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CN102933080A - 制备氨基甲酰基吡啶酮衍生物和中间体的方法 - Google Patents

制备氨基甲酰基吡啶酮衍生物和中间体的方法 Download PDF

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CN102933080A
CN102933080A CN2011800155276A CN201180015527A CN102933080A CN 102933080 A CN102933080 A CN 102933080A CN 2011800155276 A CN2011800155276 A CN 2011800155276A CN 201180015527 A CN201180015527 A CN 201180015527A CN 102933080 A CN102933080 A CN 102933080A
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H.王
S.N.古德曼
D.曼斯
M.科瓦尔斯基
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Abstract

本发明涉及氨基甲酰基吡啶酮衍生物和中间体的制备。

Description

制备氨基甲酰基吡啶酮衍生物和中间体的方法
发明领域
本发明涉及制备可用作HIV整合酶抑制剂的氨基甲酰基吡啶酮衍生物和中间体。
背景技术
在WO 2006/116764(相当于受让于Shionogi & Co. Ltd.的美国系列号11/919386)中描述了具有HIV整合酶抑制活性的化合物。所述化合物被公开为多环氨基甲酰基吡啶酮衍生物。还公开了制备它们的方法。在这些化合物的实例中，包括下列多环氨基甲酰基吡啶酮衍生物：
Figure 686321DEST_PATH_IMAGE001
。
公开的用于制备这些化合物的方法是非常费力的，涉及多达14步。因此，本领域亟需找到具有更高效率的制备这些化合物的方式。
发明内容
本发明提供了制备下列化合物的改进方法：
。
在一个方面，本发明为方法，其包括在存在M+-OR，其中R为烷基、芳基或苄基，并且M+为碱金属阳离子的情况下，使3-{[2,2-双(甲氧基)乙基]氨基}-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯(式I)：
Figure 694784DEST_PATH_IMAGE003
I
与式II的草酸酯：
Figure 89993DEST_PATH_IMAGE004
II
接触，以形成式III的吡啶酮：
Figure 966682DEST_PATH_IMAGE005
III。
在第二方面，本发明方法包括使用选择性水解剂来选择性地水解式III的吡啶酮：
Figure 789144DEST_PATH_IMAGE005
III
其中R为烷基、芳基或苄基，
以形成式IV的吡啶酮羧酸：
Figure 56178DEST_PATH_IMAGE006
IV
其中R为烷基、芳基或苄基，
选择性大于90%。
在第三方面，本发明为方法，其包括使式VII化合物：
VII
与镁或锂阳离子和亲核阴离子接触以形成式VIII化合物：
Figure 737006DEST_PATH_IMAGE008
VIII。
在第四方面，本发明为化合物，其选自：
Figure 730370DEST_PATH_IMAGE009
。
在第五方面，本发明为方法，其包括使式IV化合物：
Figure 547016DEST_PATH_IMAGE006
IV
其中R为烷基、芳基或苄基，
与乙酸和催化量的强质子酸接触以形成式V的吡啶酮羧酸醛：
Figure 284028DEST_PATH_IMAGE010
V
其中R为烷基、芳基或苄基。
本发明的方法可用于制备具有HIV整合酶抑制活性的化合物。
具体实施方式
下列方案例示了制备式VIII化合物((3S,11aR)-N-[(2,4-二氟苯基)甲基]-6-羟基-3-甲基-5,7-二氧代2,3,5,7,11,11a-六氢[1,3]噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺)的一般方法。
方案：
Figure 807413DEST_PATH_IMAGE012
在上述方案中，在足以形成3-(二甲基氨基)-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯的条件下使4-甲氧基乙酰乙酸酯与DMFDMA (N,N-二甲基-1,1-双(甲氧基)甲胺)接触。这种中间体与氨基乙醛缩二甲醇的反应导致形成3-{[2,2-双(甲氧基)乙基]氨基}-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯(I)。
然后，在M+-OR的存在下使化合物I与草酸酯(II)接触以形成吡啶酮(III)。每一R为 C1-C5-烷基、芳基或苄基；M+为碱金属阳离子，例如锂、钠或钾。优选地，所述碱金属阳离子为锂，并且所述草酸酯的R基团与来自 M+-OR的R基团相同。优选地，R为 C1-C5-烷基，尤其是 C1-C2-烷基。特别优选的草酸酯是乙二酸二甲酯和乙二酸二乙酯。特别优选的碱金属醇盐是甲醇锂和乙醇锂。优选地，当所述草酸酯为乙二酸二甲酯时，所述碱金属醇盐为甲醇锂。优选地，当所述草酸酯为乙二酸二乙酯时，所述碱金属醇盐为乙醇锂。
用LiOH选择性地水解吡啶酮 (III)以形成吡啶酮羧酸(IV)。惊人地，相对于吡啶酮 (III)在2-位的酯，水解吡啶酮 (III)在5-位的甲酯的选择性为至少90%。
使吡啶酮羧酸 (IV) 与乙酸和催化量的强质子酸接触以形成吡啶酮羧酸醛 (V)。合适的强质子酸的实例包括甲磺酸、硫酸、甲苯磺酸和盐酸。然后，使醛(V)与(2S)-2-氨基-1-丙醇接触以形成((3S,11aR)-3-甲基-6-(甲氧基)-5,7-二氧代-2,3,5,7,11,11a-六氢[1,3]噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸) (VI)接触。
在耦合条件下使化合物VI与2,4-二氟苄胺接触以形成 (3S,11aR)-N-[(2,4-二氟苯基)甲基]-3-甲基-6-(甲氧基)-5,7-二氧代-2,3,5,7,11,11a-六氢[1,3]噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺 (VII)。
