CN113896690B - 一种异噁唑啉类驱虫药氟雷拉纳的制备方法 - Google Patents
一种异噁唑啉类驱虫药氟雷拉纳的制备方法 Download PDFInfo
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- CN113896690B CN113896690B CN202111385270.5A CN202111385270A CN113896690B CN 113896690 B CN113896690 B CN 113896690B CN 202111385270 A CN202111385270 A CN 202111385270A CN 113896690 B CN113896690 B CN 113896690B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
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- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 14
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- MLBZKOGAMRTSKP-UHFFFAOYSA-N fluralaner Chemical compound C1=C(C(=O)NCC(=O)NCC(F)(F)F)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 MLBZKOGAMRTSKP-UHFFFAOYSA-N 0.000 description 4
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- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 3
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- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 description 1
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- BTEVDFJXGLQUDS-UHFFFAOYSA-N methyl 3,5-dichlorobenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(Cl)=C1 BTEVDFJXGLQUDS-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种异噁唑啉类驱虫药氟雷拉纳的制备方法。以4‑[3‑(3,5‑二氯苯基)‑4,4,4‑三氟丁基‑2‑烯酰基]‑2‑甲基‑苯甲酸乙酯和盐酸羟胺为起始原料，在相转移催化剂和缚酸剂催化下进行环合反应，再发生碱性水解反应，最后与2‑氨基‑N‑(2,2,2‑三氟乙基)乙酰胺进行缩合反应得到氟雷拉纳。本发明合成路线简短，反应条件温和，操作简便，转化率高，适合工业化生产，纯度可达到99.5％以上，单杂均小于0.1％。
Description
技术领域
本发明属于化学或药物化学领域，具体涉及一种氟雷拉纳的制备方法。
背景技术
2004年日本的日产化学工业株式会社(NissanChemical industries Japan)成功研发合成了异唑啉类的广谱驱虫剂氟雷拉纳(英文名：Fluralancr)，并在2005年取得了国际专利的授权，该化合物专利到期时间为2025年。化学结构式如下：
氟雷拉纳是最新上市兽药Bravecto(咀嚼片)的活性物质，一种新的内吸性杀虫剂和杀螨剂，适用于治疗狗身上的虱子及跳蚤。于2014年4月在德国、西班牙、意大利、法国、荷兰及英国上市，主要用于动物体内外杀虫，上市的药物成分为R和S构型的混合物。此咀嚼片是最早并且是唯一一种能够快速有效杀灭虱子及跳蚤的兽用医疗用品。2016年7月美国FDA批准了默克公司申请的
(Fluralaner外用溶液)用于治疗猫和狗身上的虱子及跳蚤，一次给药有效期长达12周。
目前报道的关于氟雷拉纳的合成路线主要有以下3条：
