A method for preparing omadacycline

Abstract

The present invention relates to the technical field of the synthesis of omadacycline, and particularly to a preparation method of omadacycline. The method comprises the following steps: the aminomethyl tetracycline intermediate M2 shown in formula I is subjected to reductive amination to obtain the crude product M3 of omadacycline, and the conditions for the reductive amination are as follows: in the presence of a transition metal catalyst, an organic base and pivalaldehyde, a hydrosilane reducing agent is used as the hydrogen source, the reaction pressure is 98 kPa to 105 kPa, the reaction temperature is 15 to 35 °C, and the reaction time is 0.5 to 48 hours. The present invention provides a safer and more environmentally friendly method for industrial production of its important intermediate, significantly shortening the reaction time, reducing the impurity content in the reaction solution, and greatly reducing the pressure of subsequent purification operations.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of omadacycline, and in particular to a preparation method of omadacycline. Background Art

[0002] Omadacycline tosylate (also known as OMC or PTK0796) is a 9-aminomethyl tetracycline derivative, a semi-synthetic compound obtained by chemically modifying the tetracycline antibiotic minocycline, specifically designed to overcome tetracycline resistance and showing strong antibacterial effects against a wide range of bacteria, including Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, atypical bacteria, and other drug-resistant bacteria. Its structural formula is as follows.

[0003]

[0004] The above compound was approved by the US FDA for marketing in 2018 for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). Currently, its synthetic route is mainly as follows:

[0005]

[0006] This route uses minocycline hydrochloride as the starting material, which is esterified with N-hydroxymethylphthalimide under strong acid conditions through the Tscherniac–Einhorn reaction to obtain intermediate M1. Subsequently, the diimide is removed with a methylamine-ethanol solution to obtain the primary amine intermediate M2. Then, omadacycline crude product M3 is obtained through reductive amination with pivalaldehyde. The omadacycline crude product is purified and then salted with methanesulfonic acid to obtain the final API.

[0007] In the above synthetic route, the synthesis of omadacycline crude product M3 from the primary amine intermediate M2 is obtained through palladium-catalyzed hydrogenation under pressure for reductive amination. In industrial production, the reaction time for this step is long, requiring about 24 hours. The hydrogenation under pressure has a high safety risk, and a large amount of palladium catalyst is used, resulting in high industrial production costs. At the same time, the purity of the omadacycline crude product M3 obtained in this step is low, only 60-70%, and the subsequent purification pressure is high.

[0008] To improve this step of the reaction, Patent US9365500B2 discloses that M2 is acid-hydrolyzed to obtain 9-aminomethyl minocycline M2B, and then omadacycline crude product M3 is obtained through reductive amination with sodium triacetoxyborohydride in the presence of indium trichloride. The synthetic route is as follows.

[0009]

[0010] Although the use of hydrogen and palladium catalyst is avoided by reductive amination with sodium triacetoxyborohydride, the addition of intermediate 9-aminomethyl minocycline M2 leads to the inversion of the configuration at the 4-position (to give the 4-β isomer) during the synthesis of M2 under acidic conditions, resulting in a lower purity of M3, increased subsequent purification pressure, and difficulty in concentration during post-treatment as DMF is used as a solvent when synthesizing M3. In addition, the reaction solution contains a large amount of salts, which are difficult to remove.

[0011] Among them, the structural formula of intermediate 9-aminomethyl minocycline (M2) is as follows:

[0012] ;

[0013] Among them, the structural formula of the 4-β isomer (4-Beta) is as follows:

[0014] . Summary of the Invention

[0015] To solve the above problems, the present invention provides a new method for preparing omadacycline from the second aminomethyl tetracycline intermediate M2 to the crude omadacycline M3 (aminomethyl tetracycline compound). This method avoids the use of high-pressure hydrogen, has mild reaction conditions, significantly shortens the reaction time, significantly improves the purity of the reaction solution product, and significantly reduces the subsequent purification pressure.

[0016] For this purpose, in the first aspect, the present invention provides a method for preparing omadacycline, comprising the following steps: subjecting the aminomethyl tetracycline intermediate M2 shown in formula I to reductive amination to obtain the crude omadacycline M3, and the conditions for the reductive amination include: in the presence of a transition metal catalyst, an organic base, and pivalaldehyde, using a hydrosilane reducing agent as the hydrogen source, with a reaction pressure of 98 kPa to 105 kPa, a reaction temperature of 15 to 35 °C, and a reaction time of 0.5 to 48 hours;

[0017] (I).

