CN104761496A - 一种右美沙芬中间体的合成方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
一种式(I)所示的右美沙芬中间体的制备方法，包括：在惰性溶剂中，稀土路易斯酸催化的条件下，(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉化合物进行环合反应得到式(I)所示的(+)-3-甲氧基-17-酰基吗喃化合物，其中R为C1–C3烷酰基、C1–C3含氧烷酰基、C1–C3含氟烷酰基、C1–C3含氯烷酰基、C1–C3磺酰基或C1–C3含氟磺酰基。本发明的优点是以(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉作为环合反应前的底物，在较低温度下实现原料高效转化从而降低能耗；环合剂选自稀土路易斯酸，避免强质子酸对设备腐蚀，减少了三废的排放；环合反应中的副产物明显降低；所用的稀土路易斯酸为催化量，降低生产成本。
Description
技术领域
本发明涉及一种右美沙芬中间体的制备方法，特别涉及一种环合反应。
技术背景：
右美沙芬(又名右甲吗喃)因其具有中枢性镇咳作用且无麻醉性和成瘾性而被广泛用于临床上治疗咳嗽，迄今为止其应用已有将近50年的历史。右美沙芬主要以氢溴酸盐的形式应用在药物中，市场上常见的感冒镇咳药如美可、白加黑感冒片(美息伪麻片)、普西兰片、帕尔克、健儿婴童咳水等均含有氢溴酸右美沙芬。然而目前国内主要依靠进口，并没有成熟的生产工艺。
环合反应是右美沙芬合成中最关键的步骤，它直接影响右美沙芬合成的总收率以及生产成本。目前关于环合反应的研究主要有两种途径，即：文献(今日药学,2008,18(4),63-64)以及中国专利申请CN201310004262，CN201310041846，CN201310051880，CN201210405684介绍的环合路线大致都是通过以下的方法：
1-(4-甲氧基)苄基-八氢异喹啉通过拆分或手性还原的方法得到单一构型的右旋体，然后通过对氮原子进行甲基化得到(+)-N-甲基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉，随后该化合物在高温(130～140℃或回流)酸性条件下发生环合反应得(+)-3-羟基-N-甲基吗啡喃(高温下容易使甲氧基脱去)，最后于苯环上再引入甲氧基，得右美沙芬。该方法中环合反应发生在强酸高温的条件下对设备要求高，而且环合后副产物多，收率低。虽然中国专利申请CN201210516024以及CN201410169133在环合反应中用三氯化铝代替磷酸，在较温和的条件下实现环化，然而采用三氯化铝的量比较大，且不能循环利用，增加了成本。
另一种途径由文献Tetraheron Lett.1987,28:4829-4832以及Org.Process Res.Dev.2014,18,174-178介绍，环合路线大致都是通过以下的方法：
单一手性化合物(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉先生成酰基化合物即(+)-N-甲酰基-1-(4-甲氧基)苄基八氢异喹啉，然后在质子酸中发生环合反应，得到(+)-N-甲酰基-3-甲氧基吗啡喃，接着通过碱性条件脱甲酰基再进行N-甲基化反应或者直接对甲酰基还原都能获得最终产物右美沙芬。此环合反应虽然在相对温和条件下实现关环，但是环合中采用大量磷酸、硫酸等，增加工业上三废的处理与排放量，并不是一条环保路线。
因此寻找一条环保、温和的环合路线，减少三废的产生，实现原料高效转化是迫切需要解决的技术问题。
发明内容
本发明主要针对环合反应中高能耗高污染低收率的问题，提供一条新的环合路线，在较温和的条件下完成环化反应，降低副产物的生成，提高右美沙芬中间体的纯度与收率。
本发明的一种式(I)所示的右美沙芬中间体的制备方法，包括步骤：
在惰性溶剂中，稀土路易斯酸催化的条件下，式(II)所示的(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉化合物进行环合反应得到式(I)所示的(+)-3-甲氧基-17-酰基吗喃化合物，
其中：R为C1–C3烷酰基、C1–C3含氧烷酰基、C1–C3含氟烷酰基、C1–C3含氯烷酰基、C1–C3磺酰基或C1–C3含氟磺酰基。
在本发明的优选方法中，所述惰性溶剂为苯、甲苯、二甲苯、正己烷、正庚烷。
在本发明的优选方法中，所述稀土路易斯酸中稀土阳离子选自钪、镧、铈、钐、钇、镱及铕；所述的稀土路易斯酸中阴离子相应的酸选自三氟甲磺酸或/和五氟苯甲酸或/和全氟辛酸。