最后，用路易斯酸将化合物VII脱甲基以形成产物(3S,11aR)-N-[(2,4-二氟苯基)甲基]-6-羟基-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢[1,3]噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺 (VIII)。合适的路易斯酸的实例包括镁盐、锂盐和钙盐，以及三卤化硼和三烷基甲硅烷基卤化物。优选的路易斯酸为镁盐和锂盐。镁盐包括诸如氯化镁、溴化镁、碘化镁和硫化镁的盐。锂盐包括诸如氯化锂、溴化锂、碘化锂和硫化锂的盐。溴化锂是优选的。
或者，在本发明的另一方面中，化合物V能够与 (3R)-3-氨基-1-丁醇接触以形成式VIa化合物：
Figure 566420DEST_PATH_IMAGE013
VIa。
在耦合条件下化合物VIa能够与2,4-二氟苄胺反应以形成式VIIa化合物：
Figure 808045DEST_PATH_IMAGE014
VIIa。
能够用MgXn或LiXn(其中X为卤化物，例如Br、Cl、F或I)将化合物VIIa脱甲基以形成VIIIa化合物：
Figure DEST_PATH_IMAGE015
VIIIa。
实施例
下列实施例例示了本发明的方法。溶剂和反应条件不意图限制本发明的范围。起始材料是本领域已知的并且容易制备或可商购。优选地，用于所述实施例的化学品是可商业获得的(例如，来自Aldrich®).
A. 1-[2,2- 双 ( 甲氧基 ) 乙基 ]-5-( 甲氧基 )-6-[( 甲氧基 ) 羰基 ]-4- 氧代 -1,4- 二氢 -3- 吡啶羧酸
在室温下搅拌4-甲氧基乙酰乙酸甲酯 (20 mL)和 DMFDMA (24 mL)的混合物 1.5 h。用 MeOH (50 mL)稀释反应混合物并加入氨基乙醛缩二甲醇 (16.7 mL)。在室温下搅拌混合物1 h，浓缩，然后用MeOH (113 mL)稀释。装入草酸二甲酯 (45.66 g) ，然后分批加入LiH (2.15 g)，同时保持反应温度低于25℃。加热反应内容物至 40℃达14 h。冷却反应混合物至-5℃并加入 LiOH (14.82 g)，同时保持反应温度低于 5℃。当添加完成时，另外搅拌混合物2 h，并在 3–5℃搅拌混合物1 h。用HCl水溶液 (2 N, 367 mL)淬灭反应混合物，保持反应温度低于5℃。当添加完成时，加入EtOAc (450 mL)并且将混合物升至20℃。过滤反应混合物并且丢弃水层。加入水 (225 mL)并且在减压下除去有机层。通过过滤收集产物并且在 50℃在真空烘箱中干燥过夜。得到作为固体的产物.
B. (3S,11aR)-3- 甲基 -6-( 甲氧基 )-5,7- 二氧代 -2,3,5,7,11,11a- 六氢 [1,3] 噁唑并 [3,2-a] 吡啶并 [1,2-d] 吡嗪 -8- 羧酸
将1-[2,2-双(甲氧基)乙基]-5-(甲氧基)-6-[(甲氧基)羰基]-4-氧代-1,4-二氢-3-吡啶羧酸(22.54 g)溶于220 mL的CH3CN中。在室温下加入HOAc (20 mL)和CH3SO3H (1.4 mL)并加热混合物至 58-65℃达19.5 h。缓慢加入丙氨醇(alaninol) (7.511g)/CH3CN (15 mL)并在 64℃搅拌所得混合物18.5 h。浓缩混合物，并将残留物再次溶于CH2Cl2 (170 mL)中。加入HCl (1 N, 170 mL)并分离各层。 用CH2Cl2 (170 mL×2)萃取水层并合并有机层并浓缩。加入MeOH (50 mL)并且再次浓缩所得混合物。加入MeOH (80 mL)并且在回流下加热所得混合物4 h，逐渐冷却至20℃并在20℃保持15 h。通过过滤收集产物并在真空下干燥.
C. (3S,11aR)-N-[(2,4- 二氟苯基 ) 甲基 ]-3- 甲基 -6-( 甲氧基 )-5,7- 二氧代 -2,3,5,7,11,11a- 六氢 [1,3] 噁唑并 [3,2-a] 吡啶并 [1,2-d] 吡嗪 -8- 甲酰胺
在1,2-二甲氧基乙烷(DME) (30 mL)中将(3S,11aR)-3-甲基-6-(甲氧基)-5,7-二氧代-2,3,5,7,11,11a-六氢[1,3]噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(3.00 g)和1,1'-羰基二咪唑(CDI) (2.15 g)制成浆状。加热混合物至 80℃达1 h。冷却所得溶液至20℃，然后用2,4-二氟苄胺(1.45 mL)处理。搅拌1 h后，用水(30 mL)淬灭混合物并在减压下除去DME。通过过滤收集产物并在50℃在真空烘箱中干燥过夜。获得作为固体的产物.
D. (3S,11aR)-N-[(2,4- 二氟苯基 ) 甲基 ]-6- 羟基 -3- 甲基 -5,7- 二氧代 -2,3,5,7,11,11a- 六氢 [1,3] 噁唑并 [3,2-a] 吡啶并 [1,2-d] 吡嗪 -8- 甲酰胺
将(3S,11aR)-N-[(2,4-二氟苯基)甲基]-3-甲基-6-(甲氧基)-5,7-二氧代-2,3,5,7,11,11a-六氢[1,3]噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(193.1 mg)溶于CH3CN (4 mL)中并加入MgBr2 (206.3 mg)。加热混合物至50℃达2 h并用HCl (0.2 N, 10 mL)淬灭。用CH2Cl2稀释混合物并将pH进一步调节至~1。用CH2Cl2 (10 mL×2)萃取水层。干燥合并的有机层并浓缩以得到产物。
或者，可以用LiBr进行脱甲基：将(3S,11aR)-N-[(2,4-二氟苯基)甲基]-3-甲基-6-(甲氧基)-5,7-二氧代-2,3,5,7,11,11a-六氢[1,3]噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(8.609 g)溶于THF (90 mL)中并加入LiBr (3.942 g)。加热混合物至回流达12 h并用 H2SO4 (0.5 M, 94.467 g)淬灭。在20℃搅拌所得悬浮液2 h并过滤。在20℃，在水-THF (50 mL-50 mL)中将固体产物再次制成浆状达2 h。通过过滤收集产物，用水-THF (1-1, 30 mL)冲洗，并在真空下干燥以得到产物。