[0018] In the present invention, the structural formula of omadacycline is shown in formula II:

[0019] (II).

[0020] The present invention uses hydrosilane reducing agents as hydrogen sources. Compared with hydrogen as a hydrogen source, the following effects are achieved: First, the problem of 4-position configuration inversion is avoided, which can improve the purity of crude omadacycline M3, simplify the post-treatment operation, and reduce the subsequent purification pressure; Second, the reaction conditions are mild, the reaction time can be shortened, and the production efficiency can be improved; Third, the amount of transition metal catalyst can be reduced, thus significantly reducing the production cost; Fourth, the high-risk operation of hydrogenation under pressure can be avoided, while the operation is simplified and the production cost is reduced.

[0021] The preparation route of the preparation method of omadacycline provided by the present invention is as follows:

[0022] 。

[0023] In some embodiments of the present invention, the reaction temperature of the reductive amination is preferably 20~30°C.

[0024] In some embodiments of the present invention, the reaction time of the reductive amination is preferably 0.75~16 hours, more preferably 1~5 hours. Optionally, the reaction time of the reductive amination is 0.75h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, or any value between any two of the above.

[0025] In some embodiments of the present invention, the transition metal catalyst is selected from at least one of palladium catalysts, rhodium catalysts, nickel catalysts, and ruthenium catalysts, preferably a palladium catalyst.

[0026] In some embodiments of the present invention, the palladium catalyst is Pd, PdCl 2 , Pd(OH) 2 , Pt black or palladium on carbon catalyst, preferably palladium on carbon catalyst.

[0027] In some embodiments of the present invention, the palladium on carbon catalyst is a supported catalyst, its active component is palladium, and the carrier is activated carbon. Based on the palladium on carbon catalyst, the loading amount of the active component palladium is 5wt%~30wt%. Optionally, the loading amount of the active component palladium is 5wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, or any value between any two of the above.

[0028] In some embodiments of the present invention, based on intermediate M2, the dosage of the palladium catalyst is 1 wt% to 50 wt%, preferably 5 wt% to 50 wt%. Optionally, the dosage of the palladium catalyst is 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, or any value between any two of the above.

[0029] In some embodiments of the present invention, based on intermediate M2, the dosage of the palladium-carbon catalyst is 1 wt% to 50 wt%, preferably 5 wt% to 50 wt%; the dosage of palladium hydroxide is 1 wt% to 50 wt%, preferably 5 wt% to 50 wt%. Optionally, the dosage of the palladium-carbon catalyst is 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, or any value between any two of the above. Optionally, the dosage of palladium hydroxide is 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, or any value between any two of the above.

[0030] In some embodiments of the present invention, the nickel catalyst is Raney nickel; based on intermediate M2, the dosage of the nickel catalyst is 10 wt% to 500 wt%, preferably 10 wt% to 100%. Optionally, the dosage of the nickel catalyst is 10 wt%, 20 wt%, 30 wt%, 40 wt%, 60 wt%, 80 wt%, 100 wt%, 120 wt%, 140 wt%, 160 wt%, 180 wt%, 200 wt%, 220 wt%, 240 wt%, 260 wt%, 280 wt%, 300 wt%, 320 wt%, 340 wt%, 360 wt%, 380 wt%, 400 wt%, 420 wt%, 440 wt%, 460 wt%, 480 wt%, 500 wt%, or any value between any two of the above.

[0031] In some embodiments of the present invention, the rhodium catalyst is RuCl 3 or RhCl(PPh 3 ) 3 ; based on intermediate M2, the dosage of the rhodium catalyst is 0.01 wt% to 30 wt%, preferably 1 wt% to 30 wt%. Optionally, the dosage of the rhodium catalyst is 0.05 wt%, 0.1 wt%, 0.5 wt%, 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, or any value between any two of the above.

