CN85103105A - 羟基-4-2h-1-苯并噻喃-2-酮衍生物的制备方法 - Google Patents
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Abstract
本发明有关羟基-4-2H-1-苯并噻喃-2-酮，用下式表示：
其中当R1是氢时，R与AR′可以形成一个四氢萘环基；当R1是氢时，R是一个羟基；AR是一个被卤素取代或未取代的联二苯基或苯氧基苯基，而AR′是一个被取代或未取代的苯基，它可以与R形成一个四氢萘环基或一个噻吩基。
这些化合物具有一系列有趣的性质，特别是可以利用来作杀鼠剂。
Description
本发明有关式（Ⅰ）所示的羟基-4-2H-1-苯-并噻喃-2-酮及它们的制备和含有它们的组合物。
这些化合物用下式表示：
其中R可以是与AR′结合成四氢萘环基;当R1是氢时，R和R1可以是羰基;当R1是氢时，R可以是一个羟基;AR可以是一个被卤素取代或未取代的联二苯或苯氧基苯，AR′是一个取代或未取代的苯基，它可以与R成为一个四氢萘环基或一个噻吩基。
这些化合物可以根据下述的一个或另外的方法制备。
当式（Ⅰ）中的RR1＝0时，产物是由羟基-4-2H-1-苯并噻喃-2-酮与式（Ⅱ）化合物反应得到：
这个反应在有溶剂如：乙醇、二噁烷等，与一个缩合剂哌啶存在下，沸腾若干小时。
当式（Ⅰ）中R＝H、R1＝OH时，用甲醇、二甲基甲酰胺或二者之一与水混合液作溶剂，借助氢硼化钠还原而得到这类化合物。其中式（Ⅰ）的化合物RR1＝O。
当R与AR′是一个四氢萘环基和R1是氢时，式（Ⅰ）中相应的化合物是羟基-4-2H-1-苯并噻喃-2-酮与下式的化合物反应制备的：
反应在含硫酸的醋酸溶剂中于20℃-150℃间进行。
当R＝OH或R和AR′是一个四氢萘环基，和R1是氢时，这类化合物以一种非对映异构体的混合物形式存在，这在薄层层析或高压液相层析中显示出来。
本发明的产品具有很多令人感兴趣的性质。特别是作为抗凝固剂的作用，这在杀野生鼠（学名：Rattus Norvegious）试验中充分显示出来。
为此，含剂量50ppm被研究物的淀粉和面粉混合物作为诱饵测试。每3天喂成年雄的或雌的鼠一次这种诱饵。通过测定其死亡率来检验其效率。结果见下面表Ⅰ中。
表 Ⅰ
（杀鼠灵（Coumafēne）＝羟基-4-（苯基-1-氧代-3-丁基）-3-2H-1苯并噻喃-2-酮）
这些化合物只处理一天也导致大鼠100%地死亡。这在下面的表Ⅱ中已示。
另一方面，经试验证实本发明的噻喃衍生物（如：式Ⅰ）优于相应的吡喃衍生物，显示出意想不到的效果。事实上，已经知通了在3位上被
表 Ⅱ
取代的羟基-4-香豆素衍生物是一类具有很强抗维生素K效能，从而被用来作杀鼠剂。门茨尔（Mentzer）的工作（生化简报25期，379-383页Bull.Soc.Chim.Biol.25.Pages 379-383，1943）从另一个角度指出：败坏翘摇素（dico-umarol）的杂环中的氧被硫代替后生成了一个不活泼的产物。这结果已为杀鼠灵（coumafēne）和它的含硫同系物硫杀鼠灵所证实。下面表Ⅲ再汇集其结果。
表 Ⅲ
根据例1，与其含氧相等量的（A）比较，（溴-4′-联二苯-4）-3，四氢-1-2-3-4-萘基-1）-3，羟基-4，2H-1-苯并噻喃-2-酮有明显优于A的活性。对Rattus rattus（一种能抗杀鼠灵的品系）;Mus musculus（一种对杀鼠灵敏感的品系）和另一种Mus musculus（一种抗杀鼠灵的品系）进行药物试验，其结果见下列三个表：
上述表中的读数表明与分子式（Ⅰ）相应的化合物，由于有苯并噻喃环与其它苯并吡喃相比有较高的活性。
另一个意想不到的效果就是本发明的化合物与它们含氧的同系物相比毒性要小。特别是对非啮齿动物毒性要小。作为例子，下面叙述一个在小猎兔犬（Beagle）上的试验：
给三只猎犬每日口服50μg/kg的例1化合物，另一组三个猎犬以同样方式每日用同样剂量的化合物A。生物检查就是与达到300秒存活时间之对照的存活时间（le temps de Quick）。图1的曲线表示猎犬存活时间延长的效果。以秒为单位的存活时间作为纵轴（TQs），以天为单位的药物处理时间作为横轴（j）。曲线1，2和3为化合物A的效率;4，5，6为化合物1的效率。字母M为动物死亡的时间。
而且，用化合物A处理犬的试验表明，随着存活时间的增加，犬死亡也很快，以致于无法解毒抢救。相反对化合物1，存活时间增加和临床状态的恶化都是逐渐进行的。当存活时间达到300秒时，我们有时就用一种古典的治疗方法，用维生素K来抢救。可以用口服来代替5mg/kg的静脉注射。三只犬的情况表明经过抢救存活时间又很快地最终回到正常值上来。
本发明的化合物，特别是例1的化合物组成了杀鼠剂成分中的抗凝结活性物质，而与被啮齿类可消耗的一种载体物质结合。
