CN100497325C - 哌嗪衍生物及其在制备喹啉酮衍生物中的用途 - Google Patents
哌嗪衍生物及其在制备喹啉酮衍生物中的用途 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 14
- 150000004885 piperazines Chemical class 0.000 title description 12
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 12
- 150000007660 quinolones Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 16
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 14
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 30
- 229910052736 halogen Inorganic materials 0.000 description 17
- 150000002367 halogens Chemical class 0.000 description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 229960004372 aripiprazole Drugs 0.000 description 9
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
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- 238000000034 method Methods 0.000 description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
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- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 4
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- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 2
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- 239000003513 alkali Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及新的哌嗪衍生物及其在制备喹啉酮衍生物,尤其是在制备阿立哌唑(aripipzole)中的用途。
Description
技术领域
本发明涉及新的哌嗪衍生物及其在制备喹啉酮衍生物,尤其是在制备阿立哌唑(aripipzole)中的用途。
背景技术
阿立哌唑为一种已知的喹诺酮衍生物,其化学名称为7-[4-[4-(2,3-二氯苯基)-1-哌嗪]丁氧基]-3,4-二-2(1H)-喹啉酮。阿立哌唑为多巴胺D2和5-羟色胺5-HT1A受体部分激动剂,5-HT2A拮抗剂。与老的抗精神分裂症药物如氟哌啶醇以及较新的非典型抗精神分裂症药如利培酮,奥氮平,齐拉西酮和奎硫平相比,同样有效,但是阿立哌唑不良反应轻,较少导致镇静、体重增加和高催乳素血症。
已知的阿立哌唑合成方法可概括为下面5种方法,
R为2,3-二氯苯基,X1是一个卤原子或是一个能进行类似于一个卤原子取代反应的基团,X2是一个卤原子。
上述方法上都要用到过量的1,4-二溴丁烷,从而导致副反应多,中间体难以纯化,后处理麻烦。
发明内容
本发明人经研究,现已发现一种新的哌嗪衍生物,将该衍生物与7-羟基-3,4-二氢-2(1H)-喹啉酮反应制备喹啉酮衍生物,尤其是阿立哌唑时,可得到高纯度的喹啉酮衍生物,尤其是阿立哌唑,后处理方便,易于工业生产。
因此,本发明第一方面涉及下式的哌嗪衍生物,
其中A为2个氢原子或=O;
B为H,OH,OR3或O-SO2R1,O-PO(R2),O-NO2
R1为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R2为OH或C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R3为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基。
本发明还涉及制备下式哌嗪衍生物的方法,
其中A为2个氢原子或=O;
B为H,OH,OR3或O-SO2R1,O-PO(R2),O-NO2
R1为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R2为OH或C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R3为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
其包括
得到式(4)化合物,其为A=O,B=H或OR3的式I化合物
R3为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
b)将a)中式(4)化合物进一步还原,得到式(5)化合物,其为A=2个氢原子,B=OH的式(I)化合物:
或c)将式(5)化合物与选自下面一种的试剂:磺酰氯、氯代磷酸、烷(芳)基磺酰氯、烷(芳)基氯代磷酸;SO3和硫酸或P2O5和磷酸、硝酸反应得到式(6)化合物,其为A=2个氢原子,B=OSO2R1,O-PO(R2),O-NO2的式(I)化合物,R,R2如上定义。
