CN107074726A - 新型抗炎化合物的合成 - Google Patents
新型抗炎化合物的合成 Download PDFInfo
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- CN107074726A CN107074726A CN201580042973.4A CN201580042973A CN107074726A CN 107074726 A CN107074726 A CN 107074726A CN 201580042973 A CN201580042973 A CN 201580042973A CN 107074726 A CN107074726 A CN 107074726A
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Abstract
根据本发明的实施方式,提供了制备式(19)的化合物的方法。采用这种方法,可以有效的制备式(19)的化合物。
Description
技术领域
本发明通常涉及合成脂氧素衍生物。特别地,其涉及脂氧素衍生物的制备和用于制备脂氧素衍生物的中间体
背景技术
脂氧素类是一系列抗炎介质。脂氧素类是短暂存活的内源产生的非经典的类花生酸类,其在炎症中的出现表示炎症消退。它们被简称为LX,脂氧合酶(LO)相互作用产物的首字母缩写。目前已经确定了两种脂氧素;脂氧素A4(LXA4)和脂氧素B4(LXB4)。
Serhan、Hamberg和Samuelsson于1984年首次描述了脂氧素类。他们报道称脂氧素类在亚微摩尔浓度下刺激超氧阴离子(O2-)产生和脱粒-与LTB4一样有效。
脂氧素类,与某些肽一样,是脂氧素A4受体(LXA4R)的高亲和力配体,脂氧素A4受体是第一个基于序列同源性被确定为甲酰肽受体,如受体(FPRL1)。通过LXA4R的脂氧素信号转导抑制趋化性、迁移、超氧化物产生和NF-κB活化。相反地,在体外通过相同受体的肽信号转导已经显示出刺激多形核细胞(PMN)的趋化性和钙动员。具有ALXR亲和力的肽倾向于是白细胞迁移和随后的吞噬作用的信号,例如急性时相蛋白、细菌肽,HIV包膜蛋白和神经毒性肽。与白三烯类似,LXA4会形成半胱氨酰-脂氧素LXC4、LXD4和LXE4。在亚纳摩尔浓度下,LXA4和LXB4抑制白三烯刺激的人中性粒细胞和内皮细胞的相互作用。脂氧素类是I型半胱氨酰白三烯受体(CysLTI)的高亲和力拮抗剂,几种白三烯(LTC4、LTD4和LTE4)介导其平滑肌收缩和嗜酸性粒细胞趋化作用。CysLT1受体也是哮喘药物孟鲁司特的作用位点。
发明内容
本申请旨在至少在一定程度上解决现有技术中存在的问题中的至少一个。因此,本申请的一个目的是提供有效制备式19的化合物及其中间体的方法。
在本发明的第一方面,提供了用于制备式19的化合物的方法,该方法包括:
在HOAC的存在下使丙炔酸乙酯与溴化锂碱在CH3CN中接触以获得式2的化合物;
使式3的化合物与THF中的正丁基锂溴代环烷烃(n-Buli bromocyclane)接触以获得式4的化合物;
使式4的化合物与HZrCp2Cl在THF中接触以获得式5的化合物;
在Pd(PPH3)2Cl2、DIBAH和ZnCl2的存在下使式2的化合物与式4的化合物接触以获得式6的化合物;
使式6的化合物与DIBAL在DCM中接触以获得式7的化合物;
使式7的化合物与CBr4、PPh3、咪唑在DCM中接触以获得式8的化合物;
使式8的化合物与P(OMe)3在CH3CN中接触以获得式9的化合物;
在室温下使式10的化合物与乙酰氯在MeOH中接触以获得式11的化合物;
在回流的条件下使式11的化合物与CDI在CH3CN中接触以获得式12的化合物;
在回流的条件下使式12的化合物与HCL在二氧六环和水的混合物中接触以获得式13的化合物,其中二氧六环与水的体积比为约3:1;
在回流的条件下使式13的化合物与Ph3PCHCO2和苯甲酸在甲苯中接触以获得式14的化合物;
在Pd/C的存在下使式14的化合物与H2在EtOH中接触以获得式15的化合物;
使式15的化合物与DCC和Cl2CHCOOH接触以获得式16的化合物;
使式16的化合物与Ph3P=CHCHO在DCM中接触以获得式17的化合物;
在LDA和HMPA的存在下使式17的化合物与式9的化合物在THF中接触以获得式18的化合物;
