CN1239487C - 制备奎替阿平的中间体及所述中间体的制备方法 - Google Patents
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- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 title abstract description 8
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D281/16—[b, f]-condensed
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
本发明涉及用于制备式(I)所示的11-[4-/2-(2-羟乙氧基)-乙基/-1-哌嗪基]二苯并[b,f]-1,4-硫氮杂(称作奎替阿平)的新的中间体,以及这两种中间体的制备方法。
Description
本发明是申请号为018040993,发明名称为“奎替阿平及其中间体的制备方法”的中国专利申请的分案申请。
技术领域
本发明涉及制备下式所示的11-[1-[4-/2-(2-羟乙氧基)乙基/-1-哌嗪基]二苯并[b,f]-1,4-硫氮杂的新方法:
其国际非专利名称为奎替阿平(quetiapine)。该化合物具有抗多巴胺和/或血清素受体拮抗剂活性,在临床上用作抗精神病药或神经安定剂。
另外,本发明还涉及在本发明新方法中所用的新中间体。
背景技术
已知按照EP240228所记载的方法,式I化合物通过下式的偕卤代亚胺
与1-(2-羟乙氧基)乙基哌嗪反应制备得到。将形成的油状粗产物经硅胶柱色谱纯化得到约0.5摩尔、产率为77.7%的产物。
用作起始原料的式XI偕卤代亚胺是通过将下式的尿烷衍生物:
进行环化反应,然后将形成的二苯并[b,f]-1,4-硫氮杂11(10H)-酮
按照EP282236记载的数据用三氯氧化磷进行卤化反应制备得到的。其中环化反应的产率为87%,卤化反应的产率为92.6%。因此,在上述已知方法中,按照式IV的尿烷衍生物计算得到的总产率为62.6%。
该已知方法在工业规模上生产被认为是困难的,并且非常不经济,其原因分别是:只有经过柱色谱纯化才能得到可接受纯度的晶体产品;并且式XI的偕卤代亚胺不太稳定,容易在湿空气中水解。当大量处理时,这种副反应降低了产率,并且水解产品污染了最终产物。另一个缺陷在于:1-(2-羟乙氧基)乙基哌嗪的制备需要若干反应步骤,从而使该已知方法更加不经济。
根据EP282236中记载的另一种方法,将下式的哌嗪衍生物:
与2-卤代乙氧基乙醇反应,得到式I产品的产率为78%。通过式XI偕卤代亚胺与哌嗪反应制备得到式XII哌嗪衍生物的产率为88%,因此,从式IV尿烷衍生物计算得出这种合成方法的总产率仅仅为55.3%。
本发明的目的是提供制备奎替阿平的一种经济方法。
发明内容
业已发现可以通过下列方法制备式I所示的11-[4-/2-(2-羟乙氧基)乙基/-1-哌嗪基]二苯并[b,f]-1,4-硫氮杂或其可药用酸加成盐达到上述发明目的:
a1)将下式的卤代乙基哌嗪基硫氮杂衍生物
其中Hal为卤原子,与乙二醇反应;或
a2)在脱水剂的存在下,环化下式的卤代乙基哌嗪衍生物
其中Hal为卤原子,然后将得到的式VIII卤代乙基-哌嗪基硫氮杂衍生物(其中Hal如上定义)与乙二醇反应;或
a3)将下式的羟乙基哌嗪衍生物
与卤化试剂反应,然后在脱水剂的存在下环化得到的式VII卤代乙基哌嗪衍生物,其中Hal为卤原子,再将得到的式VIII卤代乙基哌嗪基硫氮杂衍生物(其中Hal如上定义)与乙二醇反应;或
a4)同时用卤化试剂和脱水剂与式VI羟乙基哌嗪衍生物反应,将得到的式VIII卤代乙基-哌嗪基硫氮杂衍生物(其中Hal为卤原子)与乙二醇反应;或