[0032] In some embodiments of the present invention, based on the intermediate M2, the dosage of the hydrosilane reducing agent is 50 wt% to 2000 wt%, preferably 150 wt% to 1600 wt%. Optionally, the dosage of the rhodium catalyst is 50 wt%, 60 wt%, 80 wt%, 100 wt%, 120 wt%, 140 wt%, 160 wt%, 180 wt%, 200 wt%, 220 wt%, 240 wt%, 260 wt%, 280 wt%, 300 wt%, 320 wt%, 340 wt%, 360 wt%, 380 wt%, 400 wt%, 420 wt%, 440 wt%, 460 wt%, 480 wt%, 500 wt%, 520 wt%, 540 wt%, 560 wt%, 580 wt%, 600 wt%, 620 wt%, 640 wt%, 660 wt%, 680 wt%, 700 wt%, 720 wt%, 740 wt%, 760 wt%, 780 wt%, 800 wt%, 820 wt%, 840 wt%, 860 wt%, 880 wt%, 900 wt%, 920 wt%, 940 wt%, 960 wt%, 980 wt%, 1000 wt%, 1120 wt%, 1140 wt%, 1160 wt%, 1180 wt%, 1200 wt%, 1220 wt%, 1240 wt%, 1260 wt%, 1280 wt%, 1300 wt%, 1320 wt%, 1340 wt%, 1360 wt%, 1380 wt%, 1400 wt%, 1420 wt%, 1440 wt%, 1460 wt%, 1480 wt%, 1500 wt%, 1520 wt%, 1540 wt%, 1560 wt%, 1580 wt%, 1600 wt%, 1620 wt%, 1640 wt%, 1660 wt%, 1680 wt%, 1700 wt%, 1720 wt%, 1740 wt%, 1760 wt%, 1780 wt%, 1800 wt%, 1820 wt%, 1840 wt%, 1860 wt%, 1880 wt%, 1900 wt%, 1920 wt%, 1940 wt%, 1960 wt%, 1980 wt%, 2000 wt%, or any value between any two of the above.

[0033] In some embodiments of the present invention, based on the intermediate M2, the dosage of pivalaldehyde is 50 wt% - 2000 wt%, preferably 50 wt% - 200 wt%, more preferably 50 wt% - 60 wt%. Optionally, the dosage of pivalaldehyde is 50 wt%, 60 wt%, 80 wt%, 100 wt%, 120 wt%, 140 wt%, 160 wt%, 180 wt%, 200 wt%, 220 wt%, 240 wt%, 260 wt%, 280 wt%, 300 wt%, 320 wt%, 340 wt%, 360 wt%, 380 wt%, 400 wt%, 420 wt%, 440 wt%, 460 wt%, 480 wt%, 500 wt%, 520 wt%, 540 wt%, 560 wt%, 580 wt%, 600 wt%, 620 wt%, 640 wt%, 660 wt%, 680 wt%, 700 wt%, 720 wt%, 740 wt%, 760 wt%, 780 wt%, 800 wt%, 820 wt%, 840 wt%, 860 wt%, 880 wt%, 900 wt%, 920 wt%, 940 wt%, 960 wt%, 980 wt%, 1000 wt%, 1120 wt%, 1140 wt%, 1160 wt%, 1180 wt%, 1200 wt%, 1220 wt%, 1240 wt%, 1260 wt%, 1280 wt%, 1300 wt%, 1320 wt%, 1340 wt%, 1360 wt%, 1380 wt%, 1400 wt%, 1420 wt%, 1440 wt%, 1460 wt%, 1480 wt%, 1500 wt%, 1520 wt%, 1540 wt%, 1560 wt%, 1580 wt%, 1600 wt%, 1620 wt%, 1640 wt%, 1660 wt%, 1680 wt%, 1700 wt%, 1720 wt%, 1740 wt%, 1760 wt%, 1780 wt%, 1800 wt%, 1820 wt%, 1840 wt%, 1860 wt%, 1880 wt%, 1900 wt%, 1920 wt%, 1940 wt%, 1960 wt%, 1980 wt%, 2000 wt%, or any value between any two of the above.

[0034] In some embodiments of the present invention, the hydrosilane reducing agent is selected from at least one of polymethylhydrosiloxane, triethylsilane, diphenylsilane, and tetramethyldisiloxane, preferably triethylsilane.

[0035] In some embodiments of the present invention, the organic base is selected from at least one of triethylamine, diethylmethylamine, and diisopropylethylamine.

[0036] In some embodiments of the present invention, based on the intermediate M2, the amount of the organic base is 1 wt% - 220 wt%, preferably 15 - 50 wt%. Optionally, the amount of the organic base is 1 wt%, 5 wt%, 10 wt%, 20 wt%, 30 wt%, 40 wt%, 60 wt%, 80 wt%, 100 wt%, 120 wt%, 140 wt%, 160 wt%, 180 wt%, 200 wt%, 220 wt%, or any value between any two of the above.