使式18的化合物与NaOH在MeOH中接触以获得式19的化合物;
n为1至5之间的整数。
采用上述方法,可以有效地制备式19的化合物。应当注意的是,在本公开中,表达“式N的化合物”也可以与表达“化合物N”互换,且术语N表示化合物的编号。例如,化合物19可与“式19的化合物”互换。
在本公开的另一方面,本文中提供了制备式6的化合物的方法,包括:
使式2的化合物与双(三苯基膦)氯化钯(II)和二异丁基氢化铝接触以获得式6的化合物,其中n为1至5之间的整数,
在本公开的一些实施方式中,接触是在THF中进行的。
在本公开的一些实施方式中,接触是在氯化锌的存在下进行的。
在本公开的一些实施方式中,双(三苯基膦)氯化钯(II)为式2的化合物的约2%至约8%。
在本公开的一些实施方式中,接触是在室温至约回流温度的温度范围内进行的。
在本公开的一些实施方式中,还包括使式6的化合物与DIBAL-D在DCM中接触以获得式7的化合物,其中n为1至5之间的整数,
在本公开的一些实施方式中,DIBAL-D的浓度为1.2M至2.0M。
在本公开的一些实施方式中,式2的化合物是通过使丙炔酸乙酯与溴化锂碱接触以获得式2的化合物的步骤制备的
在本公开的一些实施方式中,丙炔酸乙酯与溴化锂碱的接触是在包括乙酸和乙腈的溶剂中进行的,且乙酸与乙腈的体积比为1:2~2:1。
在本公开的一些实施方式中,丙炔酸乙酯与溴化锂碱的接触是在约40℃至约回流温度的温度范围内进行的。
在本公开的另一方面,本文提供了制备式14的化合物的方法,包括:
使式13的化合物与(三苯基亚正膦基)乙酸乙酯(ethyl(triphenylphosphoranylidene)acetate)和苯甲酸接触以获得式14的化合物
在本公开的一些实施方式中,接触是在室温至约回流温度的温度下进行的。
在本公开的一些实施方式中,接触是在甲苯中进行的。
在本公开的另一方面,提供了制备式18的化合物的方法,包括:
使式9的化合物与式17的化合物接触以获得式18的化合物,其中n为1至5之间的整数,
在本公开的一些实施方式中,接触是在碱的存在下进行的,其中该碱选自由LDA、n-BuLi和NaH组成的组。
在本公开的一些实施方式中,碱的浓度为约1.1M至约1.5M。
在本公开的一些实施方式中,接触是在-78℃至室温的温度下进行的。
具体实施方式
总之,以下方案示出了如本文所述的用于制备脂氧素衍生物的方法(n=1、2、3、4、5)。
方法I
已经发现本文中所描述的制备脂氧素衍生物的方法提供了令人惊讶且意料不到地提高产量和纯度的脂氧素衍生物和用于合成脂氧素衍生物的中间体。方法I示出了采用本发明的方法从化合物1至脂氧素衍生物的合成路线。如下所示,可以以可以组合形成总分子的三个主要片段(A、B和C)来制备方法I或方案I中的脂氧素衍生物。目标化合物可以通过Witting反应所采用的路线(片段D+E)来制备。片段D可以通过Witting反应所采用的路线(片段F+G)来制备。片段E可以通过锆氢化钯催化交叉偶联反应所采用的路线(片段H+I)来制备。这种合成路线利用了多个意想不到的发现。
方案I
目标产物的总的合成工艺路线反应条件温和、环境污染少且合成工艺可靠。脂氧素衍生物的合成工艺是成熟的反应。已经发现,相比于采用其它方法,本方法获得的产品不仅提高了中间体化合物的产量和纯度,而且提高了终产物(脂氧素衍生物)的产量和纯度。
实施例
以下缩写用于实施例和整个公开中。
CDI 1,1'-羰二咪唑
DCM 二氯甲烷
DCC 二环己基碳二亚胺
DIBAL 二异丁基氢化铝
GC 气相色谱
LDA 二异丙基氨基锂
n-BuLi 正丁基锂
PBr3 三溴化磷
THF 四氢呋喃
合成(5S,6R,7E,9E,11Z,13E)-15-环丙基-5,6-二羟基二十碳烷-7,9,11,13-四烯酸
步骤1:3-溴丙烯酸乙酯
将含有丙炔酸乙酯(5.0g,51mmol)和乙酸(10mL)和乙腈(10mL)中的溴化锂(4.3g,51mmol)的混合物在60℃下搅拌2小时。然后,将水(50mL)倒入混合物中并用乙酸乙酯萃取。有机相用Na2SO4进行干燥,过滤掉硫酸盐,并浓缩得到8.2g化合物2。产率:91%。GC/MS:177;
1H-NMR(DMSO-d6):δ=6.80(d,J=10.8Hz,1H),6.62(d,J=10.8Hz,1H),1.40(q,2H),0.85(t,3H).
