CN103554034A - 化合物[2-(羟基-4-哒嗪甲基)-3,4-二氢萘酚-1-(2h)-酮]的制备 - Google Patents

化合物[2-(羟基-4-哒嗪甲基)-3,4-二氢萘酚-1-(2h)-酮]的制备 Download PDF

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CN103554034A
CN103554034A CN201310568986.8A CN201310568986A CN103554034A CN 103554034 A CN103554034 A CN 103554034A CN 201310568986 A CN201310568986 A CN 201310568986A CN 103554034 A CN103554034 A CN 103554034A
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pyridazine
hydroxyl
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dihydronaphthol
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CN103554034B (zh
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唐海峰
韩欣蔚
周小光
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Beijing vicome Boyuan Pharmaceutical Technology Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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Abstract

本发明提供了一种化合物2-（羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮的制备方法，属精细化工技术领域。本发明以二氯甲烷为溶剂，吡咯烷为催化剂，三氟甲磺酸为辅助催化剂，将4-哒嗪甲醛与3,4-二氢萘酚-1-(2H)-酮以1.0:0.9～1.0:1.2的摩尔比，在室温下反应20～24h即得。本发明采用催化剂吡咯烷和助催化剂三氟甲磺酸的毒性和挥发性较小，安全环保；合成条件温和（室温），合成时间短（24h内完成），反应效率高，成本低，有利于工业化生产。

Description

化合物[2-(羟基-4-哒嗪甲基)-3,4-二氢萘酚-1-(2H)-酮]的制备
技术领域
本发明属精细化工技术领域，涉及一种哒嗪类化合物2-(羟基-4-哒嗪甲基)-3,4-二氢萘酚-1-(2H)-酮的制备方法。 
背景技术
哒嗪类化合物是一类N杂苯环类化合物，在生物医药领域有着重要的应用，例如，哒嗪酮类化合物可作为磷酸二酯酶10A(PDE10A)的抑制剂用于治疗精神分裂症、药物成瘾、帕金森症等疾病。将不同基团引入到哒嗪结构中，能产生具有杀菌活性的哒嗪类衍生物，在新型高效农药创制中起着重要作用。哒嗪类化合物-2-(羟基-4-哒嗪甲基)-3,4-二氢萘酚-1-(2H)-酮是一种典型的哒嗪类，其结构式如下:
Figure 2013105689868100002DEST_PATH_IMAGE002
 
