噻唑烷二酮及其衍生物的合成
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摘要
噻唑烷-2,4-二酮是合成多种药物的重要中间体。以噻唑烷二酮为母体对其3位和5位进行结构修饰得到的一系列噻唑烷二酮类衍生物，这些化合物大都具有不同的药理活性，很多已成为临床应用或临床研究中的药物。近年来，一种新型的胰岛素增敏剂(insulinsensitizer)5-取代噻唑烷-2,4-二酮系列衍生物作为新型口服降血糖药物在国外已被研制开发并受到广泛关注。噻唑烷二酮类(thiazolidinediones，TZDs)胰岛素增敏剂在体内可激活主要在脂肪细胞中表达的过氧化物酶体增殖活化受体γ(PPARγ)并可导致多种由脂肪细胞分泌的与胰岛素抵抗相关的激素和代谢物质的减少，除具有降血糖活性外，还可对“胰岛素抵抗综合症”(insulin resistancesyndrome，IRS)的一系列异常表现有改善作用。目前，糖尿病已成为继肿瘤和心脑血管病之后的严重非传染性疾病，因此，噻唑烷二酮类胰岛素增敏剂的研制和开发将对糖尿病以及与胰岛素抵抗的相关疾病的治疗产生重大的积极影响。
目的：研究噻唑烷-2,4-二酮(Ⅰ)及其衍生物5-(4-羟基苄基)噻唑烷-2,4-二酮(Ⅱ)、5-[4-[2-N-甲基-N-(2-吡啶基)氨基]乙氧基]苄基噻唑烷基-2,4-二酮(罗格列酮，Ⅲ)和5-[[4-[2-(1-吲哚基)乙氧基]苄基]噻唑烷-2，4-二酮(DRF-2189，Ⅳ)的合成路线及工艺。
中文摘要
方法：化合物（1）：以硫晚和氯乙酸乙酯为原料，
经环合、中和制得2一亚氨基4＠哩酮即假乙内酚硫服，
再水解制得目标化合物门人
化合物门）：以三种不同物质为起始原料，采用
三条不同路线进行合成：1．以对氨基酚为起始原料，
经重氮化，再与丙烯酸乙酯经麦尔外因芳基取代反应得
到2．氯上一N经基苯基）丙酸乙酯，该化合物与流眼环
合、水解制得目标化合物门 人 2．以对硝基苯胺为起
始原料，经重氨化反应，再与丙烯酸乙酯发生麦尔外因
芳基取代反应得到2一氯上一N硝基苯基）丙酸乙酯，该
化合物与硫眼环合、水解得5人4硝基节基）嘎吱烷《，
4二酮，经铁粉／氯化控还原得到5－N氨基等基）噎叹
烷么个二酮，最后经重氮化、水解制得目标化合物门 L
3．以对羟基苯甲醛为起始原料，与化合物（I）在冰
乙酸和响咤作催化剂的条件下发生克脑文格反应，再经
镁粉／甲醇还原制得目标化合物门人
化合物 （ill：以 2一氯毗院为原料，在氮气流下与
2一甲氨基乙醇缩合制得 21N一甲基一N上十毗院基）氨基】乙
醇，再应用相转移催化反应以TEBA为相转移催化剂，
制备＊［2－m一甲基一N－2／0L鹏基）氨基］乙氧基］苯甲醛，再
与医哇烷上，4二酮缩合，经镁／甲醇还原制得目标化合
物门11）。
化合物（IV人 以回跌为起始原料，在 TBAB的作
用下，吼跌和l，2二氯乙烷经固一液相转移催化反应制
备得到l－u一氯乙基）哨跺，再与5．N羟基节基）暖
唯烷上，4二酮门1发生缩合反应制得目标化合物出人
中文摘要
结果：合成出惨哩烷《，4二酮（I）及其衍生物
5－（个羟基节基）暖哩烷一2，4一二酮（11）、5－［4［2－N一甲
基一N－Q叩 陵基）氨基］乙氧基］节基上，4暖吐烷基H
酮（罗格歹酮，Ill）和 5－［［4－［2－（一间保基）乙氧基1苦
基］暖哩烷上，4－H酮（DRF上，IV人化合物（I人
门）的熔点、IR光谱及元素分析均符合文献要求；化
合物门）的熔点、UV、IR、’HNMR、MS等波谱及元
素分析均符合其结构特征。
化合物（l）白主要 IR（KBr，cm＊）：3050，2800，
1730，166O．兀素分析：Q山u0＊S，理论计算值（ ）：C，
30．76弓 H，2．58；N，11．96；实验值（％）：C，30．70；
H，2．51；N，门产0c
化合物（11）自主要的 IR（KBr，Cm＊）：2930，1739，
1680．元素分析：C；爿＊0石，理论计算值（％）：C，53．79：
H，4＊6：N，6．28；实验值（％）：C，53．＊2 H，4＊0 Z
N，5．99。
化合物（if）的主要 IR（KBr，cm”’）：2930，1739，
1694，1609，1＊0．’HNM R（6）8＊（IH，d，毗院6
位氢人7．l u，d，苯环上与亚甲基相邻的两个氢人
6．8仪，d，苯环上与乙氧基相邻的两个氢），3．06（3，S，
N－CH3） MS In／e（％）：357（M十，10），135二），121（100），
107仪0）元素分析：C；a；郝心术，理论计算值（O）：C，
60．48；H，5．36；N，11．76；实验值（％）：C，60．72；H，
5．41；N，11．46。
结论：
l、以流脉和氯乙酸乙酯为原料，合成了重要的多种药物
3
中文摘要
中间体暖哩烷上，4二酮，产品质量符合文献要求。该
路线原料易得、收率较高、操作简便，适合工业
