技术领域technical field
本发明涉及抗结核候选药物PA-824的合成方法，属于药物化学领域。The invention relates to a synthesis method of an anti-tuberculosis candidate drug PA-824, belonging to the field of medicinal chemistry.
背景技术Background technique
PA-824是一种硝基咪唑吡喃类化合物，对敏感和耐药结核杆菌有效，可以杀死处在潜伏期的结核杆菌，并且与一线的抗结核药物无交叉耐药现象。2002年，全球抗结核联盟（TB联盟）和美国国立过敏和传染病研究所达成协议，将PA-824作为新型抗结核药物研究，现已经进入Ⅱ期临床，同时其作为活性组分与莫西沙星、吡嗪酰胺组成新的复方制剂—PaMZ，目前也处于Ⅱ期临床。PA-824 is a nitroimidazole pyran compound, which is effective against sensitive and drug-resistant Mycobacterium tuberculosis, can kill Mycobacterium tuberculosis in the incubation period, and has no cross-resistance with first-line anti-tuberculosis drugs. In 2002, the Global Alliance Against Tuberculosis (TB Alliance) and the National Institute of Allergy and Infectious Diseases of the United States reached an agreement to use PA-824 as a new type of anti-tuberculosis drug research, and it has now entered phase II clinical trials. Star and pyrazinamide form a new compound preparation—PaMZ, which is currently in Phase II clinical trials.
PA-824，淡黄色结晶性粉末，分子式为：C13H12N3O5F3，分子量为：359。PA-824由Pathogenesis公司合成，其合成路线中采用了硅保护基以及大量的四丁基氟化铵等试剂，价格高昂。PA-824, light yellow crystalline powder, molecular formula: C13 H12 N3 O5 F3 , molecular weight: 359. PA-824 is synthesized by Pathogenesis Company, and its synthetic route adopts silicon protecting group and a large amount of reagents such as tetrabutylammonium fluoride, and the price is high.
发明内容Contents of the invention
本发明目的在于对现有的PA-824的合成方法进行改进，避免低温反应，开发出一条简单易行、操作简单、易于规模化制备的新方法。The purpose of the present invention is to improve the existing PA-824 synthesis method, avoid low-temperature reaction, and develop a new method that is simple, easy to operate, and easy to prepare on a large scale.
本发明实现过程如下：The realization process of the present invention is as follows:
硝基咪唑吡喃类抗结核候选药物PA-824的合成方法，包括如下步骤：The synthetic method of nitroimidazole pyran class anti-tuberculosis drug candidate PA-824 comprises the following steps:
（1）化合物1硝基化得到化合物2；(1) Compound 1 was nitrated to obtain compound 2;
（2）化合物2再次硝基化得到化合物3；(2) Compound 2 was nitrated again to obtain compound 3;
（3）在氯苯中，化合物3进行热重排得到化合物4；(3) In chlorobenzene, compound 3 undergoes thermal rearrangement to obtain compound 4;
（4）化合物4和(S)-(+)-缩水甘油丁酸酯进行亲核开环反应得到化合物5；(4) Nucleophilic ring-opening reaction of compound 4 and (S )-(+)-glycidyl butyrate to obtain compound 5;
（5）在CH2Cl2中，化合物5与3,4-二氢吡喃在催化剂PPTS作用下对羟基进行保护，得到化合物6；(5) In CH2 Cl2 , compound 5 and 3,4-dihydropyran were used to protect the hydroxyl group under the catalyst PPTS to obtain compound 6;
（6）化合物6进行酯水解及分子内亲核关环反应，得到化合物7；(6) Compound 6 undergoes ester hydrolysis and intramolecular nucleophilic ring closure reaction to obtain compound 7;
（7）化合物7脱保护得到化合物8；(7) Deprotection of compound 7 to obtain compound 8;
（8）化合物8与等摩尔量4-三氟甲氧基溴苄反应，得到最终产物PA-824。(8) Compound 8 was reacted with an equimolar amount of 4-trifluoromethoxybenzyl bromide to obtain the final product PA-824.