下面举例说明，但本发明并不受此限制。例1：〔（溴-4′-联二苯基-4）3-四氢-1，2，3，4-萘基-1〕-3，羟基-4，2H-〔1〕-苯并噻喃-酮-2.C31H23BrO2S（式1），分子量＝539、34。
把含有14.2克（0.08摩尔）的氢基-4-2H-1-苯并噻喃-2-酮和30.2克（0.08摩尔）的（溴-4′联二苯基-4）-3-四氢-1，2，3，4-萘酚-1的溶液在110℃下加到60毫升的醋酸当中。然后加2.6毫升浓硫酸，继续加热3个小时。冷却后把反应液倒入水中。然后用乙醚萃取。乙醚液用稀苏打水洗涤;析出不溶性油相来，然后用10N的盐酸再提取。用乙酸乙酯萃取后，蒸发浓缩，然后把得到的油相通过一个硅胶柱层析，再用氯仿洗脱，所得溶液在甲苯中再结晶。可以得到9.5克（所得率为22%）的白色固体。
rc＝0∶1600-1620cm-1。
重量分析：
碳% 氢% 溴% 硫% 氧%
计算值 69.01 4.30 14.81 5.94 5.93
测定值 68.97 4.15 14.85 5.82
薄层层析的检测表明两种异构体的比例有变化，而其中一种占大部分。熔点水平是较平缓的。本产品熔点（PFG）为203-227℃。通过纯化可以分离两部分异构体。占大部分的异构体在甲苯中重结晶。熔点为227-230℃。占小部分的则熔点为209-221℃。
例2：〔（溴-4′-苯氧基）-4-苯基）-3，四氢-1，2，3，4-萘基-1〕-3-羟基-4-2H-1-苯并噻喃-2-酮。
C31H23BrO3S（见式2）分子量＝555，47。
从6克（0.015摩尔）的〔（溴-4′-苯氧基）-4-苯基，四氢-1，2，3，4-萘酚基-1和2.7克的（0.015摩尔）的羟基-4-2H-1-苯并噻喃-2-酮制备例1。正己烷处理后得到一种固体。其熔点：95-105℃，IRrC＝0∶1595。
重量分析：碳% 氢% 氯% 氧% 硫%
计算值 67.03 4.17 14.39 8.64 5.77
测定值 67.22 4.23 14.09 5.79
例3：〔（氯-4′-联二苯基-4）-3-四氢-1，2，3，4-萘酚基-1〕-3，羟基-4-2H-〔1〕-苯并噻喃-酮-2见式3） C31H23ClO2S，分子量＝495，01。
按例1，从7克（0.04摩尔）的羟基-4-2H-1-苯并噻喃-2-酮和13.4克（0.04摩尔）的（氯-4′-联二苯-4）-3，四氢-1，2，3，4-萘酚-1制备。在乙酸乙酯中提纯后得到一种白色的固体熔点（PFG：）为220-222℃，IRrC＝0∶1590。
重量分析：
碳% 氢% 氯% 氧% 硫%
计算值 75.21 4.68 7.16 6.46 6.48
测定值 75.19 4.72 7.02 6.20
例4：〔（溴4′-联二苯基-4）-3，氧化-3，苯基-1〕丙基-3-羟基-4-2H-〔1〕-苯并噻喃-酮-2（见式4）
C30H21BrO3S，分子量＝541，45。
把5克（0.020摩尔）的羟基-4-2H-1-苯并噻喃-酮-2和9.1克（0.025摩尔）的（溴-4′-联二苯基-4）-3，苯基-1-丙烯酮-3加于50毫升含0.4毫升哌啶的乙醇中。使这悬浮液回流，再加入需要量的二噁烷。然后混合液再回流6小时。冷却到室温，再使不溶部分脱水，过滤，充分冷却不熔物与液滤。形成的沉淀再干燥并经过硅胶柱提纯，然后在甲苯中重结晶。最后得到一种透明的固体，熔点（PFG）为169-171℃，IRrC＝0-1580。
重量分析：
碳% 氢% 溴% 氧% 硫%
计算值 66.54 3.91 14.76 8.87 5.92
测定值 66.43 3.82 14.73 5.80
例5：〔（溴-4′-联二苯基-4）-3，羟基-3，苯基-1〕丙基-3-羟基-4-2H-〔1〕-苯并噻喃-酮-2（见式5）
C30H23BrO3S，分子量＝543，46。
把7.9克（0.0146摩尔）的例4产品，70毫升的乙醇，1.7克（0.043摩尔）的苏打片置于250毫升的反应器中。在30℃下以每次1.1克（0.0292摩尔）的小份额加入氢硼化钠。将其放在30-35℃下2小时。将其过滤，滤液倒入水-浓盐酸混合液（600毫升-30毫升）。然后用硅胶柱提纯，用125∶75∶25的环己烷-氯仿-甲醇混合液洗脱，再使得到的白色沉淀脱水干燥。熔点：110-120℃，IRrC＝0∶1600。
重量分析：
碳% 氢% 溴% 氧% 硫%
计算值 66.30 4.27 14.71 8.83 5.90
测定值 66.25 4.28 14.82 5.86
例6：〔（氯-4′-联二苯基-4）-3，氧代-3，苯基-1〕丙基-3-羟基-4-2H-〔1〕-苯并噻喃-酮-2（见式6）
C30H21ClO3S，分子量＝496，99
根据例4从8.7克（0.0273摩尔）的氯-4′-联二苯基-4）-3，苯基-1-丙烯酮-3和5.3克（0.03摩尔）的羟基-4-2H-〔1〕-苯并噻喃-酮-2制备。在甲苯中纯化后得到一种白色固体。熔点为171-173℃，IRrC＝0∶1590。
重量分析：
