C11a-OH tetracycline compound and synthesis method thereof

Abstract

The invention provides a C11a-OH tetracycline compound. The structural formula of the C11a-OH tetracycline compound is shown as a formula (I): # imgabs0 #, wherein R1 is hydrogen or acylamino; r2 is hydrogen, halogen or dimethylamino; r3, R4 and R5 are hydrogen or hydroxyl; the invention also provides a synthesis method of the 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, stirring, slowly adding peroxide into the round-bottom flask at room temperature, reacting for 2 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and carrying out reverse preparation to obtain the target C11a-OH tetracycline compound (2), the synthesis method of the C11a-OH tetracycline compound is realized for the first time, and the method is simple, efficient, wide in application range and easy for large-scale production.

Description

Technical Field

[0001] The invention relates to the field of chemical industry, and in particular to a C11a-OH tetracycline compound and a synthesis method thereof. Background Art

[0002] Tetracycline is a broad-spectrum antibiotic that has good inhibitory ability against a variety of bacteria and fungi, including Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria. Studies have shown that its antibacterial mechanism is related to magnesium ion coordination. O11 and O12 of tetracycline bind to ribosomes through magnesium ions, thereby exerting an inhibitory effect. The only method disclosed in the prior art is to produce a hydroxyl group at the C11a position of tetracycline through a biosynthetic method, thereby preventing it from coordinating with magnesium ions, causing the decomposition of tetracycline, and resulting in bacterial resistance. At present, there is no public general structural formula of tetracycline compounds with a hydroxyl group at the C11a position and its chemical synthesis method.

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

[0004] In order to solve the technical problems existing in the prior art, the present invention discloses a C11a-OH tetracycline compound, and the specific technical scheme is as follows:

[0005] The present invention provides a C11a-OH tetracycline compound, the structural formula of which is formula (I):

[0006]

[0007] in:

[0008] R1 is hydrogen or amide;

[0009] R2 is hydrogen, halogen or dimethylamino;

[0010] R3, R4, and R5 are hydrogen or hydroxy.

[0011] The present invention also provides a method for synthesizing a C11a-OH tetracycline compound, comprising the following steps:

[0012] A polar solvent and a tetracycline raw material (1) are sequentially added to a round-bottom flask, and peroxide is slowly added thereto at room temperature after stirring. After reacting for 2 hours, the solvent is evaporated off under reduced pressure, and the target C11a-OH tetracycline compound (2) is obtained after reverse preparation. The reaction formula is as follows:

[0013]

[0014] Furthermore, the polar solvent includes ethers and water.

[0015] Furthermore, the ethers include tetrahydrofuran.

[0016] Furthermore, it also includes a solubilizing agent, and the solubilizing agent is a Lewis acid.

[0017] Furthermore, the dissolution agent is boron trifluoride ether or boron trifluoride acetic acid.

[0018] Furthermore, the molar ratio of the tetracycline raw material (1) to the dissolution promoter is 1:0-1:6.

[0019] Furthermore, the peroxide is meta-chloroperbenzoic acid (m-CPBA).

[0020] Furthermore, the molar ratio of the tetracycline raw material (1) to meta-chloroperbenzoic acid is 1:1-1:4.

[0021] Furthermore, during the reverse preparation process, the volume ratio of acetonitrile or methanol (+0.8% formic acid) and water was gradually changed from 1:19 to 1:3.

[0022] The present invention has the following beneficial effects:

[0023] 1. The C11a-OH tetracycline compound provided by the present invention is a finished product obtained by a chemical synthesis method for the first time, and its corresponding general structural formula and chemical properties are disclosed, which can be applied to the study of bacterial resistance mechanism and further research on degradation products.

[0024] 2. The synthesis method of the C11a-OH tetracycline compound provided by the present invention is simple, efficient, has a wide range of applications, and is easy to mass produce.

[0025] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. DETAILED DESCRIPTION

[0026] Embodiments of the present invention are described in detail below, and examples of the embodiments are shown, wherein the same or similar reference numerals throughout represent the same or similar elements or elements with the same or similar functions. The following embodiments are exemplary and are intended to be used to explain the present invention, and should not be construed as limiting the present invention.

