A c11a-oh tetracycline compound and a method of synthesis thereof

Abstract

The application provides a synthesis method of a C11a-OH tetracycline compound, which comprises the following steps: sequentially adding a polar solvent and a tetracycline raw material (1) into a round-bottom flask, slowly adding meta-chloro peroxide benzoic acid into the round-bottom flask at room temperature after stirring, removing the solvent by rotary evaporation under reduced pressure after reacting for 2 hours, and obtaining a target C11a-OH tetracycline compound (2) through reversed-phase preparation, and a reaction formula is as formula (II). (II) The synthesis method of the C11a-OH tetracycline compound is realized for the first time, the method is simple and efficient, has wide application range, and is easy to scale up.

Description

Technical Field

[0001] This invention relates to the field of chemical engineering, specifically to a C11a-OH tetracycline compound and its synthesis method. Background Technology

[0002] Tetracyclines are a class of broad-spectrum antibiotics with good inhibitory effects on a variety of bacteria and fungi, including Gram-positive, Gram-negative, and anaerobic bacteria. Studies have shown that their antibacterial mechanism is related to magnesium ion coordination; the O11 and O12 groups of tetracycline bind to ribosomes via magnesium ions, thereby exerting an inhibitory effect. Existing technologies only disclose methods for generating a hydroxyl group at the C11a position of tetracycline through biosynthesis, thereby preventing its coordination with magnesium ions, causing tetracycline decomposition, and leading to bacterial resistance. Currently, there are no publicly disclosed general structural formulas or chemical synthesis methods for tetracycline compounds with a hydroxyl group at the C11a position.

[0003] Therefore, it is necessary to provide a new technical solution. Summary of the Invention

[0004] To address the technical problems existing in the prior art, this invention discloses a method for synthesizing C11a-OH tetracycline compounds, the specific technical solution of which is as follows:

[0005] This invention provides a method for synthesizing C11a-OH tetracycline compounds, comprising the following steps:

[0006] A polar solvent and tetracycline raw material (1) were added sequentially to a round-bottom flask. After stirring, m-chloroperoxybenzoic acid was slowly added to the flask at room temperature. After reacting for 2 hours, the solvent was removed by rotary evaporation under reduced pressure. The target C11a-OH tetracycline compound (2) was obtained by reverse phase preparation. The reaction formula is shown in formula (II).

[0007] ,

[0008] (II)

[0009] in:

[0010] R1 is a hydrogen or amide group;

[0011] R2 is hydrogen, halogen, or dimethylamino group;

[0012] R3, R4, and R5 are hydrogen or hydroxyl groups.

[0013] Furthermore, the polar solvent is an ether or water.

[0014] Furthermore, the ether is tetrahydrofuran.

[0015] Furthermore, it also contains Lewis acids.

[0016] Furthermore, the Lewis acid is boron trifluoride ether or boron trifluoride acetic acid.

[0017] Furthermore, the molar ratio of the tetracycline raw material (1) to the Lewis acid is 1:0-1:6.

[0018] Furthermore, the molar ratio of the tetracycline raw material (1) to m-chloroperoxybenzoic acid is 1:1-1:4.

[0019] Furthermore, during the reverse-phase preparation process, the volume ratio of acetonitrile or methanol + 0.8% formic acid and water gradually changes from 1:19 to 1:3.

[0020] The present invention has the following beneficial effects:

[0021] 1. The C11a-OH tetracycline compound provided by this invention is the first product obtained by chemical synthesis, and its corresponding general structural formula and chemical properties are disclosed, which can be applied to the study of bacterial drug resistance mechanisms and further degradation products.

[0022] 2. The method for synthesizing C11a-OH tetracycline compounds provided by this invention is simple, efficient, widely applicable, and easy to scale up for production.

[0023] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Detailed Implementation

[0024] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0025] In the description of this invention, it should be understood that the terms "upper," "lower," "top," "bottom," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing the invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the invention. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0026] In this invention, unless otherwise explicitly specified and limited, the terms "installation," "connection," "linking," and "fixing," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal communication of two components or the interaction between two components. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0027] Example 1

[0028] Synthesis of compound C11a-OH oxytetracycline (2-1):

[0029]

[0030] To a 100 mL round-bottom flask, oxytetracycline 1-1 (100 mg, 0.217 mmol, 1.0 equiv.), 5 mL of tetrahydrofuran, and boron trifluoride diethyl ether (0.11 mL, 0.87 mmol, 4.0 equiv.) were added sequentially. Then, m-chloroperoxybenzoic acid (75 mg, 0.53 mmol, 2.0 equiv.) was slowly added at room temperature. After stirring for 2 hours at room temperature, the reaction was stopped, the solvent was evaporated under reduced pressure, and the mixture was separated by reverse phase to give 60.9 mg of the target compound 2-1 (59% yield).

