Method for synthesizing tulathromycin key intermediate based on methyl sulfoxide imidazole ionic liquid

Abstract

The invention discloses a method for synthesizing a tulathromycin key intermediate based on methyl sulfoxide imidazole ionic liquid. According to the method, methyl sulfoxide imidazole ionic liquid is adopted to replace an oxidizing agent dimethyl sulfoxide in a tulathromycin synthesis method to oxidize hydroxyl at the 4 ''position, and the tulathromycin key intermediate-2 '-carbobenzoxycarbonyl-4' '-oxoazithromycin A is prepared in an odorless and odorless manner at the yield of 85% or above. According to the method disclosed by the invention, volatile dimethyl sulfide with high foul odor cannot be generated in the reaction process, the method is safe to operators and the environment, the ionic liquid is easy to separate and recycle, and the method has important significance on a method for efficiently oxidizing 4 ''-site hydroxyl of azithromycin A.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of a key intermediate for synthesizing tulathromycin, namely 2'-benzyloxycarbonyl-4”-oxo azithromycin A. Background Art

[0002] Tulathromycin is a third-generation macrolide antibiotic developed by Pfizer for animals only, with the trade name Draxxin. In China, tulathromycin has been officially included in the veterinary antimicrobial drug catalog. The molecular formula of tulathromycin is C 41 H 79 N3O 12 with a relative molecular mass of 806.23. The three basic amino groups of tulathromycin endow the drug with unique pharmacological properties and can promote the exertion of drug efficacy. Tulathromycin is mainly used for swine respiratory disease syndrome and bovine respiratory diseases caused by Pasteurella multocida, Mycoplasma pneumoniae, etc. The birth of tulathromycin not only improves the disease prevention and treatment of animals such as cattle and sheep, but also reduces the risk of bacterial drug resistance to a certain extent.

[0003] In the patent W09856802A1 of Pfizer in the United States, the synthesis method of tulathromycin was reported for the first time. The synthetic route is divided into four steps in total. The first step is the protection reaction of azithromycin A with benzyl chloroformate to obtain 2'-benzyloxycarbonyl azithromycin A; the second step is to use dimethyl sulfoxide as an oxidant to oxidize the hydroxyl group at the 4” position, and then the protecting group is removed under a hydrogen atmosphere; the third step is to add trimethylsulfonium iodide, sodium hydride and dimethyl sulfoxide for epoxidation reaction of the 4” position carbonyl group; the fourth step is to add n-propylamine for reaction to obtain tulathromycin. In the second step of this method, dimethyl sulfoxide is used as an oxidant, and dimethyl sulfoxide will be reduced to volatile dimethyl sulfide with a foul smell during the reaction. The specific synthetic route is as follows:

[0004]

[0005]

[0006] ZhongSheng Pharmaceutical Co., Ltd. reported a synthetic route of tulathromycin in the patent CN102786569A. The synthetic route has 4 steps in total. The first step is the protection reaction of azithromycin A with 4-dimethylaminopyridine and di-tert-butyl dicarbonate; the second step is to use dimethyl sulfoxide as an oxidant to oxidize the hydroxyl group at the 4” position, and then the protecting group is removed; the third step is an epoxidation reaction with trimethylsulfonium bromide; the fourth step is a reaction with n-propylamine to obtain tulathromycin. Using di-tert-butyl dicarbonate for protection can avoid using precious metal palladium for hydrogenation deprotection, but di-tert-butyl dicarbonate is relatively expensive, and highly foul-smelling volatile compounds dimethyl sulfide will be generated during Swern oxidation. The specific synthetic route is as follows:

[0007]

[0008]

[0009] In recent years, for the 4''-hydroxyl group of azithromycin A, the Swern oxidation reaction using DMSO as the oxidant is still mainly employed. During the reaction process, highly malodorous and volatile dimethyl sulfide is generated, which has an impact on operators and the environment. Therefore, it is of great significance to explore a method for oxidizing the 4''-hydroxyl group of azithromycin A that is odorless, economical, and efficient. Summary of the Invention

[0010] In view of the above problems, the present invention provides a method for synthesizing the key intermediate of tulathromycin, 2'-benzyloxycarbonyl-4''-oxoazithromycin A, based on methylsulfoxide imidazole ionic liquid. This method is a green synthesis method that can avoid the generation of highly malodorous and volatile dimethyl sulfide.