[0037] In some embodiments of the present invention, the transition metal catalyst is a palladium catalyst, and the hydrosilane reducing agent is selected from at least one of polymethylhydrosiloxane, triethylsilane, diphenylsilane, and tetramethyldisiloxane. The mass ratio of the transition metal catalyst to the hydrosilane reducing agent is 1:2 - 1000, preferably 1:2 - 100, and more preferably 1:4 - 90. Optionally, the mass ratio of the transition metal catalyst to the hydrosilane reducing agent is 1:2, 1:4, 1:8, 1:10, 1:14, 1:18, 1:20, 1:40, 1:60, 1:80, 1:100, 1:140, 1:180, 1:200, 1:240, 1:280, 1:300, 1:340, 1:380, 1:400, 1:440, 1:480, 1:500, 1:540, 1:580, 1:600, 1:640, 1:680, 1:700, 1:740, 1:780, 1:800, 1:840, 1:880, 1:900, 1:940, 1:980, 1:1000, or any value between any two of the above.

[0038] In some embodiments of the present invention, the transition metal catalyst is a palladium-on-carbon catalyst, and the hydrosilane reducing agent is triethylsilane. The mass ratio of the palladium-on-carbon catalyst to the triethylsilane is 1:2 - 300, preferably 1:2 - 30, and more preferably 1:4 - 25. Optionally, the mass ratio of the palladium-on-carbon catalyst to the triethylsilane is 1:2, 1:4, 1:8, 1:10, 1:14, 1:18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:60, 1:65, 1:70, 1:80, 1:90, 1:100, 1:120, 1:140, 1:160, 1:180, 1:200, 1:220, 1:240, 1:260, 1:280, 1:300, or any value between any two of the above.

[0039] In some embodiments of the present invention, the reductive amination comprises the following steps:

[0040] S1. Dissolve the aminomethyltetracycline intermediate M2, the organic base, and pivalaldehyde in an organic solvent and mix them. Add a transition metal catalyst, and then add a hydrosilane reducing agent to carry out a reaction to obtain a reaction mixture.

[0041] S2. Filter the reaction mixture. After adding water to the filtrate, adjust the pH to less than 7, preferably 3 - 6. Add a first poor solvent and then separate the layers to obtain an organic layer and an aqueous layer. Discard the organic layer with polar impurities. Adjust the pH of the aqueous layer to 7 - 9, use an extractant to extract the product in the aqueous layer to obtain an extraction layer. Drop the extraction layer into a second poor solvent to precipitate a solid. Filter, wash, and dry to obtain the crude omadacycline.

[0042] In some embodiments of the present invention, the organic solvent is selected from methanol or ethanol, or a mixed solvent of dichloromethane and methanol, ethanol, or isopropanol. Preferably, the content of dichloromethane in the mixed solvent is 5wt% - 95wt%. Optionally, the content of dichloromethane in the mixed solvent is 5wt%, 10wt%, 20wt%, 30wt%, 40wt%, 50wt%, 60wt%, 70wt%, 80wt%, 90wt%, 95wt%, or any value between any two of the above.

[0043] In some embodiments of the present invention, the first poor solvent is selected from at least one of methyl tert - butyl ether and isopropyl ether.

[0044] In some embodiments of the present invention, the second poor solvent is selected from at least one of methyl tert - butyl ether and n - heptane.

[0045] In some embodiments of the present invention, the reductive amination specifically includes the following steps:

[0046] (1) Dissolve the aminomethyltetracycline intermediate M2, triethylamine, and pivalaldehyde in an organic solvent (5V - 30V, where V refers to the volume multiple of the solvent). Stir for 1 h, then add a transition metal catalyst (1wt% - 30wt%, based on the intermediate M2), and then slowly add a hydrosilane reducing agent as a hydrogen source (1 - 10eq, where eq refers to the molar equivalent multiple, based on the intermediate M2). Monitor the reaction by liquid phase after reacting for 1 h until the reaction is complete to obtain a reaction mixture.

[0047] (2) Filter the reaction mixture. Add a first poor solvent and water to the filtrate, and adjust the pH to acidic. Separate and remove small - polarity impurities by layering. Then adjust the pH of the aqueous layer, extract the product with dichloromethane, and drop it into a second poor solvent to precipitate a solid. Filter, rinse, and dry to obtain the crude omadacycline, and obtain omadacycline after purification.