上述步骤（1）中，在浓H2SO4中，化合物1与浓HNO3进行硝基化得到化合物2，反应温度为100~125℃，反应时间为6~8h，化合物1、浓H2SO4与浓HNO3用量的摩尔比为1:2:4。In the above step (1), compound 1 is nitrated with concentrated HNO3 in concentrated H2 SO4 to obtain compound 2, the reaction temperature is 100~125°C, and the reaction time is6 ~8h. The molar ratio of SO4 to concentrated HNO3 is 1:2:4.
上述步骤（2）中，在乙酸和乙酸酐中，化合物2与发烟硝酸反应进行再次硝基化得到化合物3，反应温度为20~50℃，反应时间为2~6h，化合物2、醋酸、醋酸酐、发烟硝酸用量的摩尔比为1:3:4:2。In the above step (2), in acetic acid and acetic anhydride, compound 2 is reacted with fuming nitric acid for further nitration to obtain compound 3. The reaction temperature is 20-50°C, and the reaction time is 2-6h. Compound2 , acetic acid, The molar ratio of acetic anhydride and fuming nitric acid is 1:3:4:2.
上述步骤（3）中，反应温度为100-120℃，反应时间为10~12h。In the above step (3), the reaction temperature is 100-120° C., and the reaction time is 10-12 hours.
上述步骤（4）中，所述反应无溶剂，反应温度为30~60℃，反应时间为2~3d，化合物4、(S)-(+)-缩水甘油丁酸酯用量的摩尔比为1：1.1~1.5。In the above step (4), the reaction is solvent-free, the reaction temperature is 30-60°C, the reaction time is 2-3d, and the molar ratio of compound4 and (S )-(+)-glycidyl butyrate is 1 : 1.1~1.5.
上述步骤（5）中，反应温度为10~40℃，反应时间为15~20h，化合物5与DHP、PPTS用量的摩尔比为3:6~9:1。In the above step (5), the reaction temperature is 10-40° C., the reaction time is 15-20 h, and the molar ratio of compound5 to DHP and PPTS is 3:6-9:1.
上述步骤（6）中，在CH3OH中，化合物6在等摩尔量的K2CO3作用下进行酯水解及分子内亲核关环反应得到化合物7，反应溶剂为CH3OH，反应温度为0~20℃，反应时间为2~5h，所述化合物6与K2CO3的摩尔比为1:1~2。In the above step (6), in CH3 OH, compound 6 undergoes ester hydrolysis and intramolecular nucleophilic ring closure reaction in CH 3 OH under the action of an equimolar amount of K2 CO3 to obtain compound 7, the reaction solvent is CH3 OH, and the reaction temperature is 0~20°C, the reaction time is 2~5h, and the molar ratio of compound 6 to K2 CO3 is 1:1~2.
上述步骤（7）中，在CH3OH中，化合物7在浓HCl作用下脱保护得到化合物8，反应溶剂为CH3OH，反应温度为20~40℃，反应时间为2~5h，化合物7与浓HCl用量的摩尔比为1:1~2。In the above step (7), in CH3 OH, compound 7 is deprotected under the action of concentrated HCl to obtain compound 8, the reaction solvent is CH3 OH, the reaction temperature is 20~40°C, the reaction time is 2~5h, and compound 7 The molar ratio to the amount of concentrated HCl is 1:1~2.
上述步骤（8）中，在DMF中，化合物8与等摩尔量4-三氟甲氧基溴苄在NaH作用下反应，得到最终产物PA-824，反应温度为-10~0℃，反应时间为10~14h，化合物8与对三甲基溴苄、NaH用量的摩尔比为1:1:1~2。In the above step (8), in DMF, compound 8 reacts with an equimolar amount of 4-trifluoromethoxybenzyl bromide under the action of NaH to obtain the final product PA-824, the reaction temperature is -10~0°C, and the reaction time is 10~14h, the molar ratio of compound 8 to p-trimethylbenzyl bromide and NaH is 1:1:1~2.