(1)MORLYAMA等以4-乙酰基-2-甲基苯甲酸为起始原料，首先制成4-乙酰基-2-甲基苯酰氯，然后与2-氨基-N-(2,2,2-三氟乙基)乙酰胺进行酰胺化反应得到4-乙酰基-2-甲基-N-[2-氧代-2-((2,2,2-三氟乙基)氨基]乙基]苯甲酰胺，再与3',5'-二氯-2,2,2-三氟苯乙酮反应制得4-[(2E)-3-(3,5-二氯苯基)-4,4,4-三氟-1-氧代-2-丁烯-1-基]-2-甲基-N-[2-氧代-2-((2,2,2-三氟乙基)氨基]乙基]苯甲酰胺，最后进行合环得到目标产物氟雷拉纳，合成路线如下所示：
(2)GARCIA-REYNAGA等以4-溴-2-甲基苯甲酸为起始原料，经过酯化、酰胺化反应得到2-甲基-4-甲醛肟基苯甲酸叔丁酯，然后与1,3-二氯-5-(1-三氟甲基-乙烯基)苯进行1,3-偶极加成环合反应得到4-[5-(3,5-二氯苯基)-4,5-二氢-5-(三氟甲基)-3-异噁唑基]-2-甲基苯甲酸叔丁酯，再经过反应最后得到4-[5-(3,5-二氯苯基)-4,5二氢-5-三氟甲基-3-异噁唑基]-2-碘-6-甲基苯甲酸中间体，得到的中间体再通过与2-氨基-N-(2,2,2-三氟乙基)乙酰胺盐酸盐反应以及去碘化反应，最终得到目标产物氟雷拉纳，合成路线如下所示：
(2)TAKAHJRO以3,5-二氯苯甲酸为起始原料，首先与甲醇进行酯化得到3,5-二氯苯甲酸甲酯，然后与三甲基(三氟甲基)硅烷反应得到[1-(3,5-二氯苯基)-2,2,2-三氟-1-甲氧基乙氧基]三甲基硅烷，然后与N-(4-乙酰基-2-甲基苯基)乙酰胺反应得到4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基)-2-甲基苯胺，再经过重氮化反应得到3-(4-溴-3-甲基苯基)-5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑，再与一氧化碳反应，得到4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基苯甲酸，最后与2-氨基-N-(2,2,2-三颌乙基)乙酰胺反应得到最终产物氟雷拉纳，合成路线如下所示。
以上3条路线中，路线(l)虽然步骤较少，但4-乙酰基-2-甲基苯甲酸与2-氨基-N-(2,2,2-三氟乙基)乙酰胺价格较贵，制取成本较高；路线(2)中，1,3-二氯-5-(1-三氟甲基-乙烯基)苯价格昂贵且关键步骤l,3-偶极加成环合反应的收率极低；路线(3)中，有气体CO参与反应，反应条件需要在5个大气压的压强下进行反应，条件较为苛刻，实验操作要求相对较高。以上路线均有一定局限性，不适合大规模生产。
因此，有待开发一种合成路线简短，反应条件温和，操作简便，收率高，适合工业化生产的高纯度氟雷拉纳制备方法。
发明内容
本发明的目的在于提供一种合成路线简短，反应条件温和，操作简便，收率高，适合工业化生产的高纯度氟雷拉纳的制备方法，具体技术方案如下：
一种异噁唑啉类驱虫药氟雷拉纳的制备方法，其特征在于，经由下述化学反应方程式制备：
上述反应方程式具体制备步骤如下：
(1)环合：在非极性溶剂和水中，按照一定比例加入4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯和盐酸羟胺、相转移催化剂，再加入缚酸剂，保温反应，保温结束后静置分层，有机层减压浓缩得到环合物；
(2)水解：将环合物中加入极性溶剂和碱，升温，保温反应，降温，调酸，抽滤，干燥，得到水解物。
(3)缩合：在溶剂中，按照一定比例加入水解物、缩合剂、2-氨基-N-(2,2,2-三氟乙基)乙酰胺，升温，保温反应，保温结束后加水分层，有机层减压浓缩，加入结晶溶剂降温结晶，抽滤，干燥，得到氟雷拉纳。
所述的非极性溶剂为乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙酸戊酯、乙酸异戊酯、乙酸己酯、甲基叔丁基醚、乙醚中的至少一种，优选为乙酸丁酯、乙酸戊酯、乙酸异戊酯、乙酸己酯、甲基叔丁基醚中的至少一种，用量为4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯重量的2-10倍，优选为3-6倍；所述的水用量是非极性溶剂用量的5％-30％；所述的盐酸羟胺与4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯的投料摩尔比为1.1-3.5：1，优选为1.5-2.5：1；所述的相转移催化剂为苄基三乙基氯化铵、四丁基溴化铵、四丁基氯化铵、四丁基硫酸氢铵、三辛基甲基氯化铵、十二烷基三甲基氯化铵、十四烷基三甲基氯化铵中的至少一种，优选为苄基三乙基氯化铵、四丁基硫酸氢铵、三辛基甲基氯化铵中的至少一种，用量与4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯的投料摩尔比为0.01-0.5：1，优选为0.05-0.3：1；所述的缚酸剂为氨水、三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂中的至少一种，优选为氢氧化钾、氢氧化锂中的至少一种，用量与4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯的投料摩尔比为1.5-4：1，优选为1.8-2.5：1；所述的保温反应温度为10-50℃，优选为10-30℃；所述的保温反应时间为0.5-6小时，优选为1-4小时；所述的减压浓缩温度为30-80℃，真空度为-0.06～-0.1MPa。
所述的极性溶剂为甲醇、异丙醇、丙酮中的至少一种，用量为环合物重量的2-10倍；所述的碱为氨水、三乙胺、碳酸钾、碳酸钠、氢氧化钾、氢氧化锂中的至少一种，用量与环合物的投料摩尔比为1.5-3：1；所述的保温反应温度为40-80℃；所述的保温反应时间为2-6小时；所述的降温终点温度为10-30℃；所述的调酸pH值终点为1-3，所用的酸为磷酸、硫酸、盐酸、硝酸、草酸(乙二酸)，亚硫酸，磷酸，丙酮酸，亚硝酸、碳酸，柠檬酸，氢氟酸，苹果酸，甲酸，丙烯酸，乙酸，丙酸，氢硫酸，次氯酸，硼酸的至少一种；所述的干燥温度为50-90℃，干燥时间为10-16小时。
所述的溶剂为乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙酸戊酯、乙酸异戊酯、乙酸己酯中的至少一种，优选为乙酸乙酯、乙酸异丙酯中的至少一种；用量为水解物重量的2-15倍，优选为水解物重量的6-15倍；所述的缩合剂为二环己基碳二亚胺、双(2-氧代-3-恶唑烷基)次磷酰氯、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐、N,N-碳酰二咪唑、二异丙基碳二亚胺、1-羟基苯并三唑与1-(3-二甲胺基丙基)-3-乙基碳二亚胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐、2-(1H-苯并三偶氮L-1-基)-1,1,3,3-四甲基脲四氟硼酸酯中的至少一种，优选为二环己基碳二亚胺、N,N-碳酰二咪唑、二异丙基碳二亚胺、1-羟基苯并三唑中的至少一种；用量与水解物的投料摩尔比为0.3-1.5：1，优选为0.8-1.3：1；所述的2-氨基-N-(2,2,2-三氟乙基)乙酰胺用量与水解物的投料摩尔比为1.05-2：1，优选为1.05-1.3：1；所述的保温反应温度为25-40℃，优选为30-35℃；所述的保温反应时间为3-7小时；所述的加水量为溶剂量0.5-2倍；所述的减压浓缩温度为30-80℃，真空度为-0.06～-0.1MPa；所述的结晶溶剂为乙腈、环己烷、正己烷、正庚烷、甲苯、乙醇、异丙醇、水、丙酮、石油醚中的至少一种，优选为环己烷、正己烷、正庚烷、甲苯中的至少一种，用量为水解物重量的6-15倍，优选为水解物重量的10-15倍；所述的干燥温度为50-90℃，干燥时间为8-16小时。
本发明的有益效果在于：
1)本发明提供的氟雷拉纳的制备方法合成路线简短，反应条件温和，操作简便，收率高，总收率为85％-90％。
2)根据本发明提供的制备方法，所制备的产品纯度可达到99.5％以上，单杂均小于0.1％。
附图说明
图1为氟雷拉纳环合物质谱谱图
图2为氟雷拉纳水解物质谱谱图
图3为氟雷拉纳水解物核磁氢谱谱图
图4为氟雷拉纳水解物核磁碳谱谱图
图5为氟雷拉纳质谱谱图
图6为氟雷拉纳核磁氢谱谱图
图7为氟雷拉纳核磁碳谱谱图
具体实施方式
下述通过具体的实施例，对本发明做详细的描述，以下实施例用于解释本发明，而不是对本发明的限制。
实施例1
(1)环合：向1L反应瓶投入4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯43.1g(0.1mol)和盐酸羟胺13.9g(0.2mol)，乙酸异戊酯350g，四丁基硫酸氢铵10.2g(0.03mol)，搅拌下分批加入氢氧化锂6.0g(0.25mol)/水30g，加完于25-30℃保温5小时，反应结束，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.09MPa，得到缩合物46.5g。HPLC检测纯度为98.1％。
[M]＝446.0(详见图1)
(2)水解：向500ml反应瓶投入上述缩合物46.5g(0.1mol)和甲醇320g,氨水20.2g(0.25mol)，升温至60-65℃保温6小时，降温10-15℃。用磷酸调pH＝2-3。抽滤，水漂洗至中性。50℃鼓风干燥16小时，得到水解物39.5g。环合和水解两步合并收率94.5％。HPLC检测纯度为99.0％。