步骤2:叔丁基二甲基(3-甲基辛-1-炔-3-基氧基)硅烷
用干燥的冰丙酮将辛-1-炔(5.5g,50mmol)在四氢呋喃(60mL)中的混合物冷却至-78℃。然后,将正丁基锂(60mmol)加入混合物中。将混合物在该温度下搅拌30分钟,然后,加入溴代环丙烷(6.6g,55mmol)。在室温下对混合物搅拌4小时。在完成反应后,用氯化铵溶液将混合物猝灭,将水(80mL)倒入混合物中并用乙酸乙酯萃取。有机相用Na2SO4进行干燥,过滤掉硫酸盐,浓缩得到粗产物并通过快速色谱法进行纯化获得5.3g化合物4。产率:71%。
1H-NMR(DMSO-d6):δ=3.01(s,1H),2.65(q,1H),1.25-1.4(m,8H),0.90(t,3H),0.2-0.3(m,4H),0.28(s,1H).
步骤3:合成化合物5
将化合物4(1.5g,10mmol)和HZrCp2Cl(3.08g,12mmol)在THF(50mL)中混合,将混合物在室温下搅拌12小时。将水(60mL)倒入混合物中,并用乙酸乙酯萃取。有机相用卤水洗涤并用Na2SO4进行干燥,过滤掉硫酸盐,并浓缩得到粗产物化合物5,用于下一步骤而无需纯化。
步骤4:合成化合物6
将化合物5(3.96g,9.5mmol)和化合物2(1.68g,9.5mmol)在THF(50mL)中混合,然后向混合物中加入双(三苯基膦)氯化钯(II)(5%,330mg)、二异丁基氢化铝(10%)和痕量ZnCl2。将混合物在氮气回流下搅拌12小时。将水(100mL)倒入混合物中,并用乙酸乙酯萃取。有机相用饱和的NaHCO3水溶液、卤水洗涤并用Na2SO4干燥,过滤掉硫酸盐,并浓缩得到粗产物,用快速色谱法纯化得到1.6g化合物6,两步产率64%。
步骤5:合成化合物7
向250-mL圆底烧瓶中装入化合物6(2.5g,10mmol)在DCM(50mL)中的溶液,然后用干燥的冰-丙酮浴冷却。在30分钟内加入50-mL的1.5M DIBAL-D在DCM中的溶液,然后将溶液在2小时内温热至0℃。通过缓慢加入2M NH4Cl(水溶液)溶液淬灭反应直到停止释放气体。反应混合物变稠,具有凝胶状物质。将其与DCM分离,用2M H2SO4溶解,然后用DCM(4×20mL)萃取。将有机层合并,然后洗涤(H2O,5%NaHCO3,卤水),用MgSO4干燥,并除去溶剂。通过柱色谱对粗产物进行纯化,得到1.8g化合物7,产率72%。
1H-NMR(DMSO-d6):δ=6.28(m,1H),6.25(m,1H),5.78(m,2H),5.68(m,1H),2.15(m,1H),1.20-1.30(m,8H),0.90(t,3H),0.3-0.5(m,5H).
步骤6:合成化合物8
向50mL圆底烧瓶中装入PBr3(1.23g,4.52mmol)然后用干燥的冰-丙酮进行冷却。在20分钟内加入化合物7(2.24g,10.8mmol)在Et2O(15mL)中的溶液。在接下来的30分钟内将溶液逐渐温热至-25℃,此时移除冷却浴。将其再搅拌3.5小时,然后倒入含有冰和固体NaHCO3(2.5g)的分液漏斗中。用Et2O(2×15mL)冲洗烧瓶,并将冲洗液加入分液漏斗中。震荡混合物直到冰融化,然后分离。水层用Et2O(2×15mL)进行萃取,将有机层合并,用卤水洗涤并用Na2SO4干燥。取出一小部分等分试样并浓缩得到粗产物化合物8,用于下一步骤而无需进一步纯化。
LC/MS:[M+H]=375
步骤7:合成化合物9
将化合物8(1.78g,6.6mmol)溶于乙腈(10mL)中,并将亚磷酸三甲酯(900mg,7.26mmol)加入溶液中。将混合物在氮气下在室温下搅拌过夜。在反应完成后,将水(60mL)倒入溶液中,并用NaHCO3(2.5g)进行萃取。用Et2O(2×15mL)冲洗烧瓶,将冲洗液加入分液漏斗中。震荡混合物直到冰融化,然后分离。水层用乙酸乙酯进行萃取。将有机相用饱和的NaHCO3水溶液、卤水进行洗涤并用Na2SO4干燥,过滤掉硫酸盐并浓缩得到粗产物,用快速色谱法进行纯化得到1.56g化合物9,产率:78%。
步骤8:(3S,4R)-6-甲氧基四氢-2H-吡喃-3,4-二醇
将(4R,5S)-四氢-2H-吡喃-2,4,5-三醇(2.68g,20mmol)溶于MeOH(30mL)中并用冰浴冷却,将乙酰氯(1.63g,21mmol)滴入溶液中。加入后,将混合物在室温下搅拌3小时。完成后,将混合物倒入水(100mL)中,并用乙酸乙酯萃取。将有机相用饱和的NaHCO3水溶液、卤水进行洗涤并用Na2SO4干燥,过滤掉硫酸盐并浓缩得到产物,用快速色谱法进行纯化得到2.2g化合物11,产率:74%。
1H-NMR(DMSO-d6):δ=4.86(m,1H),3.86(s,2H),3.34(s,3H),3.25(m,2H),2.68(s,2H),1.86(m,2H).
