CN113861252A - 泰拉霉素的合成 - Google Patents
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- GUARTUJKFNAVIK-QPTWMBCESA-N Tulathromycin A Chemical compound C1[C@](OC)(C)[C@@](CNCCC)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](CC)[C@@](C)(O)[C@H](O)[C@@H](C)NC[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C GUARTUJKFNAVIK-QPTWMBCESA-N 0.000 title claims abstract description 28
- 229960002859 tulathromycin Drugs 0.000 title claims abstract description 27
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims abstract description 4
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- 238000002360 preparation method Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
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- 239000003814 drug Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- 229910019142 PO4 Inorganic materials 0.000 description 2
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- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
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- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
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- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
本发明涉及泰拉霉素的合成,具体为(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)‑2‑乙基‑3,4,10‑三羟基‑13‑[[3S,4S,6R,8R]‑8‑甲氧基‑4,8‑二甲基‑1,5‑二氧杂螺[2,5]辛‑6‑基]氧基)3,5,8,10,12,14‑六甲基‑11‑[[3,4,6‑三脱氧‑3‑(二甲基氨基)‑β‑D‑己吡喃木糖基]氧基]‑1‑氧杂‑6‑氮杂环十五烷‑15‑酮一水合物在溶剂和三氟甲磺酸镱存在下与正丙胺发生反应,实现泰拉霉素的合成。
Description
技术领域
本发明属于化学合成领域,具体涉及泰拉霉素的合成。
背景技术
泰拉霉素(Tulathromycin),又名土拉霉素、托拉霉素,商品名为“Draxxin”(中文名称为“瑞克新”或“瑞可新”)。该药是美国辉瑞动物保健品公司于上世纪90年代末研究开发出的一种新型红霉素类合成兽药,属于动物专用的大环内酯类半合成抗生素,主要用于治疗和防治动物由胸膜肺炎放线杆菌、支原体、巴氏杆菌、副嗜血杆菌、支气管败血性博德特菌等引起的呼吸系统疾病。大量研究发现,泰拉霉素能够选择性穿透革兰氏阴性菌病原体,用于牛和猪的由敏感菌引起的呼吸系统感染性疾病及由牛莫拉氏菌引起牛传染性角膜炎的防治。该药于2004年10月被欧盟兽医医学咨询委员会批准在欧盟上市,2005年5月被美国FDA批准在美国上市,中国农业部于2008年在农业部第957号公告中批准使用该药,该药剂型为注射剂。泰拉霉素由于在使用过程中存在浓度低、作用时间长、最小抑制浓度低、用量少、注射水溶性好、整体治疗成本低、使用方便等优点,受到了兽药界广泛关注,行业内把该药称之为具有划时代革命性的产品。
泰拉霉素结构比较复杂,具有18个手性中心,且包含多个活性基团(包含5个羟基、一个大环内酯基、三个胺基),化学名为:(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-二脱氧-3-C-甲基-3-O-甲基-4-C-[(丙基氨基)甲基]α-L-己吡喃核糖基)氧基]-2-乙基-3,4,10-三羟基-3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮。化合物由于含有三个胺基基团,因此在溶液中呈弱负电性,从而有利于穿透阴性菌膜,高效率地刺激肽酰tRNA从核糖体上分离,从而抑制细菌转肽过程,使肽链的合成和延长受阻,从而影响细菌蛋白质的合成。泰拉霉素的化学结构式如下:
由于泰拉霉素结构复杂,含有多个手性中心,且包含多个活性基团,因而合成难度大。美国辉瑞公司专利WO9856802/US6420536/CN1295240C从去甲基阿奇霉素出发,以氯甲酸苄酯保护2″位的羟基,然后采用Swern氧化条件氧化4′的羟基,随后中间体再使用Corey-Chaykovsky环氧化条件对羰基进行环氧化反应,得到环氧化合物。环氧化合物再经过Pd/C氢化脱除Cbz保护基,所得产物再经过正丙胺与分子中的环氧三元环发生亲核加成反应,实现泰拉霉素的制备。相关合成路线如下:
专利CN1295240C实施例5描述了正丙胺和三元环中间体反应的步骤,具体为三元环中间体((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-乙基-3,4,10-三羟基-13-[[3S,4S,6R,8R]-8-甲氧基-4,8-二甲基-1,5-二氧杂螺[2,5]-辛-6-基]氧基)3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮)的一水合物以异丙醇为溶剂在大大过量的正丙胺(25当量)的存在下,55-55℃加热反应长达30小时才能反应完毕。由于中间体化合物同样含多个活性基团(羟基、大环内酯基、胺基等),反应时间越长,导致的杂质也就也多,特别是正丙胺亲核进攻环氧时会产生的异构体杂质。另外,大大过量的正丙胺不仅会使原料成本提高,也会导致三废处理中氨氮的含量提高,给废水、废溶剂的绿色环保处置带来很高的费用。正是基于该反应杂质多,所以文献大多采用将制备生成的泰拉霉素粗品成双磷酸盐,然后对双磷酸盐进行精制,最后再游离制备得到比较纯的泰拉霉素。相关合成路线如下:
文献《精细化工》(2012,29,795-799)同样描述了2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-乙基-3,4,10-三羟基-13-[[3S,4S,6R,8R]-8-甲氧基-4,8-二甲基-1,5-二氧杂螺[2,5]-辛-6-基]氧基)3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮一水合物和正丙胺的开环反应,随后加入磷酸成磷酸盐。该反应条件只使用了10倍当量的正丙胺,但是把反应温度提高到了70℃,反应时间同样长达30小时。
考虑到泰拉霉素是一个大品种,每年市场的需求在数十吨甚至百吨以上,因此,如何克服现有技术制备泰拉霉素存在的一些缺陷,提供一种更加适合工业生产泰拉霉素的制备方法成为进一步放大生产和市场推广该产品急需解决的问题。
发明内容
本发明的目的在于提供一条制备(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-二脱氧-3-C-甲基-3-O-甲基-4-C-[(丙基氨基)甲基]α-L-己吡喃核糖基)氧基]-2-乙基-3,4,10-三羟基-3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮(泰拉霉素)的方法。
研究发现,(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-乙基-3,4,10-三羟基-13-[[3S,4S,6R,8R]-8-甲氧基-4,8-二甲基-1,5-二氧杂螺[2,5]-辛-6-基]氧基)3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮一水合物(化合物式I)在溶剂和添加物存在下与正丙胺发生反应,可以快速的实现环氧环的开环,实现(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-二脱氧-3-C-甲基-3-O-甲基-4-C-[(丙基氨基)甲基]α-L-己吡喃核糖基)氧基]-2-乙基-3,4,10-三羟基-3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮(泰拉霉素)的制备。相关反应式如下:
反应所使用的溶剂包括甲醇、乙醇、丙二醇、异丙醇以及这些溶剂任意组合的混合溶剂。
反应所使用的添加物为三氟甲磺酸镱。
反应所使用的正丙胺当量为化合物式I当量的1-2当量。
反应的温度为40-60℃
反应时间为2-5小时。
本发明的制备方法,可以将正丙胺的使用当量大幅度降低,反应时间缩短,且所产生的泰拉霉素粗品不需要通过成磷酸盐成盐纯化,可以直接通过简单纯化得到泰拉霉素产品,具有好的产业化前景。
具体实施方式
以下典型实施例用来说明本发明,在本领域内的技术人员对本发明所做的简单替换和改进等均属于本发明所保护的技术方案之内。
实施例一:泰拉霉素的制备
四口烧瓶中依次加入(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-乙基-3,4,10-三羟基-13-[[3S,4S,6R,8R]-8-甲氧基-4,8-二甲基-1,5-二氧杂螺[2,5]-辛-6-基]氧基)3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D-己吡喃木糖基]氧基]-1-氧杂-6-氮杂环十五烷-15-酮一水合物(化合物式I)(110g,143.8mmol)和异丙醇(500mL),室温搅拌溶解。然后向反应体系中依次加入正丙胺(12.75g,215.7mmol,1.5eq)和三氟甲磺酸镱(8.9g,14.4mmol,0.1eq)。加入完毕后,体系加热至50℃搅拌反应3小时。反应完全后,体系高真空减压浓缩去除有机溶剂,向残余物中加入DMF(450mL),加热至80℃溶解,趁热过滤,滤液搅拌缓慢降温至5℃左右,搅拌析晶2小时,过滤,固体使用提前冷却至5℃的正庚烷(50mL)漂洗,所得固体55℃高真空干燥得白色固体(87.2g,75.2%)。1H-NMR(MeOD-D4,400MHz)δppm 0.83-1.24(m,31H),1.29(s,3H),1.35-1.43(m,1H),1.46-2.01(m,10H),2.25-2.29(m,1H),2.32(s,6H),2.53-2.57(t,2H,J=8.0Hz),2.64-2.98(m,6H),3.22-3.27(m,1H),3.38(s,3H),3.41-3.42(m,1H),3.64-3.66(d,1H,J=8.0Hz),3.68-3.78(m,1H),4.23-4.25(m,1H),4.51-4.55(m,2H),4.93-4.96(m,1H),5.00-5.01(d,1H,J=4.0Hz);13C-NMR(CDCl3,150MHz)δ ppm 9.51,11.31,11.91,14.35,15.29,15.57,16.30,17.41,21.17,21.60,22.06,23.03,27.36,28.98,29.96,34.05,40.47,41.61,42.21,45.30,49.16,49.91,52.77,56.48,57.14,65.64,67.84,68.64,71.17,72.55,73.83,74.11,76.42,77.89,79.02,83.91,95.77,103.09,178.36;Mass 404,(M+2H+)/2。
Claims (6)
2.如权利要求1所示的方法,反应所使用的溶剂包括甲醇、乙醇、丙二醇、异丙醇以及这些溶剂任意组合的混合溶剂。
3.如权利要求1所示的方法,反应所使用的添加物为三氟甲磺酸镱。
4.如权利要求1所示的方法,反应所使用的正丙胺当量为化合物式I当量的1-2当量。
5.如权利要求1所示的方法,反应的温度为40-60℃。
6.如权利要求1所示的方法,反应时间为2-5小时。
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