[M]＝418.0(详见图2)
1HNMR(CDCl3)δ：2.73(s,3H),3.76-3.80(d,1H),4.15-4.18(d,1H),7.46(s,1H),7.56(s,2H),7.60-7.62(d,2H),8.14-8.16(d,1H),11.34(s,1H)。(详见图3)
13CNMR(CDCl3):21.97,43.82,87.10-87.83,120.29,122.56,124.22,124.82，125.23,127.08,129.78,130.16,130.43,131.53,132.14,135.64,138.81,142.09,155.40,172.47。(详见图4)
(3)缩合：向1L反应瓶投入水解物41.8g(0.1mol)，乙酸异戊酯300g，搅拌下加入2-氨基-N-(2,2,2-三氟乙基)乙酰胺20.3g(0.13mol)，N,N-碳酰二咪唑21.1g(0.13mol)，30℃保温7小时，反应结束，加水100g搅拌20分钟，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.09MPa，加入甲苯420g，降温析晶。抽滤，滤饼于50℃鼓风干燥16小时，得到氟雷拉纳51.7g，收率为92.9％。HPLC检测氟雷拉纳纯度为99.8％，水解物0.04％，其它未知单杂小于0.08％。
[M]＝556.0(详见图4)
1HNMR(CDCl3)δ：2.43(s,3H),3.73-3.77(d,1H),3.89-3.92(t,2H),4.10-4.14(d,1H),4.23-4.24(d,2H),7.27-7.30(d,1H),7.43-7.54(m,6H),7.68(s,1H)。(详见图5)
13CNMR(CDCl3):19.49，40.34-41.17，43.58-43.91,87.056-87.78,120.60,122.63-122.81,124.31，124.89,125.03,125.21,127.652，129.43-129.52,129.74,135.68,137.26-137.31,138.96,169.36-169.82。(详见图6)
实施例2
(1)环合：向1L反应瓶投入4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯43.1g(0.1mol)和盐酸羟胺7.6g(0.11mol)，乙酸丁酯250g，苄基三乙基氯化铵1.14g(0.005mol)，搅拌下分批加入氢氧化钾8.4g(0.15mol)/水20g，加完于25-30℃保温2小时，反应结束，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.1MPa，得到缩合物46.8g。HPLC检测纯度为98.0％。
(2)水解：向500ml反应瓶投入上述缩合物46.8g(0.1mol)和异丙醇320g,氢氧化钾10.1g(0.18mol)/水25g，升温至40-45℃保温4小时，降温10-15℃。用30％盐酸调pH＝1-2。抽滤，水漂洗至中性。60℃鼓风干燥15小时，得到水解物39.7g。环合和水解两步合并收率94.9％。HPLC检测纯度为99.1％。
(3)缩合：向1L反应瓶投入水解物41.8g(0.1mol)，乙酸丁酯600g，搅拌下加入2-氨基-N-(2,2,2-三氟乙基)乙酰胺17.2g(0.11mol)，二环己基碳二亚胺(DCC)30.9g(0.15mol)，40℃保温3小时，反应结束，加水150g搅拌20分钟，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.1MPa，加入异丙醇300g，降温析晶。抽滤，滤饼于60℃鼓风干燥15小时，得到氟雷拉纳50.9g，收率为91.5％。HPLC检测氟雷拉纳纯度为99.7％，水解物0.05％，其它未知单杂小于0.08％。
实施例3
(1)环合：向1L反应瓶投入4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯43.1g(0.1mol)和盐酸羟胺11.1g(0.16mol)，甲基叔丁基醚280g，三辛基甲基氯化铵4.04g(0.01mol)，搅拌下分批加入碳酸钠15.9g(0.15mol)/水60g，加完于25-30℃保温2小时，反应结束，静止分层，上层有机层减压浓缩，温度为40℃，真空度为-0.08MPa，得到缩合物46.3g。HPLC检测纯度为98.2％。
