CN1054846C - 在制备具有抗糖尿病和抗肥胖症性能的芳香氨基醇衍生物中的中间化合物的用途 - Google Patents

在制备具有抗糖尿病和抗肥胖症性能的芳香氨基醇衍生物中的中间化合物的用途 Download PDF

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CN1054846C
CN1054846C CN96107153A CN96107153A CN1054846C CN 1054846 C CN1054846 C CN 1054846C CN 96107153 A CN96107153 A CN 96107153A CN 96107153 A CN96107153 A CN 96107153A CN 1054846 C CN1054846 C CN 1054846C
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藤田岳
吉冈孝雄
堀越大能
吉冈慎二
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Abstract

两种具有下式的制备芳香氨基衍生物的新颖的中间化合物用途
式中R7代表氢原子或乙酸基
将这些中间化合物应用于制备芳香氨基醇衍生物。

Description

在制备具有抗糖尿病和抗肥胖症性能的芳香氨基醇衍生物中的中间化合物的用途
本发明涉及用于制备以具有2-[2-(取代的苯氧基)-1-甲基乙基]氨基乙醇结构为其特征并具有有价值的抗糖尿病和抗肥胖症活性的一系列化合物的两种中间化合物。而且这一系列化合物能够治疗和预防高脂血和高血糖以及通过抑制醛糖还原酶的作用也可以对于治疗和预防糖尿病综合症有效。它们在治疗和预防与肥胖症有关的高血压和骨质疏松症也是有效的。本发明也提供了制备本发明化合物的方法。
现已发现两种用于制备一个限定的系列的新2-[2-取代的苯氧基-1-甲基乙基]氨基乙醇衍生物的新颖中间化合物。该衍生物具有有价值的抗糖尿病和抗肥胖症活性和低毒性，以及几乎没有副作用；这些化合物也具有抑制醛糖还原酶作用的能力，因此，对于治疗和预防糖尿病综合症也是有效的。它们也可有效地治疗和预防与肥胖症相关的高血压和骨质疏松症。
因此，本发明的一个目的是提供这种类型的化合物。
本发明的另一目的是提供应用这些化合物作为制备具有抗糖尿病和抗肥胖症活性，并优选地具有低毒性，以及几乎没有副作用的化合物的中间化合物。
本发明的化合物是具有下式的化合物
Figure C9610715300041
式中R7表示一个氢原子或一个乙酰基。
这些中间化合物特别可用于制备如下的式(I)化合物及其可作药用的盐
Figure C9610715300051
其中：
R0代表氢原子、甲基或羟甲基；
R1代表5-甲基噻唑烷-2，4-二酮基团；
R2和R3各自代表氢原子；
X代表氧原子；和
Ar代表如下的式(II)或(III)基团：
其中：
R4代表氢原子、卤原子、羟基、羟甲基、具有1至5个碳原子的烷氧基、具有1至5个碳原子的烷基、具有1至6个碳原子的脂族羧酸酰氧基、硝基、氰基、其中芳烷基的部分定义如下的芳烷氧基、其中芳基部分的定义如下的芳氧基、其定义如下的芳基或具有1至4个碳原子的卤代烷基；
R5代表氢原子、卤原子、羟基、具有1至5个碳原子的烷氧基、具有1至5个碳原子的烷基或硝基；和
R6代表氢原子、卤原子、羟基、具有1至5个碳原子的烷氧基或具有1至5个碳原子的烷基；
所说的芳烷基部分是具有1至3个碳原子的烷基，该烷基被定义如下的1个或2个芳基所取代；
所说的芳基是具有6至10个环碳原子的碳环芳基，它们是未取代的或被至少1个选自其定如下的取代基B的取代基所取代；