[0048] The beneficial effects of the present invention are as follows:

[0049] As a new drug of 9-aminomethyltetracycline derivatives with excellent efficacy, omadacycline tosylate, the present invention provides a safer and more environmentally friendly method for industrial production of its important intermediate, significantly shortening the reaction time, greatly reducing the production cost, reducing the impurity content in the reaction solution, and greatly reducing the pressure of subsequent purification operations. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 It is the HPLC chromatogram of the reaction solution obtained in Example 1 of the present invention;

[0051] Figure 2 It is the HPLC chromatogram of the crude omadacycline obtained in Example 1 of the present invention;

[0052] Figure 3 It is the HPLC chromatogram of the crude omadacycline obtained in Comparative Example 1 of the present invention;

[0053] Figure 4 It is the HPLC chromatogram of the reaction solution obtained in Comparative Example 2 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0054] The technical solutions of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention. For those not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For the reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0055] In the following examples and comparative examples, the 10% palladium-carbon catalyst means that the content of the active component palladium in the catalyst is 10 wt%, and its carrier is activated carbon.

[0056] In the following examples and comparative examples, the purity of the reaction solution and the purity of M3 are calculated by the area normalization method after detecting the corresponding samples by high-pressure liquid chromatography. Among them, the purity of the reaction solution refers to the content of omadacycline in the reaction solution, and the purity of M3 refers to the content of omadacycline in M3.

[0057] In the following examples and comparative examples, the yield after purification refers to: actual synthesis mass / theoretical synthesis mass * 100%, that is, the total reaction yield.

[0058] In the following examples and comparative examples, eq refers to the molar equivalent multiple.

[0059] Example 1

[0060] In a 5000 mL reaction flask, add 1600 g of methanol, 200 g of M2 (0.39 mol, 1.0 eq), 78.6 g of triethylamine (0.78 mol, 2.0 eq), and 100 g (1.168 mol, 3.0 eq) of pivalaldehyde. Control the temperature in the reaction flask at 25 °C and stir and mix for 1 h. Add 15 g of 10% palladium on carbon catalyst (dosage 7.5% w / w, based on M2), and dropwise add 345 g of polymethylhydrosiloxane PMHS. After the addition is complete, keep the reaction at atmospheric pressure and 25 °C for 1 h. After the reaction is completed, a reaction solution is obtained. The reaction solution is detected by high-performance liquid chromatography to obtain Figure 1 , and the mass content of omadacycline in the reaction solution is calculated by the area normalization method, which is the purity of the reaction solution. The purity of the reaction solution is 71.2 wt%, and the content of the 4-β isomer is 3.9 wt%.

[0061] Filter the reaction solution. Add water to the obtained filtrate, adjust the pH to acidic (pH = 4), add methyl tert-butyl ether, and the filtrate is separated into an organic phase and an aqueous phase. Discard the organic layer with polar impurities, adjust the pH of the aqueous layer to 8, then add dichloromethane to the aqueous layer for extraction to obtain a dichloromethane layer. The dichloromethane layer is concentrated and then dropped into methyl tert-butyl ether for crystallization, filtration, washing, and drying to obtain the crude omadacycline M3. The crude omadacycline M3 is detected by high-performance liquid chromatography to obtain Figure 2 , and the mass content of omadacycline in M3 is calculated by the area normalization method, which is the purity of the crude omadacycline M3. The purity of the crude omadacycline M3 is 87.1 wt%, and the content of the 4-β isomer is 3.3 wt%.

[0062] Column purification is carried out on the crude omadacycline M3 to obtain 137.9 g of omadacycline, and the yield after purification is 63.9 wt%.

[0063] Example 2

[0064] In a 200 mL reaction flask, add 80 g of methanol, 10 g of M2, 4 g of triethylamine, and 5 g of pivalaldehyde. Control the temperature in the reaction flask at 20 °C and stir and mix for 1 h. Add 5 g of 10% palladium hydroxide, and dropwise add 20 g of triethylsilane. After the addition is complete, raise the temperature to 45 °C and react at atmospheric pressure for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution obtained is 71.1 wt%, the content of the 4-β isomer is 3.4 wt%, the purity of the crude omadacycline M3 is 86.2 wt%, the content of the 4-β isomer is 3.3 wt%, and the yield after purification is 59.2 wt%.

[0065] Example 3

[0066] In a 50 mL reaction flask, add 10 g of absolute ethanol, 1 g of M2, 0.34 g of triethylamine, and 0.6 g of pivalaldehyde. Control the temperature in the reaction flask at 20 °C and stir to mix for 1 h. Add 0.2 g of 10% palladium-carbon catalyst, and dropwise add 2 g of triethylsilane. After the addition is complete, raise the temperature to 40 °C and react under atmospheric pressure for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution is 69.1 wt%, and the content of the 4-β isomer is 2.9 wt%. The purity of the crude omadacycline M3 is 83.2 wt%, the content of the 4-β isomer is 3.2 wt%, and the yield after purification is 58.3 wt%.

