A c4-position oxyglycosyl tetracycline compound and a method for synthesizing the same
A multi-step synthetic method using specific reagents was employed to synthesize C4-oxyglycoside tetracycline compounds, solving the synthetic challenges in existing technologies and providing novel compounds with antibacterial resistance, suitable for large-scale production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- YANCHENG DAFENG AREA TIANSHENG JOINT PHARM CO LTD
- Filing Date
- 2023-11-02
- Publication Date
- 2026-07-10
AI Technical Summary
Existing technologies lack effective synthetic methods to prepare tetracycline compounds with C4-position (S) hydroxyl groups and C4-oxyglycosides, which cannot meet the needs of combating bacterial resistance.
A multi-step synthetic method was adopted, including the use of reagents such as N-chlorosuccinyl ether, CeCl3·7H2O, NaBH4, NaH, p-toluenesulfonic acid monohydrate and boron trifluoride diethyl ether, to achieve the synthesis of C4-oxyglycoside tetracycline compounds through a series of reactions.
The method achieves the chiral inversion of the C4 hydroxyl group and the synthesis of C4 oxyglycoside tetracycline compounds. It is simple, efficient, widely applicable, and easy to scale up for production.
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Figure CN117567531B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical engineering, specifically to a C4-oxyglycoside tetracycline compound and its synthesis method. Background Technology
[0002] Tetracyclines are a class of broad-spectrum antibiotics that are highly effective against a variety of bacteria and fungi, including Gram-positive, Gram-negative, and anaerobic bacteria. Currently, tetracycline compounds can be classified into three categories based on their origin: I. Natural tetracyclines (tetracycline, chlortetracycline, oxytetracycline); II. Semi-synthetic tetracyclines (minocycline, doxycycline, kaempferol, etc.); and III. Fully synthetic tetracyclines (epracycline, etc.).
[0003]
[0004] Recent reports have identified and isolated several novel C4-oxoglycoside tetracyclines, characterized by their C4 (S) hydroxyl configuration and the construction of the C4 oxoglycoside. However, the synthesis of the C4 (S) hydroxyl configuration and the C4 oxoglycoside of tetracyclines has not yet been reported. With the increasing tetracycline resistance in bacteria, screening for novel active C4 oxoglycoside tetracyclines and their clinical application is urgently needed.
[0005] Therefore, it is necessary to provide a new technical solution. Summary of the Invention
[0006] To address the technical problems existing in the prior art, this invention discloses a C4-oxyglycoside tetracycline compound, the specific technical solution of which is as follows:
[0007] This invention provides a structure with the formula (Ⅰ):
[0008]
[0009] in:
[0010] R1 is hydrogen or methyl;
[0011] R2 is hydrogen, halogen, or dimethylamino group;
[0012] R3, R4, R5, R6, and R7 are hydrogen or alkoxy groups.
[0013] This invention also discloses a method for synthesizing a C4-oxyglycoside tetracycline compound, which includes the following steps:
[0014] S1, tetracycline hydrochloride raw material (1), concentrated hydrochloric acid and water were added sequentially to a round-bottom flask. N-chlorosuccinimide (NCS) was added at room temperature. After the raw material slowly dissolved, a yellow solid gradually precipitated out. After 0.5 h, the mixture was filtered to obtain the crude hemiketal product compound (2-1) and compound (2-2), as shown in formula (II):
[0015]
[0016] S2, the above hemiketal compound (2-1) and compound (2-2) were dissolved in methanol, and CeCl3·7H2O was added to it. The mixture was stirred at 0°C for 10 min. NaBH4 was slowly added and stirred under the same conditions for 0.5 h. After the reaction was completed, excess NaBH4 was quenched with HCl. The mixture was extracted three times with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The mixture was filtered, the solvent was evaporated under reduced pressure, and the compounds (3-1) and (3-2) were obtained by reverse phase separation.