所说的取代基B选自卤原子、具有1至4个碳原子的烷基、具有1至3个碳原子的烷氧基、硝基、具有1至4个碳原子的卤代烷基和羟基。
上述的这些式(I)化合物作为新的化合物在申请号为92114826.7的未批准的中国专利申请中作了叙述和提出了权利要求。
本发明也提供了制备下式化合物的方法
Figure C9610715300061
式中R7的定义如上所述
该制备方法包括下列步骤：
(i)将对羟基苯甲醛与噻唑烷-2，4-二酮反应，以制成5-(4-乙酸基亚苄基)噻唑-2，4-二酮；
(ii)将所制成的5-(4-乙酸基亚苄基)噻唑烷-2，4-二酮氢化，以制成5-(4-乙酸基苄基)噻唑烷-2，4-二酮；
(iii)将所制成的5-(4-乙酸基苄基)噻唑烷-2，4-二酮与三苯甲基氯化物反应，以制成5-(4-乙酸基苄基)-3-三苯甲基-噻唑烷-2，4-二酮；以及
(iv)任意选择地水解所得到的化合物。
本发明也提供了应用下式化合物
Figure C9610715300071
(式中R7的定义如上)作为制备以下式(I)化合物的中间化合物
Figure C9610715300072
式中Ar，R0，X，R1，R2和R3的定义如上所述。
本发明的中间化合物还可转化成例如下述的一种式(XI)化合物
Figure C9610715300073
(式中X，R1，R2和R3的定义如上所述)然后与式(XIII)化合物反应(步骤A)
Figure C9610715300074
(式中R0和Ar的定义如上所述而Z3代表氢原子或羟基-保护基)以制成式(XIV)化合物
(式中，R0，R1，R2，R3，X，Ar和Z3的定义如上所述)
然后将所制成的式(XIV)化合物还原，以制成式(XV)化合物
Figure C9610715300082
(式中，R0，R1，R2，R3，X，Ar和Z3的定义如上所述)然后，如有需要，使式中Z3代表羟基-保护基的化合物脱保护，以制成式(I)化合物
用Z3代表的羟基-保护基的性质对于本发明来说并不是关键的性质，通常可用作羟基-保护基的任何这类基团，都可同等地用于本反应。这些基团的实例包括：四氢吡喃基，甲氧基甲基，二苯基甲基，三苯甲基，三甲基甲硅烷基，叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基。如果需要将保护基除去，在步骤A1和B1之后正如现有技术已熟知的那样，脱除保护基反应的性质取决于保护基的性质，而且所应用的反应也是已熟知的。在T.W.Green的《在有机合成中的保护基团》John Wiley & Sons和J.F.W.McOmie的《在有机化学中的保护基团》，Plenum Press，提供了这类脱除反应的实例，在此已将在这些文章中所公开的内容加入本文中作为参考。
在上述反应的步骤A中，式(XIV)的化合物是通过式(XI)的氨基化合物与式(XIII)的羰基化合物反应来制备的。该反应可在有或没有脱水剂的存在下进行，这些脱水剂如无水碳酸钠，无水碳酸钾，无水硫酸钠，无水氯化钙，无水硫酸镁或脱水分子筛。
通常，该反应较好是在一种溶剂存在下进行，溶剂的性质不是关键性的，只要该溶剂对反应没有有害的影响以及可溶解该反应试剂至某种程度就可使用。适用的溶剂的实例包括：烃类，该烃类可以是脂肪族的或芳香族的，例如苯、甲苯、二甲苯、己烷和庚烷；卤代烃类，特别是卤代脂肪烃，如氯仿，二氯甲烷和四氯化碳；醚类如乙醚、四氢呋喃和二噁烷；酰胺类，如二甲基甲酰胺、二甲基乙酰胺、六甲基磷酸三酰胺；醇类，如甲醇和乙醇；亚砜类，如二甲基亚砜；环丁砜；以及上述溶剂中的一种或几种的混合物。