[0031] Compound 2-1: Yellow solid, melting point 242.0-245.6°C. o C, -34 (c 0.1, H2O). Compound 2-1 is converted to compound 3-1 under deuterated hydrochloric acid conditions. Characterization of compound 3-1: 1 H NMR (400 MHz, 0.1 M DCl inD2O) δ 7.55 (t, J = 8.1, 1.7 Hz, 1 H), 7.06 (dd, J = 7.7, 1.7 Hz, 1 H), 7.00(dd, J = 8.4, 1.7 Hz, 1 H), 4.13 (dd, J = 8.8, 1.7 Hz, 1 H), 3.95 (m, 1 H), 3.66 (dt, J = 8.9, 2.0 Hz, 1 H), 3.13 (s, 3 H), 2.95 (s, 3 H), 2.79 (m, 1 H), 1.53 (s, 3 H) ppm. 13C NMR (0.1 M DCl in D2O) δ 199.9, 194.5, 187.0, 171.6,161.4, 148.0, 137.8, 118.0, 115.2, 113.5, 102.7, 99.4, 85.6, 79.9, 74.5,69.7, 66.7, 60.2, 43.9, 42.4, 17.7 ppm. HRMS (ESI) calcd for C 22 H 25 N2O 10 + [M+H] + 477.1504, found 477.1489.

[0032] Example 2

[0033] Synthesis of compound C11a-OH tetracycline (2-2):

[0034]

[0035] Tetracycline 1-2 (500 mg, 1.13 mmol, 1.0 equiv.), 30 mL of tetrahydrofuran, and boron trifluoride acetic acid (0.62 mL, 4.5 mmol, 4.0 equiv.) were added sequentially to a 100 mL round-bottom flask. Then, m-chloroperoxybenzoic acid (390 mg, 2.26 mmol, 2.0 equiv.) was slowly added at room temperature. After stirring for 2 hours at room temperature, the reaction was stopped, the solvent was evaporated under reduced pressure, and the mixture was separated by reverse phase to give 354 mg of the target compound 2-2 in 69% yield.

[0036] Compound 2-2: Yellow solid, melting point 202.0-204.1°C. o C, -122 (c 0.1, H2O). 1H NMR(400 MHz, DMSO-d6) δ 17.79 (br, 1 H), 12.02 (s, 1 H), 9.27 (br, 1 H), 8.94(br, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 6.97 (d, J =8.3 Hz, 1 H), 6.41 (s, 1 H), 5.84 (br, 1 H), 3.40 (m, 1 H, overlapped with water), 2.89 (br, 1 H), 2.65-2.55 (m, 2 H), 2.34 (s, 6 H), 2.07-2.00 (m, 1H), 1.56 (s, 3H) ppm. 13 C NMR (101 MHz, DMSO-d6) δ 198.7, 162.2, 148.6,137.5, 117.1, 116.6, 113.6, 79.1, 70.5, 48.1, 43.2, 41.7, 24.7, 21.9 ppm. HRMS (ESI) calcd for C22H24N2O9Na + [M+Na] + 483.1374, found 483.1377.

[0037] Example 3

[0038] Synthesis of compound C11a-OH chlortetracycline (2-3):

[0039]

[0040] To a 100 mL round-bottom flask, chlortetracycline hydrochloride 1-3 (500 mg, 0.97 mmol, 1.0 equiv.), 10 mL of water, and boron trifluoride acetic acid (0.52 mL, 3.88 mmol, 4.0 equiv.) were added sequentially. Then, m-chloroperoxybenzoic acid (336 mg, 1.94 mmol, 2.0 equiv.) was slowly added at room temperature. After stirring for 2 hours at room temperature, the reaction was stopped, and the target compound 2-3 was separated by reverse phase to obtain 310 mg of the target compound 2-3 in 64% yield.

[0041] Compounds 2-3: Yellow solids, melting point 164.8-166.0 °C. o C, -30 (c 0.1, H2O). 1H NMR(400 MHz, DMSO-d6) δ 18.14 (br, 1 H), 11.33 (s, 1 H), 9.30 (br, 1 H), 9.05(br, 1 H), 7.73 (br, 1 H), 7.63 (d, J = 8.9 Hz, 1 H), 6.97 (d, J = 8.9 Hz, 1H), 6.60 (br, 1 H), 4.37 (s, 1 H), 3.49-3.35 (m, 2 H), 3.02-2.94 (m, 1 H), 2.66-2.60 (m, 1 H), 2.47 (s, 6 H), 2.18-2.13 (m, 1 H), 1.69 (s, 3 H) ppm. 13 CNMR (101 MHz, DMSO-d6) δ 204.9, 198.3, 191.9, 172.9, 163.2, 160.2, 145.1,140.2, 123.2, 118.4, 114.4, 100.1, 80.0, 78.3, 71.8, 44.1, 41.7, 34.5, 25.0,20.3 ppm. HRMS (ESI) calcd for C 21 H 23 ClN2O9Na + [M+Na] + 517.0984, found 517.0973.