[0011] The method for synthesizing the key intermediate of tulathromycin based on methylsulfoxide imidazole ionic liquid provided by the present invention is as follows: Dissolve methylsulfoxide imidazole ionic liquid in dichloromethane. After the temperature is lowered to -60 to -78 °C, add oxalyl chloride and react at this temperature for 0.5 to 2 hours. Then add 2'-benzyloxycarbonyl azithromycin A and continue to react at this temperature for 0.5 to 3 hours. Then add 4-dimethylaminopyridine (DMAP) or triethylamine and continue to react at this temperature for 5 to 15 minutes. Quench with water, separate the layers, and the organic phase is dried, concentrated, and separated by column chromatography to obtain the key intermediate of tulathromycin, namely 2'-benzyloxycarbonyl-4''-oxoazithromycin A. The reaction equation is as follows:

[0012]

[0013] In the above synthesis method, preferably, the addition amount of oxalyl chloride is 2 to 4 times the molar amount of 2'-benzyloxycarbonyl azithromycin A.

[0014] In the above synthesis method, preferably, the addition amount of methylsulfoxide imidazole ionic liquid is 4 to 8 times the molar amount of 2'-benzyloxycarbonyl azithromycin A.

[0015] In the above synthesis method, preferably, the addition amount of 4-dimethylaminopyridine or triethylamine is 5 to 8 times the molar amount of 2'-benzyloxycarbonyl azithromycin A.

[0016] The structure of the above methylsulfoxide imidazole ionic liquid is as follows:

[0017]

[0018] In the formula, n represents an integer from 5 to 11, R represents CH3 or H, and TsO -Represents p-toluenesulfonate.

[0019] Furthermore, the above-mentioned n is preferably 5, 7, 9 or 11.

[0020] The synthetic route and specific preparation method of the above-mentioned methyl sulfoxide imidazole ionic liquid are as follows:

[0021]

[0022] Step a: React an aqueous solution of sodium methanethiolate with a compound of formula I at room temperature for 36 to 60 hours. After the reaction is completed, add chloroform for extraction. After washing the organic layer with water, dry it over anhydrous sodium sulfate, filter, and concentrate to obtain a compound of formula II.

[0023] Step b: Dissolve the compound of formula II, triethylamine, and trimethylamine hydrochloride in dichloromethane. After cooling to -10 to 5 °C, add p-toluenesulfonyl chloride, and transfer it to room temperature for reaction for 1.5 to 3 hours; after the reaction is completed, add water and adjust the pH to 6 to 7 with dilute hydrochloric acid, separate the layers, wash the organic layer with water, dry it over anhydrous sodium sulfate, filter, concentrate, and separate by silica gel column chromatography to obtain a compound of formula III.

[0024] Step c: Dissolve the compound of formula III and the compound of formula IV in acetonitrile and react at 40 to 75 °C for 30 to 60 hours. After the reaction is completed, concentrate the reaction solution, wash it with methyl tert-butyl ether, and then dry it under vacuum to obtain compound V.

[0025] Step d: Dissolve compound V in methanol. After cooling to -10 to 5 °C, add an aqueous hydrogen peroxide solution with a mass concentration of 30%, and transfer it to room temperature for reaction for 4 to 6 hours. After the reaction is completed, add sodium sulfite to quench, filter by suction, spin-dry the remaining solvent, add acetonitrile, filter by suction, and concentrate to obtain the methyl sulfoxide imidazole ionic liquid VI.

[0026] In the above step a, the molar ratio of the compound of formula I to sodium methanethiolate is 1:2 to 5.

[0027] In the above step b, the molar ratio of the compound of formula II to p-toluenesulfonyl chloride, triethylamine, and trimethylamine hydrochloride is 1:1.1 to 2:1.5 to 3:0.1.

[0028] In the above step c, the molar ratio of the compound of formula III to the compound of formula IV is 1:1.5 to 3.

