CN104080785B - 用于制备hiv附着抑制剂哌嗪前药化合物的方法 - Google Patents
用于制备hiv附着抑制剂哌嗪前药化合物的方法 Download PDFInfo
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- CN104080785B CN104080785B CN201380007908.9A CN201380007908A CN104080785B CN 104080785 B CN104080785 B CN 104080785B CN 201380007908 A CN201380007908 A CN 201380007908A CN 104080785 B CN104080785 B CN 104080785B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 68
- 238000000034 method Methods 0.000 title claims abstract description 33
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title description 16
- 239000000651 prodrug Substances 0.000 title description 12
- 229940002612 prodrug Drugs 0.000 title description 12
- 239000003112 inhibitor Substances 0.000 title description 9
- 239000002253 acid Substances 0.000 claims description 15
- -1 alkylammonium halides Chemical class 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- XLKDJOPOOHHZAN-UHFFFAOYSA-N 1h-pyrrolo[2,3-c]pyridine Chemical class C1=NC=C2NC=CC2=C1 XLKDJOPOOHHZAN-UHFFFAOYSA-N 0.000 claims description 3
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 3
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 claims description 3
- 238000010306 acid treatment Methods 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 claims description 3
- DLGYNVMUCSTYDQ-UHFFFAOYSA-N azane;pyridine Chemical compound N.C1=CC=NC=C1 DLGYNVMUCSTYDQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
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- 238000005859 coupling reaction Methods 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- VUNXBQRNMNVUMV-UHFFFAOYSA-N phenyl(piperazin-1-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)N1CCNCC1 VUNXBQRNMNVUMV-UHFFFAOYSA-N 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
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- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 claims 4
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 claims 4