研究表明，该化合物可作为细胞色素酶P450的抑制剂，具有抗肿瘤、消炎等作用，因而在医药合成领域具有重要作用。
Rolf  W. Hartmann(Journal of Medicinal Chemistry,1996, 39(4), 834-841)报道，以乙醇作为溶剂，二乙胺为催化剂，4-哒嗪甲醛与3,4-二氢萘酚-1-(2H)-酮在冷藏的环境下反应14天可得到化合物-2-(羟基-4-哒嗪甲基)-3,4-二氢萘酚-1-(2H)-酮。由于催化剂二乙胺易挥发且有急毒性，不利于环保；另外，反应在冷藏条件下进行，且反应时间较长，合成效率低，成本高，不利于工业生产。
发明内容
本发明的目的是针对现有技术中存在的问题，提供一种效率高、成本低、绿色环保的化合物2-(羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮的制备方法。
本发明化合物2-(羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮的制备，是以二氯甲烷为溶剂，吡咯烷为催化剂，三氟甲磺酸为辅助催化剂，将4-哒嗪甲醛与3,4-二氢萘酚-1-(2H)-酮以1.0 : 0.9～1.0 : 1.2的摩尔比，在室温下反应20～24h即得。其反应方程式为：
Figure 2013105689868100002DEST_PATH_IMAGE004
。
所述催化剂吡咯烷与辅助催化剂三氟甲磺酸的摩尔比为1:1～1:5，催化剂吡咯烷与辅助催化剂三氟甲磺酸的总用量为反应物总摩尔量的10% ～30%。
本发明相对现有技术具有以下优点：
1、以吡咯烷和三氟甲磺酸为催化剂，毒性和挥发性较小，安全环保；
2、合成条件温和（室温），合成时间短（24h内完成），反应效率高，成本低，有利于工业化生产。
具体实施方式
下面通过具体实施例对本发明2-(羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮的制备方法作进一步说明。
仪器和试剂：核磁共振波谱用Bruker公司Mercruy-Plus 400 MHz型核磁共振波谱仪测定，以氘代DMSO为溶剂，TMS为内标；高分辨质谱用VG ZAB HS高分辨质谱仪测定；实验中所用3,4-二氢萘酚-1-(2H)-酮为AlfaAesar试剂，所用二氯甲烷，乙酸乙酯，石油醚均为国产A. R.级试剂。
实施例1、取10M的反应管作为反应器，称取7.1mg吡咯烷溶于2.0 mL二氯甲烷中，然后加入15.0mg三氟甲磺酸，在室温下搅拌10min，依次加入146mg 3,4-二氢萘酚-1-(2H)-酮和110mg 4-哒嗪甲醛，在室温下反应22h，薄层色谱跟踪反应，反应结束后，直接柱色谱分离得到白色固体产品180mg即为目标产物，产率为71%。
所得产品熔点为：125 ~126 ℃。
所得产品的核磁数据如下：
1H NMR (DMSO-d 6, 400 MHz, TMS): 9.28 (d, 1.6 Hz, 1H), 9.22-9.16 (m, 1H), 7.71-7.66 (m, 1H), 7.40-7.32 (m, 2H), 7.58-7.52 (m, 1H), 7.81 (dd, 7.8 Hz, 1.2 Hz, 1H), 5.80 (d, 4.9 Hz, 1H), 5.60-5.58 (m, 1H), 3.04-2.90 (m, 1H), 2.99-2.84 (m, 2H), 2.08-1.96 (m, 1H), 1.70-1.62 (m, 1H).
所得产品的高分辨质谱结果如下：
HRMS (ESI) for [M+1],calcd for 254.1055, found 254.1049。
以上鉴定结果证明所得产品为化合物2-（羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮。
实施例2、取50 mL圆底烧瓶为反应器，称取71mg吡咯烷溶于20mL二氯甲烷中，然后加入150mg氟甲磺酸，室温下搅拌15min，然后依次加入0.75g 3,4-二氢萘酚-1-(2H)-酮和0.60g 4-哒嗪甲醛，在室温条件下反应24h，薄层色谱跟踪反应，反应结束后，反应液浓缩，柱色谱分离得到白色固体产品0.86g，产率为66%。
所的产品的熔点、核磁数据、质谱分析数据同实施例 1。

Claims (3)

1.一种化合物2-(羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮的制备方法，是以二氯甲烷为溶剂，吡咯烷为催化剂，三氟甲磺酸为辅助催化剂，将4-哒嗪甲醛与3,4-二氢萘酚-1-(2H)-酮以1.0 : 0.9～1.0 : 1.2的摩尔比，在室温下反应20～24h即得。
2.根据权利要求1所述化合物2-(羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮的制备方法，其特征在于：所述催化剂吡咯烷与辅助催化剂三氟甲磺酸的总用量为反应物总摩尔量的10%～30%。
3.根据权利要求2所述化合物2-(羟基-4-哒嗪甲基）-3,4-二氢萘酚-1-(2H)-酮的制备方法，其特征在于：所述催化剂吡咯烷与辅助催化剂三氟甲磺酸的摩尔比为1:1～1:5。
CN201310568986.8A 2013-11-15 2013-11-15 化合物[2-(羟基-4-哒嗪甲基)-3,4-二氢萘酚-1-(2h)-酮]的制备 Active CN103554034B (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080214552A1 (en) * 2004-06-29 2008-09-04 Rudiger Fischer Substituted Pyridazinecarboxamides and Derivatives Thereof
CN101591230A (zh) * 2008-05-27 2009-12-02 天津药物研究院 2,4-二羟基查尔酮类衍生物、其制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080214552A1 (en) * 2004-06-29 2008-09-04 Rudiger Fischer Substituted Pyridazinecarboxamides and Derivatives Thereof
CN101591230A (zh) * 2008-05-27 2009-12-02 天津药物研究院 2,4-二羟基查尔酮类衍生物、其制备方法和用途

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