[0017] S3, add compound (3-1) and NaH to a round-bottom flask in sequence. After purging with nitrogen three times, add N,N-dimethylformamide (DMF) to the flask at 0°C. React at this temperature for 10 min. Add BnBr to the flask and react at 0°C for 6 h. Quench the reaction with saturated NH4Cl solution. Extract the flask three times with ethyl acetate. Concentrate the solvent under reduced pressure. Prepare compound (4) by reverse-phase preparation of the aqueous and organic phases together, as shown in formula (Ⅲ).
[0018]
[0019] S4, compound (4) was dissolved in tetrahydrofuran, p-toluenesulfonic acid monohydrate was added to it, and the reaction was carried out at 40°C for 12 h. The solvent was then concentrated under reduced pressure and purified by reverse phase preparation to obtain compound (5).
[0020] S5, compound (5), compound (6) and desiccant were added to the Shrek tube in sequence. After nitrogen purging three times, dichloromethane was added. Boron trifluoride ether was dissolved in dichloromethane and slowly added to the Shrek tube at -78°C. The reaction was carried out at this temperature for 2 hours. The reaction was then quenched with saturated NaHCO3 solution. The mixture was extracted three times with ethyl acetate. The solvent was concentrated under reduced pressure and purified by reverse phase preparation to obtain compound (7).
[0021] Furthermore, compound 7 includes 7α and 7β, with the following structural formula:
[0022]
[0023] Furthermore, in step S1, the molar ratio of the tetracycline hydrochloride and N-chlorosuccinyl is 1:2 to 1:3.5.
[0024] Furthermore, the optimal molar ratio of the tetracycline hydrochloride to N-chlorosuccinyl is 1:2.5.
[0025] Furthermore, in step S2, the molar ratio of the hemiacetal to the reducing agent NaBH4 is 1:2.5-1:4, and the molar ratio of the hemiacetal to CeCl3·7H2O is 1:4-1:10.
[0026] Furthermore, the optimal molar ratio of the hemiacetal to the reducing agent NaBH4 is 1:3, and the optimal molar ratio of the hemiacetal to CeCl3·7H2O is 1:8.
[0027] Furthermore, in step S3, the molar ratio of the tetracycline compound (3-1) to NaH is 1:3-1:6, and the molar ratio of the tetracycline compound (3-1) to BnBr is 1:1-1:3.
[0028] Furthermore, the optimal molar ratio of the tetracycline compound (3-1) to NaH is 1:4.5-1:5, and the optimal molar ratio of the tetracycline compound (3-1) to BnBr is 1:1.2-1:1.5.
[0029] Furthermore, in step S4, the molar ratio of the tetracycline compound (4) and p-toluenesulfonic acid monohydrate is 1:4-1:10.
[0030] Furthermore, the optimal molar ratio of the tetracycline compound (4) to p-toluenesulfonic acid monohydrate is 1:5-1:8.
[0031] Furthermore, in step S5, the molar ratio of the tetracycline compound (5) to the compound (6) is 1:2-1:4, the molar ratio of the tetracycline compound (5) to F3B·OEt2 is 1:3-1:8, and the weight ratio of the tetracycline compound (5) to the desiccant Drierite is 1:1-1:5.
[0032] Furthermore, the optimal molar ratio of the tetracycline compound (5) and compound (6) is 1:3-1:3.5, the optimal molar ratio of the tetracycline compound (5) and F3B·OEt2 is 1:4-1:5, and the optimal weight ratio of the tetracycline compound (5) and desiccant Drierite is 1:2-1:3.
[0033] Furthermore, the compound (6) is an acetyl donor.
[0034] Furthermore, in the reverse preparation process of step S3, the ratio of CH3CN to H2O gradually changes from 3:7 to 4:1; in the reverse preparation process of step S4, the ratio of CH3CN to H2O gradually changes from 3:7 to 5:1; and in the reverse preparation process of step S5, the ratio of CH3CN to H2O gradually changes from 3:7 to 8:1.
[0035] The present invention has the following beneficial effects:
[0036] The present invention provides a C4-oxyglycoside tetracycline compound and its synthesis method, which for the first time realizes a method for synthesizing C4-oxyglycoside tetracycline compounds by chiral reversal of the C4 hydroxyl group. This method is simple, efficient, widely applicable, and easy to scale up for production.