- TYYCNSUODPEVQP-UHFFFAOYSA-N 8-[(4-fluorophenyl)sulfonylamino]-4-(3-pyridin-3-ylpropyl)octanoic acid Chemical compound C=1C=CN=CC=1CCCC(CCC(=O)O)CCCCNS(=O)(=O)C1=CC=C(F)C=C1 TYYCNSUODPEVQP-UHFFFAOYSA-N 0.000 claims 4
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 claims 4
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 claims 4
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 claims 4
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 claims 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 claims 2
- UARAJVWWZDPPRE-UHFFFAOYSA-N C([ClH]CCCCCCCCCCCCCC)Cl Chemical compound C([ClH]CCCCCCCCCCCCCC)Cl UARAJVWWZDPPRE-UHFFFAOYSA-N 0.000 claims 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- NELWQUQCCZMRPB-UBPLGANQSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-2-methyloxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 NELWQUQCCZMRPB-UBPLGANQSA-N 0.000 claims 2
- 238000006555 catalytic reaction Methods 0.000 claims 2
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 claims 2
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- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 claims 1
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- 208000011580 syndromic disease Diseases 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229940111527 trizivir Drugs 0.000 description 1
- 229940023080 viracept Drugs 0.000 description 1
- 229940098802 viramune Drugs 0.000 description 1
- 229940087450 zerit Drugs 0.000 description 1
- 229940052255 ziagen Drugs 0.000 description 1
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Abstract
记载了利用起始原料(BBB)制备化合物(AAA)的方法。
Description
相关申请的交叉引用
本非临时申请要求2012年2月8日提交的美国临时申请系列号61/596,362的权益。
发明领域
本发明涉及制备可用作抗病毒剂的HIV附着抑制剂化合物的方法,具体而言,涉及制备鉴定为1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1-[(膦酰基氧基)甲基]-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪的哌嗪前药化合物的方法。本发明还涉及通过本文所述的方法获得的化合物,包括中间体。
发明背景