[0027] In the description of the present invention, it should be understood that the terms "upper", "lower", "top", "bottom", "inner", "outer", etc., indicating directions or positional relationships, are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific direction, be constructed and operated in a specific direction, and therefore cannot be understood as limiting the present invention. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0028] In the present invention, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected", "fixed" and the like should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, it can be the internal connection of two elements or the interaction relationship between two elements. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0029] Example 1

[0030] Synthesis of compound C11a-OH oxytetracycline (2-1):

[0031]

[0032] Oxytetracycline 1-1 (100 mg, 0.217 mmol, 1.0 equiv.), 5 mL of tetrahydrofuran and boron trifluoride ether (0.11 mL, 0.87 mmol, 4.0 equiv.) were added to a 100 mL round-bottom flask in sequence. Meta-chloroperbenzoic acid (75 mg, 0.53 mmol, 2.0 equiv.) was slowly added at room temperature, and the reaction was stopped after stirring at room temperature for 2 hours. The solvent was dried under reduced pressure and the target compound 2-160.9 mg was obtained by reverse phase separation with a yield of 59%.

[0033] Compound 2-1: yellow solid, melting point 242.0-245.6°C, Compound 2-1 was converted into compound 3-1 under deuterated hydrochloric acid conditions. Characterization of compound 3-1: 1 H NMR(400MHz,0.1M DCl in D2O) δ7.55(t,J=8.1,1.7Hz,1H),7.06(dd,J=7.7,1.7Hz,1H),7.00(dd,J=8.4,1.7Hz,1H),4.13(dd,J=8.8,1 .7Hz,1H),3.95(m,1H),3.66(dt,J=8.9,2.0Hz,1H),3.13(s,3H),2.95(s,3H),2.79(m,1H),1.53(s,3H)ppm. 13C NMR(0.1M DCl in D2O)δ199.9,194.5,187.0,171.6,161.4,148.0,137.8,118.0,115.2,113.5,102. 7,99.4,85.6,79.9,74.5,69.7,66.7,60.2,43.9,42.4,17.7ppm.HRMS(ESI)calcd for C 22 H 25 N2O 10 + [M+H] + 477.1504,found477.1489.

[0034] Example 2

[0035] Synthesis of compound C11a-OH tetracycline (2-2):

[0036]

[0037] 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 to a 100 mL round-bottom flask in sequence. Meta-chloroperbenzoic acid (390 mg, 2.26 mmol, 2.0 equiv.) was slowly added at room temperature, and the reaction was stopped after stirring at room temperature for 2 hours. The solvent was dried under reduced pressure and the target compound 2-2 was obtained by reverse phase separation with a yield of 69%.

[0038] Compound 2-2: yellow solid, melting point 202.0-204.1°C, 1 H NMR (400MHz, DMSO-d6) δ17.79(br,1H),12.02(s,1H),9.27(br,1H),8.94(br,1H),7.62(t,J=8.0Hz, 1H),7.19(d,J=7.8Hz,1H),6.97(d,J=8.3Hz,1H),6.41(s,1H),5.84(br,1H),3.40(m,1H,overlapped with water),2.89(br,1H),2.65-2.55(m,2H),2.34(s,6H),2.07-2.00(m,1H),1.56(s,3H)ppm. 13C NMR(101MHz,DMSO-d6)δ198.7,162.2,148.6,137.5,117.1,116.6,113.6,79.1,70.5,48.1,43.2,41.7,24.7,21.9ppm.HRMS(ESI)calcd forC22H24N2O9Na + [M+Na] + 483.1374, found 483.1377.

[0039] Example 3

[0040] Synthesis of compound C11a-OH chlortetracycline (2-3):

[0041]

[0042] 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 to a 100 mL round-bottom flask in sequence. Meta-chloroperbenzoic acid (336 mg, 1.94 mmol, 2.0 equiv.) was slowly added at room temperature, and the reaction was stopped after stirring at room temperature for 2 hours. The target compound 2-3 was separated by reverse phase to obtain 310 mg, with a yield of 64%.

[0043] Compound 2-3: yellow solid, melting point 164.8-166.0°C, 1 HNMR (400MHz, DMSO-d6) δ18.14(br,1H),11.33(s,1H),9.30(br,1H),9.05(br,1H),7.73(br,1H),7.63(d,J=8.9Hz,1H),6.97(d,J=8.9Hz, 1H),6.60(br,1H),4.37(s,1H),3.49-3.35(m,2H),3.02-2.94(m,1H),2.66-2.60(m,1H),2.47(s,6H),2.18-2.13(m,1H),1.69(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ204.9,198.3,191.9,172.9,163.2,160.2,145.1,140.2,123.2, 118.4,114.4,100.1,80.0,78.3,71.8,44.1,41.7,34.5,25.0,20.3ppm.HRMS(ESI)calcd for C 21 H23 ClN2O9Na + [M+Na] + 517.0984, found 517.0973.

