CN102372618B - 2-卤-1-(4-溴-3-氟苯基)乙酮的实用合成方法 - Google Patents
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Abstract
本发明涉及一种2-卤-1-(4-溴-3-氟苯基)乙酮的实用合成方法。本发明中α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮是以4-溴-3-氟碘苯为原料,经与格式试剂处理后于卤代乙酸相对应的Weinreb酰胺反应直接得到得到α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮。本发明解决了现有文献工艺中合成路线相对较长,操作复杂,后处理困难,不易放大等缺点,提供了一种以4-溴-3-氟碘苯为原料,合成路线简洁,工艺选择合理,原料成本低,原料简单易得,操作和后处理方便,总收率高,易于放大,可进行大规模生产的α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮的合成方法。
Description
技术领域
本发明涉及一种2-卤-1-(4-溴-3-氟苯基)乙酮的实用合成方法。
背景技术
2-卤-1-(4-溴-3-氟苯基)乙酮是一个非常重要的中间体.以此为原料可以通过酮的α位, 羰基或芳香环上的一些反应能合成很多天然或非天然的化合物.也正因为此化合物表现出如此优越的反应特性,药物化学家们可以对它进行不同的修饰得到不同的化合物,从而进行SAR研究进而筛选出一些高效的药物候选分子,因此引起了药物化学界的广泛关注.典型的例子是从2-溴-1-(4-溴-3-氟苯基)乙酮出发,药物化学们合成了具有很高FAAH抑制活性的分子(WO2009151991)。
2-卤-1-(4-溴-3-氟苯基)乙酮的合成,目前的方法主要是从4-溴-3-氟甲苯出发,首先通过高锰酸钾氧化得到4-溴-3-氟苯甲酸,然后和二甲基羟胺反应得到相应的Weinreb酰胺,再和甲基格式试剂反应得到4-溴-3-氟苯乙酮,最后α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮.
现有技术的缺点：
1.路线相对较长,致使总收率不高;2,高锰酸钾氧化生成大量的二氧化锰,致使操作不便,后处理麻烦3, α卤化后处理麻烦; 4, 不易放大。
发明内容
本发明开发一条α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮的合成工艺,避免具有路线合成路线相对较长,操作复杂,后处理麻烦,不易于放大等缺点。
技术方案
本发明中α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮是以4-溴-3-氟碘苯为原料,经与格式试剂处理后于卤代乙酸相对应的Weinreb酰胺反应直接得到得到α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮.反应式如下:
上述工艺中,格式试剂可以为异丙基格式试剂,乙基格式试剂等. 原子X代表卤素原子,可以为氟原子,氯原子,溴原子和碘原子.反应溶剂为四氢呋喃,乙醚等. 4-溴-3-氟碘苯和格式试剂反应的温度为0℃,反应时间为1小时. 卤代乙酸相对应的Weinreb酰胺加入的温度为-70℃,反应温度为室温,反应时间为1小时。
有益效果
本发明解决了现有文献工艺中合成路线相对较长,操作复杂,后处理困难,不易放大等缺点,提供了一种以4-溴-3-氟碘苯为原料,合成路线简洁,工艺选择合理,原料成本低,原料简单易得,操作和后处理方便,总收率高,易于放大,可进行大规模生产的α卤化得到2-卤-1-(4-溴-3-氟苯基)乙酮的合成方法。
具体实施方式
以下结合实施例对本发明作进一步详细描述。
实施列 1 2-氯-1-(4-溴-3-氟苯基)乙酮的合成