HIV-1(人类免疫缺陷病毒1)感染仍然是一个主要医学问题,2011年底全世界仍有数千万人感染。HIV和AIDS(获得性免疫缺陷综合征)的病例数目快速上升。例如,2005年,报道了约500万例新感染,且310万人死于AIDS。目前可用于治疗HIV的药物包括核苷逆转录酶(RT)抑制剂或已批准的单一丸剂组合:齐多夫定(zidovudine)(或AZT或Retrovir®)、去羟肌苷(didanosine)(或Videx®)、司他夫定(stavudine)(或Zerit®)、拉米夫定(lamivudine)(或3TC或Epivir®)、扎西他滨(zalcitabine)(或DDC或Hivid®)、阿巴卡韦丁二酸盐(abacavir succinate)(或Ziagen®)、泰诺福韦酯反丁烯二酸盐(Tenofovir disoproxilfumarate salt)(或Viread®)、恩曲他滨(emtricitabine)(或FTC或Emtriva®)、Combivir®(含有-3TC加AZT)、Trizivir®(含有阿巴卡韦、拉米夫定和齐多夫定)、Epzicom®(含有阿巴卡韦和拉米夫定)、Truvada®(含有Viread®和Emtriva®);非核苷逆转录酶抑制剂:奈韦拉平(nevirapine)(或Viramune®)、地拉韦啶(delavirdine)(或Rescriptor®)和依发韦仑(efavirenz)(或Sustiva®)、Atripla®(Truvada® + Sustiva®),和依曲韦林(etravirine);和肽模拟蛋白酶抑制剂或已批准制剂:沙奎那韦(saquinavir)、茚地那韦(indinavir)、利托那韦(ritonavir)、奈非那韦(nelfinavir)、安普那韦(amprenavir)、洛匹那韦(lopinavir)、Kaletra®(洛匹那韦和利托那韦)、地瑞那韦(darunavir)、阿扎那韦(atazanavir)(Reyataz®)和替拉那韦(tipranavir)(Aptivus®)和整合酶抑制剂,诸如雷特格韦(raltegravir)(Isentress®);和进入抑制剂,诸如恩夫韦地(enfuvirtide)(T-20)(Fuzeon®)和马拉韦罗(maraviroc)(Selzentry®)。
此外,HIV附着抑制剂为结合于HIV表面糖蛋白gp120且干扰表面蛋白gp120与宿主细胞受体CD4的相互作用的新型抗病毒化合物亚类。因此,其在HIV生命周期的第一阶段防止HIV附着于人类CD4 T细胞且阻断HIV复制。已经努力改进HIV附着抑制剂的性质,以获得具有作为抗病毒剂的最大效用和效力的化合物。
具体而言,一种HIV附着抑制剂化合物现在已经表现出针对HIV的相当威力。该化合物被鉴定为1-(4-苯甲酰基-哌嗪-1-基)-2-[4-甲氧基-7-(3-甲基-[1,2,4]三唑-1-基)-1H-吡咯并[2,3-c]吡啶-3-基]-乙烷-1,2-二酮,记载并描述于以其整体并入本文的U.S.7,354,924:
。
上述化合物是被称为1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1-[(膦酰基氧基)甲基]-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪的前药的母体化合物。它被记载并描述于美国专利号7,745,625,其以其整体并入本文作为参考。该化合物由下式代表:
。
已经记载了制备该前药化合物的各种方法,包括在'625参考文献中详述的那些。具体而言,'625参考文献包括用于酰化、烷基化和磷酸化的各种方法。另一篇专利参考文献,2012年1月27日提交的题为“METHODS OF MAKING HIV ATTACHMENT INHIBITOR PRODRUGCOMPOUND AND INTERMEDIATES”的U.S.S.N. 13/359,708,也详述了用于制备哌嗪前药化合物的各种程序。这些包括多步骤方法,其使用化合物作为起始原料,随后将其溴化,然后硝化。进一步,向化合物引入三唑基,然后进一步连接由双羰基隔开的哌嗪部分。
本领域中现在需要制备针对HIV有用的哌嗪前药化合物的新方法。这些方法应当在总产率和原料通量两者方面为制备前药分子提供进一步全面且有效的手段。
发明概述
在第一个实施方案中,本发明提供了制备式I的化合物的方法
所述方法包括:
(a) 使化合物1与酰氯化合物反应,以形成化合物2;然后
(b) 使化合物2与二取代的胺(R2)2NH在碱中接触,以产生化合物3;其后
(c) 使化合物3与二羟基化合物在酸溶液中反应,其中羟基之间的连接基是C1–C6烷基,以得到化合物4;且
(d) 使化合物4与化合物在酸中反应,以产生化合物5;