该反应可以在一个广的温度范围内发生，而选择精确的反应温度对于本发明来说并不是关键性的。通常，本发明的反应在冰冷的温度至所用溶剂的沸点温度范围内都可容易地进行，反应所需的时间视乎许多因素，而特别是反应温度和试剂的性质而定。反应时间也可有很大的差别。但是在许多情况下反应是在上面所概括的较好条件下进行，由0.5至1.0小时已足够。
该反应较好是在一种溶剂如一种烃或一种醇存在下，以冰冷的温度至回流温度在1至5小时的一段时间内进行，更好的是，反应在苯中，于回流温度进行1至3小时，并除去反应得到的水份。
在上述反应的步骤B中，式(XV)的化合物是通过还原式(XIV)的化合物来制备的，而式(XIV)化合物可以如在步骤A中所述来制备。该反应通常是应用一种还原剂或在催化剂存在下通过氢化来进行。所应用的还原剂的性质对于本发明来说并不是关键性的，通常用于这类反应的任何还原剂均可等同地应用，适合的还原剂的实例包括：金属氢化物，如硼氢化铝，硼氢化钠，氰基硼氢化钠，氢化铝锂或氰化二异丁基铝。通常，反应较好是在一种溶剂存在下进行，溶剂的性质并不是关键性的，只要该溶剂对于该反应没有不良的影响，并至少能溶解该试剂至某种程度即可。适合的溶剂的实例包括：烃类，该烃类可以是脂肪族烃类或芳香族烃类，如苯、甲基、二甲苯、己烷或庚烷；醚类，如乙醚、四氢呋喃或二恶烷；酰胺类如二甲基甲酰胺、二甲基乙酰胺或六甲基磷酸三酰胺；醇类，如甲醇、乙醇或异丙醇；以及上述溶剂的任何两种或多种的混合物。
反应可在一个广的温度范围内进行，而选择精确的反应温度对于本发明来说并不是关键性的。通常，从冰冷的温度至热的温度例如50℃或更高，反应都可轻易地进行，反应所需的时间取决于许多因素特别是反应温度和试剂的性质而变化也很大。然而，在许多情况下从0.5小时至几天的一段时间内已足够。
反应的进行较好是应用硼氢化钠或氰基硼氢化钠在一种醇溶剂存在下，并在冰冷温度至50℃进行1至24小时。
当还原反应在催化剂存在下通过氢化作用来进行时，所应用的催化剂可以是通常应用于催化还原作用的任何催化剂，而催化剂的性质对于本发明来说并不是关键性的，优选的催化剂的实例包括披钯木炭或氧化铂。通常，反应较好是在一种溶剂存在下进行，溶剂的性质并不是关键性的，只要该溶剂的性质对于反应没有不良影响而且至少可溶解反应试剂至某种程度。适合的溶剂的实例包括：醚类，如乙醚、四氢呋喃或二恶烷；酰胺类，如二甲基甲酰胺或二甲基乙酰胺；醇类，如甲醇、乙醇或异丙醇；酯类，如乙酸甲酯或乙酸乙酯；以及上述溶剂中的两种或几种溶剂的混合物，当应用钯催化剂时，催化氢化作用较好是在中等或高压力下进行，优选的压力是在1至5kg/cm2。当应用铂催化剂时，氢化作用较好是在大气压力下进行，反应可在一个宽的温度范围内进行，对于本发明来说选择精确的反应温度并不是关键性的。通常，在温度范围为室温至50℃该反应可轻易地进行。该反应也可优选地在一种醇溶剂特别是甲醇或乙醇存在下进行。
其中R0代表氢原子的那些式(XIII)化合物，即式(XVI)的化合物
Figure C9610715300111
可通过综合于下述反应路线B的过程来制备：
反应路线  B
Figure C9610715300113
在上述的各式中，Ar和Z3的定义如上所述而R代表一个低级烷基，优选的是具有1至4个碳原子的烷基，例如，在上述关于取代基B的举例。
在这个反应路线的第1步骤中，通过常规的方法，例如在Organic Syntheses I，pp.，336所述，来处理式(f)的化合物，以得到式(g)的化合物。在此已将该文献所公开的内容加入本文中作参考。