碳% 氢% 氯% 氧% 硫%
计算值 72.50 4.26 7.13 9.66 6.45
测定值 72.76 4.37 7.25 6.21
例7：〔（氯-4′-联二苯基-4）-3，羟基-3，苯基-1〕丙基-3，羟基-4-2H-〔1〕-苯并噻喃-酮-2（见式7）
C30H23ClO3S，分子量＝499.
根据例5从8克（0.0161摩尔）的例6的产品，1.9克（0.0474摩尔）的苏打片，50毫升二甲基甲酰胺，10毫升的水和1.2克（0.0322摩尔）的氢硼化钠制备。分离出一种淡灰褐色的产品。其熔点为105-125℃（分解温度）。IRrC＝0∶1585。
重量分析：
碳% 氢% 氯% 硫% 氧%
计算值 72.20 4.65 7.11 6.42 9.62
测定值 72.24 5.01 7.17 6.21
例8：〔（溴-4′-联二苯基-4）-3，氧代-3（噻吩基-2）-1〕丙基-3，羟基-4-2H-〔1〕-苯并噻喃-酮-2（见式8）C23H19BrO3S2，分子量＝547，47。
根据例4从11克（0.03摩尔）的（溴-4-联二苯基-4）3-（噻吩基-2）-1-丙烯酮-3和5.8克（0.033摩尔）的羟基-4-2H-〔1〕苯并噻喃-酮-2制备的。在乙酸中重结晶得到一种白色的固体。其熔点为140-145℃。IRrC＝0∶1600。
重量分析：
碳% 氢% 溴% 硫% 氧%
计算值 61.42 3.50 14.60 11.71 8.77
测定值 61.65 3.52 12.00
Claims (1)
1、一种制造羟基-4-2H-1-苯并噻喃-2-酮衍生物的方法，该衍生物具有下列分子式：
式中R1是氢，R和AR′可以是一个四氢萘基环；R和R1可以是一个羰基；当R是氢时，R1可以是羟基；AR是一个联二苯基或苯氧基苯基或一个被卤素取代的苯氧基苯基；AR′是一个苯基或一个噻吩基或当R1为氢时可以与R形成一个四氢萘环基，其特征是它是由羟基-4-2H-1-苯并噻喃-2-酮与含有下式的化合物反应得到的，
其中AR′和R形成四氢萘基；当RR1是羰基时它与具下列通式的一个化合物
反应；当R=H和R1=OH时这些化合物是通过具有分子式
的化合物还原得来的。
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| FR8405794A FR2562893B1 (fr) | 1984-04-12 | 1984-04-12 | Derives de l'hydroxy-4-2h-1-benzothiopyran-2-one, leurs preparations et applications dans le domaine rodenticide |
| CN85103105A CN85103105B (zh) | 1984-04-12 | 1985-04-25 | 羟基-4-2h-1-苯并噻喃-2-酮衍生物的制备方法 |
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| CN105037323A (zh) * | 2008-11-14 | 2015-11-11 | 菲布罗根有限公司 | 作为hif羟化酶抑制剂的苯并噻喃衍生物 |
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| GB8729557D0 (en) | 1987-12-18 | 1988-02-03 | Shell Int Research | Rodenticidal composition |
| US5278186A (en) * | 1990-02-10 | 1994-01-11 | Takeda Chemical Industries, Ltd. | Chromene derivatives, their production and use |
| US5449514A (en) * | 1990-09-11 | 1995-09-12 | Liphatech, Inc. | Bait block |
| AU5118693A (en) * | 1992-10-15 | 1994-05-09 | Idemitsu Kosan Co. Ltd | Cyclohexanedione derivative |
| FR2765579A1 (fr) * | 1997-07-01 | 1999-01-08 | Lipha | Nouveaux derives de 4-hydroxy-2h-1-(thio)pyran-2-ones leurs preparations et leurs utilisations comme rodonticides |
| DE10318553A1 (de) * | 2002-05-07 | 2003-11-27 | Bayer Cropscience Ag | Rodentizide Ködersysteme |