(e) 使化合物5与Me-X4在碱中或与MeO-R3在酸中接触,以产生化合物6;且
(f) 然后使用[O]在化合物6上进行氧化反应,以得到化合物7;且
(g) 向化合物7引入三唑基,然后进行官能团互换反应,以获得上述化合物(I),其中:
R1 = -H、-Boc、-Piv、-SO2芳基、-CH2S芳基、-CH2OP(O)(OR)2、-CH2OR、-CH2芳基;
R2 = 各自独立地-H、-CO2R、-SO2芳基、-CHO;
R3和R4 = 各自独立地-H、-CO2R、-CH2SR、-CH2OR、-CH(OR)2、-CH(OR)(NR2)、-CH(NR2)2、(C1-C6)烷基;
R = 各自独立地-H、-C1-C6烷基、-芳基、-CH2芳基;
X1 = -H、-Cl、-Br、-I、;
X2 = -Cl、-Br、-I、-N(R2)2、-OSO2R;
X3 = 各自独立地-H、-OR、-NR2-Cl、-Br、-I、-SR、-SO2R、-SO3R、-SR2 +;
且X4 = -Cl、-Br、-I、OTs(甲苯磺酸酯基)、+NR3、-吡啶鎓、和。
在该实施方案中,优选R1是–SO2芳基。本文中的芳基优选为苯基。还优选X1是-H。此外,优选X3是-H。还优选二羟基化合物是乙二醇。
在一个进一步实施方案中,本发明涉及制备式I的化合物的方法
所述方法包括:
(a) 使化合物1与酰氯化合物反应,以形成化合物2;然后
(b) 使化合物2与二取代的胺(R2)2NH在碱中接触,以产生化合物3;其后
(c) 使化合物3与二羟基化合物在酸溶液中反应,其中羟基之间的连接基是C1–C6烷基,以得到化合物4;且
(d) 使化合物4与化合物在酸中反应,以产生化合物5;
(e) 使化合物5与在Me-X4在碱中或与MeO-R3在酸中接触,以产生化合物6;且
(f) 然后使用[O]在化合物6上进行氧化反应,以得到化合物;且
(g) 向化合物7引入三唑基9,以获得上述化合物(I),其中:
R1 = -H、-Boc、-Piv、-SO2芳基、-CH2S芳基、-CH2OP(O)(OR)2、-CH2OR、-CH2芳基;
R2 = 各自独立地-H、-CO2R、-SO2芳基、-CHO;
R3 = -H、-CO2R、-CH2SR、-CH2OR、-CH(OR)2、-CH(OR)(NR2)、-CH(NR2)2;
R = 各自独立地-H、-C1-C6烷基、-芳基、-CH2芳基;
X1 = -H、-Cl、-Br、-I、;
X2 = -Cl、-Br、-I、-N(R2)2、-OSO2R;
X3 = 各自独立地-H、-OR、-NR2、Cl、-Br、-I、-SR、-SO2R、-SO3R、-SR2 +;
且X4 = -Cl、-Br、-I、-OTs、+NR3、-吡啶鎓、和。
在该进一步实施方案中,优选R1是–SO2芳基。本文中的芳基优选为苯基。还优选X1是-H。此外,优选X3是-H。还优选二羟基化合物是乙二醇。
在另一个实施方案中,提供了制备式I化合物 的方法,
所述方法包括:
(a) 使化合物1与酰氯化合物反应,以形成化合物2;然后
(b) 使化合物2与二取代的胺(R2)2NH在碱中接触,以产生化合物3;其后
(c) 使化合物3与二羟基化合物在酸溶液中反应,其中羟基之间的连接基是C1–C6烷基,以得到化合物4;且
(d) 使化合物4与化合物在酸中反应,以产生化合物5;
(e) 使化合物5与Me-X4在碱中或与MeO-R3在酸中接触,以产生化合物6;然后
(f) 使用[O]在化合物6上进行氧化反应,以得到化合物7;且
(g) 进行活化反应,以得到所得化合物10;然后
(h) 在Cu离子和配体存在的情况下向化合物10引入三唑基9,以得到上面式(I)的化合物,其中:
R1 = -H、-Boc、-Piv、-SO2芳基、-CH2S芳基、-CH2OP(O)(OR)2、-CH2OR、-CH2芳基;
R2 = 各自独立地-H、-CO2R、-SO2芳基、-CHO;
R3 = -H、-CO2R、-CH2SR、-CH2OR、-CH(OR)2、-CH(OR)(NR2)、-CH(NR2)2;
R = 各自独立地-H、-C1-C6烷基、-芳基、-CH2芳基;
X1 = -H、-Cl、-Br、-I、;
X2 = -Cl、-Br、-I、-N(R2)2、-OSO2R;
X3和X5 = 各自独立地-H、-OR、-NR2、-Cl、-Br、-I、-SR、-SO2R、-SO3R、-SR2 +;