[0067] Example 4

[0068] In a 50 mL reaction flask, add 8 g of methanol, 1 g of M2, 0.4 g of triethylamine, and 0.5 g of pivalaldehyde. Control the internal temperature at 20 °C and stir to mix for 1 h. Add 0.3 g of 5% palladium-carbon catalyst, and dropwise add 3 g of diphenylsilane. After the addition is complete, react under atmospheric pressure at 30 °C for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution is 67.8 wt%, and the content of the 4-β isomer is 3.3 wt%. The purity of the crude omadacycline M3 is 81.5 wt%, the content of the 4-β isomer is 3.1 wt%, and the yield after purification is 59.6 wt%.

[0069] Example 5

[0070] In a 50 mL reaction flask, add 5 g of methanol, 5 g of ethanol, 1 g of M2, 0.4 g of triethylamine, and 0.6 g of pivalaldehyde. Control the temperature in the reaction flask at 20 °C and stir to mix for 1 h. Add 0.2 g of 10% palladium-carbon catalyst, and dropwise add 16 g of tetramethyldisiloxane. After the addition is complete, react under atmospheric pressure at 20 °C for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution is 70.4 wt%, and the content of the 4-β isomer is 3.7 wt%. The purity of the crude omadacycline M3 is 84.2 wt%, the content of the 4-β isomer is 3.2 wt%, and the yield after purification is 59.1 wt%.

[0071] Example 6

[0072] In a 200 mL reaction flask, add 80 g of methanol, 10 g of M2, 4 g of triethylamine, and 5 g of pivalaldehyde. Control the temperature in the reaction flask at 20 °C and stir to mix for 1 h. Add 5 g of 10% rhodium on carbon, and dropwise add 20 g of triethylsilane. After the addition is complete, raise the temperature to 35 °C and react at atmospheric pressure for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution obtained is 69.2 wt%, the content of the 4-β isomer is 3.9 wt%, the purity of the crude omadacycline M3 is 86.2 wt%, the content of the 4-β isomer is 3.3 wt%, and the yield after purification is 60.2 wt%.

[0073] Example 7

[0074] In a 250 mL reaction flask, add 80 g of methanol, 10.00 g of M2 (0.0194 mol, 1.0 eq), 3.93 g of triethylamine (0.0388 mol, 2.0 eq), and 5.01 g (0.0582 mol, 3.0 eq) of pivalaldehyde. Control the temperature in the reaction flask at 25 °C and stir to mix for 1 h. Add 0.75 g of 10% palladium on carbon catalyst (dosage 7.5% w / w, based on M2), and dropwise add 25.89 g of polymethylhydrosiloxane PMHS. After the addition is complete, keep the reaction at atmospheric pressure and hold the temperature at 15 °C for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution obtained is 59.2 wt%, the content of the 4-β isomer is 3.3 wt%, the purity of the crude omadacycline M3 is 74.2 wt%, the content of the 4-β isomer is 3.7 wt%, and the yield after purification is 50.1 wt%.

[0075] Example 8

[0076] In a 250 mL reaction flask, add 80 g of methanol, 10.00 g of M2 (0.0194 mol, 1.0 eq), 3.93 g of triethylamine (0.0388 mol, 2.0 eq), and 5.01 g (0.0582 mol, 3.0 eq) of pivalaldehyde. Control the temperature in the reaction flask at 25 °C and stir to mix for 1 h. Add 0.75 g of 10% palladium on carbon catalyst (dosage 7.5% w / w, based on M2), and dropwise add 25.89 g of polymethylhydrosiloxane PMHS. After the addition is complete, keep the reaction at atmospheric pressure and hold the temperature at 35 °C for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution obtained is 63.8 wt%, the content of the 4-β isomer is 6.3 wt%, the purity of the crude omadacycline M3 is 74.2 wt%, the content of the 4-β isomer is 6.5 wt%, and the yield after purification is 52.1 wt%.

[0077] Example 9

[0078] In a 250 mL reaction flask, add 80 g of methanol, 10.00 g of M2 (0.0194 mol, 1.0 eq), 3.93 g of triethylamine (0.0388 mol, 2.0 eq), and 5.01 g (0.0582 mol, 3.0 eq) of pivalaldehyde. Control the temperature in the reaction flask at 25 °C and stir to mix for 1 h. Add 0.75 g of 10% palladium on carbon catalyst (dosage 7.5% w / w, based on M2). Dropwise add 12.45 g of polymethylhydrosiloxane PMHS. After the addition is complete, keep the reaction at atmospheric pressure and 25 °C for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution obtained is 46.5 wt%, the content of the 4-β isomer is 1.9 wt%, the purity of the crude omadacycline M3 is 62.4 wt%, the content of the 4-β isomer is 2.8 wt%, and the yield after purification is 53.2 wt%.