2,4-thiazolidinedione is an important intermediate that is used to synthesize manifold pharmaceuticals. A series of thiazolidine-2,4-diones was obtained by the chemical modifications of the substituents at the 3-position or the 5-position of the thiazolidine ring, among of which had different pharmacological properties. A number of them have been underwent clinical or preclinical investigation to treat a certain diseases. In recent years, as a newly insulin sensitzers, several thiazolidinedine derivatives having 5-substitute-2, 4-thiazolidinedione structures were developed and there has been a resurgence of interest in the development of novel antihyperglycemic agents which can reverse the insulin resistance in non-insulin-dependent diabetes mellitus patients. Thiazolidinediones exert their effects by stimulating the Peroxisome proliferator activated receptor- y (PPAR- y ) which is predominantly expressed in adipose tissue and leading to the reduced production of many factors that were believed to cause insu
lin resistance. In addition to their hypoglycemic effect, thiazolidinediones can also alleviate many abnomalities associated with " insulin resistance syndrome" (IRS). Now, diabetes
mellitus that is severe non-contagion ailment is followed by tumour and macrovascular and cardiovascular diseases. The development of thiazolidinediones as a newly insulin sensitzers will have singnificant positive impacts on the treatment of type 2 diabetes and other conditions associate with insulin resistance.
Objective: To develop a modification of the general route for the synthesis of 2,4-thiazolidinedione (I) and its derivatives which are 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (II), 5-[4-[2-N-Methyl-N-(2-pyridyl)amino]ethoxyl-]benzylthiazolidine-2,4-dione (Rosiglitazone, III ) and 5-[4-[2-( 1 -indolyl)ethoxy]benzyl]thiazolidine-2,4-dione(I V).
Methods: compound (I) was synthesized by using thiourea and ethyl chloroacetate as raw materials. The reaction of thiaourea with ethyl chloroactate through cyclocondenstion, neutralization with sodium acetate afforded 2-imino-4-thiazolidone that is pseudothiohydanto-in then subjected to acid hydrolysis to obtain 2,4-thiazolidinedione.