[0037] 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
[0038] To further illustrate the technical means and effects achieved by the present invention, the following detailed description is provided in conjunction with the embodiments.
[0039] This invention discloses a C4-oxyglycoside tetracycline compound with the following structural formula:
[0040]
[0041] in:
[0042] R1 is hydrogen or methyl;
[0043] R2 is hydrogen, halogen, or dimethylamino group;
[0044] R3, R4, R5, R6, and R7 are hydrogen or alkoxy groups.
[0045] This invention also discloses a method for synthesizing a C4-oxyglycoside tetracycline compound:
[0046] Synthesis of C4-(S)-hydroxy compounds
[0047]
[0048] Synthesis of mixtures 2-1 and 2-2
[0049] Example 1
[0050] Tetracycline hydrochloride raw material 1 (50 g, 104 mmol, 1.0 equiv.), 10 mL concentrated hydrochloric acid and 1 L water were added sequentially to a 100 mL round-bottom flask. N-chlorosuccinimide (NCS) (35 g, 260 mmol, 2.5 equiv.) was added at room temperature. After the raw material slowly dissolved, a yellow solid gradually precipitated out. After 0.5 h, the mixture was filtered to obtain crude hemiketal products 2-1 and 2-2, totaling 34.6 g, with a yield of 80%.
[0051] Example 2
[0052] Tetracycline hydrochloride raw material 1 (5 g, 10.4 mmol, 1.0 equiv.), 1 mL concentrated hydrochloric acid and 100 L water were added sequentially to a 100 mL round-bottom flask. N-chlorosuccinimide (NCS) (4.1 g, 31 mmol, 3.0 equiv.) was added at room temperature. After the raw material slowly dissolved, a yellow solid gradually precipitated out. After 0.5 h, the mixture was filtered to obtain a total of 29 g of crude hemiketal products 2-1 and 2-2, with a yield of 68%.
[0053] Compound 2-1 is unstable and readily transforms into 2-2.
[0054] Compound 2-2: Yellow solid, melting point 199-201℃. αD 25-58° (c 0.1, MeOH). 1 H NMR (400MHz, DMSO-d6) δ17.63(br,1H),12.12(s,1H),9.36(br,2H),7.61(t,J=8.1Hz,1H),7.20(br,1H),7.11(d,J=7.8Hz,1H),6.95(d,J=8.3Hz,1H),6 .83(br,1H),4.09(d,J=4.9Hz,1H),3.05-3.02(m,1H),2.69(dt,J=14.3,3. 3Hz,1H),2.54-2.50(m,1H),2.45(br,1H),1.91(s,3H)ppm.HRMS(ESI)calcd for C 20 H 19 NO9Na + [M+Na] + 438.0796, found 438.0794.
[0055] Synthesis of compounds 3-1 and 3-2
[0056] Example 3
[0057] The hemiketal compounds 2-1 and 2-2 (1.5 g, 3.1 mmol, 1.0 equiv.) were dissolved in 30 mL of methanol, and CeCl3·7H2O (9.2 g, 24.8 mmol, 8.0 equiv.) was added. The mixture was stirred at 0 °C for 10 min. NaBH4 (351 mg, 9.3 mmol, 3.0 equiv.) was slowly added and stirred for 0.5 h under the same conditions. After the reaction was complete, excess NaBH4 was quenched with 1 N HCl, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Compound 3-1 was prepared by reverse phase reaction, yielding 293 mg (20% yield) and compound 3-2, yielding 313 mg (21% yield).
[0058] Example 4
[0059] The hemiketal compounds 2-1 and 2-2 (200 mg, 0.48 mmol, 1.0 equiv.) were dissolved in 5 mL of methanol, and CeCl3·7H2O (1.1 g, 2.9 mmol, 6.0 equiv.) was added. The mixture was stirred at 0 °C for 10 min. NaBH4 (45 mg, 1.2 mmol, 2.5 equiv.) was slowly added and stirred for 0.5 h under the same conditions. After the reaction was complete, excess NaBH4 was quenched with 1 N HCl, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Compound 3-1 was prepared by reverse phase resection, yielding 50 mg (25% yield) and compound 3-2, yielding 416 mg (23% yield).