本发明以咪唑为原料制备硝基咪唑吡喃类抗结核候选药物PA-824，原料易得，避免了低温反应，工艺路线操作简单、易于规模化制备。The invention uses imidazole as a raw material to prepare the nitroimidazole pyran anti-tuberculosis candidate drug PA-824, the raw material is easy to obtain, low-temperature reaction is avoided, the process route is simple to operate, and it is easy to prepare on a large scale.
具体实施方式Detailed ways
下面对本发明的实施例作详细说明：本实施例在以本发明技术方案为前提下进行实施，给出了详细地实施方式和过程，但本发明的保护范围不限于下述的实施例。The following is a detailed description of the embodiments of the present invention: this embodiment is implemented on the premise of the technical solution of the present invention, and detailed implementation methods and processes are provided, but the protection scope of the present invention is not limited to the following embodiments.
硝基咪唑吡喃类抗结核候选药物PA-824的合成方法，括如下步骤：The synthetic method of nitroimidazole pyran class anti-tuberculosis drug candidate PA-824 comprises the following steps:
（1）在浓H2SO4中，化合物1与4倍的浓HNO3反应进行硝基化，得到化合物2；(1) In concentrated H2 SO4 , compound 1 was reacted with 4 times concentrated HNO3 for nitration to obtain compound 2;
（2）在乙酸和乙酸酐中，化合物2与发烟硝酸反应进行再次硝基化，得到化合物3；(2) In acetic acid and acetic anhydride, compound 2 was reacted with fuming nitric acid for re-nitration to obtain compound 3;
（3）在氯苯中，化合物3进行热重排，得到化合物4；(3) Compound 3 undergoes thermal rearrangement in chlorobenzene to obtain compound 4;
（4）化合物4和(S)-(+)-缩水甘油丁酸酯进行亲核开环反应得到化合物5；(4) Nucleophilic ring-opening reaction of compound 4 and (S )-(+)-glycidyl butyrate to obtain compound 5;
（5）在CH2Cl2中，化合物5与3,4-二氢吡喃在催化剂PPTS作用下对羟基进行保护，得到化合物6；(5) In CH2 Cl2 , compound 5 and 3,4-dihydropyran were used to protect the hydroxyl group under the catalyst PPTS to obtain compound 6;
（6）在CH3OH中，化合物6在等摩尔量的K2CO3作用下进行酯水解及分子内亲核关环反应，得到化合物7；(6) In CH3 OH, compound 6 was subjected to ester hydrolysis and intramolecular nucleophilic ring closure reaction under the action of an equimolar amount of K2 CO3 to obtain compound 7;
（7）在CH3OH中，化合物7在浓HCl作用下脱保护，得到化合物8；(7) In CH3 OH, compound 7 was deprotected under the action of concentrated HCl to obtain compound 8;
（8）在DMF中，化合物8与等摩尔量4-三氟甲氧基溴苄在NaH作用下反应，得到最终产物PA-824。(8) In DMF, compound 8 was reacted with an equimolar amount of 4-trifluoromethoxybenzyl bromide under the action of NaH to obtain the final product PA-824.
上述步骤（1）中，反应温度为100~125℃，反应时间为6~8h，化合物1、浓H2SO4与浓HNO3用量的摩尔比为1:2:4，后处理过程包括萃取、洗涤、干燥及减压除去溶剂，得化合物2。In the above step (1), the reaction temperature is 100~125°C, the reaction time is 6~8h, the molar ratio of compound1 , concentratedH2SO4 and concentratedHNO3 is 1:2:4, and the post- treatment process includes extraction , washing, drying and removing the solvent under reduced pressure to obtain compound 2.
上述步骤（2）中，反应温度为20~50℃，反应时间为2~6h，化合物2与醋酸、醋酸酐、发烟硝酸用量的摩尔比为1:3:4:2，后处理过程包括萃取、洗涤、干燥及减压除去溶剂，得化合物3。In the above step (2), the reaction temperature is 20-50°C, the reaction time is 2-6h, the molar ratio of compound2 to acetic acid, acetic anhydride, and fuming nitric acid is 1:3:4:2, and the post-treatment process includes Extract, wash, dry and remove the solvent under reduced pressure to obtain compound 3.