[0079] Example 10

[0080] In a 250 mL reaction flask, add 80 g of methanol, 10.00 g of M2 (0.0194 mol, 1.0 eq), 3.93 g of triethylamine (0.0388 mol, 2.0 eq), and 5.01 g (0.0582 mol, 3.0 eq) of pivalaldehyde. Control the temperature in the reaction flask at 25 °C and stir to mix for 1 h. Add 0.75 g of 10% palladium on carbon catalyst (dosage 7.5% w / w, based on M2). Dropwise add 25.89 g of polymethylhydrosiloxane PMHS. After the addition is complete, keep the reaction at atmospheric pressure and 25 °C for 18 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution obtained is 65.4 wt%, the content of the 4-β isomer is 6.3 wt%, the purity of the crude omadacycline M3 is 72.3 wt%, the content of the 4-β isomer is 6.8 wt%, and the yield after purification is 58.6 wt%.

[0081] Comparative Example 1

[0082] In a reaction flask, add 240 ml of methanol and cool down to 10 °C. While stirring, add 30.0 g of M2 (0.058 mol, 1.0 eq). Control the temperature at 15 °C and dropwise add 15.9 g of triethylamine (0.157 mol, 2.7 eq). After the addition is complete, add 21.4 g of pivalaldehyde (0.248 mol, 4.3 eq). After purging with nitrogen, add 13.8 g of 10% palladium on carbon catalyst (dosage 46% w / w, based on M2). After purging with nitrogen twice, purge with hydrogen three times, then pressurize with hydrogen to 5.0 ± 0.3 kg / m2 and keep the reaction at 25 °C for 24 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution obtained is 69.8 wt%, and the content of the 4-β isomer is 4.2 wt%.

[0083] After the reaction, relieve the pressure, filter with diatomite pad after nitrogen replacement. Add ammonium sulfite solution to the filtrate, adjust the pH of the filtrate to 4.5, then extract with dichloromethane once, temporarily store the organic phase. Then adjust the pH of the aqueous layer to 6.5, extract with dichloromethane again, temporarily store the organic phase. Adjust the pH of the aqueous layer to 7.5, and extract with dichloromethane three times. Combine the organic phases obtained from the five extractions, concentrate under reduced pressure to 8 - 10% of the initial volume, add n - heptane and methyl tert - butyl ether, filter by suction, wash, and vacuum - dry the wet product to obtain crude omadacycline M3. The subsequent treatment operations are the same as those in Example 1. The crude omadacycline M3 is detected by high - performance liquid chromatography to obtain Figure 3 , and by area normalization method, the purity of the crude omadacycline M3 is calculated to be 84.8%, and the content of the 4 - β isomer is 4.9 wt%.

[0084] After column purification of the crude omadacycline M3, 19.5 g of omadacycline is obtained, and the yield after purification is 60.3 wt%.

[0085] Comparative Example 2

[0086] Add 200 ml of a mixed solvent of methanol and water (90% vol methanol) to a reaction flask, add M2 (40.0 g), then adjust the pH of the solution to about 3 with trifluoroacetic acid, heat up to 40 °C and keep the reaction for 2 h until the reaction is complete. Cool down to room temperature, adjust the pH of the solution to about 7 with triethylamine, add isopropanol and stir to precipitate a solid, filter, wash, and dry under reduced pressure to obtain M2B.

[0087] Dissolve M2B in 400 ml of DMF, add indium trichloride (0.2 eq), triethylamine (3.0 eq) and pivalaldehyde (1.5 eq) at room temperature. After adding, stir for 30 min, add sodium triacetoxyborohydride (2.0 eq) and keep the reaction for 3 h until the reaction is complete. Gas is evolved during the reaction, and the gas is directly discharged to the atmosphere. The reaction system maintains normal pressure. After the reaction, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The reaction solution is detected by high - performance liquid chromatography to obtain Figure 4 , and by area normalization method, the purity of the reaction solution is calculated to be 53.4%, and the content of the 4 - β isomer is 7.1 wt%.