在本发明的优选方法中，所述稀土路易斯酸由所述稀土阳离子与所述酸根阴离子中的一种或一种以上制备而成。
在本发明的优选方法中，式(II)所示化合物与稀土路易斯酸投料摩尔比为(0.01-1.0):1。
在本发明的优选方法中，环合反应的温度为0-80℃。
在本发明的优选方法中，环合反应的温度为10-40℃。
在本发明的优选方法中，所述的方法还包括步骤：式(III)所示的(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉化合物在有机溶剂中通过滴加与酰基R对应的酸或酸酐或酯或酰氯，得到式(II)所示的(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉化合物，反应通式如下：
在本发明的优选方法中，式(III)所示的化合物制备式(II)所示的化合物过程中，所用的有机溶剂选自二氯甲烷、DMF、、四氢呋喃、二氧六环、乙腈；反应温度为-10℃～50℃；所述酸或酸酐或酯或酰氯与式(III)所示的化合物投料摩尔比为(0.5-1.5):1；及反应时间为1-5小时。
本发明的优点是：(1)以(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉作为环合反应前的底物，在较低温度下实现原料高效转化从而降低能耗；(2)环合剂选自稀土路易斯酸，避免强质子酸对设备腐蚀，减少了三废的排放；(3)环合反应中的副产物明显降低；(4)所用的稀土路易斯酸为催化量，降低生产成本。
具体实施方式：
本发明涉及右美沙芬中间体的合成主要包括如下步骤
(1)式(II)所示化合物(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的合成，其反应通式为：
其中，R为C1–C3烷酰基、C1–C3含氧烷酰基、C1–C3含氟烷酰基、C1–C3含氯烷酰基、C1–C3磺酰基或C1–C3含氟磺酰基。
拆分后的八氢异喹啉衍生物先经10％氢氧化钠溶液解离得式(III)所示的化合物，然后将式(III)所示的化合物溶于三乙胺的二氯甲烷溶液中并缓慢加入酸或酸酐或酯或酰氯得式(II)所示的化合物。其中，酸或酸酐或酯或酰氯与式(III)所示的化合物投料摩尔比为(0.5–1.5):1。
(2)由式(II)所示的化合物通过环合反应得到式(I)所示的中间体化合物，反应通式为：
惰性溶剂中，以稀土路易斯酸作环合催化剂，低温下进行环合反应，反应时间为3-10小时。
稀土路易斯酸中稀土阳离子优选镧离子；惰性溶剂优选甲苯、二甲苯，更优选甲苯；(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉与稀土路易斯酸投料摩尔比优选1：(0.01–1)，更优选1：(0.01–0.5)。
本发明的优选实施例中以三氟甲磺酸镧作环合剂，甲苯作溶剂，(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉与稀土路易斯酸投料摩尔比为1:(0.01-0.5)，反应温度为室温。
得到的中间体(I)可按如下路线制备右美沙芬：
下面通过实施例对本发明作进一步的说明，其目的仅在于更好的理解本发明的内容而非限制本发明的保护范围。
实施例
(1)八氢异喹啉的解离
制备例1
(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备(解离反应制备式III化合物)
将拆分后的八氢异喹啉衍生物(500.0g)加入已配好的氢氧化钠水溶液(10％NaOH,1000mL)中室温下搅拌半个小时，待上层出现淡黄色油状物后加入二氯甲烷萃取(800mL*3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏除去有机溶剂，得浅黄色溶液(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉，其核磁数据如下所示：
1H NMR(400MHz,CDCl3)δ:1.52–2.15(m,10H),2.46(dd,J＝10.8Hz,13.6Hz,1H),2.67–2.73(m,1H),2.95–3.01(m,2H),3.24(d,J＝10.8Hz,1H),3.77(s,3H),6.84(d,J＝8.8Hz,2H),7.13(d,J＝8.8Hz,2H).HRMS(EI)calcd for C17H23NO:257.1780,found:257.1783.