a5)将式IV的尿烷衍生物与下式的1-(2-羟乙基)哌嗪反应:
然后同时用卤化试剂和脱水剂与形成的式VI羟乙基哌嗪衍生物反应,把得到的式VIII卤代乙基哌嗪基硫氮杂衍生物(其中Hal为卤原子)与乙二醇反应;和,如果需要,用可药用的无机酸或有机酸将得到的产物转变成酸加成盐。
另外,本发明包括下式的新哌嗪衍生物
其中,或者
R1为氢原子,
R2与R3形成氧原子,而
R4为氢原子;或者
R1与R2形成与其相邻氮原子和碳原子之间的化学键,
R3与R4形成相邻碳原子之间的化学键,而
X表示羟基或卤原子,
及其与无机酸或有机酸形成的酸加成盐。
这些新的哌嗪衍生物是本发明新方法的中间体。
具体实施方式
优选实施方案描述
在本发明的方法a1)中,应用Williamson’s合成的通常反应方式。首先,用金属钠或任何其它合适的无机碱将乙二醇转变成其醇化物。通常来说,钠和乙二醇均需过量;按照1摩尔式VIII卤代乙基-哌嗪基硫氮杂衍生物计算,合适地为1.5-1.7摩尔钠和20-30摩尔、优选25-27摩尔乙二醇。反应温度通常为50-150℃、优选约100℃。通常来说,反应进行5-15小时,通常为9小时。
在本发明的方法a2)中,优选的起始化合物为式VII卤代乙基哌嗪衍生物,其中Hal为氯原子,合适的脱水剂为五氧化二磷。合适地,还可以把三氯氧化磷加入到反应混合物中,然后优选在反应混合物的沸点温度下进行环化反应。将形成的式VIII卤代乙基哌嗪基硫氮杂衍生物按照方法a1)记载的方法转变成式I产物。
在本发明的方法a3)中,合适地应用亚硫酰氯或优选应用三氯氧化磷作为卤化试剂。卤化反应在惰性有机溶剂中进行,或者也可以把过量的卤化试剂用作溶剂。通常来说,在反应混合物的沸点温度下进行卤化反应。按照方法a2)记载的方法将形成的式VII卤代乙基哌嗪衍生物转化成式I产物。
在本发明的方法a4)中,在一个步骤中进行式VI羟乙基哌嗪衍生物的卤化反应和随后的环化反应,不需要分离在卤化反应中形成的式VII卤代乙基哌嗪衍生物。合适的卤化试剂为三氯氧化磷,优选的脱水剂为五氧化二磷。可以把惰性有机溶剂加入到反应混合物中,或者把过量的卤化试剂用作溶剂。合适地,在反应混合物的沸点温度下进行反应。在大多数情况下,反应时间为6-10小时、优选7-8小时。经反应结束后,将反应混合物倾入到水中,调节成碱性,然后用不与水混溶的有机溶剂例如二氯甲烷提取。然后,按照方法a1)记载的相关反应步骤制备得到式I产物。
在本发明的方法a5)中,在惰性有机溶剂中将式VI尿烷衍生物与1-(2-羟乙基)哌嗪反应,其中所用的溶剂通常为非极性有机溶剂,优选甲苯。通常在高于室温的温度下进行反应,优选在所用溶剂的沸点温度下进行反应。反应时间相对较短,通常在2小时内完全完成反应。首先,用碱的水溶液洗涤反应混合物,然后用水除去形成的苯酚,干燥有机相,蒸发。用有机溶剂结晶残余物。按照本发明方法a4)记载的相关方法将形成的式VI羟乙基哌嗪衍生物转变成式I产物。
可以按照本领域已知的方法将式I产物转化成可药用的酸加成盐。优选地,制备半延胡索酸盐。如果需要,可以按照本领域已知的方法将式I碱从其酸加成盐中释放出来。
式IV尿烷衍生物可以按照文献记载的已知方法制备:将下式的2-氨基-二苯硫化物
与下式的氯甲酸苯酯
反应。
从式IV尿烷衍生物计算,式I化合物以本发明方法制备的总产率为66-67%。本发明方法的反应步骤容易进行,起始化合物和试剂容易得到。本发明方法不含有任何会带来困难或导致产率较低的步骤。形成的式I奎替阿平的纯度高。
本发明的中间体式VI羟乙基哌嗪衍生物、式VII卤代乙基哌嗪衍生物和式VIII的卤代乙基哌嗪基硫氮杂衍生物均为新化合物。