通常，该反应是通过将式(f)的化合物与氰氢酸反应或与三甲基甲硅烷氰化物在碘化锌存在下，以及在有或没有溶剂存在下来进行，以制备氰醇衍生物，然后将所得到的氰醇化合物用一种酸来水解，形成氰醇化合物的反应通常通过一个广范围的温度，例如由冰冷至热的、优选从室温至100℃的温度来进行，用酸进行催化水解作用，所用的酸，通常是用常规的酸，例如一种无机酸，如盐酸或硫酸，或者一种有机酸如对甲基苯磺酸或乙酸，在过量的水存在下并在反应混合物的回流温度至室温进行几十分钟至几十小时，优选的是通过在回流下加热，并在盐酸或硫酸存在下进行30分钟至10小时。
接着，酯化如此得到的式(g)化合物可通过用酸催化的酯化作用或用酯化剂如重氮烷或卤代烷加碱来处理，以制备式(h)的化合物。
酸催化的酯化作用可通过将式(g)化合物与例如过量的醇，在有或没有溶剂存在下，并优选在一种无机酸如盐酸或硫酸存在下，或在一种有机酸，如对甲苯磺酸存在下，在一种适合的温度，例如由室温至加热的温度进行一段适当的时间例如进行几小时至几天来实现。
应用重氮烷的酯化反应，较好是在一种溶剂存在下进行，这些溶剂例如一种醇，如甲醇或乙醇；一种烃，这种烃可以是脂肪烃或芳香烃，如苯、甲苯、二甲苯、己烷或庚烷；一种醚，如乙醚、四氢呋喃或二恶烷；或者上述溶剂的任何两种或几种溶剂的混合物。该反应可在一个广的温度范围内进行，精确的反应温度对于本发明来说并不是关键的。通常，在冰冷的温度至加热的温度，较优选是从冰冷的温度至60℃可轻易地进行该反应，反应所要求的时间也可有很大的不同，这取决于许多因素，特别是反应温度和所用的试剂和溶剂的性质。
在应用碱和卤代烷的酯化反应中，可以应用的碱的实例包括碱金属碳酸盐，如碳酸钾或碳酸钠。该反应通常和优选在溶剂存在下进行，对于所应用的碱的性质来说并没有具体的限制，只要是对于该反应或所涉及的试剂没有不良的影响而且至少可以溶解所用的试剂至某种程度。适合的溶剂的实例包括：醇类，如甲醇或乙醇；醚类，如乙醚、四氢呋喃或二噁烷；烃类，如苯、甲苯、二甲苯、己烷或庚烷；酰胺类，如二甲基甲酰胺，二甲基乙酰胺或六甲基磷酸三酰胺；以及上述溶剂中的任何两种或几种溶剂的混合物。反应可在一个广的温度范围内进行，而对于本发明来说精确的反应温度并不是关键性的。通常，反应在室温或加热下可轻易地进行，反应所要求的时间取决于许多因素特别是反应温度和所应用的试剂和溶剂的性质而有很大的变化。然而，除了反应是在上述所概括的优选条件下进行之外，由几小时至几天的时间是足够的。
在步骤3中，应用常规的羟基-保护基保护所得到的式(h)化合物，以制备式(i)的化合物。可以应用作羟基-保护基的实例包括：四氢吡喃基、甲氧基甲基、二苯基甲基、三苯甲基、三甲基甲硅烷基、叔丁基二甲基甲硅烷基以及叔丁基二苯基甲硅烷基，例如在T.W.Green的《Protective Groups in Organic Syntheses》，JohnWiley & Sons；和J.F.W.McOmie的《Prvtective Groups inOrgainic Chemstry》，Plenum Press中的有关叙述。
在步骤4中，式(XVI)的化合物可由式(i)化合物通过常规的方法来制备，例如，将式(i)的化合物在放入丙酮-干冰浴中已经预冷的烃溶剂如己烷、庚烷、苯、甲苯或二甲苯中与二异丁基氢化铝反应。
式(XVI)的化合物也可经下述反应路线C概括的步骤来制备：
反应路线C
(其中Ar，Z3和R的定义如上所述)
在这个反应路线的步骤1中，通过常规方法使式(i)的化合物与例如金属氢化物，如氢化铝锂或二异丁基氢化铝反应，以生成式(j)的化合物。
在该反应通常并且较好是在一种溶剂存在下进行。对于所用的溶剂除了要求对反应或所涉及的试剂没有不良的作用以及至少能够溶解试剂至某种程度之外，并没有特别的限制。适合的溶剂的实例包括醚类如乙醚、四氢呋喃和二噁烷。
然后，使所得到的式(j)的化合物通过常规的方法，例如应用三氧化硫/吡啶复合物或铬氧化剂或经过Swern氧化反应在步骤2中氧化，以生成式(XVI)的化合物。
