CN1137096C - 制备(-)顺式-3-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-哌啶的方法 - Google Patents
制备(-)顺式-3-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-哌啶的方法 Download PDFInfo
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Abstract
本发明公开了一种制备(-)顺式-3-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-哌啶的方法,其特征在于,将1-甲基-哌啶-4-酮转化成氢溴化物,随后用溴转变成3(R,S)-溴-1-甲基-4-氧代哌啶氢溴化物,然后与1,3,5-三甲氧基苯反应形成3(R,S)-溴-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶氢溴化物。通过将反应溶液搅拌到有机溶剂中,3(R,S)-溴-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶氢溴化物起始分离成固体,随后将该产物与水进行混合,然后通过搅拌转化成3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶。将如此制备的产物催化氢化成外消旋3,4-顺式醇,随后通过用手性辅助试剂从外消旋3,4-顺式醇进行外消旋混合物分离,得到对映体醇的(-)顺式-3-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-哌啶。
Description
(-)顺式-3-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-哌啶(II)是合成作为cyclin-依赖性蛋白激酶第一有效抑制剂的flavopiridol(I)(HMR1275或L86-8275)时的中心构件(参见,例如Sedlacek,HansHarald;Czech,Joerg;Naik,Ramachandra;Kaur,Gurmeet;Worland,Peter;Losiewicz,Michael;Parker,Bernard;Carlson,Bradley;Smith,Adaline;等人的Flavopiridol(L868275;NSC 649890),
一种用于肿瘤治疗的新的 激酶抑制剂,Int.J.Oncol.(1996),9(6),1143-1168或
Czech,Joerg; Hoffmann,Dieter;Naik,Ramachandra;Sedlacek,Hans-Harald,
黄酮L 86-8275的抗肿瘤活性,Int.J.Oncol.(1995),6(1),31-36)。
以前在EP-B0241003和EP-B0366061中描述的制备(II)的方法费时,而且包括在工业上难以操作的各种反应(硼氢化、Swern氧化、硼氢化钠还原)。现已惊人地发现一种简单得多的制备方法,在方案1中给出。
方案1:
的方法包括:
转化成氢溴化物,或
a2)在随后溴化之前,通过将1-甲基哌啶-4-酮加入HBr/冰乙酸溶液中而将1-甲基哌啶-4-酮(III)直接转化成氢溴化物,然后
并根据需要另外加入乙酸酐以去除反应形成的水
d1)通过将所述反应溶液搅拌到合适的有机溶剂如甲基叔丁基醚、二氯甲烷等中,首先将化合物(VI)作为固体分离,然后将所得产物与水进行混合,并通过在50-100℃,优选在60-80℃下进行搅拌,生成3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)
或
d2)直接用水处理包含化合物(VI)的反应混合物,并且在50-100℃,优选在60-80℃下通过搅拌进行反应,生成3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII),然后
d3)将按照d1)或d2)得到的反应混合物冷却,如果需要,进一步用水进行稀释并在0-30℃下通过加入碱水溶液,优选氢氧化钠水溶液将pH值调节至大于12,沉淀出3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII),通过吸滤过滤出所得粗品,然后根据需要进行纯化,即,将其再次放入盐酸水溶液中,过滤并视需要用水不混溶溶剂如乙酸乙酯进行萃取,然后通过加入碱水溶液,优选氢氧化钠水溶液将水相调节至pH值大于12,沉淀出3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII),如果需要,通过使用一种或多种合适的有机溶剂(例如丙酮、异丙醇、二异丙基醚)或这些溶剂的混合物来提取沉淀产物,以进一步纯化,然后