上述的新中间体特征在于式IX。因此,优选的式IX新哌嗪衍生物为下列化合物:-式VI的羟乙基哌嗪衍生物及其酸加成盐;
-式VII的卤代乙基哌嗪衍生物,其中Hal如上定义,及其酸加成盐;和
-式VIII的卤代乙基哌嗪基硫氮杂衍生物,其中Hal如上定义,及其酸加成盐。
特别优选的式VII卤代乙基哌嗪衍生物为N-[4-(2-氯乙基)哌嗪-1-羰基]-2-氨基二苯基硫化物及其酸加成盐。
特别优选的式VIII卤代乙基哌嗪基硫氮杂衍生物为11-[4-(2-氯乙基)哌嗪-1-基]-二苯并[b,f]-1,4-硫氮杂及其酸加成盐。
可以按照与本发明方法相关的上述方法制备这些新中间体。
本发明通过下列实施例作进一步发明。
式IV起始化合物的制备
2-苯基硫代苯基氨基甲酸苯酯
把20.13g(0.1摩尔)2-氨基二苯基硫化物溶解于250ml二氯甲烷中,将形成的溶液冷却到5℃。将18.79g(15.1ml,0.12摩尔)氯甲酸苯酯溶解于26ml二氯甲烷中的溶液的一半缓缓加入到上述搅拌的2-氨基二苯基硫化物溶液中,然后,将所述氯甲酸苯酯的另一半溶液和3.0g(0.075摩尔)氢氧化钠和9.2g(0.0875摩尔)碳酸钠在50ml水中的溶液同时加入,注意使内部温度不超过10℃。加完上述溶液后,将反应混合物在室温下搅拌3小时,分离有机相,用总量为250ml的稀盐酸洗涤3次,用无水硫酸镁干燥,蒸发。残余物用正己烷结晶。
这样,得到29g(90.2%)标题化合物。
熔点:90-91℃。
元素分析:C19H15NO2S(321.401)
计算值:C 71.01%,H 4.70%,N 4.36%,S 9.98%;
实测值:C 71.19%,H 4.69%,N 4.33%,S 9.84%。
实施例1
N-[4-(2-羟乙基)哌嗪-1-羰基]-2-氨基二苯基硫化物-式VI化合物
将32.1g(0.1摩尔)2-苯基硫代苯基氨基甲酸苯酯溶解于600ml甲苯中,然后在搅拌下往该溶液中加入13.0g(0.1摩尔)1-(2-羟乙基)哌嗪。让该反应混合物在沸点温度下搅拌反应2小时,然后冷却至室温,用600ml 1N氢氧化钠溶液洗涤,然后每次用200ml水洗涤两次。用无水硫酸镁干燥有机相,蒸发。残余物用10∶1比例的正己烷-乙酸乙酯混合物重结晶,过滤,用正己烷洗涤,干燥。
这样得到白色晶体形式的标题化合物33.9g(94.8%)。熔点:96-98℃。
分析:C19H23N3O2S(357.478)
计算值:C 63.84%,H 6.49%,N 11.75%,S 8.97%;
实测值:C 63.57%,H 6.52%,N 11.71%,S 9.02%。
实施例2
N-[4-(2-氯乙基)哌嗪-1-羰基]-2-氨基二苯基硫化物-式VII标题化合物
将18.8g(0.05摩尔)N-[4-(2-羟乙基)哌嗪-1-羰基]-2-氨基二苯基硫化物在65ml亚硫酰氯中回流加热15分钟,然后蒸发,残余物用正己烷结晶。获得18.5g(89.7%)产物,其为标题化合物的盐酸盐。
熔点:180-183℃。
碱的形成:
把2.78g(0.0275摩尔)三乙胺加入到10.31g(0.025摩尔)上述盐酸盐的250ml异丙醇溶液中,将该反应混合物在室温下搅拌1小时,倾入到水中,用二氯甲烷提取,用无水硫酸镁干燥,蒸发。这样得到8.0g(85.1%)标题化合物。
与苯磺酸形成的盐
把3.48g(0.022摩尔)苯磺酸在10ml乙醇中的溶液加入到7.5g(0.02摩尔)标题碱化合物在15ml乙醇中的溶液中。将该溶液在室温下搅拌1小时,然后用冰水冷却,过滤并干燥。这样得到6.6g(60.8%)产物,其为标题化合物的苯磺酸盐。熔点:110-112℃。
分析:C25H28ClN3O4S2(534.101)
计算值:C 56.22%,H 5.28%,N 7.87%,Cl 6.64%,S 12.01%;