[0060] Compound 3-1: Yellow solid, melting point 174-176℃, αD 25-272° (c 0.1, MeOH). 1 H NMR (400MHz, DMSO-d6) δ18.29(br,1H),15.34(s,1H),11.84(s,1H),9.05(br,2H),7.53(t,J=8.0Hz,1H),7.09(d,J=7.6Hz,1H),6.91(d,J=8.0Hz,1H ),6.76(br,1H),4.92(s,1H),4.73(br,1H),2.69(dd,J=11.2,5.0Hz,1H), 2.46-2.41(m,1H),2.18-2.14(m,1H),1.51-1.35(m,1H),1.48(s,3H)ppm. 13C NMR(101MHz,DMSO-d6)δ173.69,161.47,148.17,136.47,117.01,115.30,114.61,95.41,68.15,43.44,41.73,22.52,18.46.HRMS(ESI)calcd forC 20 H 19 NO9Na + [M+Na] + 440.0952, found 440.0956.
[0061] Compound 3-2: Yellow solid, melting point 199-201℃. αD 25-58° (c 0.1, MeOH). 1 H NMR(400MHz,DMSO-d6)δ18.29(br,1H),15.17(s,1H),11.82(s,1H),8.98(br,2 H),7.53(t,J=8.0Hz,1H),7.11(d,J=7.6Hz,1H),6.91(d,J=8.3Hz,1H),6.75(s ,1H),5.75(d,J=7.0Hz,1H),4.96(s,1H),4.06(br,1H),2.85(dd,J=9.5,6.7Hz ,1H),2.40-2.34(m,1H),2.06-1.99(m,1H),1.80-1.70(m,1H),1.51(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ193.68,192.76,173.59,161.37,148.13,136.47,116.9 6,115.45,114.48,106.13,68.15,42.26,41.01,22.78,22.07.HRMS(ESI)calcd for C 20 H 19 NO9Na + [M+Na] + ,440.0952,found 440.0948.
[0062] Synthesis of C4 oxoglycosides
[0063]
[0064] Synthesis of Compound 4
[0065] Example 5
[0066] Compound 3-1 (2 g, 4.8 mmol, 1.0 equiv.) and NaH (960 mg, 24.0 mmol, 5.0 equiv.) were added sequentially to a 100 mL round-bottom flask. After purging with nitrogen three times, 10 mL of N,N-dimethylformamide (DMF) was added at 0 °C, and the reaction was allowed to proceed for 10 min. Then, BnBr (855 μL, 7.2 mmol, 1.5 equiv.) was added. The reaction was continued at 0 °C for 6 h, quenched with saturated NH4Cl solution, and extracted three times with ethyl acetate (30 mL). The solvent was concentrated under reduced pressure, and the aqueous and organic phases were purified by reverse-phase preparation (CH3CN / H2O = 3:7 to 4:1) to give compound 4 1.18 g, 48% yield.
[0067] Example 6
[0068] Compound 3-1 (2 g, 4.8 mmol, 1.0 equiv.) and NaH (864 mg, 21.6 mmol, 4.5 equiv.) were added sequentially to a 100 mL round-bottom flask. After purging with nitrogen three times, 10 mL of N,N-dimethylformamide (DMF) was added at 0 °C, and the reaction was allowed to proceed for 10 min. Then, BnBr (855 μL, 7.2 mmol, 1.5 equiv.) was added. The reaction was continued at 0 °C for 6 h, quenched with saturated NH4Cl solution, and extracted three times with ethyl acetate (30 mL). The solvent was concentrated under reduced pressure, and the aqueous and organic phases were purified by reverse-phase preparation (CH3CN / H2O = 3:7 to 4:1) to give compound 4 1.1 g, 45% yield.