对于具有光学活性的式(XVI)化合物，有可能得到在标记*1的位置上具有一个不对称碳原子的式(IV)化合物的立体异构体，即，当式(XIV)的氨基化合物是光学活性化合物而R0代表一个氢原子时，具有由任何所需的(*1R，*3R)，(*1R，*3S)，(*1S，*3R)，或(*1S，*3S)组合形成的立体异构化学的式(IV)化合物可以分别进行制备。
再者，应用可用于常规光学解析的任何光学活性胺例如(+)-或(-)-麻黄素或(d)-或(l)-1-苯基乙胺，式(g)的化合物可以被解析成-(R)和(S)化合物。
下述实施例说明本申请的中间化合物的制备，同时，以下所述的这些制备，说明了这些中间化合物转化成如以上所限定的式(I)化合物的方法。
实施例1
5-(4-乙酸基苄基)-3-三苯甲基-噻唑烷-2，4-二酮
1(a)5-(4-乙酸基亚苄基)噻唑烷-2，4-二酮
在150℃下将含200克对羟基苯甲醛，229克的噻唑烷-2，4-二酮，280克的乙酸钠和660毫升的二甲基乙酰胺的混合物搅拌1小时，然后使其冷却，将540毫升的二甲基乙酰胺和370毫升的乙酸酐加入到该反应混合物中。然后在50℃下将该反应混合物搅拌1.5小时，此后，将其倒入水中。过滤收集沉淀的固体，用水洗涤，在无水硫酸钠上干燥，得到标题化合物。
1(b)5-(4-乙酸基苄基)噻唑烷-2，4-二酮
将2.0克5-(4-乙酸基亚苄基)噻唑烷-2，4-二酮(如上述步骤(a)所述的制备)溶于80毫升乙酸中，然后在大气压力和90℃下在有2.0克10％重量/重量技钯木炭的存在下，使氢气通过该溶液5小时，将该溶液氢化。在该过程结束时，过滤掉催化剂，并用甲苯稀释滤液。蒸馏除去作为甲苯共沸物的乙酸溶剂。通过加入甲苯和己烷到浓缩物中，分离出的晶体，通过过滤而收集并干燥得到标题化合物。
1(c)5-(4-乙酸基苄基)噻唑烷-3-三苯基甲基-噻唑烷-2，4-二酮
将3.43克的三甲胺加入到含9.0克5-(4-乙酸基苄基)噻唑烷-2，4-二酮(如上述步骤(b)所述的制备)的70毫升二氯甲烷溶液中，然后将含9.54克三苯甲基氯的30毫升二氯甲烷溶液逐滴加入到该反应混合物中。在室温下将该混合物搅拌1小时，此后，在相同温度下使其静置隔夜。在该过程结束时，将反应混合物与水和乙酸乙酯混合，分离有机层，用饱和氯化钠水溶液洗涤，并在无水硫酸钠上干燥。在减压下蒸馏掉溶剂，并将分离出的晶体用己烷和乙酸乙酯的混合物洗涤并干燥，得到标题化合物。
                     实施例2
5-(4-羟基苄基)-3-三苯基甲基-噻唑烷-2，4-二酮
在冰冷却同时，将在10毫升甲醇中的2.99克28％重量/体积的甲醇钠的甲醇溶液逐滴加入到含7.86克5-(4-乙酸基苄基)-3-三苯基甲基-噻唑烷-2，4-二酮(如上述步骤(c)所述的制备)70毫升甲苯溶液中，将得到的混合物在室温下搅拌1小时，此后，使其在相同温度下静置隔夜。反应混合物pH值通过加入1N的盐酸水溶液调节至4，用乙酸乙酯萃取该混合物。用水洗涤萃取液并在无水硫酸钠上干燥。在减压下蒸馏除去溶剂，收集残余物中的晶体，并用己烷洗涤并干燥，得到标题化合物。
                      制备例1
5-{4-[2(R)-氨基丙氧基]苄基}噻唑烷-2，4-二酮三氟乙酸酯1(a)5-{4-[2(R)-叔丁氧基羰基氨基丙氧基]苄基}-3-三苯基甲基噻唑烷-2，4-二酮