Compound (II) was synthesized by using three different compounds as raw materials through three different synthetic routes respectively. The first route was as follows: diazotization of p-aminophenol and subsequent Meerwin arylation reaction with ethyl acrylate gave ethyl 2-chloro-3-(4-hydroxyphenyl) propionate followed the cyclocondensation with thiourea, then subjected to acid
hydrolysis to obtain 5-(4-hydroxybenzyl)thiazolidine-2,4-dione. The second route was as follows: diazotization of p-nitroaniline and subsequent Meerwin arylation reaction with ethyl aery late gave ethyl 2-chloro-3-(4-nitrophenyl) propionate followed the cyclocondensation with thiourea yielded 5-(4-nitrobenzyl)thiazolidine-2,4-dione, which was reduced in the presence of iron powder/ammonium chloride to give 5-(4-aminobenzyl)thiazolidine-2,4-dione, then subjected to diazotization and acid hydrolysis to obtain 5-(4-hydroxy-benzyl)thiazolidine-2,4-dione.The third route was as follows: the p-hydroxybenzaldehyde underwent Knoevenagal condensation with compound (I) in the presence of piperdinium benzoate in refluxing toluene with azeotropic removal of water to give 5-(4-hydroxybenzylid-ene)thiazolidine-2,4-dione, which was reducede by magnesium /methanol to obtain 5-(4-hydroxybenzyl)thiazo-lidine-2,4-dione.
Compound (III) was synthesized by using 2-chloro-pyridine as raw materials. The reaction of 2-chloro-pyridine with 2-(methylamino)ethanol under nitrogen afforded 2-(methyl-2-pyridinylamino)ethanol, then subjected to condesation with /-fluorobenzaldehyde in the presence of TEBA which as a phase transfer catalyst to obtain 4-[2-N-methyl-N-(2-pyridyl)amino]ethoxyl]benzal-dehyde, which followed the Knoevenagal condensation with 2,4-thiazoli-dinedione (I) gave 5-[4-[2-N-methyl-N-(-
2-pyridyl)amino)ethoxyl]phenyl]-methylene]thiazolidine-2, 4-dione, which were redu
目的：研究噻唑烷-2,4-二酮(Ⅰ)及其衍生物5-(4-羟基苄基)噻唑烷-2,4-二酮(Ⅱ)、5-[4-[2-N-甲基-N-(2-吡啶基)氨基]乙氧基]苄基噻唑烷基-2,4-二酮(罗格列酮，Ⅲ)和5-[[4-[2-(1-吲哚基)乙氧基]苄基]噻唑烷-2，4-二酮(DRF-2189，Ⅳ)的合成路线及工艺。
中文摘要
方法：化合物（1）：以硫晚和氯乙酸乙酯为原料，
经环合、中和制得2一亚氨基4＠哩酮即假乙内酚硫服，
再水解制得目标化合物门人
化合物门）：以三种不同物质为起始原料，采用
三条不同路线进行合成：1．以对氨基酚为起始原料，
经重氮化，再与丙烯酸乙酯经麦尔外因芳基取代反应得
到2．氯上一N经基苯基）丙酸乙酯，该化合物与流眼环
合、水解制得目标化合物门 人 2．以对硝基苯胺为起
始原料，经重氨化反应，再与丙烯酸乙酯发生麦尔外因
芳基取代反应得到2一氯上一N硝基苯基）丙酸乙酯，该
化合物与硫眼环合、水解得5人4硝基节基）嘎吱烷《，
4二酮，经铁粉／氯化控还原得到5－N氨基等基）噎叹
烷么个二酮，最后经重氮化、水解制得目标化合物门 L
3．以对羟基苯甲醛为起始原料，与化合物（I）在冰
乙酸和响咤作催化剂的条件下发生克脑文格反应，再经
镁粉／甲醇还原制得目标化合物门人
化合物 （ill：以 2一氯毗院为原料，在氮气流下与
2一甲氨基乙醇缩合制得 21N一甲基一N上十毗院基）氨基】乙
醇，再应用相转移催化反应以TEBA为相转移催化剂，
