抗精神病药3－（1－｛3－[（4－（2-嘧啶基））－1－哌嗪基]｝丙基）氨-2H－1,4－苯并噁嗪与抗球虫药尼卡巴嗪的合成研究
摘要
第一部分 抗精神病药主要是用于治疗精神分裂症及其它精神障碍的药物。传统的抗精神病药在患者长期服用之后，出现了锥体外系症状、治疗依从性差、增加了复发危险性，甚至导致永久性残疾。第二代抗精神病药对认知缺陷的治疗作用优于传统抗精神病药。可控制阳性症状、改善注意障碍和神经心理功能，但因阻滞中脑边缘系统的多巴胺传递对认知功能有不良影响。
3-(1-{3-[(4-(2-嘧啶基))-1-哌嗪基]}丙基)氨-2H-1，4-苯并噁嗪是一种新型抗精神病药。该药在键合D_4受体亚原型方面具有亲和性和选择性，所以在治疗多种神经心理上的或情感方面的错乱以及其它多巴胺能的障碍性错乱是有用的，也能治疗使用传统的抗精神病药而导致的锥体外系副作用。
本研究基于专利方法，通过六步合成该化合物并对其中关键步骤进行了改进，获得了令人满意的结果。在对第二步的合成方法进行研究时，使用酸解和碱解改变了文献中的肼解。这样不仅避免了使用毒性肼和使用球-球蒸馏装置，而且使产率得到了提高，并得出了最佳的酸解和碱解条件。在第五、六步合成中，通过改变反应温度以及在反应过程中加入少量的碱作为催化剂，使产率得到了极大的提高。
第二部分 抗球虫药物主要是为了控制球虫所引起的动物疾病，是目前饲料中广泛应用的一类重要药物添加剂。在高密度、大批量生产的情况下，以饲料添加剂的形式将抗球虫药添加于饲料中，防治畜禽球虫病，是一种行之有效的方法，已在世界各国广泛采用。
尼卡巴嗪几乎对所有鸡艾美耳球虫均具有高或中等活性。尼卡巴嗪主要作用于球虫第二代裂殖体，对鸡虫的活性高峰期为第四天，即对第二代裂殖体活性最强。组织培养结果表明，尼卡巴嗪对第一代裂殖体也有抑制作用。本品对球虫兼抑制和杀灭作用，即既有预防又有治疗作用，即使在感染48小时或72小时后投药，亦能充分抑制球虫。自1955年间世后，一直很有效。
以往中试合成尼卡巴嗪时，通过四步合成该化合物。本研究主要是对第一、二步进行了改进，原方法中采用高成本的邻苯二甲酸二丁酯作溶剂，现采用低成本的三光气作原料，改两步反应为一步反应，不仅缩短了路线，提高了产率，而且有利于由实验室小试向工业化生产的转化。
The first part Antipsychotic drugs are used to treat schizophrenia and other mental blockade. Conventional antipsychotic drugs have, after a long-time taking, extrapyramindal side effects, bad treatment compliance, and also the increasing danger of relapse, even the permanent disability. The second-generation antipsychotic drugs, superior to the conventional ones, are mainly used to treat cognitive deficits, to control masculine symptom, to improve attention blockade and to better neuropsychological function. However, the tendency of blockading dopamine of limbic brain system may bring adverse effects to cognitive function.
As a new antipsychotic drug, 3-(1-[3-{(4-pyrimidin-2-yl) piperazin-l-yl}]propyl)amino-2H-l,4-benzoxazine has high affinity and selectivity in binding the D4 receptor. It is therefore useful in the treatment of a variety of neuropsychological or affective disorders, dopaminergic blockade disorders and extrapyramindal side effects caused by the use of conventional neuroleptic agents.
We synthesized the target compound by six steps based on the patent and made great improvements in the key steps and got the satisfied results. In the second step, the hydrolysis with acid or base was used instead of the hydrazinolysis. Thus, we avoided using toxic hydrazine hydrate and Kugelrohr apparatus and at the same time improved the yields in the best hydrolysis conditions. In the fifth and sixth steps, the target compound was obtained by changing the reaction temperature and adding a little of base as catalyst. By doing so, we made the yield improved dramatically.