(2)(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备(以制备例1的产物为原料)
制备例2：(+)-N-甲酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备
500mL三口烧瓶中依次加入(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)、DCM(300mL)以及NaOH(7.78g)，机械搅拌将其溶解，室温下缓慢加入甲酸乙酯(29.0g)，加料完后继续反应3小时至原料完全消失。加水(200mL)分相，二氯甲烷(150mL*3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂得浅黄色粘稠液即(+)-N-甲酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉。其核磁数据如下所示：
1H NMR(400MHz,CDCl3)δ:1.77–1.60(m,4H),1.94–1.82(m,4H),3.08–2.75(m,2H),3.31(dd,J＝13.2,6.5Hz,0.35H),3.58(broad s,0.65H),3.77(s,3H),4.37(dd,J＝13.2,6.5Hz,0.65H),4.68(broad s,0.35H),6.80(m,2H),6.97(m,1.31H),7.05(m,0.71H),7.39(s,0.64H),7.92(s,0.34H).13C NMR(100MHz,CDCl3)δ:22.7,22.8,22.9,27.6,27.7,29.7,30.0,30.1,30.8,33.3,36.2,37.4,40.3,53.2,55.1,80.7,113.5,114.0,127.6,127.8,128.8,129.8,129.9,130.2,130.4,158.1,158.3,160.8,161.0.HRMS(EI)calcd for C18H23NO2:285.1729,found:285.1730.
制备例3：(+)-N-乙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备
500mL三口烧瓶中依次加入(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)、DCM(300mL)以及Et3N(50.0g)，机械搅拌将其溶解，室温下缓慢滴加入乙酸酐(32.0g)，加料完后继续反应3小时至原料完全消失。加水(200mL)分相，二氯甲烷(150mL*3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂得浅黄色粘稠液即(+)-N-乙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉。其核磁数据如下所示：
1H NMR(400MHz,CDCl3)δ:1.48(s,1.5H),1.35(s,1.5H),1.63–1.70(m,4H),1.78(d,J＝16.0Hz,1H),1.92(d,J＝18.4Hz,3H),2.04–2.26(m,2H),2.69–2.81(m,1H),2.84–3.04(m,2H),3.47(dd,J＝5.6Hz,13.2Hz,0.4H),3.78(s,3H),3.82(d,J＝10.0Hz,0.6H),4.67(dd,J＝5.6Hz,13.2Hz,0.6H),4.89(broad s,0.4H),6.80(q,J＝10.4Hz,16.4Hz,2H),7.03(q,J＝8.4Hz,11.2Hz,2H).13C NMR(100MHz,CDCl3)δ:20.8,21.6,222.7,22.8,22.9,27.8,28.0,29.7,29.9,30.0,30.4,34.1,36.4,37.2,40.5,54.2,55.1,55.2,61.0,113.4,113.9,127.8,128.2,129.0,129.3,130.3,130.4,130.5,158.0,158.4,168.4,169.3.HRMS(ESI)calcd for C19H25NO2H+([M+H]+):300.1964,found:300.1968.
制备例4：(+)-N-丙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备
500mL三口烧瓶中依次加入(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)、DCM(300mL)、Et3N(59.0g)，机械搅拌将其溶解，冰水浴中缓慢滴加丙酰氯(43.0g)，加料毕置于室温下反应3小时原料完全消失。加水(200mL)分相，二氯甲烷(150mL*3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂得浅黄色粘稠液即(+)-N-丙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉。其核磁数据如下所示：
1H NMR(400MHz,CDCl3)δ:0.68(t,J＝7.6Hz,1.5H),0.95(t,J＝7.6Hz,1.5H),1.53–2.17(m,12H),2.60–2.71(m,1H),2.77–2.95(m,2H),3.41(dd,J＝5.6Hz,13.2Hz,0.5H),3.66(s,3H),3.79(broad d,J＝9.6Hz,0.5H),4.59(dd,J＝5.6Hz,13.2Hz,0.5H),4.81(broad s,0.5H),6.70(dd,J＝5.6Hz,12.4Hz,2H),6.94(dd,J＝5.6Hz,12.4Hz,2H).13C NMR(100MHz,CDCl3)δ:8.3,8.6,21.7,21.8,21.9,24.7,25.7,26.8,27.1,28.9,29.0,29.5,33.3,35.6,36.2,38.6,53.1,54.1,54.2,58.8,112.3,112.9,126.6,127.3,128.2,128.3,129.4,129.5,129.6,157.0,157.3,170.8,171.6.HRMS(ESI)calcd for C20H27NO2H+([M+H]+):314.2120,found:314.2111.