| GB0211019D0 (en) * | 2002-05-14 | 2002-06-26 | Syngenta Ltd | Novel compounds |
| JP4629724B2 (ja) | 2007-12-20 | 2011-02-09 | 三菱自動車工業株式会社 | インジェクタの取付け構造 |
| FR3045050B1 (fr) * | 2015-12-11 | 2019-06-21 | Liphatech | Stereo-isomere de configuration de la difethialone, composition et appat rodonticide le comprenant et procede de lutte contre des rongeurs cibles nuisibles |
| FR3045051B1 (fr) | 2015-12-11 | 2019-04-05 | Liphatech | Stereo-isomere de configuration de la difethialone, composition et appat rodonticide le comprenant et procede de lutte contre des rongeurs cibles nuisibles |
| FR3045049B1 (fr) * | 2015-12-11 | 2019-04-05 | Liphatech | Stereo-isomere de configuration de la difethialone, composition et appat rodonticide le comprenant et procede de lutte contre des rongeurs cibles nuisibles |
| FR3045048B1 (fr) * | 2015-12-11 | 2019-04-05 | Liphatech | Stereo-isomere de configuration de la difethialone, composition et appat rodonticide le comprenant et procede de lutte contre des rongeurs cibles nuisibles |
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| CA547244A (en) * | 1957-10-08 | Litvan Franz | 3-substituted 4-hydroxycoumarins and process for their production | |
| US3022317A (en) * | 1956-01-20 | 1962-02-20 | Geigy Chem Corp | 3-benzyl-4-hydroxycoumarin and a process for the preparation of derivatives of 3-benzyl-4-hydroxycoumarin |
| US3764693A (en) * | 1969-11-21 | 1973-10-09 | Lipha | A rodenticidal compositions containing 4-hydroxy coumarins |
| FR2351653A1 (fr) * | 1976-05-21 | 1977-12-16 | Mo Khim T | Derive de thio-1 hydroxy-4 coumarine, leur procede de preparation et leurs applications |
| EP0098629B1 (en) * | 1982-06-14 | 1987-08-26 | Shell Internationale Researchmaatschappij B.V. | Anti-coagulants of the 4-hydroxycoumarin type, the preparation thereof, and rodenticidal compositions (baits) comprising such anti-coagulants |
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| CN105037323A (zh) * | 2008-11-14 | 2015-11-11 | 菲布罗根有限公司 | 作为hif羟化酶抑制剂的苯并噻喃衍生物 |
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