The second part Anticoccidials, mainly used to control animal diseases caused by coccidis, are extensively applied to the current animal feed as an additive. However, under the circumstances of high-density and large-mass produce, adding anticoccidials to animal feed as feed additive to prevent livestock coccidiosis is an efficient and worldwide method.
Nicarb has high or mediate activity to almost all chicken Eimeria. It is mainly used to control the second-generation schizont of coccidis with the activity peak to coccidis on the forth day. In other words, it has the strongest activity to the second-generation schizont. The results of tissue culture show that Nicarb has inhabitation function to the first-generation schizont. Such a product also has the function of inhabitation and kill. That is to say, it has the function of prevention and treatment. Even if it is used at 48h or 72h after infection, nicarb can also efficiently inhabitate coccidis. It has been efficient since it came out in 1955.
The previous synthesis of Nicarb in industry usually included four steps, this paper mainly made improvement in the first and second steps. We adopted cheap triphosgene as material instead of high-cost dibutyl phthalate. As a result, we could shorten the synthesis routes, improve the yield and easily transform from preparation to manufacture.
3-(1-{3-[(4-(2-嘧啶基))-1-哌嗪基]}丙基)氨-2H-1，4-苯并噁嗪是一种新型抗精神病药。该药在键合D_4受体亚原型方面具有亲和性和选择性，所以在治疗多种神经心理上的或情感方面的错乱以及其它多巴胺能的障碍性错乱是有用的，也能治疗使用传统的抗精神病药而导致的锥体外系副作用。
本研究基于专利方法，通过六步合成该化合物并对其中关键步骤进行了改进，获得了令人满意的结果。在对第二步的合成方法进行研究时，使用酸解和碱解改变了文献中的肼解。这样不仅避免了使用毒性肼和使用球-球蒸馏装置，而且使产率得到了提高，并得出了最佳的酸解和碱解条件。在第五、六步合成中，通过改变反应温度以及在反应过程中加入少量的碱作为催化剂，使产率得到了极大的提高。
第二部分 抗球虫药物主要是为了控制球虫所引起的动物疾病，是目前饲料中广泛应用的一类重要药物添加剂。在高密度、大批量生产的情况下，以饲料添加剂的形式将抗球虫药添加于饲料中，防治畜禽球虫病，是一种行之有效的方法，已在世界各国广泛采用。
尼卡巴嗪几乎对所有鸡艾美耳球虫均具有高或中等活性。尼卡巴嗪主要作用于球虫第二代裂殖体，对鸡虫的活性高峰期为第四天，即对第二代裂殖体活性最强。组织培养结果表明，尼卡巴嗪对第一代裂殖体也有抑制作用。本品对球虫兼抑制和杀灭作用，即既有预防又有治疗作用，即使在感染48小时或72小时后投药，亦能充分抑制球虫。自1955年间世后，一直很有效。
以往中试合成尼卡巴嗪时，通过四步合成该化合物。本研究主要是对第一、二步进行了改进，原方法中采用高成本的邻苯二甲酸二丁酯作溶剂，现采用低成本的三光气作原料，改两步反应为一步反应，不仅缩短了路线，提高了产率，而且有利于由实验室小试向工业化生产的转化。
The first part Antipsychotic drugs are used to treat schizophrenia and other mental blockade. Conventional antipsychotic drugs have, after a long-time taking, extrapyramindal side effects, bad treatment compliance, and also the increasing danger of relapse, even the permanent disability. The second-generation antipsychotic drugs, superior to the conventional ones, are mainly used to treat cognitive deficits, to control masculine symptom, to improve attention blockade and to better neuropsychological function. However, the tendency of blockading dopamine of limbic brain system may bring adverse effects to cognitive function.
As a new antipsychotic drug, 3-(1-[3-{(4-pyrimidin-2-yl) piperazin-l-yl}]propyl)amino-2H-l,4-benzoxazine has high affinity and selectivity in binding the D4 receptor. It is therefore useful in the treatment of a variety of neuropsychological or affective disorders, dopaminergic blockade disorders and extrapyramindal side effects caused by the use of conventional neuroleptic agents.