制备例5：(+)-N-三氟乙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备
500mL三口烧瓶中依次加入(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)、DCM(300mL)、Et3N(59.0g)，机械搅拌将其溶解，室温下缓慢滴加三氟乙酸酐(95.1g)，反应4小时原料完全消失。加水(200mL)分相，二氯甲烷(150mL*3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂得浅黄色粘稠液即(+)-N-三氟乙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉。其核磁数据如下所示：
1H NMR(400MHz,CDCl3)δ:1.60–1.92(m,8H),2.14–2.21(m,2H),2.82(dd,J＝7.6Hz,14.0Hz,1H),3.01–3.09(m,2H),3.72(dd,J＝4.8Hz,14.0Hz,1H),3.77(s,3H),4.77(broad s,1H),6.79(d,J＝8.8Hz,2H),7.04(d,J＝8.8Hz,2H).13C NMR(100MHz,CDCl3)δ:22.6,22.8,27.6,29.8,30.6,36.2,39.7,55.1,56.1,113.7,127.8,128.1,129.1,130.3,155.0,155.3,158.4.HRMS(ESI)calcd for C19H22NO2F3Na+([M+Na]+):376.1500,found:376.1494.
制备例6：(+)-N-乙氧羰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备
500mL三口烧瓶中依次加入(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)、DCM(300mL)、Et3N(59.0g)，机械搅拌将其溶解，冰水浴中缓慢滴加氯甲酸乙酯(50.4g)，滴加完毕后转入室温下反应，3小时原料完全消失。加水(200mL)分相，二氯甲烷(150mL*3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂得浅黄色粘稠液即(+)-N-乙氧羰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉。其核磁数据如下所示：
1H NMR(400MHz,CDCl3)δ:0.94(t,J＝7.2Hz,2H),2.16(t,J＝6.8Hz,1H),1.57–1.72(m,5H),1.88–2.15(m,5H),2.63–3.01(m,3H),3.64–3.68(m,0.6H),3.74(s,3H),3.78–3.82(m,1H),4.01–4.04(m,0.8H),4.12(dd,J＝6.0Hz,13.2Hz,0.6H),4.25(broad d,J＝7.2Hz,0.6H),4.47(broad s,0.4H),6.78(d,J＝8.0Hz,2H),7.04(q,J＝8.0Hz,17.2Hz,2H).13C NMR(100MHz,CDCl3)δ:14.3,14.7,23.0,27.9,30.0,30.1,36.5,36.9,37.2,37.6,55.2,56.5,57.3,60.7,113.5,128.1,128.5,128.9,130.3,130.7,131.0,155.2,155.3,158.0,158.1.HRMS(ESI)calcd for C20H27NO3H+([M+H]+):330.2069,found:330.2064.
制备例7：(+)-N-甲磺酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备
500mL三口烧瓶中依次加入(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)、DCM(300mL)、Et3N(59.0g)，机械搅拌将其溶解，室温下缓慢滴加甲磺酸酐(81.2g)，反应3小时原料完全消失。加水(200mL)分相，二氯甲烷(150mL*3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂二氯甲烷，冷却后放置，得浅黄色粉末固体即(+)-N-甲磺酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉。其核磁数据如下所示：
m.p.130-132℃；1H NMR(400MHz,CDCl3)δ:1.58(broad s,5H),1.84(d,J＝5.6Hz,3H),2.07(d,J＝16.8Hz,1H),2.18(broad s,4H),2.60(dd,J＝9.6Hz,14.0Hz,1H),2.91(dd,J＝4.0Hz,14.4Hz,1H),2.99–3.06(m,1H),3.59(dd,J＝6.4Hz,14.4Hz,1H),3.69(s,3H),4.03(broad d,J＝8.0Hz,1H),6.75(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H).13CNMR(100MHz,CDCl3)δ:22.7,23.0,28.0,29.4,30.1,37.8,38.5,39.8,55.2,58.8,113.7,128.1,128.8,130.5,130.8,158.3.HRMS(ESI)calcd for C18H25NO3SH+([M+H]+):336.1633,found:336.1636.