[0044] Example 4

[0045] Synthesis of compound C11a-OH demeclocycline (2-4):

[0046]

[0047] Demeclocycline hydrochloride 1-4 (500 mg, 0.97 mmol, 1.0 equiv.) and 10 mL of water were added to a 100 mL round-bottom flask in sequence. Meta-chloroperbenzoic acid (345 mg, 2.0 mmol, 2.0 equiv.) was slowly added thereto at room temperature, and the reaction was stopped after stirring at room temperature for 2 hours. The target compound 2-4 was separated by reverse phase to obtain 357 mg, with a yield of 74%.

[0048] Compound 2-4: yellow solid, melting point 155.2-156.8°C, 1 H NMR(400MHz,DMSO-d6)δ17.50(br,1H),12.00(s,1H),9.18(br,1H),8.92(br,1H),7.71(d,J=9.0 Hz,1H),7.05(d,J=9.0Hz,1H),6.34(br,1H),6.01(br,1H),4.95(s,1H),3.35(m,1H,overlapped with water),2.92-2.85(m,1H),2.67-2.56(m,2H),2.32(s,6H),1.83-1.72(m,1H)ppm. 13 C NMR(101MHz,DMSO-d6)δ198.0,163.7,161.4,161.3,141.2,138.3,138.2,123.0,122 .9,119.5,115.1,78.7,78.3,65.9,65.7,43.3,42.2,34.5,24.7ppm.HRMS(ESI)calcd for C 21 H 21 ClN2O9Na + [M+Na] + 503.0828, found 503.0826.

[0049] Example 5

[0050] Synthesis of compound C11a-OH sancycline (2-5):

[0051]

[0052] Sancycline 1-5 (300 mg, 0.72 mmol, 1.0 equiv.), 15 mL of tetrahydrofuran and boron trifluoride acetic acid (0.39 mL, 2.88 mmol, 4.0 equiv.) were added to a 100 mL round-bottom flask in sequence. Meta-chloroperbenzoic acid (248 mg, 1.44 mmol, 2.0 equiv.) was slowly added at room temperature, and the reaction was stopped after stirring at room temperature for 2 hours. The solvent was dried and then separated by reverse phase to obtain 224 mg of the target compound 2-5 with a yield of 72%.

[0053] Compound 2-5: yellow solid, melting point 142.1-144.2°C, 1 H NMR (400MHz, DMSO-d6) δ17.82(br,1H),11.96(s,1H),9.17(br,1H),9.00(br,1H),7.49(t,J=7 .9Hz,1H),6.92(br,1H),6.83(d,J=8.3Hz,1H),6.79(d,J=7.4Hz,1H),3.35(m,1H,overlapped with water),2.97-2.86(m,2H),2.71-2.65(m,2H),2.37(s,6H),1.82-1.70(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ202.9,197.6,173.1,162.8,162.8,143.8,143.8,137.4,137.3,119.1,115 .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.

[0054] Example 6

[0055] Synthesis of compound C11a-OH minocycline (2-6):

[0056]

[0057] Minocycline hydrochloride 1-6 (500 mg, 1.09 mmol, 1.0 equiv.) and 10 mL of water were added to a 100 mL round-bottom flask in sequence. Meta-chloroperbenzoic acid (376 mg, 2.18 mmol, 2.0 equiv.) was slowly added thereto at room temperature, and the reaction was stopped after stirring at room temperature for 2 hours. The target compound 2-6 was separated by reverse phase to obtain 288 mg, with a yield of 56%.