We synthesized the target compound by six steps based on the patent and made great improvements in the key steps and got the satisfied results. In the second step, the hydrolysis with acid or base was used instead of the hydrazinolysis. Thus, we avoided using toxic hydrazine hydrate and Kugelrohr apparatus and at the same time improved the yields in the best hydrolysis conditions. In the fifth and sixth steps, the target compound was obtained by changing the reaction temperature and adding a little of base as catalyst. By doing so, we made the yield improved dramatically.
The second part Anticoccidials, mainly used to control animal diseases caused by coccidis, are extensively applied to the current animal feed as an additive. However, under the circumstances of high-density and large-mass produce, adding anticoccidials to animal feed as feed additive to prevent livestock coccidiosis is an efficient and worldwide method.
Nicarb has high or mediate activity to almost all chicken Eimeria. It is mainly used to control the second-generation schizont of coccidis with the activity peak to coccidis on the forth day. In other words, it has the strongest activity to the second-generation schizont. The results of tissue culture show that Nicarb has inhabitation function to the first-generation schizont. Such a product also has the function of inhabitation and kill. That is to say, it has the function of prevention and treatment. Even if it is used at 48h or 72h after infection, nicarb can also efficiently inhabitate coccidis. It has been efficient since it came out in 1955.
The previous synthesis of Nicarb in industry usually included four steps, this paper mainly made improvement in the first and second steps. We adopted cheap triphosgene as material instead of high-cost dibutyl phthalate. As a result, we could shorten the synthesis routes, improve the yield and easily transform from preparation to manufacture.
引文
[1] He,X. S.,Woodruff, K.,Brodbec, R. B.,Med.Lett., 1997,7(15),23-992402
[2] He,X.S.,US 6,100,255(Cl.514-224.2;C07D413/12), PV63,923,31 Oct 1997; 10pp
[3] He,X.S.,WO99 23,092(Cl.C07D403/00),962.022,31 Oct 1997;43pp
[4] Richard, A., Glennon,Noreen A.N., etc., J. Med.Chem., 1988, 31, 1968～1971
[5] Magid A., Abou-Gharbia, etc., J. Med. Chem., 1999, 42, 5077～5094
[6] William L.M., Marvis E. H., J. Org. Chem.,1997, 42(3), 466～472
[7] Emanuela L. etc. J. Chem. Soc.,Chem.Commun., 1992, 1623～1624
[8] Charles E.,Jillus W. and Jan V. H. J. Chem. Soc.,Chem.Commun., 1985, 300～301
[9] Yusuke IZUMI,Chem. Lett., 1990, 12,2171～2174
[10] Stabler R., Peter K..Tetrahedron Letters. 1980. 21. 4061～4064
[11] 殷斌烈，陈芬儿，刘桂桂等，湖北化工，1991(1)：21～24
[12] 王道全，周荣灿，张涛等，中国医药工业杂志，1993，24(11)：485～486
[13] Jin, M.R.,Faming Zhuanli Shenqing Gongkai Shuomingshu,CN 1,075,139 (Cl. C07C275/30); 6pp.