制备例8：(+)-N-三氟甲磺酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉的制备
500mL三口烧瓶中依次加入(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)、DCM(300mL)、Et3N(59.0g)，机械搅拌将其溶解，冰盐浴中缓慢滴加三氟甲磺酸酐(87.5g)，滴加完毕后转入室温下反应，3小时原料完全消失。加水(200mL)分相，二氯甲烷(150mL*3)萃取，合并有机相，饱和NaCl洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂，冷却后放置，得浅黄色固体即(+)-N-三氟甲磺酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉。其核磁数据如下所示：
m.p.65-67℃；1H NMR(400MHz,CDCl3)δ:1.61–1.73(m,5H),1.82–1.98(m,3H),2.10–2.21(m,2H),2.90–3.01(m,3H),3.72(dd,J＝7.2Hz,14.4Hz,1H),3.78(s,3H),4.16(broad s,1H),6.83(d,J＝8.4Hz,2H),7.07(d,J＝8.4Hz,2H).13C NMR(100MHz,CDCl3)δ:22.6,22.8,28.0,30.0,38.2,40.4,55.1,60.0,113.9,128.3,128.9,130.6,158.6.HRMS(EI)calcd for C18H22F3NO3S:389.1272,found:389.1276.
(3)Grewe环合反应制备(+)-3-甲氧基-17-酰基吗喃(右美沙芬中间体)
制备例9：(用现有技术的常规反应)(+)-3-甲氧基-17-甲酰基吗喃的制备
500mL三口烧瓶，上至温度计，回流冷凝管。依次加入(+)-N-甲酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(50.0g)，85％磷酸(250mL)于反应瓶中，缓慢升温至80℃，保温10小时。反应结束后，冷却至室温，加水(200mL)淬灭反应，甲苯萃取(400mL*3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩(取两滴浓缩液加甲醇稀释送HPLC检测纯度)，然后经减压精馏得淡黄色粘稠液，收率79％。其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ:0.94–1.62(m,10H),2.29(d,J＝9.6Hz,1H),2.37(t,J＝12.8Hz,0.5H),2.58(t,J＝17.6Hz,1H),2.86(t,J＝12.8Hz,0.5H),3.03–3.14(m,1H),3.19(dd,J＝4.0Hz,12.8Hz,0.5H),3.61(broad s,0.5H),3.71(s,3H),4.07(dd,J＝4.0Hz,12.8Hz,0.5H),4.55(broad s,0.5H),6.65(d,J＝8.4Hz,1H),6.76(s,1H),6.94(t,J＝8.4Hz,1H),7.90(s,0.5H),8.07(s,0.5H).13C NMR(100MHz,CDCl3)δ:160.7,160.6,158.7,158.6,140.1,129.1,128.0,127.5,111.4,111.3,55.2,53.7,46.3,45.0,43.7,42.0,41.1,40.8,38.8,38.7,36.5,36.4,34.9,32.2,30.8,26.3,26.2,21.9.HRMS(EI)calcd for C18H23NO2:285.1729,found:285.1730.
以下制备例使用本发明的稀土路易斯酸催化反应
制备例10：(+)-3-甲氧基-17-甲酰基吗喃的制备
500mL三口烧瓶中依次加入(+)-N-甲酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)，甲苯(300mL)，机械搅拌溶解，相继加入三氟甲磺酸镧(37.0g)，室温下反应8小时。反应结束后抽滤，回收三氟甲磺酸镧，甲苯洗涤并合并有机相，减压蒸馏除去溶剂得淡黄色粘稠液(取两滴浓缩液加甲醇稀释送HPLC检测)，然后经减压精馏得淡黄色粘稠液，收率93％。
制备例11：(+)-3-甲氧基-17-乙酰基吗喃的制备
500mL三口烧瓶，依次加入(+)-N-乙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)，甲苯(300mL)，机械搅拌溶解，再加入三氟甲磺酸镧(38.1g)，室温下反应8小时。反应结束后抽滤，甲苯洗涤并合并有机相，减压蒸馏除去溶剂得淡黄色粘稠液(取两滴浓缩液加甲醇稀释送HPLC检测)，然后经减压精馏得淡黄色粘稠液，收率96％。其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ:0.96–1.62(m,10H),2.01(d,J＝38.8Hz,3H),2.19(d,J＝22.4Hz,0.3H),2.29(d,J＝10.4Hz,1H),2.55(q,J＝17.6Hz,29.2Hz,1H),2.82(t,J＝13.2Hz,0.7H),2.99–3.10(m,1H),3.38(d,J＝14.0Hz,0.6H),3.70(s,3H),3.82(broad s,0.4H),4.27(d,J＝14.0Hz,0.4H),4.76(broad s,0.6H),6.63(d,J＝8.4Hz,1H),6.74(s,1H),6.93(d,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ:20.9,21.0,25.2,25.3,25.7,28.6,30.0,30.6,34.6,35.3,36.6,39.8,40.1,50.0,42.7,43.5,45.9,52.0,54.1,110.1,110.3,126.5,127.4,127.9,128.0,139.2,157.4,157.5,167.7,167.9.HRMS(ESI)calcd for C19H25NO2H+([M+H]+):300.1964,found:300.1968.