其中可能会在还原时少量生成的3,4-反式醇可通过从合适的溶剂(如丙酮)中结晶而去除,或
其中R为(C1-C16)-烷基、(C6-C14)-芳基-(C1-C16)-烷基、或(C6-C14)-芳基,且在结构式(IXa)中还可以是羧基-(C2-C6)-烷基;
得到化合物(Xa)和(Xb),由此可通过已知方法释放出化合物(VIII),
f1)通过已知方法,使用合适的手性辅助试剂如酮蒎酸(ketopinicacid)进行拆分,由化合物(VIII)得到对映体纯的顺式醇(II),或
其中R为(C1-C16)-烷基、(C6-C14)-芳基-(C1-C16)-烷基、或(C6-C14)-芳基,且在结构式(Xa)中还可以是羧基-(C2-C6)-烷基,
然后通过已知方法将这些物质转化成化合物(II),
其中可以交换反应步骤e)和f)的顺序,即,早在烯丙基醇(VII)阶段或由其得到的化合物(IXa)和(IXb)阶段时进行拆分。
类似于文献(Trost等人,JACS 1994,116,10320)所述的方法,酯(IXa)或碳酸酯(IXb)适用于去外消旋,生成对映体醇的酯。氢化和酯分解之后,得到(-)顺式-3-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-哌啶(II)。
3(R,S)-溴-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶氢溴化物(VI)和3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)在制备(-)顺式-3-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-哌啶(II)时都是有价值的中间体。
实施例:
实施例1:
3(R,S)-溴-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶氢溴化物(VI)的制备
将75.7毫升(0.44摩尔)33%HBr(在冰乙酸中)加入200毫升的冰乙酸中,然后在20-25℃下,在冰冷却下,快速滴加50克(0.44摩尔)1-甲基哌啶-4-酮(III)。在20-25℃下,在30分钟内,将70.4克(0.44摩尔)溴滴加到如此所得氢溴化物的悬浮液中,得到一种透明的黄色溶液。在25℃下另外搅拌15分钟,然后将67.2克(0.40摩尔)1,3,5-三甲氧基苯(V)加入反应溶液中。在25℃下搅拌1小时。然后加入300毫升甲基叔丁基醚,这时产物沉积为油状。倾析上层清液,再次用300毫升甲基叔丁基醚搅拌残余物并倾析上层清液。然后用150毫升二氯甲烷搅拌该残余物,结晶出产物。通过吸滤过滤出所得3(R,S)-溴-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶氢溴化物(VI),用50毫升二氯甲烷洗涤,然后真空干燥。
产量:147克几乎无色的晶体
熔点:190-192℃
MS(ES+):342.2(M+H)+
实施例2:
3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)的制备
将50克(0.118摩尔)3(R,S)-溴-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶氢溴化物(VI)在100毫升水中,在回流下加热2小时。将反应混合物冷却至20℃,然后通过滴加30毫升30%氢氧化钠溶液将pH值调节至12.5。短暂时间之后,结晶出一种浅棕色沉淀物。在5-10℃下另外搅拌该混合物1小时,然后通过吸滤过滤出该沉淀产物,然后用30毫升水进行洗涤。用20毫升丙酮搅拌该粗品,吸滤过滤,然后真空干燥。
产量:25.2克无色晶体
熔点:125-127℃
MS(Cl+):280.3(M+H)+
实施例3:
3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)的制备
将75.7毫升(0.44摩尔)33%HBr(在冰乙酸中)加入100毫升的冰乙酸中,然后在20-25℃下,在冰冷却下,快速滴加50克(0.44摩尔)1-甲基哌啶-4-酮(III)。在20-25℃下,在氮气下,在30分钟内,将70.4克(0.44摩尔)溴滴加到如此所得氢溴化物的悬浮液中,得到一种透明的黄色溶液。在25℃下另外搅拌60分钟,然后将67.2克(0.40摩尔)1,3,5-三甲氧基苯(V)加入反应溶液中。在25℃下搅拌1小时。之后,加入400毫升水,然后将该混合物加热回流3小时。将该反应混合物在室温下放置过夜,用400毫升水稀释,然后冷却至10℃,然后在此温度下,于4小时内,向搅拌良好的该混合物中滴加总共320毫升的浓氢氧化钠溶液(滴加之后的pH值为10.7)。在此过程中,烯丙基醇(VII)首先沉淀为轻微油状,但搅拌较长时间之后就变成固体,因此可通过吸滤过滤出。通过吸滤过滤出该深黄色沉淀物,水洗,然后充分干燥。用80毫升丙酮搅拌该粗品,吸滤过滤,然后真空干燥。