[14] Wang,D.Q.,Zhang,T.,Cheng ,F.H., etc., Faming Zhuan li Shenqing Gongkai Shuomingshu CN1,033,179 (Cl.C07C 127/19);6pp
[15] Zhuang, H.S., Zhang, F., Liao,Y.,etc., FuzhouDaxueXuebao zi ran ke xue ban, 1994,22(3), 82～5(ch)
[16] Rainer B.Fred,E.R., Journal of Chromatography,1987, 397,13～24
[17] Hideko,K.and Kosuke,K., Heterocycles,2002,57(7), 1299～1302
[18] Stanley, R. and Peter K., Tetrahedron Letters, 1980,21,4061～4064
[19] Corey, E.J. and William,S.J., Tetrahedron Letters,1975,31,2647～2650
[20] Nadukkudy, V.E., Muthusami,S. and Danaboyina,R., Synthetic Communication, 1999,29(22),4007～4014
[21] U．S．FDA编著，国家商检局FDA-ADAM译，动物组织及饲料中兽药分析手册，1985，中国对外经济贸易出版社
[22] 梁志健，上海医药，2002，23(11)：502～504
[23] 樊能廷，有机合成事典，1992，北京理工大学出版社
[24] 陈芬儿主编，有机药物合成法，1998，中国医药科技出版社
[25] 赵瑞祥，中国医药报，2002．11．8
[26] 李辉，张学芳，黄自勇等，临床精神医学杂志，2001，11(6)：316
[27] 刘美丽，仝富强等，畜禽业，2002，5：10～12
[28] 孟庆玲，当代养殖业，1998，11：9～10
[29] 夏镇夷主编．中国医学百科全书精神病学分卷，1982，上海科学技术出版社
[30] 赵靖平，中国新药杂志，2002，11(2)：110～112
[31] 中国兽药典委员会编．中华人民共和国兽药典，二○○○年版。
[2] He,X.S.,US 6,100,255(Cl.514-224.2;C07D413/12), PV63,923,31 Oct 1997; 10pp
[3] He,X.S.,WO99 23,092(Cl.C07D403/00),962.022,31 Oct 1997;43pp
[4] Richard, A., Glennon,Noreen A.N., etc., J. Med.Chem., 1988, 31, 1968～1971
[5] Magid A., Abou-Gharbia, etc., J. Med. Chem., 1999, 42, 5077～5094
[6] William L.M., Marvis E. H., J. Org. Chem.,1997, 42(3), 466～472
[7] Emanuela L. etc. J. Chem. Soc.,Chem.Commun., 1992, 1623～1624
[8] Charles E.,Jillus W. and Jan V. H. J. Chem. Soc.,Chem.Commun., 1985, 300～301
[9] Yusuke IZUMI,Chem. Lett., 1990, 12,2171～2174
[10] Stabler R., Peter K..Tetrahedron Letters. 1980. 21. 4061～4064
[11] 殷斌烈，陈芬儿，刘桂桂等，湖北化工，1991(1)：21～24
[12] 王道全，周荣灿，张涛等，中国医药工业杂志，1993，24(11)：485～486
[13] Jin, M.R.,Faming Zhuanli Shenqing Gongkai Shuomingshu,CN 1,075,139 (Cl. C07C275/30); 6pp.
[14] Wang,D.Q.,Zhang,T.,Cheng ,F.H., etc., Faming Zhuan li Shenqing Gongkai Shuomingshu CN1,033,179 (Cl.C07C 127/19);6pp
[15] Zhuang, H.S., Zhang, F., Liao,Y.,etc., FuzhouDaxueXuebao zi ran ke xue ban, 1994,22(3), 82～5(ch)
[16] Rainer B.Fred,E.R., Journal of Chromatography,1987, 397,13～24
[17] Hideko,K.and Kosuke,K., Heterocycles,2002,57(7), 1299～1302
[18] Stanley, R. and Peter K., Tetrahedron Letters, 1980,21,4061～4064
[19] Corey, E.J. and William,S.J., Tetrahedron Letters,1975,31,2647～2650
[20] Nadukkudy, V.E., Muthusami,S. and Danaboyina,R., Synthetic Communication, 1999,29(22),4007～4014
[21] U．S．FDA编著，国家商检局FDA-ADAM译，动物组织及饲料中兽药分析手册，1985，中国对外经济贸易出版社
[22] 梁志健，上海医药，2002，23(11)：502～504
[23] 樊能廷，有机合成事典，1992，北京理工大学出版社
[24] 陈芬儿主编，有机药物合成法，1998，中国医药科技出版社
[25] 赵瑞祥，中国医药报，2002．11．8
[26] 李辉，张学芳，黄自勇等，临床精神医学杂志，2001，11(6)：316
[27] 刘美丽，仝富强等，畜禽业，2002，5：10～12
[28] 孟庆玲，当代养殖业，1998，11：9～10
[29] 夏镇夷主编．中国医学百科全书精神病学分卷，1982，上海科学技术出版社
[30] 赵靖平，中国新药杂志，2002，11(2)：110～112
[31] 中国兽药典委员会编．中华人民共和国兽药典，二○○○年版。