制备例12：(+)-3-甲氧基-17-丙酰基吗喃的制备
500mL三口烧瓶，依次加入(+)-N-丙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)，甲苯(300mL)，机械搅拌溶解，相继加入三氟甲磺酸镧(37.0g)，室温下反应8小时。反应结束后抽滤，甲苯洗涤并合并有机相，减压蒸馏除去溶剂得淡黄色粘稠液(取两滴浓缩液加甲醇稀释送HPLC检测)，然后经减压精馏得淡黄色粘稠液，收率95％。其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ:1.02–1.11(m,4H),1.21–1.61(m,9H),2.14–2.36(m,3.4H),2.54(q,J＝17.6Hz,45.6Hz,1H),2.79(t,J＝13.2Hz,0.6H),3.05(t,J＝18.4Hz,1H),3.43(dd,J＝4.4Hz,13.6Hz,0.6H),3.70(s,3H),3.88(broad s,0.4H),4.30(dd,J＝4.4Hz,13.6Hz,0.4H),4.78(broad s,0.6H),6.64(d,J＝8.4Hz,1H),6.75(d,J＝2.4Hz,1H),6.92(t,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ:14.3,16.3,16.4,29.7,61.6,62.4,62.5,115.9,116.0,123.8,127.2,129.3,131.7,132.2,134.5,135.7,135.8,152.8,156.1,165.3.HRMS(ESI)calcd for C20H27NO2H+([M+H]+):314.2120,found:314.2111.
制备例13：(+)-3-甲氧基-17-三氟乙酰基吗喃的制备
500mL三口烧瓶，依次加入(+)-N-三氟乙酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)，甲苯(300mL)，机械搅拌溶解，再加入三氟甲磺酸镧(33.1g)，室温下反应8小时。反应结束后抽滤，甲苯洗涤并合并有机相，减压蒸馏除去溶剂得淡黄色粘稠液(取两滴浓缩液加甲醇稀释送HPLC检测)，然后经减压精馏得淡黄色粘稠液，收率96％。其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ:1.05–1.14(m,1H),1.26–1.76(m,9H),2.39(d,J＝10.4Hz,1H),2.61–2.78(m,1.4H),2.98–3.05(m,0.6H),3.17–3.25(m,1H),3.69(d,J＝13.6Hz,0.6H),3.80(s,3H),4.10(broad s,0.4H),4.29(d,J＝13.6Hz,0.4H),4.78(broad s,0.6H),6.76(d,J＝8.4Hz,1H),6.85(s,1H),7.05(t,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ:20.8,25.1,25.2,25.5,29.5,30.5,35.0,36.7,39.8,40.9,42.6,43.4,48.4,54.2,110.4,110.5,126.0,126.4,128.1,138.8,157.7.HRMS(ESI)calcd for C19H22NO2F3Na+([M+Na]+):376.1500,found:376.1494.
制备例14：(+)-3-甲氧基-17-乙氧羰基吗喃的制备
500mL三口烧瓶，依次加入(+)-N-乙氧羰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)，甲苯(300mL)，机械搅拌溶解，再加入三氟甲磺酸镧(35.6g)，室温下反应8小时。反应结束后抽滤，甲苯洗涤并合并有机相，减压蒸馏除去溶剂得淡黄色粘稠液(取两滴浓缩液加甲醇稀释送HPLC检测)，然后经减压精馏得淡黄色粘稠液，收率94％。其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ:1.08(t,J＝12.4Hz,1H),1.22–1.36(m,7H),1.9–1.67(m,5H),2.36(d,J＝10.8Hz,1H),2.63–2.69(m,2H),3.05–3.13(m,1H),3.79(s,3H),3.90(d,J＝13.6Hz,0.5H),4.09–4.15(m,2.5H),4.25(broad s,0.5H),4.39(broad s,0.5H),6.71(dd,J＝2.4Hz,8.4Hz,1H),6.83(d,J＝2.4Hz,1H),7.00(t,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ:14.2,14.7,14.8,22.1,26.4,31.3,31.6,36.6,37.6,38.2,41.4,41.7,43.9,44.0,49.7,50.0,55.2,61.1,61.2,111.0,111.1,111.3,129.1,140.5,155.7,158.4.HRMS(ESI)calcd for C20H27NO3H+([M+H]+):330.2069,found:330.2064.