实测值:C 55.96%,H 5.35%,N 7.73%,Cl 6.50%,S 12.05%。
实施例3
11-[4-(2-氯乙基)-1-哌嗪基]-二苯并[b,f]-1,4-硫氮杂-式VIII化合物
方法A)
把由8.2g(0.02摩尔)N-[4-(2-氯乙基)-哌嗪-1-羰基]-2-氨基二苯基硫盐酸盐、84ml三氯氧化磷和8.5g(0.06摩尔)五氧化二磷组成的混合物在沸点温度下反应15小时。将溶液冷却,然后彻底蒸发,将残余物倾入到冰水中,加入氨水将溶液调节至碱性,用二氯甲烷提取。蒸发有机相,将残余物用二异丙基醚结晶,过滤后干燥。
这样得到5.4g(75.4%)标题化合物,熔点:113-115℃。
方法B)
将由35.7g(0.1摩尔)N-[4-(2-羟乙基)-哌嗪-1-羰基]-2-氨基二苯基硫化物、200ml三氯氧化磷和31.2g(0.22摩尔)五氧化二磷组成的混合物回流加热7小时。将溶液冷却,蒸发,残余物用冰水处理,用氨水调节至碱性,用二氯甲烷提取,用无水硫酸镁干燥,然后蒸发。用二异丙基醚结晶残余物,过滤晶体并干燥。
这样得到28.6g(80%)标题化合物。熔点:114-116℃。
分析:C19H20ClN3S(357.908)
计算值:C 63.76%,H 5.63%,N 11.74%,Cl 9.91%,S 8.96%;
实测值:C 63.70%,H 5.67%,N 11.68%,Cl 9.89%,S 9.07%。
实施例4
11-[4-/2-(2-羟乙氧基)乙基/-1-哌嗪基]二苯并[b,f]-1,4硫氮杂半延胡索酸盐-式I化合物
将1.17g金属钠溶解于50ml乙二醇中,然后往所得溶液中加入10.7g(0.03摩尔)11-[4-(2-氯乙基)-1-哌嗪基]-二苯并[b,f]-1,4硫氮杂在60ml甲苯中的溶液。将反应混合物在100℃下搅拌9小时,冷却后,加入210ml水。分离后,用稀盐酸提取甲苯相,加入氨水调节溶液至碱性,用二氯甲烷提取,用无水硫酸镁干燥该有机溶液,减压蒸发。
这样得到11.27g(98%)标题碱化合物。
盐的形成:
将10g(0.026摩尔)由上述方法获得的碱溶解于130ml乙醇中,然后往该溶液中加入3.13g(0.027摩尔)延胡索酸。在搅拌下将混合物回流加热25分钟,然后冷却至室温。将该混合物在冰箱中维持过夜,然后过滤晶体,用冷乙醇洗涤,干燥。
这样得到9.8g(85.4%)标题化合物,熔点:172-174℃。
分析:C46H54N6O8S2(883.107)
计算值:C 62.56%,H 6.16%,N 9.52%,S 7.26%;
实测值:C 62.19%,H 6.19%,N 9.57%,S 7.24%。
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US7030116B2 (en) | 2000-12-22 | 2006-04-18 | Aventis Pharmaceuticals Inc. | Compounds and compositions as cathepsin inhibitors |
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CA2516646A1 (en) * | 2003-02-22 | 2004-09-10 | Teva Pharmaceutical Industries Ltd. | Synthesis of quetiapine and pharmaceutically acceptable salts thereof |
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