产量:55克浅黄色晶体
熔点:125-127℃
MS(Cl+):280.3(M+H)+ 1H-NMR(dmso-d6):δ(ppm)6.15(s,2H);5.65(dd,1H);4.20(m,1H);3.80(s,3H);3.75(s,6H);3.31(dd1H);2.89(m,1H);2.84(dd,1H);2.71(d,1H);2.57(dd,1H);2.24(s,3H)
实施例4:
3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)的制备
将75.7毫升(0.44摩尔)33%HBr(在冰乙酸中)加入100毫升的冰乙酸中,然后在20-25℃下,在冰冷却下,快速滴加50克(0.44摩尔)1-甲基哌啶-4-酮(III)。在20-25℃下,在氮气下,在30分钟内,将70.4克(0.44摩尔)溴滴加到如此所得氢溴化物的悬浮液中,得到一种透明的黄色溶液。在25℃下另外搅拌60分钟,然后将67.2克(0.40摩尔)1,3,5-三甲氧基苯(V)加入反应溶液中。15分钟之后,在冷却下另外加入40.8克(0.4摩尔)乙酸酐,然后将该混合物在25℃下搅拌1小时。之后,加入750毫升水,然后将该混合物在80℃下加热9.5小时。将该反应混合物冷却至5-10℃,然后通过在30分钟内滴加200毫升浓氢氧化钠溶液将pH值调节至5.5。在此过程中,沉淀出未反应的1,3,5-三甲氧基苯。过滤该悬浮液,然后在5-10℃下,通过另外使用200毫升浓氢氧化钠溶液将滤液的pH值调节至14。在此过程中,烯丙基醇(VII)起始沉淀为轻微油状,但搅拌较长时间之后就变成固体,因此可随后容易吸滤过滤。将该批料在室温下放置过夜。通过吸滤过滤出浅黄色的沉淀物,用300毫升水洗涤至中性pH值,然后充分干燥。粗品产量:87.2克浅黄色晶体。用100毫升丙酮搅拌该粗品,吸滤过滤,然后真空干燥。
产量:73克浅黄色晶体
熔点:125-127℃
MS(Cl+):280.3(M+H)+
实施例5:
外消旋3,4-顺式醇(VIII)的制备
将3.5克(12.5毫摩尔)3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)溶解在100毫升甲醇中,与0.35克催化剂(5%Pd/C,事先用MeOH洗涤)混合,然后在50巴的氢气压力下,在Buechi高压釜中,在50℃下氢化15小时。过滤出催化剂,将滤液在真空下在旋转式蒸发器上进行蒸发,然后用4毫升丙酮搅拌残余物。过滤出所得产物,然后真空干燥。
产量:2.7克无色晶体
熔点:131-132℃
MS(Cl+):282.3(M+H)+
实施例6:
外消旋3,4-顺式醇(VIII)的制备
将10.0克(35.8毫摩尔)3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)溶解在100毫升甲醇中,与1.5克催化剂(5%Pd/C,事先用MeOH洗涤)混合,然后在50巴的氢气压力下,在Buechi高压釜中,在50℃下氢化39小时。过滤出催化剂,将滤液在真空下在旋转式蒸发器上进行蒸发,然后用20毫升丙酮搅拌残余物。过滤出所得产物,然后真空干燥。
产量:9.2克无色晶体
熔点:131-132℃
MS(Cl+):282.3(M+H)+
实施例7:
3(R,S)-乙酰氧基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(IXa)[R=甲基]的制备
将2.79克(10毫摩尔)3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)溶解在15毫升乙酸酐中,然后在100℃下搅拌4小时。将该溶液在真空下在旋转式蒸发器上进行蒸发,然后将残余物溶解在10毫升水中,用氢氧化钠溶液将pH值调节至大于12,然后每次用20毫升乙酸乙酯萃取2次。将合并的有机相用10毫升饱和氯化钠溶液进行洗涤,在硫酸钠上进行干燥,然后在真空下在旋转式蒸发器上进行蒸发。
产量:2.55克油
MS(ES+):322.2(M+H)+
实施例8:
3(R,S)-甲基氧基氧代氧基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(IXb)[R=甲基]的制备
