CN105418502B - 一种用于合成帕罗西汀的中间体及其制备方法和用途 - Google Patents

一种用于合成帕罗西汀的中间体及其制备方法和用途 Download PDF

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CN105418502B
CN105418502B CN201510291876.0A CN201510291876A CN105418502B CN 105418502 B CN105418502 B CN 105418502B CN 201510291876 A CN201510291876 A CN 201510291876A CN 105418502 B CN105418502 B CN 105418502B
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冯小明
张宇
刘小华
姚乾
林丽丽
朱国良
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Zhejiang Raybow Pharmaceutical Co ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Abstract

本发明涉及帕罗西汀技术领域，具体涉及一种帕罗西汀的中间体及其制备方法和用途，所述方法具体为：下式I化合物与式II化合物在手性氧化胺L与稀土金属化合物Ln(OTf)3形成的络合物催化下，有机碱存在下进行反应制备得到下列的式III化合物：其中R1为烷基，苯基或苄基；R2，R3，R4各自独立地为C1‑C6的烷基或C6‑C10芳基；所述的手性氧化胺L具有如下结构：其中n＝1,2；R＝Ph‑,2,6‑Me2C6H3‑,2,6‑Et2C6H3‑,2,6‑iPr2C6H3‑,Ph2CH‑。

Description

一种用于合成帕罗西汀的中间体及其制备方法和用途
技术领域
本发明涉及帕罗西汀技术领域，具体涉及一种帕罗西汀的中间体及其制备方法和用途。
背景技术
帕罗西汀适应症为治疗各种类型的抑郁症，包括伴有焦虑的抑郁症及反应性抑郁症。其化学名称为反-(-)-3-[(1,3-苯并二噁茂-5-基-氧)甲基]-4-(4-氟苯基)哌啶，其具有如下结构：
而具有下列式III结构的化合物为合成帕罗西汀的常用中间体，
由式III化合物制备得到帕罗西汀可以按照WO2009005647A2中提供的方法，其提供了如下反应方程式：
现有文献中公开的式III化合物的制备方法通常有以下两种，例如：
杂志精细化工中间体，2007，37(3)，41-44公开了一种制备消旋式III化合物的方法，该方法为4-氟肉桂酸乙酯与3-(甲基氨基)-3-氧代丙酸乙酯进行反应得到消旋的式III化合物，该化合物需要进行拆分才能够得到光学纯的式III化合物，原料损失严重，导致成本的增加。
Tetrahedron:Asymmetry 22(2011)1-3中公开了如下方法：
该方法以手性辅助剂(R)-4-苯基-2-噁唑啉酮与对氟肉桂酸反应制备得到手性酰胺(R)-3-(3-(4-氟苯基)丙烯酰)-4-苯基恶唑烷-2-酮，再与3-(甲基氨基)-3-氧代丙酸乙酯在氢化钠存在下发生共轭加成、环合得到式III化合物。氢化钠，易燃易爆，对反应条件要求苛刻，不利用大规模的工业化生产，并且，经技术人员按照实施例提供的方法重复路线，得到的产物光学纯度差，收率低。
因此，有必要开发新的用于制备式III化合物的合成工艺，以满足工业化大生产的需求。
发明内容
为了解决现有路线制备得到式III化合物光学纯度低，收率低等缺点，本发明提供了如下技术方案：
一种具有如下式I结构的化合物：
其中R2，R3，R4各自独立地为氢，C1-C6的烷基或C6-C10芳基；
优选的R2，R3，R4各自独立地为氢，甲基，乙基，丙基，苯基，4-甲基苯基，3-甲基苯基。
优选的，所述式I化合物选自下列结构：
另外，本发明提供了一种具有如下式III化合物的制备方法，
由式I化合物与式II化合物在手性氧化胺L与稀土金属化合物Ln(OTf)3形成的络合物催化下，有机碱存在下进行反应制备得到：
其中R1为烷基，苯基或苄基，优选为C1-C6的烷基，苯基或苄基；
R2，R3，R4各自独立地为C1-C6的烷基或C6-C10芳基；
所述的手性氧化胺L具有如下结构：
其中n＝1,2；R＝Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-；
优选的，所述的手性氧化胺L为L-PiMe2具有如下结构：
其中R为2,6-Me2C6H3。
所述的稀土金属化合物Ln(OTf)3中的Ln表示为镧系金属，具体可以为La，Ce，Pr，Nd，Pm，Sm，Eu，Gd，Tb，Dy，Ho，Er，Tm，Yb，Lu。
优选的所述的稀土金属化合物Ln(OTf)3为三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸铒[Er(OTf)3]。
所述的有机碱优选为胺类，具体可以为三乙胺，二异丙基乙胺，三甲胺，三正丙胺，三正丁胺，二甲基苯胺，二乙基苯胺，二甲基苄胺，二乙基苄胺，1,8-二氮杂环[5,4,0]十一烯-7(DBU)。
所述的反应溶剂选自烷烃类，如戊烷、己烷、庚烷等；卤代烃类，如二氯乙烷、氯仿等；芳烃类，如甲苯、乙苯、异丙苯；醚类，如四氢呋喃、甲基叔丁基醚、2-甲基四氢呋喃等，酯类，如乙酸乙酯、乙酸异丙酯等；
所述的反应温度优选为30-35℃。