[0042] Example 4

[0043] Synthesis of compound C11a-OH demethylchlortetracycline (2-4):

[0044]

[0045] Add 500 mg of demethylchlortetracycline hydrochloride 1-4 (1.0 mmol) and 10 mL of water to a 100 mL round-bottom flask. Then, slowly add m-chloroperoxybenzoic acid (345 mg, 2.0 mmol, 2.0 equiv.) to the mixture at room temperature. After stirring for 2 hours at room temperature, stop the reaction. Separate the mixture using a reverse phase to obtain 357 mg of the target compound 2-4 (74% yield).

[0046] Compounds 2-4: yellow solids, melting point 155.2-156.8°C. o C, -7.0 (c 0.06, MeOH). 1HNMR (400 MHz, DMSO-d6) δ 17.50 (br, 1 H), 12.00 (s, 1 H), 9.18 (br, 1 H), 8.92 (br, 1 H), 7.71 (d, J = 9.0 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 1 H), 6.34(br, 1 H), 6.01 (br, 1 H), 4.95 (s, 1 H), 3.35 (m, 1 H, overlapped with water), 2.92-2.85 (m, 1 H), 2.67-2.56 (m, 2 H), 2.32 (s, 6 H), 1.83-1.72 (m,1 H) ppm. 13 C NMR (101 MHz, DMSO-d6) δ 198.0, 163.7, 161.4, 161.3, 141.2,138.3, 138.2, 123.0, 122.9, 119.5, 115.1, 78.7, 78.3, 65.9, 65.7, 43.3, 42.2,34.5, 24.7 ppm. HRMS (ESI) calcd for C 21 H 21 ClN2O9Na + [M+Na] + 503.0828, found503.0826.

[0047] Example 5

[0048] Synthesis of compound C11a-OH kaempferol (2-5):

[0049]

[0050] To a 100 mL round-bottom flask, add 300 mg (0.72 mmol, 1.0 equiv.) of kaempferol 1-5, 15 mL of tetrahydrofuran, and 0.39 mL (2.88 mmol, 4.0 equiv.) of boron trifluoride acetic acid. Then, slowly add m-chloroperoxybenzoic acid (248 mg, 1.44 mmol, 2.0 equiv.) at room temperature. After stirring for 2 hours at room temperature, stop the reaction. After evaporating the solvent by rotary evaporation, separate by reverse phase to obtain 224 mg of the target compound 2-5, in 72% yield.

[0051] Compounds 2-5: Yellow solids, melting point 142.1-144.2°C. o C, -15 (c 0.24, MeOH). 1 H NMR(400 MHz, DMSO-d6) δ 17.82 (br, 1 H), 11.96 (s, 1 H), 9.17 (br, 1 H), 9.00(br, 1 H), 7.49 (t, J = 7.9 Hz, 1 H), 6.92 (br, 1 H), 6.83 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1 H), 3.35 (m, 1 H, overlapped with water), 2.97-2.86 (m, 2 H), 2.71-2.65 (m, 2 H), 2.37 (s, 6 H), 1.82-1.70 (m, 2 H) ppm. 13 CNMR (101 MHz, DMSO-d6) δ 202.9, 197.6, 173.1, 162.8, 162.8, 143.8, 143.8,137.4, 137.3, 119.1, 115.5, 115.5, 115.3, 115.3, 80.6, 78.1, 77.6, 43.3,42.9, 42.3, 34.5, 29.3, 27.5. ppm. HRMS (ESI) calcd for C 21 H 22 N2O8Na + [M+Na] + 453.0268, found 453.0257.

[0052] Example 6

[0053] Synthesis of compound C11a-OH minocycline (2-6):

[0054]

[0055] Minocycline hydrochloride 1-6 (500 mg, 1.09 mmol, 1.0 equiv.) and 10 mL of water were added sequentially to a 100 mL round-bottom flask. Then, m-chloroperoxybenzoic acid (376 mg, 2.18 mmol, 2.0 equiv.) was slowly added at room temperature. After stirring for 2 hours at room temperature, the reaction was stopped. The target compound 2-6 was separated by reverse phase to obtain 288 mg of minocycline hydrochloride, in 56% yield.