将13.2克偶氮二羰酸二乙酯逐滴加入到含20.7克的三苯膦的300毫升苯溶液中，将该混合物在室温下搅拌30分钟。在该过程结束时，将35.0克5-(4-羟基苄基)-3-三苯基甲基-噻唑烷-2，4-二酮(如上述步骤(d)所述的制备)加入到该混合物中，在室温下将得到的混合物搅拌1小时。再将13.2克(R)-2-叔丁氧基羰基氨基-1-丙醇加入到混合物中，并使其静置隔夜，在该时间结束时，分三或四次依次将40.9克的三苯膦，23.68毫升的偶氮二羧酸二乙酯和33克(R)-2-叔丁氧基羰基氨基-1-丙醇加入到该反应混合物中，将该混合物搅拌2天。搅拌完毕后，通过减压蒸馏除去苯溶剂，将残余物使用1∶3(体积)的乙酸乙酯和己烷的混合物作为洗脱液，通过硅胶柱色谱法纯化，得到30克晶体状标题化合物，熔点为153-157℃。
Figure C9610715300171
1(b)5-{4-[2(R)-氨基丙氧基]苄基}噻唑烷-2，4-二酮三氟乙酸酯
在冰冷却情况下，将500毫升三氟乙酸逐滴加入到含85.5克5-{4-[2(R)-叔丁氧基羰基氨基丙氧基]苄基}-3-三苯基甲基-噻唑烷-2，4-二酮[如上述步骤(e)所述所备)的700毫升二氯甲烷溶液中，在室温下将得到的混合物搅拌4小时。在该过程结束时，将反应混合物与二氯甲烷溶剂和三氟乙酸通过减压蒸馏分离，将苯和少量乙酸乙酯的混合物加入到残余物中。过滤收集沉淀出的晶体并从甲醇和乙酸乙酯的混合物中重结晶，得到晶体状标题化合物，熔点为162-166℃。
Figure C9610715300172
                   制备例2
(R)-α-叔丁基二甲基甲硅烷氧基-3-氯代苯基乙酸甲酯
在冰冷却的同时，将含31.6克的叔丁基二甲基甲硅烷基氯的200毫升二甲基甲酰胺溶液逐滴加入到含28克(R)-3-氯代扁桃酸甲酯(制备例47中所述的方法制备)和28.5克咪唑的300毫升二甲基甲酰胺溶液中，并将得到的混合物在相同温度下搅拌30分钟，此后，使其在40℃下静置隔夜。在该过程结束时，在减压下蒸发浓缩反应混合物，并将残余物与水和乙酸乙酯混合，分离乙酸乙酯层，并在无水硫酸钠上干燥，然后在减压下蒸馏除去溶剂。然后使用1∶15(体积)的乙酸乙酯和己烷的混合物作洗脱液，通过硅胶柱色谱法纯化得到的残余物，从而得到晶体状标题化合物，熔点为36-38℃。
                 制备例3
(R)-α-叔丁基二甲基甲硅烷氧基-α-(-3-氯代苯基)-乙醛
将26克(R)-α-叔丁基二甲基二甲基甲硅烷氧基-3-氯苯基乙酸甲酯(如制备例2中所述的方法制备)在1000毫升无水己烷和500毫升无水甲苯的混合物中的溶液冷却到-60℃，然后124毫升的1M氢化二异丁基铝的己烷溶液逐滴加入到该冷却的溶液中。在相同温度下将得到的混合物搅拌3小时，此后，向其中加入10毫升的水，使反应混合物的温度逐渐升至室温。然后使反应混合物与水和乙酸乙酯混合，此后，将其搅拌30分钟。使用Celite(商标名)助滤剂过滤掉不溶物质，从过滤中分离乙酸乙酯层，并在无水硫酸钠上干燥。在减压下蒸馏除去乙酸乙酯溶剂，将残物使用1∶60(体积)的乙酸乙酯和己烷的混合物作为洗脱液，通过硅胶柱色谱法进行纯化，从而得到标题化合物，其具有Rf＝0.36(使用1∶60(体积)的乙酸乙酯和己烷作为展开溶剂，用硅胶薄层色谱法)。
                制备例4
5-[4-{2(R)-[2(R)-(3-氯苯基)-2-叔丁基二甲基甲硅烷氧基乙基氨基]丙氧基}苄基]噻唑烷-2，4-二酮
将含有36.5克的5-{4-[2(R)-氨基丙氧基]苄基}噻唑烷-2，4-二酮三氟乙酸酯(如制备例1所述的制备)，98.4克的(R)-α-(叔丁基二甲基甲硅烷氧基)-α-(3-氯苯基)乙醛(如制备例3所述的制备)和400毫升无水甲醇的混合物在室温下搅拌2.5小时，然后分批将29.0克的氰基硼氢化钠加入到该混合物，并同时使其在冰-氯化钠浴中冷却。在室温下使反应混合物静置隔认，此后，在减压下蒸馏除去甲醇溶剂，将得到的残余物与水和乙酸乙酯混合，分离乙酸乙酯层和并用氯化钠水溶液洗涤，在无水硫酸钠上干燥。在减压下馏除去乙酸乙酯溶剂，然后使用2∶1(体积)的乙酸乙酯和己烷的混合物作洗脱液，通过硅胶柱色谱法纯化得到的残余物，从而得到标题化合物。