本发明还涉及下式哌嗪衍生物在制备喹啉酮衍生物中的用途,
其中A为2个氢原子或=O;
B为H,OH,OR3或O-SO2R1,O-PO(R2),O-NO2;
R1为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R2为OH或C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R3为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
其包括将上述哌嗪衍生物与下式化合物反应,其中A,B如上定义
根据本发明,本发明中所用式(3)化合物为已知化合物,其可按文献中方法制备或市购。
根据本发明,本发明中的喹啉酮衍生物优选为阿立哌唑。
根据本发明,本发明的哌嗪衍生物优选为:4-[4-(2,3二氯苯基)-1-哌嗪]-丁酸乙酯,1-[(4-羟基)-丁基]-4-(2,3-二氯-苯基)哌嗪或4-[4-[(2,3-二氯苯基)-1-哌嗪]丁基对甲苯磺酸酯。
根据本发明,A为=O的哌嗪衍生物可通过下面反应路线A制备
反应路线A
在上面反应路线A中,X为卤素,可为F,Cl,Br,I,B为H或O-R3,R3为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;反应可在反应温度为0~200℃,最好为室温至150C℃;于选自下面的溶剂如醚如1,4-二氧六环,四氢呋喃,乙二醇二甲醚等,芳香烃如苯、甲苯、二甲苯等,低级醇如甲醇、乙醇、异丙醇等,C1-6极性溶剂如N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、乙腈等中,在碱性化合物如无机碱如碳酸钙、碳酸钠、氢氧化钠、碳酸氢钠、氨基钠、氢化钠等或有机碱如三乙胺、三丙胺、吡啶、喹啉等存在下进行。再者,根据需要反应中可加入碱金属卤化物如碘化钠、碘化钾作为催化剂,式(3)与式(4)的摩尔数无特别限定,优选是1:1。
A=2H,B=OH的本发明哌嗪衍生物可通过反应路线B制备
反应路线B
在反应路线B中,反应可在如反应路线1的溶剂和温度下进行,可用催化加氢,金属与醇或酸,金属硼氢化物,硼烷,氢化钠等方法还原。
A=2H,B为非OH的本发明哌嗪衍生物可通过反应路线C制备,
反应路线C
在反应路线C中,此处B为O-SO2R1,O-PO(R2),O-NO2,R1为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基,R2为OH或C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基。
化合物(5)可与磺酰氯、氯代磷酸、烷(芳)基磺酰氯、烷(芳)基氯代磷酸;SO3和硫酸或P2O5和磷酸、硝酸反应。反应温度为0~200℃,最佳为0~150℃,溶剂可用醚、氯仿或二氯甲烷,DMSO或DMF等溶剂。
阿立哌唑可如反应路线D所示制备
反应路线D
其中A为2H或=O;
B为H,OH,OR3或O-SO2R1,O-PO(R2),O-NO2
R1为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R2为OH或C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基;
R3为C1-4烷基或苯基或一或二取代的苯基,取代基选自C1-4烷基,卤素或硝基。
反应可在如路线1的溶剂中进行,反应温度为-20~200C℃,适宜的温度为-10~150C℃,可用碱或脱水剂进行反应,碱如路线1所述,脱水剂可为二环己基碳二亚胺(DCC),或用Mitsunobu偶联反应生成(1)。
具体实施方式
熔点测定采用YTR-3型熔点仪(天津大学精密仪器厂产),核磁共振谱采用Varian INOVA-400核磁共振仪,元素分析采用CARLO-ERBA 1106元素分析仪,质谱采用Q-Tof micro质谱仪。
实施例1
4-[4-(2,3二氯苯基)-1-哌嗪]-丁酸乙酯的制备
将2,3-二氯苯哌嗪盐酸盐26.8g,溴丁酸乙酯14.2ml,二甲亚砜50ml。碳酸钾69g于60C℃下反应4小时,以水稀释,乙酸乙酯萃取3次,水洗,无水硫酸钠干燥,过滤,减蒸至干,得浅黄色粘稠液体,HPLC分析主要成分含量在95%以上。以乙酸乙酯-正己烷为层析液,过硅胶柱得4-[4-(2,3二氯苯基)-1-哌嗪]-丁酸乙酯31.8g。
1H-NMR(CDCl3):δ 1.31(3H,t),δ 1.70(2H,q),δ 2.36(2H,t),δ2.48(2H,t),δ 2.80(4H,t),δ 3.09(4H,t),δ 4.23(2H,fourfold),δ 6.96(1H,m),δ 7.15(2H,多峰)
实施例2
1-[(4-羟基)-丁基]-4-(2,3-二氯-苯基)哌嗪的制备
硼氢化钠9g,加四氢呋喃150ml,三氟化硼以醚72.5ml滴入,降温至10C,4-[4-(2,3-二氯苯基)-1-哌嗪]丁酸乙酯(22g)溶于四氢呋喃50ml,滴入上述混合液中,升温至室温反应2小时,加冰降温,滴加3N盐酸,分出水层,有机层蒸干,得浅黄色粘稠液体,HPLC分析主要成分含量在90%以上。以乙酸乙酯-正己烷为层析液,过硅胶柱得1-[(4-羟基)-丁基]-4-(2,3-二氯-苯基)哌嗪(5)17g。
1H-NMR(CDCl3):δ 1.70(4H,m),δ 2.05(2H,t),δ 3.30(4H,宽峰),δ3.58(4H,宽峰),δ 3.59(2H,t),δ 6.94(1H,m),δ 7.14(2H,多峰)
实施例3