[0088] Quench the reaction with methanol after the reaction is over, concentrate under reduced pressure to remove the solvent, and then directly perform column purification to obtain 22.3 g of omadacycline, and the yield after purification is 51.7 wt%.

[0089] Comparative Example 3

[0090] Add 80 g of methanol, 10.00 g of M2 (0.0194 mol, 1.0 eq), and 5.01 g (0.0582 mol, 3.0 eq) of pivalaldehyde into a 250 mL reaction flask. Control the temperature in the reaction flask at 25 °C and stir and mix for 1 h. Add 0.75 g of 10% palladium on carbon catalyst (dosage 7.5% w / w, based on M2). Dropwise add 25.89 g of polymethylhydrosiloxane PMHS. After the addition is complete, keep the reaction at atmospheric pressure and 25 °C for 1 h. After the reaction is completed, a reaction solution is obtained. The subsequent treatment operations are the same as those in Example 1. The purity of the reaction solution is 55.2 wt%, the content of the 4-β isomer is 4.2 wt%, the purity of the crude omadacycline M3 is 70.4 wt%, the content of the 4-β isomer is 4.6 wt%, and the yield after purification is 51.1 wt%.

[0091] The reaction solutions, purities of M3, and yields of the products in the above examples and comparative examples are shown in the following table.

[0092] Table 1

[0093]

[0094] It can be seen from this that compared with the comparative examples, the reaction time of the examples of the present invention is shortened, the β-isomer does not increase, the purity of the reaction solution and the purity of the obtained crude product are improved, the pressure of subsequent column purification is reduced, and at the same time the yield is higher than that of the comparative examples.

[0095] The above description of the embodiments is to enable those of ordinary skill in the art to understand and apply the present invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the embodiments here, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention according to the disclosure of the present invention should be within the protection scope of the present invention.

Claims

1. A method for preparing omadacycline, characterized in that: The following steps are involved: The aminomethyltetracycline intermediate M2 is subjected to reductive amination to obtain a crude omadacycline product M3, wherein the reductive amination conditions include: in the presence of a transition metal catalyst, an organic base and pivalaldehyde, a hydrosilane reducing agent is used as a hydrogen source, the reaction pressure is 98 kPa to 105 kPa, the reaction temperature is 15 to 35° C., and the reaction time is 0.5 to 48 hours; Among them, the transition metal catalyst is a palladium catalyst or a rhodium carbon catalyst, the palladium catalyst is Pd, PdCl2, Pd(OH)2 or a palladium carbon catalyst; the hydrogen silane reducing agent is selected from at least one of polymethyl hydrogen siloxane, triethylsilane, diphenylsilane, and tetramethyldisiloxane; the organic base is selected from at least one of triethylamine, diethylmethylamine, and diisopropylethylamine.

2. The preparation method according to claim 1, characterized in that: The palladium-carbon catalyst is a supported catalyst, the active component of which is palladium, and the carrier is activated carbon. Based on the palladium-carbon catalyst, the loading amount of the active component palladium is 5wt% to 30wt%.

3. The preparation method according to claim 1, characterized in that Based on the intermediate M2, the amount of the palladium catalyst used is 1wt%~50wt%.

4. The preparation method according to any one of claims 1 to 3, characterized in that Based on the intermediate M2, the amount of the hydrosilane reducing agent is 50wt% to 2000wt%; and / or Based on the intermediate M2, the amount of pivalaldehyde is 50wt% to 2000wt%; and / or Based on the intermediate M2, the amount of the organic base used is 1wt%~220wt%.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The mass ratio of the transition metal catalyst to the hydrosilane reducing agent is 1:2-1000.

6. The preparation method according to claim 5, characterized in that: The transition metal catalyst is a palladium-carbon catalyst, and the hydrosilane reducing agent is triethylsilane, and the mass ratio of the palladium-carbon catalyst to the triethylsilane is 1:2-300.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The reductive amination comprises the following steps: S1, dissolving the aminomethyltetracycline intermediate M2, an organic base and pivalaldehyde in an organic solvent, adding a transition metal catalyst, and then adding a hydrosilane reducing agent to react to obtain a reaction mixture; S2. Filter the reaction mixture, add water to the filtrate, adjust the pH to less than 7, add a first poor solvent and separate the layers to obtain an organic layer and an aqueous layer, discard the organic layer, adjust the pH of the aqueous layer to 7-9, extract the product in the aqueous layer with an extractant to obtain an extraction layer, add the extraction layer dropwise into a second poor solvent, precipitate a solid, filter, wash and dry to obtain a crude omadacycline product.

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