[0029] In the above step d, the molar ratio of compound V to hydrogen peroxide is 1:3 to 8.

[0030] The beneficial effects of the present invention are as follows:

[0031] The present invention uses methylsulfoxide imidazole ionic liquid to replace dimethyl sulfoxide, an oxidant in the synthesis method of tulathromycin, to oxidize the hydroxyl group at the 4''-position, so as to prepare 2'-benzyloxycarbonyl-4''-oxoazithromycin A, avoiding the generation or use of dimethyl sulfide with a strong stench and high volatility, and preparing 2'-benzyloxycarbonyl-4''-oxoazithromycin A odorlessly with a yield of more than 85%. The method of the present invention is safe for operators and the environment, and the ionic liquid is easy to separate, recycle and utilize, which is of great significance for the method of efficiently oxidizing the hydroxyl group at the 4''-position of azithromycin A. Detailed implementation mode

[0032] The following further describes the present invention in detail with reference to the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0033] 2'-Benzyloxycarbonyl azithromycin A used in the examples was prepared according to the method disclosed in patent CN102295672A.

[0034] Example 1

[0035] 1. Preparation of methylsulfoxide imidazole ionic liquid VI-1

[0036]

[0037] Step a: Weigh 63.071 g (180.00 mmol) of an aqueous solution of sodium methyl mercaptide with a mass fraction of 20% and 8.197 g (60.00 mmol) of 6-chloro-1-hexanol into a flask, and react at room temperature for 48 hours. After the reaction is completed, add chloroform for extraction twice. After the organic layer is washed with water twice, it is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 8.260 g of colorless liquid 6-methylthio-1-hexanol with a yield of 93%.

[0038] The structural characterization data of 6-methylthio-1-hexanol are as follows: 1 H NMR (600 MHz, CDCl3) δ 3.63 (t, J = 6.6 Hz, 2H), 2.51–2.47 (m, 2H), 2.08 (s, 3H), 1.62–1.55 (m, 4H), 1.45 (s, 1H), 1.43–1.35 (m, 4H); 13 C NMR (151 MHz, CDCl3) δ 62.87, 34.21, 32.63, 29.08, 28.54, 25.38, 15.53.

[0039] Step b: Weigh 4.500g (30.35mmol) 6-methylthio-1-hexanol, 4.607g (45.53mmol) triethylamine and 0.291g (3.04mmol) trimethylamine hydrochloride in a flask, add 35mL dichloromethane to dissolve and cool to 0°C, add 6.943g (36.42mmol) p-toluenesulfonyl chloride dissolved in 30mL dichloromethane with a constant pressure dropping funnel, and move to room temperature to react for 1.5 hours after the addition is complete. After the reaction is completed, add 35mL distilled water to the reaction solution, adjust the pH to 6-7 with dilute hydrochloric acid, separate the liquids, wash the organic layer with water twice, dry it with anhydrous sodium sulfate, filter, concentrate, and separate it by silica gel column chromatography (ethyl acetate: petroleum ether = 1:15, V / V) to obtain 8.301g colorless oily liquid 6-methylthiohexyl p-toluenesulfonate, with a yield of 90%.

[0040] The structural characterization data of 6-methylthiohexyl p-toluenesulfonate are: 1 H NMR(600MHz, CDCl3)δ7.78(d,J=8.2Hz,2H),7.34(d,J=8.1Hz,2H),4.01(t,J=6.4Hz,2H), 2.46–2.42(m,5H),2.07(s,3H),1.66–1.62(m,2H),1.56–1.50(m,2H),1.35–1.29(m,4H); 13 C NMR (151MHz, CDCl3) δ144.70,133.17,129.84,127.89,70.51,34.06,28.84,28.73,28.06,25.03,21.66,15.53.

[0041] Step c: Weigh 2.917 g (9.64 mmol) of 6-methylthiohexyl p-toluenesulfonate and 1.298 g (13.50 mmol) of 1,2-dimethylimidazole in a flask, add 10 mL of acetonitrile, and react at 70°C for 36 hours. After the reaction, concentrate the reaction solution, stir and wash with methyl tert-butyl ether three times, and vacuum dry. 3.689 g of white solid compound V-1 is obtained, with a yield of 96%.