所述的式I化合物与L的摩尔用量比优选为1：(0.005～0.04)，更优选为1：(0.01～0.03)。
所述的式I化合物与Ln(OTf)3的摩尔用量比优选为1：(0.005～0.04)，更优选为1：(0.01～0.03)。
所述的式I化合物与所述有机碱的摩尔用量比优选为1：(1～4)，更优选为1：(1～2)。
进一步地，本发明提供了一种式I化合物的制备方法：
由下列的式IV化合物与对氟肉桂酸在脱水剂和有机碱存在下缩合得到，
其中R2，R3，R4的定义与上文定义相同。
所述的脱水剂优选为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、二环己基碳化二胺(DCC)、六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)等；
所述有机碱为N-甲基吗啉，三乙胺，二异丙基乙胺，三甲胺，三正丙胺，三正丁胺，二甲基苯胺，二乙基苯胺，二甲基苄胺，二乙基苄胺或1,8-二氮杂环[5,4,0]十一烯-7等。
所述的反应溶剂选自烷烃类，如戊烷、己烷、庚烷等；卤代烃类，如二氯乙烷、氯仿等；芳烃类，如甲苯、乙苯、异丙苯；醚类，如四氢呋喃、甲基叔丁基醚、2-甲基四氢呋喃等，酯类，如乙酸乙酯、乙酸异丙酯等。
所述反应的反应温度为20℃至回流，优选为20-30℃。
所述的式I化合物与脱水剂的摩尔用量比优选为1：(1～3)，更优选为1：(1～2)。
所述的式I化合物制备过程中化合物I与所用有机碱的摩尔用量比为1：(1～3)，更优选为1：(1～2)。
优选的，本发明采用如下方案制备式I化合物：
下列的式IV化合物与对氟肉桂酸在脱水剂和有机碱存在下缩合反应，得到的缩合产物浓缩后用有机溶剂提纯得到所述的式I化合物。
其中提纯过程中所用到的溶剂为己烷、庚烷、石油醚、甲苯、甲基叔丁基醚(MTBE)、乙酸乙酯中的一种或这几种的混合物；优选的提纯所用溶剂为石油醚/乙酸乙酯，庚烷、己烷/乙酸乙酯，或庚烷/乙酸乙酯，甲苯，或MTBE。
利用本发明提供的技术方案在制备式III化合物，反应原料转化率高，只需经过重结晶操作即可得到收率且光学纯度高的产物，因此具有很高的工业应用价值。
附图说明：
图1为IIIa化合物消旋对照液HPLC谱图；
图2为按照实施例2制备得到的IIIa化合物HPLC谱图；
图3为按照实施例1制备得到的Ia化合物氢谱谱图。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
所述的式I化合物可以按照下列实施例制备得到：
通用方法：式I化合物的制备
向250ml圆底烧瓶中依次称入吡唑IV化合物(30mmol)和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)(30～45mmol)，N-甲基吗啉(30～45mmol)加入100-200mL二氯甲烷溶解，再慢慢加入对氟肉桂酸(30mmol)，反应过夜，用水洗涤，浓缩干，用石油醚/乙酸乙酯(或庚烷，或己烷/乙酸乙酯，或庚烷/乙酸乙酯，或甲苯，或MTBE等)结晶得到21-29mmol对氟肉桂酰吡唑化合物III纯品，收率为70-97％。
所述的式III化合物可以按照下述方法制备得到：
通用方法：式III化合物的制备
向干燥的反应瓶中，依次称入金属催化剂Ln(OTf)3(0.01-0.03mol)，手性配体L(0.02mol)，对氟肉桂酰吡唑III(0.2mol)，置换氮气3次，加入300mL二氯甲烷在35℃下活化10-30min，依次加入单酰胺II(0.2mol)和Et3N(0.2-0.4mol)，于30-50℃下反应40-100小时，反应液用稀盐酸洗涤，浓缩干，用石油醚/乙酸乙酯结晶得到0.016-0.0174mol催化产物，收率为80-87％。
优选的实施方式：
实施例1：式Ia化合物的制备
向250ml圆底烧瓶中依次称入吡唑(30mmol)和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)(30mmol)，N-甲基吗啉(30mmol)加入100mL二氯甲烷溶解，再慢慢加入对氟肉桂酸(30mmol)，反应过夜，用水洗涤，浓缩干，用石油醚/乙酸乙酯结晶得到7.2g对氟肉桂酰3,5二甲基吡唑纯品，收率为97％，
1H-NMR(400MHz,CDCl3),δ＝7.858-7.861(m,2H),δ＝7.646-7.681(m,2H,),δ＝7.074-7.117(m,2H),δ＝6.011(s,H),δ＝2.618(s,3H),δ＝2.287(s,3H).
ESI-MS(m/z)＝244.9[M+H]：
熔点：92.5-94.5℃。
实施例2：式I化合物的制备
向干燥的反应瓶中，依次称入金属催化剂Yb(OTf)3(0.02mol)，手性配体L-PiMe2(0.02mol)，对氟肉桂酰3,5二甲基吡唑(0.2mol)，置换氮气3次，加入300mL二氯甲烷在35℃下活化20min，依次加入单酰胺(0.2mol)和Et3N(0.2mol)，于30-50℃下反应60-80小时，反应液用稀盐酸洗涤，浓缩干，用石油醚/乙酸乙酯结晶得到51g催化产物，收率为87％，HPLC纯度为94.65％，ee 99.12％，产物HPLC谱图如图2。
实施例3-10是按照实施例1的方法同法操作所得到的试验数据：
实施例11-18是按照实施例2的方法同法操作所得到的试验数据：
实施例19-是按照实施例2的方法同法操作，选用不同的催化剂L所得到的试验数据：