制备＊［2－m一甲基一N－2／0L鹏基）氨基］乙氧基］苯甲醛，再
与医哇烷上，4二酮缩合，经镁／甲醇还原制得目标化合
物门11）。
化合物（IV人 以回跌为起始原料，在 TBAB的作
用下，吼跌和l，2二氯乙烷经固一液相转移催化反应制
备得到l－u一氯乙基）哨跺，再与5．N羟基节基）暖
唯烷上，4二酮门1发生缩合反应制得目标化合物出人
中文摘要
结果：合成出惨哩烷《，4二酮（I）及其衍生物
5－（个羟基节基）暖哩烷一2，4一二酮（11）、5－［4［2－N一甲
基一N－Q叩 陵基）氨基］乙氧基］节基上，4暖吐烷基H
酮（罗格歹酮，Ill）和 5－［［4－［2－（一间保基）乙氧基1苦
基］暖哩烷上，4－H酮（DRF上，IV人化合物（I人
门）的熔点、IR光谱及元素分析均符合文献要求；化
合物门）的熔点、UV、IR、’HNMR、MS等波谱及元
素分析均符合其结构特征。
化合物（l）白主要 IR（KBr，cm＊）：3050，2800，
1730，166O．兀素分析：Q山u0＊S，理论计算值（ ）：C，
30．76弓 H，2．58；N，11．96；实验值（％）：C，30．70；
H，2．51；N，门产0c
化合物（11）自主要的 IR（KBr，Cm＊）：2930，1739，
1680．元素分析：C；爿＊0石，理论计算值（％）：C，53．79：
H，4＊6：N，6．28；实验值（％）：C，53．＊2 H，4＊0 Z
N，5．99。
化合物（if）的主要 IR（KBr，cm”’）：2930，1739，
1694，1609，1＊0．’HNM R（6）8＊（IH，d，毗院6
位氢人7．l u，d，苯环上与亚甲基相邻的两个氢人
6．8仪，d，苯环上与乙氧基相邻的两个氢），3．06（3，S，
N－CH3） MS In／e（％）：357（M十，10），135二），121（100），
107仪0）元素分析：C；a；郝心术，理论计算值（O）：C，
60．48；H，5．36；N，11．76；实验值（％）：C，60．72；H，
5．41；N，11．46。
结论：
l、以流脉和氯乙酸乙酯为原料，合成了重要的多种药物
3
中文摘要
中间体暖哩烷上，4二酮，产品质量符合文献要求。该
路线原料易得、收率较高、操作简便，适合工业
2,4-thiazolidinedione is an important intermediate that is used to synthesize manifold pharmaceuticals. A series of thiazolidine-2,4-diones was obtained by the chemical modifications of the substituents at the 3-position or the 5-position of the thiazolidine ring, among of which had different pharmacological properties. A number of them have been underwent clinical or preclinical investigation to treat a certain diseases. In recent years, as a newly insulin sensitzers, several thiazolidinedine derivatives having 5-substitute-2, 4-thiazolidinedione structures were developed and there has been a resurgence of interest in the development of novel antihyperglycemic agents which can reverse the insulin resistance in non-insulin-dependent diabetes mellitus patients. Thiazolidinediones exert their effects by stimulating the Peroxisome proliferator activated receptor- y (PPAR- y ) which is predominantly expressed in adipose tissue and leading to the reduced production of many factors that were believed to cause insu
lin resistance. In addition to their hypoglycemic effect, thiazolidinediones can also alleviate many abnomalities associated with " insulin resistance syndrome" (IRS). Now, diabetes
mellitus that is severe non-contagion ailment is followed by tumour and macrovascular and cardiovascular diseases. The development of thiazolidinediones as a newly insulin sensitzers will have singnificant positive impacts on the treatment of type 2 diabetes and other conditions associate with insulin resistance.