[0042] The structural characterization data of compound V-1 are as follows: HRMS (C 12 H 23 N2S + )m / z[M] + :227.1580 (calculated value 227.1576); 11H NMR (600 MHz, DMSO-d6) δ 7.64 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 4.09 (t, J = 7.3 Hz, 2H), 3.74 (s, 3H), 2.57 (s, 3H), 2.45 (t, J = 7.3 Hz, 2H), 2.28 (s, 3H), 2.02 (s, 3H), 1.72–1.67 (m, 2H), 1.51 (dd, J = 14.8, 7.4 Hz, 2H), 1.37 (dd, J = 15.5, 7.3 Hz, 2H), 1.27 (dt, J = 15.0, 7.4 Hz, 2H); 13 13C NMR (151 MHz, DMSO-d6) δ 146.31, 144.68, 138.01, 128.49, 125.95, 122.77, 121.32, 47.91, 35.12, 33.56, 29.54, 28.80, 28.01, 25.63, 21.24, 15.16, 9.60.

[0043] Step d: Weigh 2.709 g (6.80 mmol) of compound V-1 into a flask, add 15 mL of methanol, cool to 0 °C, and dropwise add 4.629 g (40.83 mmol) of 30% hydrogen peroxide aqueous solution. After the addition is complete, transfer the mixture to room temperature and react for 5 hours. After the reaction is completed, quench with sodium sulfite, filter by suction, rotary evaporate the remaining solvent, add acetonitrile, filter by suction, and concentrate to obtain 2.548 g of pale yellow oily methylsulfoxide imidazole-based ionic liquid VI-1, and the reaction yield is 94%.

[0044] The structure characterization data of methylsulfoxide imidazole-based ionic liquid VI-1 is: HRMS (C 12 H 23 ON2S + ) m / z [M] + : 243.1530 (calculated value 243.1526); 11H NMR(600MHz,DMSO-d6)δ7.65(d,J = 2.0Hz,1H),7.62(d,J = 2.0Hz,1H),7.46(d,J = 8.0Hz,2H),7.11(d,J = 7.8Hz,2H),4.10(t,J = 7.3Hz,2H),3.74(s,3H),2.73(dd,J = 8.1,5.1Hz,1H),2.62(dd,J = 9.1,4.2Hz,1H),2.57(s,3H),2.51(s,3H),2.28(s,3H),1.71(dd,J = 15.0,7.5Hz,2H),1.61(dd,J = 15.4,7.6Hz,2H),1.41(dd,J = 17.1,7.7Hz,2H),1.32–1.27(m,2H); 13 13C NMR(151MHz,DMSO-d6)δ146.26,144.70,138.04,128.51,125.94,124.97,122.77,121.32,53.43,47.85,38.50,35.12,29.39,28.02,25.69,22.23,21.25,9.60。

[0045] 2. Synthesis of the key intermediate of tulathromycin - 2'-carbobenzyloxy - 4”-oxoazithromycin A

[0046] Weigh 0.667 g (1.61 mmol) of methylsulfoxide imidazole ionic liquid VI - 1 and dissolve it in 15 mL of dichloromethane. Cool it to -78 °C, slowly add 0.088 g (0.69 mmol) of oxalyl chloride, react at -78 °C for 1 hour, then slowly add 0.200 g (0.23 mmol) of 2'-carbobenzyloxyazithromycin A dissolved in 4 mL of dichloromethane. Continue to react at -78 °C for 2.5 hours, then add 0.208 g (16.10 mmol) of DMAP dissolved in 2 mL of dichloromethane. Take a sample after reacting for 6 minutes. By high performance liquid chromatography detection, the yield of 2'-carbobenzyloxy - 4”-oxoazithromycin A is 86%. This reaction process is odorless.