[0058] Compound 2-6: yellow solid, melting point 216-219.3°C, 1 H NMR (400MHz, DMSO-d6) δ17.80(br,1H),11.76(s,1H),9.20-9.00(br,2H),7.43(d,J=8.9Hz,1H),6.82(d,J=8.8Hz,1H),6.78(br,1H),3.35(m,1H,overlapped with water),3.05(dd,J=16.4,4.0Hz,1H),2.90-2.80(m,1H),2.65-2.56(m,2H),2.53(s,6H),2.34(s,6H),1.83-1.70(m,2H)ppm. 13 CNMR(101MHz,DMSO-d6)δ198.6,158.7,142.9,137.4,129.3,115.5,115.5,77.6,44.4,43.1,42.1,34.4,28.2,24.7ppm.HRMS(ESI)calcd for C 23 H 27 N3O8Na + [M+Na] + 496.1690, found 496.1690.

[0059] Example 7

[0060] Synthesis of compound C11a-OH tigecycline (2-7):

[0061]

[0062] Tigecycline 1-7 (300 mg, 0.51 mmol, 1.0 equiv.) and 15 mL of water were added to a 100 mL round-bottom flask in sequence. Meta-chloroperbenzoic acid (176 mg, 1.02 mmol, 2.0 equiv.) was slowly added thereto at room temperature, and the reaction was stopped after stirring at room temperature for 2 hours. The target compound 2-7 was separated by reverse phase to obtain 210 mg, with a yield of 68%.

[0063] Compound 2-7: yellow solid, melting point 194.0-196.3°C, 1 HNMR(400MHz,DMSO-d6)δ12.16(br,1H),10.21(br,1H),9.14(s,1H),8.71(br,1H),8.45(s,1H),6.87(br,1H),3.40-3.20(m,3H,overlapped with water),3.00(dd,J=16.3,4.0Hz,1H),2.90-2.80(m,1H),2.65-2.56(m,2H),2.53(s,6H),2.30(s,6H),1.82-1.73(m,2H),1.09(s,9H)ppm. 13 C NMR(101MHz,DMSO-d6)δ204.9,199.1,193.3,190.0,174.2,170.8,164.7,148.4,142.7,131.6,131.4,125.5,118 .7,115.4,82.1,81.4,78.4,78.0,70.8,67.2,51.9,46.3,44.8,44.7,44.1,43.6,34.9,28.4ppm.HRMS(ESI)calcd for C 29 H 39 N5O9Na + [M+Na] + 624.2640, found 624.2627.

[0064] In the structural formula of the C11a-OH tetracycline compound obtained in the above example, positions R1 to R5 thereof, which are not specially marked, all represent hydrogen bonds.

[0065] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification.

[0066] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify and vary the above embodiments within the scope of the present invention.

Claims

1. A C11a-OH tetracycline compound, characterized in that Its structural formula is formula (I): in: R1 is hydrogen or amide; R2 is hydrogen, halogen or dimethylamino; R3, R4, and R5 are hydrogen or hydroxy.

2. A method for synthesizing a C11a-OH tetracycline compound, characterized in that: The steps include: A polar solvent and a tetracycline raw material (1) are sequentially added to a round-bottom flask, and peroxide is slowly added thereto at room temperature after stirring. After reacting for 2 hours, the solvent is evaporated off under reduced pressure, and the target C11a-OH tetracycline compound (2) is obtained after reverse preparation. The reaction formula is as follows:

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

4. The method for synthesizing the C11a-OH tetracycline compound according to claim 3, characterized in that: The ethers include tetrahydrofuran.

5. The method for synthesizing the C11a-OH tetracycline compound according to claim 2, characterized in that: Also included is a chaotropic agent, which is a Lewis acid.

6. The method for synthesizing the C11a-OH tetracycline compound according to claim 5, characterized in that: The dissolution promoter is boron trifluoride ether or boron trifluoride acetic acid.

7. The method for synthesizing the C11a-OH tetracycline compound according to claim 5, characterized in that: The molar ratio of the tetracycline raw material (1) to the dissolution promoter is 1:0-1:

6.

8. The method for synthesizing the C11a-OH tetracycline compound according to claim 2, characterized in that: The peroxide is meta-chloroperbenzoic acid (m-CPBA).

9. The method for synthesizing the C11a-OH tetracycline compound according to claim 8, characterized in that: The molar ratio of the tetracycline raw material (1) to meta-chloroperbenzoic acid is 1:1-1:

4.

10. The method for synthesizing a C11a-OH tetracycline compound according to claim 1, characterized in that: During the reverse preparation process, the volume ratio of acetonitrile or methanol (+0.8% formic acid) and water was gradually changed from 1:19 to 1:3.

Images