将8.37克(30毫摩尔)3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)溶解在83.7毫升四氢呋喃中,然后用12.4毫升(90毫摩尔)三乙胺进行处理。将该混合物冷却至5℃,在15分钟内滴加2.55毫升(33毫摩尔)的氯甲酸甲酯,然后将该混合物在5-10℃下另外搅拌3小时。由于TLC检测表明仍有起始原料,因此另外加入1.0毫升(12.9毫摩尔)氯甲酸甲酯,将该混合物再搅拌1小时。加入50毫升水,然后每次用50毫升乙酸乙酯将该混合物萃取两次。将合并的有机相用30毫升饱和氯化钠溶液进行洗涤,在硫酸钠上干燥,然后在真空下在旋转式蒸发器上进行蒸发。
产量:8.7克油,放置之后变成固体
MS(ES+):338.2(M+H)+
实施例9:
外消旋顺式酯(Xa)[R=甲基]的制备
将15.33克3(R,S)-乙酰氧基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(IXa)[R=甲基]苯磺酸盐溶解在153毫升甲醇中,过滤通过活性炭,将滤液与1.53克催化剂(5%Rh/C)混合,然后在18巴的氢气压力下,在Buechi高压釜中,在50℃下氢化24小时。过滤出催化剂,将滤液在真空下在旋转式蒸发器上进行蒸发。将残余物溶解在50毫升水中,然后通过加入浓氢氧化钠溶液将pH值调节至大于12。短暂时间之后,基质沉淀。过滤出所得产物,水洗,然后真空干燥。
产量:8.5克无色晶体
熔点:115-117℃
MS(Cl+):324.2(M+H)+
实施例10:
由(Xa)[R=甲基]制备外消旋3,4-顺式醇(VIII)
将1.61克(5毫摩尔)外消旋顺式酯(Xa)[R=甲基]在20毫升甲醇中与5毫升浓盐酸一起加热回流8小时。真空去除甲醇,用10毫升水处理残余物,然后通过使用浓氢氧化钠溶液将pH值调至大于12。在此过程中,产物沉淀。过滤出所得产物,水洗,然后真空干燥。
产量:1.1克无色晶体
熔点:131-132℃
MS(Cl+):282.4(M+H)+
Claims (3)
的方法,包括:
a1)按照已知方法,将1-甲基哌啶-4-酮(III)
转化成氢溴化物,或
a2)在随后溴化之前,通过将1-甲基哌啶-4-酮加入HBr冰乙酸溶液中而将1-甲基哌啶-4-酮(III)直接转化成氢溴化物,然后
并根据需要另外加入乙酸酐以去除反应形成的水
d1)通过将所述反应溶液搅拌到合适的有机溶剂中,首先将化合物(VI)作为固体分离,然后将所得产物与水进行混合,并通过在50-100℃下进行搅拌,生成3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)
或
d2)直接用水处理包含化合物(VI)的反应混合物,然后在50-100℃下通过搅拌进行反应,生成3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII),然后
d3)将按照d1)或d2)得到的反应混合物冷却,如果需要,进一步用水进行稀释并在0-30℃下通过加入碱水溶液将pH值调节至大于12,沉淀出3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII),通过吸滤过滤出所得粗品,然后根据需要进行纯化,即,将其再次放入盐酸水溶液中,过滤并视需要用水不混溶溶剂进行萃取,然后通过加入碱水溶液将水相调节至pH值大于12,沉淀出3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII),如果需要,通过用一种或多种合适的有机溶剂或这些溶剂的混合物进行搅拌来提取沉淀产物,以进一步纯化,然后
其中可能会在还原时少量生成的3,4-反式醇可通过从合适的溶剂中结晶而去除,或
e2)为了氢化,采用化合物(VII)的易得到的酯(IXa)或碳酸酯(IXb)
其中R为(C1-C16)-烷基、(C6-C14)-芳基-(C1-C16)-烷基、或(C6-C14)-芳基,且在结构式(IXa)中还可以是羧基-(C2-C6)-烷基;
得到化合物(Xa)和(Xb),由此可通过已知方法释放出化合物(VIII),
f1)通过已知方法,使用合适的手性辅助试剂进行拆分,由化合物(VIII)得到对映体纯的顺式醇(II),或
其中R为(C1-C16)-烷基、(C6-C14)-芳基-(C1-C16)-烷基、或(C6-C14)-芳基,且在结构式(Xa)中还可以是羧基-(C2-C6)-烷基,
然后通过已知方法将这些物质转化成化合物(II),
其中可以交换反应步骤e)和f)的顺序,即,早在烯丙基醇(VII)阶段或由其得到的化合物(IXa)和(IXb)阶段时进行拆分。
2.3(R,S)-溴-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶氢溴化物(VI)。
3.3(R,S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(VII)。