制备例15：(+)-3-甲氧基-17-甲磺酰基吗喃的制备
500mL三口烧瓶，依次加入(+)-N-甲磺酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)，甲苯(300mL)，机械搅拌溶解，再加入三氟甲磺酸镧(34.9.0g)，室温下反应8小时。反应结束后抽滤，甲苯洗涤并合并有机相，减压蒸馏除去溶剂得淡黄色粘稠液(取两滴浓缩液加甲醇稀释送HPLC检测)，然后经减压精馏得淡黄色粘稠液，收率92％。其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ:0.93–1.03(m,1H),1.17–1.47(m,6H),1.57–1.65(m,2H),1.72(d,J＝12.8Hz,1H),2.28(d,J＝12.8Hz,1H),2.64–2.75(m,2H),2.81(s,3H),3.04(dd,J＝5.6Hz,18Hz,1H),3.44(dd,J＝4.0Hz,4.4Hz,1H),3.71(s,3H),3.99(broad s,1H),6.65(d,J＝8.4Hz,1H),6.74(s,1H),6.95(d,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ:22.0,26.3,26.4,31.1,36.4,37.5,39.4,39.9,41.6,44.7,51.9,55.2,111.3,111.4,127.8,129.0,140.0,158.7.HRMS(ESI)calcd for C18H25NO3SH+([M+H]+):336.1633,found:336.1636.
制备例16：(+)-3-甲氧基-17-三氟甲磺酰基吗喃的制备
500mL三口烧瓶，依次加入(+)-N-三氟甲磺酰基-1-(4-对甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉(100.0g)，甲苯(300mL)，机械搅拌溶解，再加入三氟甲磺酸镧(30.1g)，室温下反应8小时。反应结束后抽滤，甲苯洗涤并合并有机相，减压蒸馏除去溶剂得淡黄色粘稠液(取两滴浓缩液加甲醇稀释送HPLC检测)，然后经减压精馏得淡黄色粘稠液，收率95％。其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ:0.94–1.04(m,1H),1.19–1.49(m,6H),1.56–1.62(m,2H),1.75(d,J＝12.4Hz,1H),2.30(d,J＝12.4Hz,1H),2.75–2.91(m,2H),3.12(dd,J＝6.0Hz,18.4Hz,1H),3.61(dd,J＝4.0Hz,13.6Hz,1H),3.71(s,3H),4.06(broad s,1H),6.68(dd,J＝2.4Hz,8.4Hz,1H),6.75(d,J＝2.4Hz,1H),6.98(d,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ:20.8,25.1,25.3,35.2,36.2,40.3,40.5,53.2,54.2,110.3,110.7,112.8,117.4,120.6,126.0,128.2,129.6,138.4,157.9.HRMS(EI)calcd for C18H22F3NO3S:389.1272,found:389.1276.