步骤9:合成化合物12
将化合物11(2.2g,14.8mmol)溶于乙腈(20mL)并向溶液中加入1,1'-羰二咪唑(2.4g,14.8mmol)。将混合物搅拌回流6小时。完成后,将混合物倒入水(100mL)中,并用乙酸乙酯萃取。有机相用1N HCl(20mL)、卤水进行洗涤并用Na2SO4干燥,过滤掉硫酸盐,并浓缩得到产物2.23g用于下一步骤。
步骤10:合成化合物13
将化合物12(2.23g,12.8mmol)溶于混合物溶液(20mL,二氧六环/H2O=3:1)中,向混合物中加入4N HCl(10mL)。然后,将混合物搅拌回流5小时。完成后,浓缩混合物得到2.0g化合物13用于下一步骤。
步骤11:(E)-4-((4S,5R)-5-(羟甲基)-2-氧代-1,3-二氧戊环-4-基)丁-2-烯酸乙
酯
将化合物13(3.2g,20mmol)溶于甲苯(30mL)和苯甲酸(20mmol)中,向溶液中加入(三苯基亚正膦基)乙酸乙酯(7.3g,21mmol)。将混合物搅拌回流过夜。完成后,将混合物浓缩得到油状产物,并溶于DCM(50mL)中,用(H2O、5%NaHCO3、卤水)洗涤,并用MgSO4干燥,除去溶剂。通过柱色谱对粗产物进行纯化得到2.86g化合物14,产率62%。
1H-NMR(DMSO-d6):δ=6.86(m,1H),5.85(d,1H),4.23-4.26(m,2H),4.04(t,2H),3.98(m,2H),2.52(m,2H),1.66(t,3H).
步骤12:4-((4S,5R)-5-(羟甲基)-2-氧代-1,3-二氧戊环-4-基)丁酸乙酯
将化合物14(2.0g,8.7mmol)溶于EtOH(15mL)中,加入Pd/C(10%,200mg)。将混合物在氢气(2tams)下在室温下搅拌过夜。然后,将溶液过滤并浓缩,得到1.86g化合物15用于下一步骤。
步骤13:4-((4S,5S)-5-甲酰基-2-氧代-1,3-二氧戊环-4-基)丁酸乙酯
将化合物15(3.0g,12.9mmol)溶于二氯乙酸(25mL)中,加入二环己基碳二亚胺(2.92g,14.1mmol)。将混合物在室温下搅拌8小时。然后,将溶液过滤并浓缩,并溶于DCM(60mL)中,用(H2O、5%NaHCO3、卤水)洗涤,用MgSO4干燥,除去溶剂得到2.8g粗产物用于下一步骤。
步骤14:4-((4S,5R)-2-氧代-5-((E)-3-氧代丙-1-烯基)-1,3-二氧戊环-4-基)丁
酸乙酯
将化合物16(2.5g,10.8mmol)溶于二氯甲烷(30mL)中,向混合物中加入Ph3P=CHCHO(3.28g,10.8mmol)。将混合物在室温下搅拌12小时。完成后,将混合物用(H2O、5%NaHCO3、卤水)洗涤,并用MgSO4干燥,并除去溶剂。通过柱色谱对粗产物进行纯化得到2.0g化合物14,产率72%。
步骤15:合成化合物18
将化合物17(3.3g,12.9mmol)溶于冷却至-78℃的THF(25mL)中,加入二异丙基氨基锂(1.65g,15.4mmol)。将混合物搅拌30分钟,并温热至室温。然后,加入六甲基磷酰胺(2.77g,15.4mmol)和化合物9。将混合物在室温下搅拌过夜。将混合物加入到冰冷的2M HCl水溶液(150mL)中。将混合物用乙酸乙酯萃取两次,合并的有机相用饱和的NaCl水溶液洗涤两次,干燥(MgSO4),过滤,并浓缩得到粗产物,用快速色谱法进行纯化得到3.55g化合物18,产率:63%。
步骤16:合成化合物19