Figure C9610715300191
                    制备例53-氯扁桃酸
在搅拌的同时，在90℃下将158克3-氯苯甲醛，111.6克的三甲基甲硅烷基腈和催化量的碘化锌的混合物加热2小时。将反应混合物进行冰冷却，并将350毫升的浓缩的盐酸水溶液加入其中。然后在回流下将得到的混合物加热1小时，此后，使其与水和乙酸乙酯混合。分离乙酸乙酯层。并与30％重量/体积的氢氧化钠水溶液混合。分离含水层，用乙酸乙酯洗涤3次，然后用浓缩的含水盐酸酸化，此后，用乙酸乙酯萃取。萃取液用水洗涤，并在无水疏酸钠上干燥。在减压下蒸馏除去溶剂，得到晶体状标题化合物，熔点为110-114℃。
                      制备例6(R)-3-氯代扁桃酸和(S)-3-氯代扁桃酸
将100克3-氯代扁桃酸(如制备例5所述的方法制备)和32.7克的(R)-(+)-1-苯基乙胺的混合物溶于甲醇和二乙醚的混合物中并从中重结晶。过滤收集得到的结晶体，并从甲醇和二乙醚的混合物中重结晶三次，然后与盐酸水溶液混合。将该混合物用乙酸乙酯萃取。萃取液在无水硫酸钠上干燥，在减压下蒸馏除去溶剂，得到晶状(R)-3-氯代扁桃酸，熔点为102-105℃
Figure C9610715300192
将盐酸加到上面得到的滤液中，并用乙酸乙酯萃取该混合物。萃取液在无水硫酸钠上干燥，在减压下蒸馏除去溶剂，将得到的残余物与32.7克的(S)-(-)-1-苯乙基胺混合，并从甲醇和二乙醚中重结晶三次，得到晶体状的(S)-3-氯代扁桃酸，熔点为101-104℃。
                      制备例7(R)-3-氯代扁桃酸甲酯
将18.3克10％重量/体积含三甲基甲硅烷基重氮甲烷的己烷溶液逐滴加入到28克的(R)-3-氯代扁桃酸(如制备例6中所述方法制备)在300毫升甲醇和700毫升苯的混合物中的溶液中，将得到的混合物搅拌1小时。在搅拌结束时，在减压下蒸馏除去溶剂，得到标题化合物，其具有[α]D 23-119.3°(C＝1.00，氯仿)和Rf＝0.36(使用1∶5(体积)的乙酸乙酯和己烷的混合物，用硅胶薄层色谱法)。
                     制备例85-[4-{2(R)-[2(R)-(3-氯苯基)-2-羟乙基氨基]丙氧基}苄基]噻唑烷-2，4-二酮(一种式(I)的化合物)
在冰冷却下，将88克四丁基氟化铵加到46.2克5-[4-{2(R)-[2(R)-(3-氯苯基)-2-叔丁基二甲基甲硅烷氧基乙基氨基]丙氧基}苄基]噻唑烷-2，4-二酮(用制备例4所述方法制备)。在500毫升四氢呋喃中的溶液中，得到的反应混合物在室温下搅拌15小时。搅拌结束后，用减压蒸馏法除去四氢呋喃溶剂，剩余物与水混合，然后用乙酸乙酯萃取，萃取液用氯化钠水溶液洗涤，然后用无水硫酸钠干燥。用减压蒸馏法除去乙酸乙酯溶剂，用乙酸乙酯和乙醇以5∶1(体积)的混合物作为洗脱液，用硅胶柱色说法纯化剩余物，将获得的粗晶体用乙酸乙酯和乙醇的混合物再结晶，得到27.1克晶体状的标题化合物，熔点为100-112℃。

Claims (3)

1.下式的一种化合物的用途
Figure C9610715300021
式中R7代表氢原子或乙酰基该用途包括将该化合物用于制备如下所示的式(I)化合物及其可作药用的盐，
Figure C9610715300022
式中：