Objective: To develop a modification of the general route for the synthesis of 2,4-thiazolidinedione (I) and its derivatives which are 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (II), 5-[4-[2-N-Methyl-N-(2-pyridyl)amino]ethoxyl-]benzylthiazolidine-2,4-dione (Rosiglitazone, III ) and 5-[4-[2-( 1 -indolyl)ethoxy]benzyl]thiazolidine-2,4-dione(I V).
Methods: compound (I) was synthesized by using thiourea and ethyl chloroacetate as raw materials. The reaction of thiaourea with ethyl chloroactate through cyclocondenstion, neutralization with sodium acetate afforded 2-imino-4-thiazolidone that is pseudothiohydanto-in then subjected to acid hydrolysis to obtain 2,4-thiazolidinedione.
Compound (II) was synthesized by using three different compounds as raw materials through three different synthetic routes respectively. The first route was as follows: diazotization of p-aminophenol and subsequent Meerwin arylation reaction with ethyl acrylate gave ethyl 2-chloro-3-(4-hydroxyphenyl) propionate followed the cyclocondensation with thiourea, then subjected to acid
hydrolysis to obtain 5-(4-hydroxybenzyl)thiazolidine-2,4-dione. The second route was as follows: diazotization of p-nitroaniline and subsequent Meerwin arylation reaction with ethyl aery late gave ethyl 2-chloro-3-(4-nitrophenyl) propionate followed the cyclocondensation with thiourea yielded 5-(4-nitrobenzyl)thiazolidine-2,4-dione, which was reduced in the presence of iron powder/ammonium chloride to give 5-(4-aminobenzyl)thiazolidine-2,4-dione, then subjected to diazotization and acid hydrolysis to obtain 5-(4-hydroxy-benzyl)thiazolidine-2,4-dione.The third route was as follows: the p-hydroxybenzaldehyde underwent Knoevenagal condensation with compound (I) in the presence of piperdinium benzoate in refluxing toluene with azeotropic removal of water to give 5-(4-hydroxybenzylid-ene)thiazolidine-2,4-dione, which was reducede by magnesium /methanol to obtain 5-(4-hydroxybenzyl)thiazo-lidine-2,4-dione.
Compound (III) was synthesized by using 2-chloro-pyridine as raw materials. The reaction of 2-chloro-pyridine with 2-(methylamino)ethanol under nitrogen afforded 2-(methyl-2-pyridinylamino)ethanol, then subjected to condesation with /-fluorobenzaldehyde in the presence of TEBA which as a phase transfer catalyst to obtain 4-[2-N-methyl-N-(2-pyridyl)amino]ethoxyl]benzal-dehyde, which followed the Knoevenagal condensation with 2,4-thiazoli-dinedione (I) gave 5-[4-[2-N-methyl-N-(-
2-pyridyl)amino)ethoxyl]phenyl]-methylene]thiazolidine-2, 4-dione, which were redu
引文
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2． Mudaliar S, Henry RR. New oral therapies for type 2 diabetes mellitus: the glitazones or insulin sensitizers. Annu Rev Med, 2001, 52: 239-257．
3． Lohray BB , Bhuahan V. Indole-containing thiazolidine-2,4-diones as novel euglycemic and hypolipidemic Agents: DRF-2189． Drugs Fut, 1999,
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2． Mudaliar S, Henry RR. New oral therapies for type 2 diabetes mellitus: the glitazones or insulin sensitizers. Annu Rev Med, 2001, 52: 239-257．
3． Lohray BB , Bhuahan V. Indole-containing thiazolidine-2,4-diones as novel euglycemic and hypolipidemic Agents: DRF-2189． Drugs Fut, 1999,
24(7): 751-757.
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