将化合物18(1.46g,3.4mmol)溶于甲醇(20mL)中,向溶液中加入2M氢氧化钠,将混合物在室温下搅拌15小时。完成后,将pH调节至5,使所需产物化合物19沉淀出来,800mg,产率:62%。
Claims (14)
1.一种用于制备式19的化合物的方法,包括:
在HOAC的存在下使丙炔酸乙酯与溴化锂碱在CH3CN中接触以获得式2的化合物;
使式3的化合物与THF中的正丁基锂溴代环烷烃接触以获得式4的化合物;
使所述式4的化合物与HZrCp2Cl在THF中接触以获得式5的化合物;
在Pd(PPH3)2Cl2、DIBAH和ZnCl2的存在下使所述式2的化合物与所述式4的化合物接触以获得式6的化合物;
使所述式6的化合物与DIBAL在DCM中接触以获得式7的化合物;
使所述式7的化合物与CBr4、PPh3、咪唑在DCM中接触以获得式8的化合物;
使所述式8的化合物与P(OMe)3在CH3CN中接触以获得式9的化合物;
在室温下使式10的化合物与乙酰氯在MeOH中接触以获得式11的化合物;
在回流的条件下使所述式11的化合物与CDI在CH3CN中接触以获得式12的化合物;
在回流的条件下使所述式12的化合物与HCL在二氧六环和水的混合物中接触以获得式13的化合物,其中二氧六环与水的体积比为约3:1;
在回流的条件下使所述式13的化合物与Ph3PCHCO2和苯甲酸在甲苯中接触以获得式14的化合物;
在Pd/C的存在下使所述式14的化合物与H2在EtOH中接触以获得式15的化合物;
使所述式15的化合物与DCC和Cl2CHCOOH接触以获得式16的化合物;
使所述式16的化合物与Ph3P=CHCHO在DCM中接触以获得式17的化合物;
在LDA和HMPA的存在下使所述式17的化合物与所述式9的化合物在THF中接触以获得式18的化合物;
使所述式18的化合物与NaOH在MeOH中接触以获得所述式19的化合物;
其中n为1至5之间的整数。
2.一种制备式6的化合物的方法,包括:
使式2的化合物与双(三苯基膦)氯化钯(II)和二异丁基氢化铝接触以获得所述式6的化合物,其中n为1至5之间的整数,
3.根据权利要求2所述的方法,其中所述接触是在THF中进行的。
4.根据权利要求2所述的方法,其中所述接触是在氯化锌的存在下进行的。
5.根据权利要求2所述的方法,其中双(三苯基膦)氯化钯(II)的摩尔量为所述式2的化合物的摩尔量的约2%至约8%。
6.根据权利要求2所述的方法,其中所述接触是在室温至约回流温度的温度范围内进行的。
7.根据权利要求2所述的方法,还包括使所述式6的化合物与DIBAL-D在DCM中接触以获得式7的化合物,其中n为1至5之间的整数,
8.根据权利要求7所述的方法,其中DIBAL-D的浓度为1.2M至2.0M。
9.根据权利要求2所述的方法,其中所述式2的化合物是通过使丙炔酸乙酯与溴化锂碱接触以获得所述式2的化合物的步骤制备的
10.根据权利要求9所述的方法,其中丙炔酸乙酯与溴化锂碱的所述接触是在包括乙酸和乙腈的溶剂中进行的,且乙酸与乙腈的体积比为1:2~2:1。
11.根据权利要求1所述的方法,其中丙炔酸乙酯与溴化锂碱的所述接触是在约40℃至约回流温度的温度范围内进行的。
12.一种制备式14的化合物的方法,包括:
使式13的化合物与(三苯基亚正膦基)乙酸乙酯和苯甲酸接触以获得所述式14的化合物
13.根据权利要求12所述的方法,其中所述接触是在室温至约回流温度的温度下进行的。
14.根据权利要求12所述的方法,其中所述接触是在甲苯中进行的。
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