上述步骤（3）中，反应溶剂为氯苯，反应温度为100-120℃，反应时间为10~12h，后处理过程包括抽滤洗涤干燥，得化合物4。In the above step (3), the reaction solvent is chlorobenzene, the reaction temperature is 100-120° C., and the reaction time is 10-12 hours. The post-treatment process includes suction filtration, washing and drying to obtain compound 4.
上述步骤（4）中，反应无溶剂，反应温度为30~60℃，反应时间为2~3d，化合物4与(S)-(+)-缩水甘油丁酸酯用量的摩尔比为1：1.1~1.5，后处理过程包括萃取、滤除不溶物、饱和NaHCO3洗涤、干燥及减压除去溶剂，柱层析，得化合物5。In the above step (4), the reaction is solvent-free, the reaction temperature is 30~60°C, the reaction time is 2~3d, and the molar ratio of compound4 to (S )-(+)-glycidyl butyrate is 1:1.1 ~1.5, the post-treatment process includes extraction, filtering out insoluble matter, washing with saturated NaHCO3 , drying and removing the solvent under reduced pressure, and column chromatography to obtain compound 5.
上述步骤（5）中，反应溶剂为CH2Cl2，反应温度为10~40℃，反应时间为15~20h，化合物5与DHP、PPTS用量的摩尔比为3:6~9：1，后处理过程包括萃取、洗涤、干燥及减压除去溶剂得化合物6。In the above step (5), the reaction solvent is CH2 Cl2 , the reaction temperature is 10~40°C, the reaction time is 15~20h, and the molar ratio of compound5 to DHP and PPTS is 3:6~9:1. The treatment process includes extraction, washing, drying and removal of solvent under reduced pressure to obtain compound6 .
上述步骤（6）中，反应溶剂为CH3OH，反应温度为0~20℃，反应时间为2~5h，化合物6与无机碱（K2CO3）用量的摩尔比为1:1~2，后处理过程包括倒入水中固体析出，抽滤、洗涤、干燥，得化合物7。In the above step (6), the reaction solvent is CH3 OH, the reaction temperature is 0-20°C, the reaction time is 2-5 hours, and the molar ratio of compound 6 and inorganic base (K2 CO3 ) is 1:1-2 , the post-treatment process includes pouring into water to precipitate solids, suction filtration, washing, and drying to obtain compound 7.
上述步骤（7）中，所述反应溶剂为CH3OH，所述反应温度为20~40℃，所述反应时间为2~5h，化合物7与无机酸（浓HCl）用量的摩尔比为1:1~2，后处理过程包括抽滤、洗涤、干燥，得化合物8。In the above step (7), the reaction solvent is CH3 OH, the reaction temperature is 20-40°C, the reaction time is 2-5h, and the molar ratio of compound 7 to inorganic acid (concentrated HCl) is 1 : 1 ~ 2, the post-treatment process includes suction filtration, washing, and drying to obtain compound 8.
上述步骤（8）中，所述反应溶剂为DMF，所述反应温度为-10~0℃，所述反应时间为10~14h，化合物8与对三甲基溴苄、NaH用量的摩尔比为1:1:1~2，后处理过程包括萃取、洗涤、干燥，得最终产物PA-824。In the above step (8), the reaction solvent is DMF, the reaction temperature is -10~0°C, the reaction time is 10~14h, and the molar ratio of compound 8 to p-trimethylbenzyl bromide and NaH is 1:1:1~2, the post-treatment process includes extraction, washing, and drying to obtain the final product PA-824.