[0056] Compounds 2-6: Yellow solids, melting point 216-219.3°C.o C, -75 (c 0.04, MeOH). 1 H NMR(400 MHz, DMSO-d6) δ 17.80 (br, 1 H), 11.76 (s, 1 H), 9.20-9.00 (br, 2 H),7.43 (d, J = 8.9 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 6.78 (br, 1 H), 3.35(m, 1 H, overlapped with water), 3.05 (dd, J = 16.4, 4.0 Hz, 1 H), 2.90-2.80(m, 1 H), 2.65-2.56 (m, 2 H), 2.53 (s, 6 H), 2.34 (s, 6 H), 1.83-1.70 (m, 2H) ppm. 13 C NMR (101 MHz, DMSO-d6) δ 198.6, 158.7, 142.9, 137.4, 129.3, 115.5,115.5, 77.6, 44.4, 43.1, 42.1, 34.4, 28.2, 24.7 ppm. HRMS (ESI) calcd forC 23 H 27 N3O8Na + [M+Na] + 496.1690, found 496.1690.

[0057] Example 7

[0058] Synthesis of compound C11a-OH tigecycline (2-7):

[0059]

[0060] Tigecycline 1-7 (300 mg, 0.51 mmol, 1.0 equiv.) and 15 mL of water were added sequentially to a 100 mL round-bottom flask. Then, m-chloroperoxybenzoic acid (176 mg, 1.02 mmol, 2.0 equiv.) was slowly added at room temperature. After stirring for 2 hours at room temperature, the reaction was stopped, and the target compound 2-7 was separated by reverse phase to obtain 210 mg of 2-7, in 68% yield.

[0061] Compounds 2-7: Yellow solids, melting point 194.0-196.3°C. o C, +44 (c 0.1, MeOH). 1 H NMR(400 MHz, DMSO-d6) δ 12.16 (br, 1 H), 10.21 (br, 1 H), 9.14 (s, 1 H), 8.71(br, 1 H), 8.45 (s, 1 H), 6.87 (br, 1 H), 3.40-3.20 (m, 3 H, overlapped withwater), 3.00 (dd, J = 16.3, 4.0 Hz, 1 H), 2.90-2.80 (m, 1 H), 2.65-2.56 (m, 2H), 2.53 (s, 6 H), 2.30 (s, 6 H), 1.82-1.73 (m, 2 H), 1.09 (s, 9 H) ppm. 13 CNMR (101 MHz, DMSO-d6) δ 204.9, 199.1, 193.3, 190.0, 174.2, 170.8, 164.7,148.4, 142.7, 131.6, 131.4, 125.5, 118.7, 115.4, 82.1, 81.4, 78.4, 78.0,70.8, 67.2, 51.9, 46.3, 44.8, 44.7, 44.1, 43.6, 34.9, 28.4 ppm. HRMS (ESI)calcd for C 29 H 39 N5O9Na + [M+Na] + 624.2640, found 624.2627.

[0062] In the structural formula of the C11a-OH tetracycline compound obtained in the above examples, unless otherwise specified, the R1 to R5 positions represent hydrogen bonds.

[0063] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can combine and integrate the different embodiments or examples described in this specification.

[0064] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for synthesizing a C11a-OH tetracycline compound, characterized in that, Includes the following steps: A polar solvent and tetracycline raw material (1) were added sequentially to a round-bottom flask. After stirring, m-chloroperoxybenzoic acid was slowly added to the flask at room temperature, and the reaction proceeded. Two hours later, the solvent was removed by rotary evaporation under reduced pressure. After reverse phase preparation, the target C11a-OH tetracycline compound (2) was obtained, and the reaction formula is shown in formula (II). ， （Ⅱ） in: R1 is a hydrogen or amide group; R2 is hydrogen, halogen, or dimethylamino; R3, R4, and R5 are hydrogen or hydroxyl groups.

2. The method for synthesizing the C11a-OH tetracycline compound according to claim 1, characterized in that, The polar solvents are ethers and water.

3. The method for synthesizing the C11a-OH tetracycline compound according to claim 2, characterized in that, The ether is tetrahydrofuran.

4. The method for synthesizing the C11a-OH tetracycline compound according to claim 1, characterized in that, It also contains Lewis acids.

5. The method for synthesizing the C11a-OH tetracycline compound according to claim 4, characterized in that, The Lewis acid is boron trifluoride. Diethyl ether or boron trifluoride acetic acid.

6. The method for synthesizing the C11a-OH tetracycline compound according to claim 4, characterized in that, The tetracycline raw material (1) and the road The molar ratio of escisic acid is 1:0 to 1:

6.

7. The method for synthesizing the C11a-OH tetracycline compound according to claim 1, characterized in that, The tetracycline raw material (1) and meta The molar ratio of chloroperoxybenzoic acid is 1:1 to 1:

4.

8. The method for synthesizing the C11a-OH tetracycline compound according to claim 1, characterized in that, In the reverse-phase preparation process, acetonitrile The volume ratio of 0.8% formic acid or methanol to water gradually changes from 1:19 to 1:3.

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