(2)水解：向500ml反应瓶投入上述缩合物46.8g(0.1mol)和甲醇460g,碳酸钠26.5g(0.25mol)/水100g，升温至75-80℃保温4小时，降温10-15℃。用甲酸调pH＝1-2。抽滤，水漂洗至中性。90℃鼓风干燥10小时，得到水解物39.3g。环合和水解两步合并收率94.0％。HPLC检测纯度为99.1％。
(3)缩合：向1L反应瓶投入水解物41.8g(0.1mol)，乙酸异丙酯550g，搅拌下加入2-氨基-N-(2,2,2-三氟乙基)乙酰胺25.0g(0.16mol)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐37.9g(0.1mol)，35℃保温4小时，反应结束，加水80g搅拌20分钟，静止分层，上层有机层减压浓缩，温度为40℃，真空度为-0.08MPa，加入环己烷260g，降温析晶。抽滤，滤饼于90℃鼓风干燥10小时，得到氟雷拉纳52.0g，收率为93.5％。HPLC检测氟雷拉纳纯度为99.5％，水解物0.07％，其它未知单杂小于0.07％。
实施例4
(1)环合：向1L反应瓶投入4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯43.1g(0.1mol)和盐酸羟胺20.8g(0.3mol)，乙酸己酯300g，四丁基氯化铵5.56g(0.02mol)，搅拌下分批加入三乙胺20.2g(0.2mol)，加完于40℃保温1小时，反应结束，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.1MPa，得到缩合物46.0g。HPLC检测纯度为98.5％。
(2)水解：向500ml反应瓶投入上述缩合物46.0g(0.1mol)和丙酮250g,氢氧化钾8.4g(0.15mol)/水25g，升温至50-55℃保温3小时，降温10-15℃。用乙酸调pH＝2-3。抽滤，水漂洗至中性。80℃鼓风干燥12小时，得到水解物39.4g。环合和水解两步合并收率94.3％。HPLC检测纯度为99.0％。
(3)缩合：向1L反应瓶投入水解物41.8g(0.1mol)，乙酸己酯400g，搅拌下加入2-氨基-N-(2,2,2-三氟乙基)乙酰胺31.2g(0.2mol)，二异丙基碳二亚胺18.9g(0.15mol)、1-羟基苯并三唑6.8g(0.05mol)，25℃保温6小时，反应结束，加水50g搅拌20分钟，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.1MPa，加入乙腈500g，降温析晶。抽滤，滤饼于80℃鼓风干燥12小时，得到氟雷拉纳51.8g，收率为93.1％。HPLC检测氟雷拉纳纯度为99.8％，水解物0.02％，其它未知单杂小于0.08％
本发明不限于上述实施例，凡依据本发明的技术实质对上述实施例作的任何简单、等同变化或修饰，均属于本发明技术范围内。
Claims (1)
1.一种异噁唑啉类驱虫药氟雷拉纳的制备方法，其特征在于，制备方法包括如下步骤：
（1）环合：向1L反应瓶投入4-[3-(3,5-二氯苯基)-4,4,4-三氟丁基-2-烯酰基]-2-甲基-苯甲酸乙酯43.1g和盐酸羟胺13.9g，乙酸异戊酯350g，四丁基硫酸氢铵10.2g，搅拌下分批加入氢氧化锂6.0g/水30g，加完于25-30℃保温5小时，反应结束，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.09MPa，得到缩合物46.5 g，HPLC检测纯度为98.1%；
（2）水解：向500ml反应瓶投入上述缩合物46.5 g和甲醇320g,氨水20.2g，升温至60-65℃保温6小时，降温10-15℃，用磷酸调pH=2-3，抽滤，水漂洗至中性，50℃鼓风干燥16小时，得到水解物39.5g，环合和水解两步合并收率94.5%，HPLC检测纯度为99.0%；
（3）缩合：向1L反应瓶投入水解物41.8g，乙酸异戊酯300g，搅拌下加入2-氨基-N-(2,2,2-三氟乙基)乙酰胺20.3g，N,N-碳酰二咪唑21.1g，30℃保温7小时，反应结束，加水100g搅拌20分钟，静止分层，上层有机层减压浓缩，温度为60℃，真空度为-0.09MPa，加入甲苯420g，降温析晶，抽滤，滤饼于50℃鼓风干燥16小时，得到氟雷拉纳51.7g，收率为92.9%，HPLC检测氟雷拉纳纯度为99.8%，水解物0.04%，其它未知单杂小于0.08%。
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