4-[4-[(2,3-二氯苯基)-1-哌嗪]丁基对甲苯磺酸酯的制备
1-[(4-羟基)-丁基]-4-(2,3-二氯-苯基)哌嗪(5)39g,三乙胺50ml,二氯甲烷100ml,降温至10C,将24.5g对甲苯磺酰氯溶于50ml二氯甲烷滴入,逐步升温至室温,搅拌反应过夜,次日过滤,除去三乙胺盐酸盐,无盐水洗三次,分三层,取中间层,加入无水乙醚,得白色片状晶体54.8g,为4-[4-[(2,3-二氯苯基)-1-哌嗪]丁基对甲苯磺酸酯。mp115~116℃。
1H-NMR(CDCl3):δ 2.27(4H,m),δ 2.32(3H,s),δ 3.32(4H,多峰),δ3.70(4H,t),δ 3.86(4H,t),δ 7.01(1H,m),δ 7.13(2H,qq)δ 7.28(1H,s),δ 7.74(2H,m)
其它如权利要求1定义的哌嗪化合物可类似于以上实施例1、2、3的合成方法制备。
实施例4
7-[4-[4-(2,3-二氯苯基)-1-哌嗪]丁氧基]3,4-二氢-2(1H)-喹啉酮的制备
加入干燥的N,N-二甲基甲酰胺200ml,7-羟基-3,4-二氢-2(1H)-喹啉酮(7)16.3g,降温至-5C℃,分数次加入氢化钠4.3g(60%),0℃反应半小时,将实例3得的对甲苯磺酸酯(6)45.7g溶于50ml二甲基甲酰胺,在0~5℃下滴入,逐步升高温度至室温,反应过夜,次日加冰醋酸10ml,使PH为中性,加水稀释,用乙酸乙酯萃取三次,水洗,无水硫酸钠干燥,减蒸干,加入无水乙醇80ml,冷冻放置析晶,析出黄色固体33.5g。以乙醇重结晶,得白色固体30.0g,为7-[4-[4-(2,3-二氯苯基)-1-哌嗪]丁氧基]-3,4-二氢-2(1H)-喹啉酮。mp139~140℃元素分析
分析项目 | 测定值(%) | 理论值(%) |
C | 61.41 61.52 | 61.55 |
H | 6.19 6.21 | 6.07 |
N | 9.34 9.35 | 9.37 |
Cl | 15.73 15.61 | 15.81 |
1HNMR(CDCl3):δ 1.71(2H,q,-N-C-CH2-C-C),
δ 1.82(2H,q,-O-C-CH2-C-C),
δ 2.50(2H,t,J=7.6,N-CH2-C-C),
δ 2.62(2H,t,J=7.6,-CO-CH2-C),
δ 2.67(4H,t,-CH2-N-CH2-(-C-C-C)),
δ 2.90(2H,t,J=7.6,ph-CH2-C-CO),
δ 3.08(4H,t,-CH2-N-CH2-(-ph)),
δ 3.98(2H,t,J=6.4,-O-CH2-C-C),
δ 6.36(1H,d,J=2.0,芳氢),
δ 6.54(1H,dd,J=2.0,8.4,芳氢),
δ 6.96(1H,dd,J=2.8,6.8,芳氢),
δ 7.04(1H,d,J=8.4,芳氢),
δ 7.12-7.17(2H,dd,芳氢),
δ 8.43(1H,s,-NH-)
MS(ESI)分子离子峰m/z448[M]+
Claims (2)
1.4-[4-(2,3-二氯苯基)-1-哌嗪]-丁酸乙酯。
2.权利要求1的化合物在制备7-[4-[4-(2,3-二氯苯基)-1-哌嗪]丁氧基]-3,4-二氢-2(1H)-喹啉酮中的用途。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4234585A (en) * | 1978-06-23 | 1980-11-18 | Boehringer Mannheim Gmbh | 1,2-Dihydroquinoline-2-one derivatives |
CN1042537A (zh) * | 1988-10-31 | 1990-05-30 | 大制药株式会社 | 喹诺酮衍生物 |
JP2002193915A (ja) * | 2000-12-28 | 2002-07-10 | Otsuka Pharmaceut Co Ltd | ベンゼンスルフォナート化合物 |
CN1576273A (zh) * | 2003-07-08 | 2005-02-09 | 重庆医药工业研究院有限责任公司 | 阿立哌唑的制备方法 |
-
2004
- 2004-04-21 CN CNB2004100340122A patent/CN100497325C/zh not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4234585A (en) * | 1978-06-23 | 1980-11-18 | Boehringer Mannheim Gmbh | 1,2-Dihydroquinoline-2-one derivatives |
CN1042537A (zh) * | 1988-10-31 | 1990-05-30 | 大制药株式会社 | 喹诺酮衍生物 |
JP2002193915A (ja) * | 2000-12-28 | 2002-07-10 | Otsuka Pharmaceut Co Ltd | ベンゼンスルフォナート化合物 |
CN1576273A (zh) * | 2003-07-08 | 2005-02-09 | 重庆医药工业研究院有限责任公司 | 阿立哌唑的制备方法 |
Non-Patent Citations (1)
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Novel antipsychotic agents......derivatives. Yasuo Oshiro et al.J.Med.Chem,Vol.41 No.5. 1998 * |
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