CN1297542C - 6－氟－1，4－二氢－4－氧代喹啉－3－羧酸衍生物的制备 - Google Patents
6－氟－1，4－二氢－4－氧代喹啉－3－羧酸衍生物的制备 Download PDFInfo
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- CN1297542C CN1297542C CNB2003101254897A CN200310125489A CN1297542C CN 1297542 C CN1297542 C CN 1297542C CN B2003101254897 A CNB2003101254897 A CN B2003101254897A CN 200310125489 A CN200310125489 A CN 200310125489A CN 1297542 C CN1297542 C CN 1297542C
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- IPTLKMXBROVJJF-UHFFFAOYSA-N azanium;methyl sulfate Chemical compound N.COS(O)(=O)=O IPTLKMXBROVJJF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- 230000015572 biosynthetic process Effects 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
6-氟-1，4-二氢-4-氧代喹啉-3-羧酸衍生物的制备例如盐酸二氟沙星，其中重要一步由2，4-二氯-5-氟苯乙酮和硫酸二甲酯或衍生物来合成，并选择了合适的溶剂使环合、水解等四步反应合并成二道工艺不经分离合在一起，使收率提高，从而显著地降低了成本。
Description
技术领域 为喹诺酮类化合物。
背景技术 其合成的方法如EP 0 131 839等记述，但存在合成步骤长，收率低，成本高等缺点。
发明内容 针对上述缺点，潜心研究，首先发明了以价廉的硫酸二甲酯的衍生物代替昂贵原甲酸三乙酯、碳酸二甲酯代替昂贵碳酸二乙酯，并将二步反应合在一起操作，减少操作步骤及设备，提高了收率降低了成本。第二，选择了合适的溶剂，第五步环合、水解反应不经分离合在一起，使收率提高，从而显著地降低了成本。
反应方程式如下：
(在下式中：R1表示甲基；R2是苯基，4-氟苯基。R3是哌嗪基，N-甲基哌嗪基。)
实施例1
2，4-二氯-5-氟苯乙酮
将2，4-二氯氟苯23.9g(0.145mol)和无水AlCl348.3g(0.36mol)投入反应瓶中，在搅拌下滴加新蒸馏的AcCl 13.5ml(0.22mol)，滴加速度以内温不超过40℃为宜，滴完后于同温度下搅拌1.5h，再于120～125℃搅拌2h。倾入150g碎冰中，放置。分出油层，水层用氯仿50ml×3提取。有机层合并，以无水Na2SO4干燥。用22×2.5cm的填料柱分离有机层，先常压回收氯仿后，减压收集90～94℃/0.27kPa馏份，得无色液体2，4-二氯-5-氟苯乙酮24g(80％)。置冰箱中过夜后固化，过滤，真空干燥器中干燥，得白色结晶，mp 32.5～34.5℃。
实施例2
α-(2，4-二氯-5-氟苯甲酰)-β-(4-氟苯胺基)丙烯酸甲酯
将54％的NaH 10g和(MeO)2CO 19g及甲苯190ml投入反应瓶中，搅拌并加热，当内温达到50℃时，开始滴加2，4-二氯-5-氟苯乙酮20g，约20min滴完。滴完后升温至回流1h，冷却至10℃以下，滴加硫酸二甲酯27g和DMF16g的复合物(硫酸二甲酯的衍生物即N-甲氧基亚甲基-N，N-二甲铵基硫酸二甲酯)，搅拌反应2h。升温至85℃搅拌反应1h。加水分层，分出有机层，有机层于室温在搅拌下加入对氟苯胺11g，搅拌反应1h。冷凝，分层，滤出固体，干燥得α-(2，4-二氯-5-氟苯甲酰)-β-(4-氟苯胺基)丙烯酸甲酯30.6g。
实施例3
7-氯-6-氟-1-对氟苯基-1，4-二氢-4-氧代喹啉-3-羧酸
将α-(2，4-二氯-5-氟苯甲酰)-β-(4-氟苯胺基)丙烯酸甲酯70g和二甲苯520ml投入反应瓶中，搅拌并加热，当内温达到70℃时，开始滴加60％的NaH 11g和氯苯60ml的混合物，约2h滴完。于同温度下再搅拌10h。加入少量水，再加入15％的NaOH溶液115g，升温至回流2h，稍冷，用30％盐酸和pH 1～3，放置过夜，过滤，洗涤，干燥得7-氯-6-氟-1-对氟苯基-1，4-二氢-4-氧代喹啉-3-羧酸53.5g，收率87.9％。
实施例4
6-氟-1-对氟苯基-7-(4-甲基-1-哌嗪基)-1，4-二氢-4-氧代喹啉-3-羧酸盐酸盐
将7-氯-6-氟-1-对氟苯基-1，4-二氢-4-氧代喹啉-3-羧酸33.5g溶于DMSO 120ml中，于90℃加入N-甲基哌嗪30ml，于110℃搅拌反应5h。减压蒸去溶剂。加入无水乙醇150ml，搅拌回流10min，室温放置过夜，滤出固体，以少量乙醇洗。将此固体放入三口瓶中，加入蒸馏水，于70～80℃在搅拌下用30％盐酸调节至pH 3，加入活性炭1.5g，回流0.5h，趁热过滤。滤液室温放置过夜，过滤，洗涤，干燥，得结晶6-氟-1-对氟苯基-7-(4-甲基-1-哌嗪基)-1，4-二氢-4-氧代喹啉-3-羧酸盐酸盐33.5g。高效液相色谱法测定其含量为99.08％。
Claims (1)
1、一种制备式(I)所表示的6-氟-1，4-二氢-4-氧代喹啉-3-羧酸衍生物的方法，其特征包括式(II)表示的苯酮衍生物与式(III)表示的硫酸二甲酯的衍生物即硫酸二甲酯和DMF的复合物即N-甲氧基亚甲基-N，N-二甲铵基硫酸二甲酯进行的反应：
在式中：R1表示甲基；R2是苯基，4-氟苯基；R3是哌嗪基，N-甲基哌嗪基。
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| CN1634891A CN1634891A (zh) | 2005-07-06 |
| CN1297542C true CN1297542C (zh) | 2007-01-31 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4730000A (en) * | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
| CN1247865A (zh) * | 1998-07-28 | 2000-03-22 | 辉瑞产品公司 | 制备喹诺酮和1,8－二氮杂萘酮羧酸的方法 |
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- 2003-12-28 CN CNB2003101254897A patent/CN1297542C/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4730000A (en) * | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
| CN1247865A (zh) * | 1998-07-28 | 2000-03-22 | 辉瑞产品公司 | 制备喹诺酮和1,8－二氮杂萘酮羧酸的方法 |
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| CN1634891A (zh) | 2005-07-06 |
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