[0047] Example 2

[0048] 1. Preparation of methylsulfoxide imidazole ionic liquid VI - 2

[0049]

[0050] In step c of this example, equimolar N - methylimidazole is used to replace 1,2 - dimethylimidazole in step c of Example 1, and other steps are the same as those in Example 1. A colorless oily methylsulfoxide imidazole ionic liquid VI - 2 is obtained with a yield of 99%.

[0051] The structural characterization data of methylsulfoxide imidazole ionic liquid VI-2 are as follows: HRMS(C 11 H 21 ON2S + ) m / z [M] + : 229.1367 (calculated value 229.1369); 1 1H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.84 (s, 3H), 2.75–2.70 (m, 1H), 2.65–2.61 (m, 1H), 2.51 (s, 3H), 2.29 (s, 3H), 1.79 (dd, J = 14.8, 7.3 Hz, 2H), 1.65–1.58 (m, 2H), 1.41 (dd, J = 17.0, 7.6 Hz, 2H), 1.27 (dt, J = 13.7, 7.0 Hz, 2H); 13 13C NMR (151 MHz, DMSO-d6) δ 146.24, 138.08, 137.03, 128.52, 125.95, 124.08, 122.73, 53.45, 49.15, 38.52, 36.20, 29.58, 27.91, 25.61, 22.21, 21.24.

[0052] 2. Synthesis of the key intermediate of telithromycin - 2'-benzyloxycarbonyl-4”-oxoazithromycin A

[0053] Weigh 6.450 g (16.10 mmol) of methylsulfoxide imidazole ionic liquid VI-2 into a round-bottom flask, add 30 mL of dichloromethane to dissolve it. After cooling to -78 °C, slowly add 0.880 g (6.90 mmol) of oxalyl chloride, react at -78 °C for 1 hour, then slowly add 2.000 g (2.30 mmol) of 2'-benzyloxycarbonyl azithromycin A dissolved in 12 mL of dichloromethane. Continue to react at -78 °C for 2.5 hours, then add 2.080 g (16.10 mmol) of DMAP dissolved in 10 mL of dichloromethane, and sample after reacting for 6 minutes. After detection by high-performance liquid chromatography, the yield of 2'-benzyloxycarbonyl-4”-oxoazithromycin A is 90%. This reaction process is odorless.

Claims

1. A method for synthesizing a key intermediate of tulathromycin based on methylsulfoxide imidazole ionic liquid, characterized in that: Dissolve the methylsulfoxide imidazole ionic liquid in dichloromethane. After cooling the temperature to -60 to -78 °C, add oxalyl chloride and react at this temperature for 0.5 to 2 hours. Then add 2'-carbobenzoxy azithromycin A and continue to react at this temperature for 0.5 to 3 hours. After that, add 4-dimethylaminopyridine or triethylamine and continue to react at this temperature for 5 to 15 minutes. Quench with water, separate the layers, and the organic phase is dried, concentrated, and separated by column chromatography to obtain the key intermediate for the synthesis of tulathromycin, namely 2'-carbobenzoxy-4”-oxo azithromycin A; The structure of the methylsulfoxide imidazole ionic liquid is as follows: Wherein n represents an integer from 5 to 11, R represents CH3 or H, and TsO - represents p-toluenesulfonate group.

2. The method for synthesizing the key intermediate of tulathromycin based on methylsulfoxide imidazole ionic liquid according to claim 1, wherein: The addition amount of the oxalyl chloride is 2 to 4 times the molar amount of 2'-carbobenzoxy azithromycin A.

3. The method for synthesizing the key intermediate of tulathromycin based on methylsulfoxide imidazole ionic liquid according to claim 1, characterized in that: The addition amount of the methylsulfoxide imidazole ionic liquid is 4 to 8 times the molar amount of 2'-carbobenzoxy azithromycin A.

4. The method for synthesizing the key intermediate of tulathromycin based on methylsulfoxide imidazole ionic liquid according to claim 1, characterized in that: The addition amount of the 4-dimethylaminopyridine or triethylamine is 5 to 8 times the molar amount of 2'-carbobenzoxy azithromycin A.

5. The method for synthesizing the key intermediate of tulathromycin based on methylsulfoxide imidazole ionic liquid according to claim 1, characterized in that: n represents 5, 7, 9 or 11.

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