[0069] Compound 4: Yellow solid, melting point 154-157℃, αD 25-312° (c 0.05, MeOH). 1 H NMR(400MHz,DMSO-d6)δ18.29(br,1H),17.11(s,1H),9.25(br,1H),9.00(br,1H),7.57 -7.50(m,3H),7.43-7.39(m,2H),7.33-7.29(m,1H),7.20(d,J=8.2Hz,2H),6.54(br,1H) ,5.84(br,1H),5.29(d,J=12.7Hz,1H),5.17(d,J=12.7Hz,1H),4.85-4.65(br,2H),2.61 (dd,J=11.3,5.4Hz,1H),2.45-2.39(m,1H),2.15(d,J=11.8Hz,1H),1.48(s,3H),1.38(q like,J=12.7Hz,1H)ppm. 13C NMR (101MHz, DMSO-d6) δ173.69,158.58,148.95,137.11,134.21,128.38,127.57,126. 95,118.79,116.58,113.81,95.67,69.85,68.56,41.55,22.94,18.09.HRMS(ESI)calcd for C 27 H 25 NO9Na + [M+Na] + 530.1422, found 530.1425.
[0070] Synthesis of Compound 5
[0071] Example 7
[0072] Compound 4 (1.2 g, 2.4 mmol, 1.0 equiv.) was dissolved in 15 mL of tetrahydrofuran, and p-toluenesulfonic acid monohydrate (2.3 g, 12.0 mmol, 5.0 equiv.) was added. The mixture was reacted at 40 °C for 12 h, and the solvent was concentrated under reduced pressure. The mixture was then purified by reverse-phase preparation (CH3CN / H2O = 3:7 to 5:1) to give compound 5 783 mg, 68% yield.
[0073] Example 8
[0074] Compound 4 (934 mg, 1.84 mmol, 1.0 equiv.) was dissolved in 15 mL of tetrahydrofuran, and p-toluenesulfonic acid monohydrate (2.8 g, 14.7 mmol, 8.0 equiv.) was added. The mixture was reacted at 40 °C for 12 h, and the solvent was concentrated under reduced pressure. The mixture was then purified by reverse-phase preparation (CH3CN / H2O = 3:7 to 5:1) to give compound 5 465 mg, 52% yield.
[0075] Compound 5: Yellow solid, melting point 145-147℃, αD 25-652° (c 0.1, MeOH). 1H NMR(400MHz,DMSO-d6)δ18.01(br,1H),14.69(s,1H),9.08(br,2H),7.65-7.60(m,3 H),7.54(d,J=8.4Hz,1H),7.45-7.40(m,2H),7.35-7.30(m,1H),7.10(d,J=7.9Hz,1H ),6.92(br,1H),5.94(s,1H),5.32(s,2H),4.78(s,1H),3.41(d,J=5.6Hz,1H),3.37 (d,J=5.8Hz,1H),2.94-2.87(m,1H),2.62(dd,J=17.8,11.7Hz,1H),2.34(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ173.25,163.58,158.61,139.33,137.20,132.73,131.72,128.38,127.50,1 26.94,120.54,116.27,114.32,110.11,107.66,97.44,69.98,42.53,25.21,14.12.HRMS(ESI)calcd for C 27 H 23 NO8Na + [M+Na] + 512.1316, found 512.1312.
[0076] Compound 6 is an acetyl donor and was synthesized according to existing literature reports.
[0077] Compound 6: A pale yellow, viscous liquid. 1 H NMR (400MHz, CDCl3) δ7.36-7.15(m,21H),6.25(dd,J=3.5,1.6Hz,1H),5.68(dd,J=10.0,3.8Hz,0. 4H),4.92-4.86(m,1.4H),4.71-4.60(m,4.2H),4.57-4.49(m,2.8H),3.99-3.92(m,1H),3.87-3.83 (m,1H),3.80-3.60(m,4.6H),3.54-3.49(m,0.4H),5.68(ddd,J=12.3,4.8,2.2Hz,0.4H),2.28(ddd ,J=13.6,5.1,1.7Hz,1H),2.05(s,1.2H),2.04(s,3H),1.88-1.79(m,1H),1.77-1.71(m,0.4H)ppm.
