonylphenyl, 4-acetoxyphenyl, 4-cyanophenyl, 4-(N,N-dimethylamide)phenyl; Ar' is phenyl, 4-iodophenyl, 4-bromophenyl, 3-methoxycarbonylphenyl, 2-naphthyl, 3-thienyl; R1 and R2 are methyl or H.

2. An S-fluoroalkyl-substituted polypeptide, characterized in that, It is prepared by removing the tert-butyl group from the S-fluoroalkyl-substituted amino acid described in Claim 1 and then condensing it with other amino acids. The structural formula of the S-fluoroalkyl-substituted polypeptide is shown as Formula II: Wherein, Ar is 4-phenylphenyl, 4-acetylphenyl, 4-methoxycarbonylphenyl, 4-acetoxyphenyl, 4-cyanophenyl, 4-(N,N-dimethylamide)phenyl; Ar' is phenyl, 4-iodophenyl, 4-bromophenyl, 3-methoxycarbonylphenyl, 2-naphthyl, 3-thienyl; R1 and R2 are H; R is methyl, isopropyl, tert-butyl.

3. A method for preparing the S-fluoroalkyl-substituted amino acid according to claim 1, characterized in that, It includes the following steps: Under an inert gas atmosphere, add trifluoromethyl olefin, benzyl bromide, manganese powder, nickel catalyst, ligand, and mercapto-containing amino acid into the solution in sequence to obtain a mixture; Under an inert gas atmosphere, react the said mixture at 0 °C, and collect the S-fluoroalkyl-substituted amino acid from the reaction product.

4. The preparation method according to claim 3, characterized in that, The molar ratio of the trifluoromethyl olefin, benzyl bromide, mercapto-containing amino acid / polypeptide, manganese powder, nickel catalyst, and ligand is 1:2 - 4:2 - 4:1 - 3:0.1 - 0.2:0.15 - 0.

2.

5. The preparation method according to claim 3, characterized in that, The trifluoromethyl olefin is at least one of 4-phenyl-α-trifluoromethylstyrene, 4-acetyl-α-trifluoromethylstyrene, 4-methoxycarbonyl-α-trifluoromethylstyrene, 4-acetoxy-α-trifluoromethylstyrene, 4-cyano-α-trifluoromethylstyrene, and 4-(N,N-dimethylamide)-α-trifluoromethylstyrene.

6. The preparation method according to claim 3, characterized in that, The said benzyl bromide derivative is at least one of 1-bromomethyl-4-iodobenzene, 1-bromomethyl-4-bromobenzene, methyl 3-bromomethyl-benzoate, 2-bromomethylnaphthalene, and 3-bromomethylthiophene.

7. The preparation method according to claim 3, characterized in that, The nickel catalyst is NiBr2·DME, and the ligand is 6,6-dimethylbipyridine.

8. The preparation method according to claim 3, wherein The amino acid is penicillamine or cysteine.

9. The preparation method according to claim 3, characterized in that, The solvent is dimethoxyethylene glycol, N,N-dimethylformamide, or a mixture of the two.

10. The preparation method according to claim 3, characterized in that, The reaction time is 24 - 48 hours.

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