实施例1Example 1
化合物2的制备Preparation of Compound2
在2000 ml的三颈瓶中加入320 ml浓H2SO4，冰浴下搅拌下慢慢加入100 g咪唑，加完后继续搅拌，溶液变澄清后，缓慢滴加240 ml浓HNO3。滴完后升温至125 ℃回流反应10 h后，停止反应，冷却至室温，倒入约10倍的碎冰中，大量白色固体析出，抽滤，用冷水洗涤，滤饼烘干后得到产物4-硝基咪唑155g，滤液用浓氨水调节pH至3-4，析出固体，抽滤，用冷水洗涤，滤饼烘干后得到产物4-硝基咪唑13 g，共得产物178 g，产率85.04%。1H-NMR (400M, d6- DMSO):δ 7.85 (s, 1H), 8.32 (s, 1H)。Add 320 ml of concentrated H2 SO4 into a 2000 ml three-necked flask, slowly add 100 g of imidazole while stirring in an ice bath, continue stirring after the addition, and slowly add 240 ml of concentrated HNO3 dropwise after the solution becomes clear. After dripping, raise the temperature to 125 °C for reflux reaction for 10 h, stop the reaction, cool to room temperature, pour into about 10 times of crushed ice, a large amount of white solid precipitates, filter with suction, wash with cold water, and dry the filter cake to obtain the product 4 -Nitroimidazole 155g, the filtrate was adjusted to pH 3-4 with concentrated ammonia water, and the solid was precipitated, suction filtered, washed with cold water, and the filter cake was dried to obtain 13 g of the product 4-nitroimidazole, and a total of 178 g of the product was obtained. 85.04%.1 H-NMR (400M, d6-DMSO):δ 7.85 (s, 1H), 8.32 (s, 1H).
化合物3的制备Preparation of compound3
将乙酸（175 ml，3.06 mol）和乙酸酐（350 ml，3.70 mol）加入到1000 ml的三口烧瓶中，冷水浴搅拌下慢慢加入4-硝基咪唑（100 g，884.4 mmol），加完之后搅拌30 min，然后在30 ℃以内缓慢滴加发烟硝酸（98%，75 ml），30 min滴完，滴加过程中可以看见反应液逐渐变黄，滴完后30 ℃恒温反应5h，TLC（石油醚:乙酸乙酯 = 2:1）检测原料点消失。将反应液倾入约10倍的碎冰中，搅拌冷却至室温，抽滤，滤饼烘干后得产物1,4-二硝基咪唑83 g，滤液收集用二氯甲烷萃取两次，饱和碳酸氢钠洗至pH呈中性，水洗一次，饱和食盐水洗一次，收集油层旋干得产物32 g，所以共得产物115 g，产率82.26%。1H NMR (400 MHz, CDCl3)：δ 8.39(s，1H), 8.53(s, 1H)。Add acetic acid (175 ml, 3.06 mol) and acetic anhydride (350 ml, 3.70 mol) into a 1000 ml three-neck flask, slowly add 4-nitroimidazole (100 g, 884.4 mmol) under stirring in a cold water bath, and complete the addition Then stir for 30 min, then slowly add fuming nitric acid (98%, 75 ml) dropwise within 30 °C, and drop it for 30 min, you can see that the reaction solution gradually turns yellow during the dropping process, and then react at a constant temperature of 30 °C for 5 hours TLC (petroleum ether: ethyl acetate = 2:1) detects that the raw material point disappears. Pour the reaction liquid into crushed ice about 10 times, stir and cool to room temperature, filter with suction, and dry the filter cake to obtain 83 g of the product 1,4-dinitroimidazole. The filtrate is collected and extracted twice with dichloromethane, saturated Wash with sodium bicarbonate until the pH is neutral, wash once with water and once with saturated brine, collect the oil layer and spin dry to obtain 32 g of the product, so a total of 115 g of the product was obtained, with a yield of 82.26%.1 H NMR (400 MHz, CDCl3 ):δ 8.39(s, 1H), 8.53(s, 1H).
化合物4的制备Preparation of Compound4
称取1,4-二硝基咪唑（26.05 g，167.60 mmol）置于250 ml圆底烧瓶中，加入120 ml的氯苯，搅拌溶解后，升温至115 ℃后加热回流12 h，有大量淡黄色固体析出。抽滤，石油醚洗，滤饼烘干后得到21.88 g淡黄色粉末，产率83% 。1H-NMR (400M, d6- DMSO):δ 8.46(s, 1H)。Weigh 1,4-dinitroimidazole (26.05 g, 167.60 mmol) into a 250 ml round-bottomed flask, add 120 ml of chlorobenzene, stir to dissolve, heat up to 115 °C and heat to reflux for 12 h, a large amount of pale A yellow solid precipitated out. After suction filtration, washing with petroleum ether, and drying the filter cake, 21.88 g of light yellow powder was obtained, with a yield of 83%.1 H-NMR (400M, d6-DMSO):δ 8.46(s, 1H).