R0代表氢原子、甲基或羟甲基；
R1代表5-甲基噻唑烷-2，4-二酮基团；
R2和R3各自代表氢原子；
X代表氧原子；和
Ar代表如下的式(II)或(III)基团：
其中：
R4代表氢原子、卤原子、羟基、羟甲基、具有1至5个碳原子的烷氧基、具有1至5个碳原子的烷基、具有1至6个碳原子的脂族羧酸酰氧基、硝基、氰基、其中芳烷基的部分定义如下的芳烷氧基、其中芳基部分的定义如下的芳氧基、其定义如下的芳基或具有1至4个碳原子的卤代烷基；
R5代表氢原子、卤原子、羟基、具有1至5个碳原子的烷氧基、具有1至5个碳原子的烷基或硝基；和
R6代表氢原子、卤原子、羟基、具有1至5个碳原子的烷氧基或具有1至5个碳原子的烷基；
所说的芳烷基部分是具有1至3个碳原子的烷基，该烷基被定义如下的1个或2个芳基所取代；
所说的芳基是具有6至10个环碳原子的碳环芳基，它们是未被取代的或被至少1个选自其定如下的取代基B的取代基所取代；
所说的取代基B选自卤原子、具有1至4个碳原子的烷基、具有1至3个碳原子的烷氧基、硝基、具有1至4个碳原子的卤代烷基和羟基。
2.根据权利要求1的用途，其中应用于制备式(I)化合物或其可作药用的盐的该化合物是5-(4-羟基苄基)-3-三苯基甲基噻唑-2，4-二酮。
3.根据权利要求1的用途，其中应用于制备式(I)化合物或其可作药用的盐的该化合物是5-(4-乙酸基苄基)-3-三苯基甲基噻唑-2，4-二酮。
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CZ343692A3 (en) 1993-12-15
AU670007B2 (en) 1996-06-27
CZ280820B6 (cs) 1996-04-17
IL103825A (en) 1998-04-05
CN1034497C (zh) 1997-04-09
GR3021245T3 (en) 1997-01-31
JP2654323B2 (ja) 1997-09-17
CN1033750C (zh) 1997-01-08
CN1106396A (zh) 1995-08-09
EP0543662A2 (en) 1993-05-26
CZ280328B6 (cs) 1995-12-13
TW233294B (zh) 1994-11-01
FI925255A (fi) 1993-05-21
HK218496A (en) 1996-12-27
HUT66816A (en) 1995-01-30
MX9206740A (es) 1993-05-31
NO924440L (no) 1993-05-21
DE69213892D1 (de) 1996-10-24
DE69213892T2 (de) 1997-04-17
HU9203638D0 (en) 1993-01-28
US5977374A (en) 1999-11-02
DK0543662T3 (zh) 1997-03-03
ZA928960B (en) 1993-05-19
IL110804A (en) 1997-07-13
NO179246B (no) 1996-05-28
CN1151401A (zh) 1997-06-11
NO179246C (no) 1996-09-04
AU7751894A (en) 1995-01-12
RU2081113C1 (ru) 1997-06-10
FI925255A0 (fi) 1992-11-19
IL103825A0 (en) 1993-04-04
CA2083323A1 (en) 1993-05-21

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