[0078] Synthesis of Compound 7
[0079] Example 9
[0080] Compound 5 (100 mg, 0.2 mmol, 1.0 equiv.), compound 6 (286 mg, 0.6 mmol, 3.0 equiv.), and 200 mg Drierite were added sequentially to a 25 mL Shrek tube. After purging with nitrogen three times, 4 mL of dichloromethane was added. Boron trifluoride diethyl ether (0.1 mL, 0.8 mmol, 4.0 equiv.) was dissolved in 0.5 mL of dichloromethane and slowly added to the mixture at -78 °C. The reaction was carried out at this temperature for 2 h. The reaction was quenched with saturated NaHCO3 solution, extracted three times with ethyl acetate (30 mL), and the solvent was concentrated under reduced pressure. The mixture was purified by reverse-phase preparation (CH3CN / H2O = 3:7 to 8:1) to give 86 mg of compound 7 (7α / 7β = 1:1.9), in 46% yield. The amounts of 7α and 7β in compound 7 are random, and their formation ratio cannot be controlled at present.
[0081]
[0082] Compound 7α-anomer: yellow solid, melting point 84℃. αD 25-294° (c 0.05, CHCl3). 1 H NMR(400MHz,DMSO-d6)δ17.94(br,1H),14.48(br,1H),9.32(br,1H),9.21(br,1H),7.55-7.50(m,3H),7.43-7.21(m,17H),7.07-7.00 (m,4H),5.34-5.18(m,3H),4.56-4.36(m,6H),3.62-3.58(m,2H),3.05(s,1H),2.88-2.83(m,1H),2.29(s,3H),1.48-1.44(m,1H)ppm. 13C NMR(176MHz,DMSO-d6)δ199.28,172.31,162.06,157.40,138.20,137.65,137.44,137 .25,136.15,127.38,127.28,127.23,127.17,127.06,126.64,126.58,126.53,126.4 9,126.39,126.33,126.25,125.94,125.79,119.23,115.42,113.37,106.40,76.73,7 5.38,72.74,71.34,70.32,69.52,68.89,67.90,33.48,27.99,13.07.HRMS(ESI)calcd for C 54 H 51 NO 12 Na + [M+Na] + 928.3303, found 928.3316.
[0083] Compound 7β anomer: yellow solid, melting point 76-78℃. αD 25-216° (c 0.05, CHCl3). 1 H NMR(400MHz,DMSO-d6)δ18.09(br,1H),14.63(s,1H),9.12(br,2H),7.67-7.56(m,4H),7.4 3(t,J=7.5Hz,2H),7.35-7.23(m,17H),7.20-7.17(m,2H),7.12-7.09(m,2H),5.30(s,3H),5 .07(br,1H),4.82(br,1H),4.77(d,J=10.9Hz,1H),4.48-4.57(m,4H),3.71-3.67(m,3H),3 .45-3.30(m,5H),3.24-3.19(m,1H),2.86-2.74(m,1H),2.38(s,3H),1.48-1.43(m,1H)ppm. 13C NMR(176MHz,DMSO-d6)δ173.31,163.56,158.61,139.32,138.64,138.46,138 .39,137.18,131.84,128.40,128.36,128.23,128.20,127.74,127.71,127.61 ,127.51,127.49,127.39,127.36,126.93,120.73,116.32,114.30,107.73,78 .66,77.80,74.55,73.98,72.26,69.99,68.98,28.99,14.27.HRMS(ESI)calcd for C 54 H 51 NO 12 Na + [M+Na] + 928.3303, found 928.3291.