化合物5的制备Preparation of compound5
将(S)-(+)-缩水甘油丁酸酯（25.90 g，163.92 mmol）加入到250 ml三颈瓶中，搅拌下，缓慢加入固体粉末2,4-二硝基咪唑（21.60 g，136.60 mmol）。升温至50 ℃，氮气保护下反应72 h，反应液呈乳胶状，TLC（石油醚:乙酸乙酯 = 2:1）检测原料点消失。将100 ml二氯甲烷及100 ml水加入到反应瓶中搅拌，混合液转移至分液漏斗中分液，水层用二氯甲烷萃取两次，合并有机相，用少量蒸馏水洗两次，再用饱和NaCl溶液洗涤一次，无水Mg2SO4干燥。减压蒸去溶剂，残留物中加入2eq硅胶粉末（200-300目）拌样，柱层析（石油醚∶乙酸乙酯 = 8∶1），得到25.65 g浅黄色油状物，产率62%。1H NMR (400 MHz，CDCl3):δ 0.96 (t,J = 7.5, 3H), 1.63-1.70 (m, 2H), 2.34-2.37 (t,J =7.2, 2H), 4.23-4.24 (m, 2H), 4.32-4.33 (m, 1H), 4.43-4.49 (m, 1H), 4.88-4.91 (m, 1H), 8.11 (s, 1H)。Add (S )-(+)-glycidyl butyrate (25.90 g, 163.92 mmol) into a 250 ml three-necked flask, and slowly add solid powder 2,4-dinitroimidazole (21.60 g, 136.60 mmol). The temperature was raised to 50 °C, and the reaction was carried out under nitrogen protection for 72 h. The reaction solution was in the form of latex, and TLC (petroleum ether: ethyl acetate = 2:1) detected that the raw material point disappeared. Add 100 ml of dichloromethane and 100 ml of water into the reaction flask and stir, transfer the mixture to a separatory funnel for separation, extract the aqueous layer twice with dichloromethane, combine the organic phases, wash twice with a small amount of distilled water, and then Wash once with saturated NaCl solution and dry overanhydrousMg2SO4 . The solvent was evaporated under reduced pressure, and 2eq silica gel powder (200-300 mesh) was added to the residue to mix the sample, and column chromatography (petroleum ether: ethyl acetate = 8:1) gave 25.65 g of light yellow oil, with a yield of 62%. .1 H NMR (400 MHz, CDCl3 ):δ 0.96 (t,J = 7.5, 3H), 1.63-1.70 (m, 2H), 2.34-2.37 (t,J = 7.2, 2H), 4.23-4.24 (m , 2H), 4.32-4.33 (m, 1H), 4.43-4.49 (m, 1H), 4.88-4.91 (m, 1H), 8.11 (s, 1H).
化合物6的制备Preparation of Compound6
称取化合物5（25.50 g，84.25 mmol）置于250 ml圆底烧瓶中，加入200 ml无水二氯甲烷溶解后，依次加入3,4-二氢吡喃（14.20 g，168.50 mmol）及PPTS（7.50 g，25.30 mmol），室温下发生反应16 h，TLC（石油醚：乙酸乙酯 = 1：1）检测原料点消失，反应液用饱和NaHCO3溶液洗涤两次，再依次用200 ml蒸馏水及200 ml饱和氯化钠溶液各洗一次，无水MgSO4干燥，减压争取溶剂后即得30.05 g粗产物，无需纯化，可直接用于下步反应。Weigh compound 5 (25.50 g, 84.25 mmol) into a 250 ml round bottom flask, add 200 ml of anhydrous dichloromethane to dissolve, then add 3,4-dihydropyran (14.20 g, 168.50 mmol) and PPTS (7.50 g, 25.30 mmol), reacted at room temperature for 16 h, TLC (petroleum ether: ethyl acetate = 1:1) detected the disappearance of raw material spots, the reaction solution was washed twice with saturated NaHCO3 solution, and then successively washed with 200 ml distilled water and 200 ml of saturated sodium chloride solution were washed once, dried with anhydrousMgSO4 , and the solvent was obtained under reduced pressure to obtain 30.05 g of crude product, which could be directly used in the next step without purification.