且X4 = -Cl、-Br、-I、-OTs、+NR3、吡啶鎓、和。所述配体选自1,2-二氨基环己烷、反-1,2-二氨基环己烷、顺-/反-二氨基环己烷、顺-N,N'-二甲基-1,2-二氨基环己烷、反-N,N'-二甲基-1,2-二氨基环己烷、顺-/反-N,N'-二甲基-1,2-二氨基环己烷、1,2-二氨基乙烷、N,N'-二甲基-1,2-二氨基乙烷、1,10-菲咯啉、4,7-二苯基-1,10-菲咯啉、5-甲基-1,10-菲咯啉、5-氯-1,10-菲咯啉、和5-硝基-1,10-菲咯啉。
在该进一步实施方案中,优选R1是–SO2芳基。本文中的芳基优选为苯基。还优选X1是-H。此外,优选X3是-H。
本文中还提供了制备式II的化合物的方法
所述方法包括:
(a) 使用酰化化合物10,以得到化合物11;然后
(b) 使化合物11与化合物13在活化反应中反应,以产生化合物14;且
(c) 在Cu离子和配体存在的情况下添加三唑基化合物9,以获得化合物15;且
(d) 使化合物17与化合物15反应,以产生化合物18;且
(e) 进行官能团互换反应,以得到上面式II的化合物;其中:
R5 = -H、-OR、-NR2、-Cl、-Br、-I、-SR;
R6 = -H、-Boc、-Piv、-SO2芳基、-CH2S芳基、CH2OP(O)(OR)2、-CH2OR、-CH2芳基、-Li、-Na、-K、-Ca、-Mg、TMG(四甲基胍);
R = 各自独立地-H、-C1-C6烷基、-芳基、-CH2芳基;
X1 = -H、-Cl、-Br、-I、;
X5 = -H、-OR、-NR2、-Cl、-Br、-I、-SR
X6 = -H、-OR、-NR2、-Cl、-Br、-I,-SR、-SO2R、-SR2 +、-OSO2R、-OSO3R;
且X7 = -Cl、-Br、-I、-OSO2R。
在该实施方案中,可以如前所述选择配体。还优选R=叔丁基,R6和X1是-H,且R5是–OMe。本文中的芳基优选为苯基。
对于本发明的一个进一步实施方案,记载了制备式III 化合物的方法,所述方法包括:
(1) 使化合物与邻苯二甲酸酐、H2O2和二氯甲烷反应,以得到化合物;且
(2) 通过使化合物ii与PyBrop反应进行PyBrop溴化反应,以制备化合物III,
其中R7 = -H、烷基、芳基、-SO2R、-C(O)OR、和-C(O)NR2;且
其中R = -H、-C1-C6烷基、芳基、-CH2芳基;并且进一步,其中PyBrop是肽偶联试剂溴代三-吡咯烷子基鏻六氟磷酸盐。本文中的芳基优选为苯基。
此外,本发明还涉及化合物,包括其药学上可接受的盐和混合物,所述化合物选自:
。
本发明还涉及用于产生化合物的方法,所述方法包括
(1) 在水存在的情况下使用溶剂从化合物去除叔丁基,以获得化合物;且
(2) 使化合物与TRIS(三(羟基甲基)氨基甲烷)和任选的第二溶剂反应,以获得化合物。
根据该方法,所述第一溶剂选自甲酸、NMP(N-甲基-2-吡咯烷酮)、DMSO、MeCN、MeOH和丙酮。所述酸选自H2SO4、HNO3、HCl、磷酸和甲酸。所述第二溶剂选自水、烷基酮、庚烷、甲苯、乙酸乙酯、DMSO、MeCN、MeOH和丙酮。甚至更优选地,所述酸为乙酸,且所述第二溶剂为丙酮。
本发明涉及下文描述的这些以及其它重要目的。
实施方案详述
除非另有明确记载,为了便于参考,许多试剂在本文中已经通过它们在本领域中普遍接受的字母缩写进行标识。
此外,除非在本申请的别处另外特定记载,否则以下术语可用于本文中且应当具有以下含义:
“烷基”基团是指饱和脂族烃,包括直链和支链基团。优选地,烷基具有1至20个碳原子(每当本文陈述数值范围(例如“1至20”)时,其是指该基团(在此情况下为烷基)可含有1个碳原子、2个碳原子、3个碳原子等,至多且包括20个碳原子)。更优选地,其为具有1至10个碳原子的中等大小的烷基。最优选地,其为具有1至4个碳原子的低级烷基。烷基可以是被取代或未被取代的。
如本文中和权利要求中所用,术语“C1-6烷基”是指具有最多且包括6个碳原子的直链或支链烷基,诸如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等。
“芳基”、“芳基”或“Ar”是指具有完全共轭的π电子系统的全碳单环或稠环多环(即,共享相邻碳原子对的环)基团。芳基的实例非限制性地是苯基、萘基和蒽基。芳基可以是被取代或未被取代的。
在本发明的一个优选实施方案中,哌嗪前药化合物的合成可以记载于下面的流程图中:
甚至更优选地,如下文进一步记载,哌嗪前药化合物的合成从N-磺酰化的吡咯1a开始。在三氯化铝存在的情况下,与2-氯代乙酰氯的Friedel-Crafts酰化,提供了3-丙烯酰吡咯衍生物2a。在四烷基铵卤化物,优选溴化物,优选四丁基溴化铵存在的情况下,N-甲酰基磺酰胺的钠盐置换2-氯代酮,提供了氨基酮3a。在二醇和酸存在的情况下,酮的缩酮保护,导致N-甲酰基保护基的裂解和所需二氧杂环戊烷4a的形成。由酸催化的与甲醛等价物的Pictet-Spengler环化提供了酮5a,所述酮5a在自由基引发剂诸如AlBN或氢过氧化枯烯存在的情况下用原甲酸三甲酯(TMOF)和酸处理,以得到6-氮杂吲哚6a。吡啶氮的氧化提供了N-氧化物7a,然后所述N-氧化物7a在碱存在的情况下用PyBrop处理,其使C7-位置溴化,在磺酰基保护基的水解后得到溴-氮杂吲哚8a。第二次Friedel-Crafts酰化至吲哚的C3上提供了草酸盐9a,所述草酸盐9a与N-苯甲酰基哌嗪偶联,以得到酰胺10a。三唑的加成在适当配体和碱存在的情况下由铜催化,以得到吲哚11c,所述吲哚11c被分离为其锂盐(或任选地作为与KBr的共盐)。吲哚氮与氯代磷酸酯14a的烷基化得到磷酸酯12a,随后叔丁酯基团的溶剂分解提供了最终化合物13a。
因此,哌嗪前药化合物的产生可以如下更确切地显示:
以上描述仅仅是示例性的,且不应当理解为以任何方式限制本发明的范围或基本原理。事实上,除了本文中显示和描述的那些以外,对本发明的各种改变对于本领域技术人员根据上述描述和实施例将是显而易见的。还期望此类改变落在所附权利要求的范围内。
Claims (4)
1.制备化合物III的方法,所述方法包括:
(1) 使化合物与邻苯二甲酸酐、H2O2和二氯甲烷反应,以得到化合物;且
(2) 通过使化合物ii与PyBrop反应进行PyBrop溴化反应,以制备化合物III,
其中R7 = -H、烷基、芳基、-SO2R、-C(O)OR、和-C(O)NR2;
其中R = -H、C1-C6烷基、-芳基、-CH2芳基。
2.化合物,所述化合物选自:
。
3.制备化合物13a的方法,所述方法包括:
(1) 在三氯化铝(AlCl3)存在的情况下使用2-氯乙酰氯()使化合物1a反应,以得到化合物2a;且
(2) 然后在四烷基卤化铵存在的情况下使化合物2a反应以由N-甲酰基磺酰胺的钠盐置换2-氯代酮,以得到氨基-酮化合物3a;且
(3) 在硫酸存在的情况下,使化合物3a与反应,以得到化合物4a;且
(4) 进行通过三氟乙酸催化的与甲醛的Pictet-Spengler环化,以得到酮化合物5a;且
(5) 在自由基引发剂存在的情况下用原甲酸三甲酯(TMOF)和酸处理化合物5a,以产生6-氮杂吲哚化合物6a;且
(6) 使用过氧化氢(H2O2)和邻苯二甲酸酐氧化化合物6a上的吡啶氮,以得到N-氧化物化合物7a;且
(7) 在碱K3PO4和NaOH存在的情况下用PyBrop处理化合物7a,以得到溴-氮杂吲哚化合物8a;且
(8) 然后酰化至化合物8a的吲哚基团的C3上,以产生草酸盐化合物9a;且
(9) 使化合物9a与N-苯甲酰基哌嗪偶合,以得到酰胺化合物10a;和
(10) 在配体和碱存在的情况下使用铜催化向化合物10a引入三唑基团,以产生化合物11a;且
(11) 任选从化合物11a形成11b或11c
(12) 使用氯代磷酸酯化合物使化合物11a、11b或11c的吲哚氮烷基化,以提供磷酸酯化合物12a;且
(13) 进行化合物12a的叔丁基的溶剂分解,以得到最终化合物13a。
4.用于制备化合物13a的方法,所述方法包括:
(1) 使用2-氯乙酰氯()使化合物1a反应,以得到化合物2a;且
(2) 然后使化合物2a反应以由N-甲酰基磺酰胺的钠盐置换2-氯代酮,以得到氨基-酮化合物3a;且
(3) 在酸存在的情况下,使化合物3a与反应,以得到化合物4a;且
(4) 进行通过酸催化的与甲醛的Pictet-Spengler环化,以得到酮化合物5a;且
(5) 在自由基引发剂存在的情况下用原甲酸三甲酯(TMOF)和酸处理化合物5a,以产生6-氮杂吲哚化合物6a;且
(6) 氧化化合物6上的吡啶氮,以得到N-氧化物化合物7a;且
(7) 用PyBrop处理化合物7a,以得到溴代氮杂吲哚化合物8a;且
(8) 然后酰化至化合物8a的吲哚基团的C3上,以产生草酸盐化合物9a;且
(9) 使化合物9a与N-苯甲酰基哌嗪偶合,以得到酰胺化合物10a;且
(10) 在配体和碱存在的情况下使用催化向化合物10a引入三唑基团,以产生化合物11a
;且
(11) 任选从化合物11a形成11b或11c
(12) 使用氯代磷酸酯化合物使化合物11a、11b或11c的吲哚氮烷基化,以提供磷酸酯化合物12a;且
(13) 进行化合物12a的叔丁基的所述溶剂分解,以得到最终化合物13a。
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