所制备的(+)-3-甲氧基-17-酰基吗喃纯度分析结果见下表：
附注：纯度分析来自高效液相色谱(HPLC)，HPLC型号：安捷伦1260；色谱条件：Cadenza CD-18(250mm×4.6mm,3um),Imtakt,Japan/280nm/30℃；流动相：乙腈：0.1％磷酸缓冲液＝25:75/1.0(ml/min)
(4)由中间体(+)-3-甲氧基-17-酰基吗啡喃制备右美沙芬
制备例17：右美沙芬的制备
100mL三口烧瓶，上至温度计、回流冷凝管，依次加入上述中间体(+)-3-甲氧基-17-酰基吗啡喃(10.0g)，氢氧化钠(2.8g)，甲醇(50mL)，机械搅拌溶解，缓慢升温至回流，保温6小时。冷却至室温，加入甲醛溶液(4.0g)，室温下继续搅拌1小时，向反应体系中分批加入还原剂硼氢化钾(1.0g)，继续搅拌1小时。反应结束后，减压蒸出部分甲醇，加水淬灭反应，甲苯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠钠干燥，减压浓缩得粗产品，甲醇/丙酮对粗产品进行重结晶，得白色固体，收率85％，其核磁数据如下所示:
1H NMR(400MHz,CDCl3)δ7.03(d,J＝8.4Hz,1H),6.80(d,J＝2.6Hz,1H),6.69(dd,J＝8.4,2.6Hz,1H),3.79(s,3H),2.98(d,J＝18.1Hz,1H),2.80(dd,J＝5.5,3.2Hz,1H),2.58(dd,J＝18.1,5.8Hz,1H),2.47–2.31(m,5H),2.07(td,J＝12.3,3.3Hz,1H),1.81(dt,J＝12.9,3.0Hz,1H),1.73(td,J＝12.6,4.8Hz,1H),1.64(d,J＝12.6Hz,1H),1.52(d,J＝8.1Hz,1H),1.45–1.25(m,5H),1.14(td,J＝12.5,3.9Hz,1H)；13C NMR(101MHz,CDCl3)δ158.21,141.73,129.83,128.50,111.08,110.70,58.02,55.18,47.31,45.38,42.79,42.09,37.28,36.68,26.81,26.59,23.38,22.26。
Claims (9)
1.一种式(I)所示的右美沙芬中间体的制备方法，其特征在于，包括步骤：
在惰性溶剂中，稀土路易斯酸催化的条件下，式(II)所示的(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉化合物进行环合反应得到式(I)所示的(+)-3-甲氧基-17-酰基吗喃化合物，
其中：R为C1–C3烷酰基、C1–C3含氧烷酰基、C1–C3含氟烷酰基、C1–C3含氯烷酰基、C1–C3磺酰基或C1–C3含氟磺酰基。
2.如权利要求1所述的方法，其特征在于：所述惰性溶剂为苯、甲苯、二甲苯、正己烷、正庚烷。
3.如权利要求1所述的方法，其特征在于：所述稀土路易斯酸中稀土阳离子选自钪、镧、铈、钐、钇、镱及铕；所述的稀土路易斯酸中阴离子相应的酸选自三氟甲磺酸或/和五氟苯甲酸或/和全氟辛酸。
4.如权利要求3所述的方法，其特征在于：所述稀土路易斯酸由所述稀土阳离子与所述酸根阴离子中的一种或一种以上制备而成。
5.如权利要求1所述的方法，其特征在于：式(II)所示化合物与稀土路易斯酸投料摩尔比为(0.01-1.0):1。
6.如权利要求1所述的方法，其特征在于：环合反应的温度为0-80℃。
7.如权利要求1所述的方法，其特征在于：环合反应的温度为10-40℃。
8.如权利要求1所述的方法，其特征在于，所述的方法还包括步骤：
式(III)所示的(+)-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉化合物在有机溶剂中通过滴加与酰基R对应的酸或酸酐或酯或酰氯，得到式(II)所示的(+)-N-酰基-1-(4-甲氧基)苄基-1,2,3,4,5,6,7,8-八氢异喹啉化合物，反应通式如下：
9.如权利要求8所述的方法，其特征在于，式(III)所示的化合物制备式(II)所示的化合物过程中，所用的有机溶剂选自二氯甲烷、DMF、、四氢呋喃、二氧六环、乙腈；反应温度为-10℃～50℃；所述酸或酸酐或酯或酰氯与式(III)所示的化合物投料摩尔比为(0.5-1.5):1；及反应时间为1-5小时。
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| CN1102143C (zh) * | 1996-10-02 | 2003-02-26 | 霍夫曼-拉罗奇有限公司 | 生产(9α,13α,14α)－1－(3－甲氧基吗啡喃－17－基)烷酮的方法 |
| CN103073494A (zh) * | 2013-02-04 | 2013-05-01 | 苏州立新制药有限公司 | ent-3-甲氧基吗喃的制备方法 |
| CN103265489A (zh) * | 2013-06-17 | 2013-08-28 | 苏州立新制药有限公司 | ent-(14S)-3-甲氧基-17-甲基吗喃的制备方法 |
| CN104119273A (zh) * | 2014-04-24 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | 一种制备右美沙芬的新方法 |
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| CN108299301A (zh) * | 2018-03-12 | 2018-07-20 | 合肥医工医药有限公司 | 一种制备高纯度二甲啡烷的方法 |
| CN115557891A (zh) * | 2022-10-28 | 2023-01-03 | 上海万巷制药有限公司 | 一种右美沙芬的制备方法 |
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