化合物7的制备Preparation of Compound 7
将化合物6粗品（30.05 g，53.90 mmol）溶解于甲醇中，降温至0 ℃，加入碳酸钾，0 ℃下搅拌1h，TLC（石油醚：乙酸乙酯 = 1：2）检测原料点消失。过滤除去碳酸钾，正己烷冲洗，抽滤，滤饼烘干后得11.25 g粗产物，无需纯化，可直接用于下步反应，产率78 %。Compound 6 crude product (30.05g, 53.90 mmol) was dissolved in methanol, cooled to 0 °C, added potassium carbonate, stirred at 0 °C for 1 h, TLC (petroleum ether: ethyl acetate = 1:2) detected that the raw material point disappeared. Potassium carbonate was removed by filtration, rinsed with n-hexane, suction filtered, and the filter cake was dried to obtain 11.25g crude product, without purification, can be directly used in the next step reaction, and the productive rate is 78%.
化合物8的制备Preparation of compound 8
将化合物7粗品(11.20 g，42.02 mmol)溶于100 ml无水甲醇中，降温至0 ℃，慢慢滴加浓盐酸11.2 ml，滴加完毕滴加完毕后撤去冰浴，自行升温至室温，继续反应2 h，有大量白色固体析出，抽滤，滤饼干燥后得6.75 g产物，产率87%。1H-NMR (400M, d6- DMSO)：δ 3.96 (d, J =12.8Hz, 1H), 4.16-4.20 (m, 1H), 4.27-4.34 (m, 2H), 4.39 (d,J = 11.1 Hz, 1H), 8.08 (s, 1H)。The crude product of compound 7 (11.20 g, 42.02 mmol) was dissolved in 100 ml of anhydrous methanol, cooled to 0 °C, and 11.2 ml of concentrated hydrochloric acid was slowly added dropwise. After continuing to react for 2 h, a large amount of white solids were precipitated, which were filtered by suction and dried to obtain 6.75 g of the product, with a yield of 87%.1 H-NMR (400M, d6-DMSO):δ 3.96 (d,J = 12.8Hz, 1H), 4.16-4.20 (m, 1H), 4.27-4.34 (m, 2H), 4.39 (d,J = 11.1 Hz, 1H), 8.08 (s, 1H).
PA-824的制备Preparation of PA-824
氮气保护下，将化合物8（6.70 g，36.20 mmol）溶于80 ml无水DMF中，加入对三氟甲氧基溴苄（11.07 g，43.44 mmol），冷却至0 ℃后加入NaH，0 ℃下搅拌30 min，自行升温至室温，继续反应4 h，TLC（石油醚：乙酸乙酯 = 1：2）检测原料点消失。用冰水淬灭反应，加入二氯甲烷萃取，有机相用无水MgSO4干燥后减压蒸除溶剂，柱层析（石油醚：乙酸乙酯 = 1：1）后得到13.33 g浅黄色固体，产率为80 %。HPLC测定纯度大于99 %，色谱条件为——色谱柱：Inertsil®ODS3 C18 column（150 mm×4.6 mm，5 μm）；检测波长：321 nm；流动相∶乙腈∶水 = 35∶65；流速：0.5 mL/min. m.p.: 149-150℃；1H NMR (400 MHz， CDCl3):δ 4.15-4.23 (m, 3H), 4.38 (d,J = 11.2 Hz, 1H), 4.61-4.64 (m, 2H), 4.73 (d,J = 8.0 Hz, 1H), 7.22 (d,J = 7.6 Hz, 2 H), 7.36 (d,J = 8.4 Hz, 2H), 7.43 (s, 1H).13C NMR (100 MHz, CDCl3)δ 149.12, 147.05, 143.63, 135.17, 129.15, 121.67, 119.12, 115.22, 70.20, 67.20, 65.53, 47.56. HRMS Calcd for C15H14F3N2O5([M+H]+): 359.0855, Found: 360.3247。Under the protection of nitrogen, compound 8 (6.70 g, 36.20 mmol) was dissolved in 80 ml of anhydrous DMF, and p-trifluoromethoxybenzyl bromide (11.07 g, 43.44 mmol) was added, cooled to 0 °C and then added with NaH, 0 °C Stir at low temperature for 30 min, warm up to room temperature by itself, continue to react for 4 h, TLC (petroleum ether: ethyl acetate = 1:2) detects that the raw material point disappears. The reaction was quenched with ice water, extracted with dichloromethane, the organic