4-溴-3-氟碘苯 (33g, 0.11mol，购自河北美星化工有限公司) 溶于17ml无水四氢呋喃，氮气保护，降温至0℃，慢慢滴加异丙基基溴化镁0.11mol溶于四氢呋喃的溶液(55 ml, 2.0M)，滴毕于0℃搅拌反应1小时。降温至-70℃，慢慢滴加2-氯-N-甲氧基-N-甲基乙酰胺 (13.6g, 0.099mol，上海宝曼生物科技有限公司) 溶于15ml无水四氢呋喃的溶液，保持温度在-60℃以下。滴毕于室温搅拌反应1小时。饱和氯化铵溶液淬灭反应，浓缩去除大部分四氢呋喃，加水及乙酸乙酯分层，乙酸乙酯层用饱和氯化钠溶液洗，无水硫酸镁干燥，过滤，旋干，所得粗产品用乙酸乙酯/石油醚结晶，得白色固体产品，真空干燥 (15 g, 60%)。
1H NMR (400 mHz, CDCl3): δ 4.64 (s, 2 H), 7.61-7.64 (dd, J=8.4, 2.0 Hz, 1 H), 7.70-7.75 (dd, J=8.8, 4.8 Hz, 1 H), 7.70-7.72 (d, J=8.4 Hz, 1 H)。
实施列2 2-溴-1-(4-溴-3-氟苯基)乙酮的合成
4-溴-3-氟碘苯(48.7 g, 0.162 mol) 溶于60ml无水四氢呋喃，氮气保护，降温至0℃，慢慢滴加乙基溴化镁0.162 mol（购自阿拉丁试剂公司）溶于乙醚的溶液(54 ml, 3.0M)，滴毕于0℃搅拌反应1小时。降温至-70℃，慢慢滴加2-溴-N-甲氧基-N-甲基乙酰胺 (26.8 g, 0.147 mol) 溶于50ml无水四氢呋喃的溶液，保持温度在-60℃以下。滴毕于室温搅拌反应1小时。饱和氯化铵溶液淬灭反应，浓缩去除大部分四氢呋喃，加水及乙酸乙酯分层，乙酸乙酯层用饱和氯化钠溶液洗，无水硫酸镁干燥，过滤，旋干，所得粗产品用乙酸乙酯/石油醚结晶，得白色固体产品，真空干燥 (20 g, 46% )。
1H NMR (400 MHz, CDCl3):δ 4.38 (s, 2 H), 7.63-7.66 (dd, J=8.4, 2.0 Hz, 1 H), 7.69-7.73 (dd, J=8.0, 6.8 Hz, 1 H), 7.72-7.75 (dd, J=10.8, 2.0 Hz, 1 H)。
Claims (4)
1.一种2-卤-1-(4-溴-3-氟苯基)乙酮的实用合成方法，其特征在于按如下步骤实现：以4-溴-3-氟碘苯为原料,经与格式试剂处理后与卤代乙酸相对应的Weinreb酰胺反应得到2-卤-1-(4-溴-3-氟苯基)乙酮，其中所述的卤代乙酸相对应的Weinreb酰胺为2-氯-N-甲氧基-N-甲基乙酰胺或2-溴-N-甲氧基-N-甲基乙酰胺。
2.根据权利要求1所述的一种2-卤-1-(4-溴-3-氟苯基)乙酮的实用合成方法，其特征在反应式如下:
其中X代表卤素原子。
3.根据权利要求1所述的一种2-卤-1-(4-溴-3-氟苯基)乙酮的实用合成方法，其特征在于4-溴-3-氟碘苯1摩尔份数与格式试剂1摩尔份数反应，其中所述的格式试剂为异丙基格式试剂、乙基格式试剂，反应溶剂为四氢呋喃、乙醚；反应的温度为0℃,反应时间为1小时；滴加2-氯-N-甲氧基-N-甲基乙酰胺或2-溴-N-甲氧基-N-甲基乙酰胺0.9摩尔份数，滴加2-氯-N-甲氧基-N-甲基乙酰胺或2-溴-N-甲氧基-N-甲基乙酰胺的温度为-70℃,加毕后反应温度为室温,反应时间为1小时，获得产物2-卤-1-(4-溴-3-氟苯基)乙酮。
4.根据权利要求1所述的一种2-卤-1-(4-溴-3-氟苯基)乙酮的实用合成方法，其特征在于所述的反应环境为氮气保护。
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| 1-(4-氯苯基)-2-环丙基-1-乙酮的合成;李鸿波等人;《化学试剂》;20101001;第32卷(第10期);第881-882页 * |
| 李鸿波等人.1-(4-氯苯基)-2-环丙基-1-乙酮的合成.《化学试剂》.2010,第32卷(第10期),第881-882页. |
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