[0084] 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 C4-oxyglycoside tetracycline compound (7), characterized in that, Includes the following steps: S1, tetracycline hydrochloride raw material (1), concentrated hydrochloric acid and water were added sequentially to a round-bottom flask. N-chlorosuccinimide (NCS) was added to the flask at room temperature. After the raw material slowly dissolved, a yellow solid gradually precipitated out. After 0.5 h, the mixture was filtered to obtain crude hemiketal product compound (2-1) and compound (2-2), as shown in formula (II). ； S2, after dissolving the above hemiketal compound (2-1) and compound (2-2) in methanol, CeCl3•7H2O was added to them. o Stirring at C for 10 min, then slowly adding NaBH4 and stirring under the same conditions for 0.5 h. After the reaction is complete, HCl is added to quench excess NaBH4, and the mixture is extracted three times with ethyl acetate. The organic phase is then dried with anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure. Compounds (3-1) and (3-2) are obtained by reverse phase separation. S3, add compound (3-1) and NaH sequentially to the round-bottom flask, purge with nitrogen three times, then 0 o Under temperature C, N,N-dimethylformamide (DMF) is added, and the reaction is carried out at this temperature for 10 min. Then BnBr is added, and 0 o After reacting for 6 h under C conditions, the reaction was quenched with saturated NH4Cl solution, then extracted three times with ethyl acetate, the solvent was concentrated under reduced pressure, and the aqueous and organic phases were purified by reverse-phase preparation to obtain compound (4), as shown in formula (III). ； S4, Dissolve compound (4) in tetrahydrofuran, add p-toluenesulfonic acid monohydrate to it, and at 40 o After reacting under C conditions for 12 h, the solvent was concentrated under reduced pressure and purified by reverse phase preparation to obtain compound (5). S5, add compound (5), compound (6) and desiccant sequentially to the Shrek tube, purge with nitrogen three times, then add dichloromethane, dissolve boron trifluoride ether in dichloromethane and heat at -78°C. o The compound was slowly added to a Shrek tube at C and reacted at this temperature for 2 h. The reaction was then quenched with saturated NaHCO3 solution, extracted three times with ethyl acetate, and the solvent was concentrated under reduced pressure. The compound (7) was obtained by reverse-phase preparation and purification.
2. The method for synthesizing the C4-oxyglycoside tetracycline compound (7) according to claim 1, characterized in that, Compound (7) includes (7α) and (7β), and its specific structural formula is as follows: 。 3. The method for synthesizing the C4-oxyglycoside tetracycline compound (7) according to claim 1, characterized in that, In step S1, the molar ratio of tetracycline hydrochloride and N-chlorosuccinimide is 1:2 to 1:3.
5.
4. The method for synthesizing the C4-oxyglycoside tetracycline compound (7) according to claim 1, characterized in that, In step S2, the molar ratio of the hemiacetal to the reducing agent NaBH4 is 1:2.5-1:4, and the molar ratio of the hemiacetal to CeCl3•7H2O is 1:4-1:
10.
5. The method for synthesizing the C4-oxyglycoside tetracycline compound (7) according to claim 1, characterized in that, In step S3, the molar ratio of the tetracycline compound (3-1) to NaH is 1:3-1:6, and the molar ratio of the tetracycline compound (3-1) to BnBr is 1:1-1:
3.
6. The method for synthesizing the C4-oxyglycoside tetracycline compound (7) according to claim 1, characterized in that, In step S4, the molar ratio of the tetracycline compound (4) and p-toluenesulfonic acid monohydrate is 1:4-1:
10.
7. The method for synthesizing the C4-oxyglycoside tetracycline compound (7) according to claim 1, characterized in that, In step S5, the molar ratio of the tetracycline compound (5) to the compound (6) is 1:2-1:4, the molar ratio of the tetracycline compound (5) to BF3•OEt2 is 1:3-1:8, and the weight ratio of the tetracycline compound (5) to the desiccant is 1:1-1:
5.
8. The method for synthesizing the C4-oxyglycoside tetracycline compound (7) according to claim 1, characterized in that, In the reverse preparation process of step S3, the ratio of CH3CN to H2O gradually changes from 3:7 to 4:1; In the reverse preparation process of step S4, the ratio of CH3CN to H2O gradually changes from 3:7 to 5:1; In the reverse preparation process of step S5, the ratio of CH3CN to H2O gradually changes from 3:7 to 8:1.