phase was dried with anhydrousMgSO4 , and the solvent was evaporated under reduced pressure. After column chromatography (petroleum ether: ethyl acetate = 1:1), 13.33 g of light yellow solid were obtained , the yield is 80%. The purity determined by HPLC is greater than 99%, and the chromatographic conditions are - chromatographic column: Inertsil® ODS3 C18 column (150 mm×4.6 mm, 5 μm); detection wavelength: 321 nm; mobile phase: acetonitrile: water = 35:65; flow rate : 0.5 mL/min. mp: 149-150°C;1 H NMR (400 MHz, CDCl3 ):δ 4.15-4.23 (m, 3H), 4.38 (d,J = 11.2 Hz, 1H), 4.61-4.64 ( m, 2H), 4.73 (d,J = 8.0 Hz, 1H), 7.22 (d,J = 7.6 Hz, 2H), 7.36 (d,J = 8.4 Hz, 2H), 7.43 (s, 1H).13 C NMR (100 MHz,CDCl3 )δ 149.12, 147.05, 143.63, 135.17, 129.15, 121.67, 119.12, 115.22, 70.20, 67.20, 65.53,47.56 . HRMS F 5 Calcd for C15 N2 +H]+ ): 359.0855, Found: 360.3247.
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| CN201410372448.6ACN104177372A (en) | 2014-07-31 | 2014-07-31 | Synthetic method of anti-tuberculosis candidate drug PA-824 |
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| CN106380451A (en)* | 2016-08-25 | 2017-02-08 | 西安天生物技术股份有限公司 | Synthesis and purification method of 2, 4-dinitroimidazole |
| CN106565744A (en)* | 2016-10-31 | 2017-04-19 | 瑞阳制药有限公司 | Crystal form of PA-824 compound and preparation method of crystal form |
| CN106632393A (en)* | 2016-12-28 | 2017-05-10 | 荆楚理工学院 | Preparation method for antituberculous candidate drug namely PA-824 |
| CN115385930A (en)* | 2022-08-19 | 2022-11-25 | 药璞(上海)医药科技有限公司 | Preparation method of Primanib |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5387297A (en)* | 1992-09-24 | 1995-02-07 | The United States Of America As Represented By The Secretary Of The Army | 2,4-dinitroimidazole- a less sensitive explosive and propellant made by thermal rearrangement of molten 1,4 dinitroimidazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106380451A (en)* | 2016-08-25 | 2017-02-08 | 西安天生物技术股份有限公司 | Synthesis and purification method of 2, 4-dinitroimidazole |
| CN106565744A (en)* | 2016-10-31 | 2017-04-19 | 瑞阳制药有限公司 | Crystal form of PA-824 compound and preparation method of crystal form |
| CN106565744B (en)* | 2016-10-31 | 2019-04-12 | 瑞阳制药有限公司 | The crystal form and preparation method thereof of PA-824 compound |
| CN106632393A (en)* | 2016-12-28 | 2017-05-10 | 荆楚理工学院 | Preparation method for antituberculous candidate drug namely PA-824 |
| CN115385930A (en)* | 2022-08-19 | 2022-11-25 | 药璞(上海)医药科技有限公司 | Preparation method of Primanib |
| CN115385930B (en)* | 2022-08-19 | 2024-04-05 | 药璞(上海)医药科技有限公司 | Preparation method of primani |
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