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DE19802449A DE19802449A1 (de) | 1998-01-23 | 1998-01-23 | Verfahren zur Herstellung von (-)cis-3-Hydroxy-1-methyl-4-(2,4,6-trimethoxypyhenyl)-piperidin |
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BR (1) | BR9814774B1 (zh) |
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DE (2) | DE19802449A1 (zh) |
DK (1) | DK1049674T3 (zh) |
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US6437136B2 (en) * | 1998-01-23 | 2002-08-20 | Aventis Pharma Deutschland Gmbh | Process for the preparation of (−)cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine |
DE19809649A1 (de) * | 1998-03-06 | 1999-09-09 | Hoechst Marion Roussel De Gmbh | Verfahren zur enzymatischen Enantiomeren-Trennung von 3(R)- und 3(S)-Hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro-pyridin bzw. der Carbonsäureester |
MX2017013383A (es) | 2015-04-20 | 2017-12-07 | Tolero Pharmaceuticals Inc | Prediccion de respuesta a alvocidib mediante perfilado mitocondrial. |
TR201911032T4 (tr) | 2015-05-18 | 2019-08-21 | Tolero Pharmaceuticals Inc | Artırılmış biyoyararlanıma sahip alvocıdıb ön ilaçları. |
AU2016301315C1 (en) | 2015-08-03 | 2022-07-07 | Sumitomo Pharma Oncology, Inc. | Combination therapies for treatment of cancer |
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KR20190099260A (ko) | 2016-12-19 | 2019-08-26 | 톨레로 파마수티컬스, 인크. | 프로파일링 펩티드 및 감도 프로파일링을 위한 방법 |
WO2019055579A1 (en) | 2017-09-12 | 2019-03-21 | Tolero Pharmaceuticals, Inc. | TREATMENT REGIME FOR CANCERS THAT ARE INSENSITIVE TO BCL-2 INHIBITORS USING THE MCL-1 ALVOCIDIB INHIBITOR |
WO2020117988A1 (en) | 2018-12-04 | 2020-06-11 | Tolero Pharmaceuticals, Inc. | Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
US11793802B2 (en) | 2019-03-20 | 2023-10-24 | Sumitomo Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (AML) with venetoclax failure |
CN110577974B (zh) * | 2019-09-10 | 2021-07-20 | 杭州澳赛诺生物科技有限公司 | 手性3-羟基-1,2,3,6-四氢吡啶的合成方法 |
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