Claims (11)

1.一种具有如下式I结构的化合物：
其中R2，R3，R4各自独立地为氢，C1-C6的烷基或C6-C10芳基。
2.根据权利要求1所述的化合物具有如下结构：
3.一种具有如下式III化合物的制备方法，
由式I化合物与式II化合物在手性氧化胺L与稀土金属化合物Ln(OTf)3形成的络合物催化下，有机碱存在下进行反应制备得到：
其中R1为烷基，苯基或苄基；
R2，R3，R4各自独立地为氢，C1-C6的烷基或C6-C10芳基；
所述的手性氧化胺L具有如下结构：
其中n＝1,2；R＝Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-；
所述的稀土金属化合物Ln(OTf)3中的Ln表示为镧系金属，选自La，Ce，Pr，Nd，Pm，Sm，Eu，Gd，Tb，Dy，Ho，Er，Tm，Yb，Lu。
4.根据权利要求3所述的制备方法，其中R1为C1-C6的烷基，苯基或苄基。
5.根据权利要求3所述的制备方法，其中所述有机碱为胺类。
6.根据权利要求3所述的制备方法，其中所述Ln(OTf)3为三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸铒[Er(OTf)3]。
7.根据权利要求3所述的制备方法，其中所述有机碱为三乙胺，二异丙基乙胺，三甲胺，三正丙胺，三正丁胺，二甲基苯胺，二乙基苯胺，二甲基苄胺，二乙基苄胺或1,8-二氮杂环[5,4,0]十一烯-7。
8.根据权利要求3所述的制备方法，反应在溶剂戊烷、己烷、庚烷、二氯乙烷、氯仿、甲苯、乙苯、异丙苯、四氢呋喃、甲基叔丁基醚、2-甲基四氢呋喃、乙酸乙酯或乙酸异丙酯中进行。
9.一种式I化合物的制备方法：
由下列的式IV化合物与对氟肉桂酸在脱水剂和有机碱存在下缩合得到，
其中R2，R3，R4的定义与权利要求1相同。
10.根据权利要求9所述的制备方法，其中所述脱水剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、二环己基碳化二胺或六氟磷酸苯并***-1-基-氧基三吡咯烷基磷。
11.根据权利要求9所述的制备方法，其中所述有机碱为N-甲基吗啉，三乙胺，二异丙基乙胺，三甲胺，三正丙胺，三正丁胺，二甲基苯胺，二乙基苯胺，二甲基苄胺，二乙基苄胺或1,8-二氮杂环[5,4,0]十一烯-7。
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