Claims (19)

1.方法，其包括在存在M+-OR，其中R为烷基、芳基或苄基；并且M+为碱金属阳离子的情况下；使3-{[2,2-双(甲氧基)乙基]氨基}-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯(式I)：
Figure 190548DEST_PATH_IMAGE001
I
与式II的草酸酯：
Figure 45372DEST_PATH_IMAGE002
II
接触，以形成式III的吡啶酮：
Figure 825109DEST_PATH_IMAGE003
III。
2.根据权利要求1所述的方法，其中 M+-OR 为甲醇锂或乙醇锂；并且所述草酸酯为乙二酸二甲酯或乙二酸二乙酯；其中在存在氢氧化锂的情况下水解所述式III化合物以形成式IV的吡啶酮羧酸：
IV。
3.根据权利要求2所述的方法，其中使所述吡啶酮羧酸与乙酸和催化量的强质子酸接触以形成式V的吡啶酮羧酸醛：
Figure 237953DEST_PATH_IMAGE005
V
其中R为烷基、芳基或苄基。
4.根据权利要求3所述的方法，其中使所述式V的吡啶酮羧酸醛与 (2S)-2-氨基-1-丙醇接触以形成式VI化合物：
Figure 60415DEST_PATH_IMAGE006
VI。
5.根据权利要求4所述的方法，其中在耦合条件下使所述式VI化合物与2,4-二氟苄胺接触以形成式VII化合物：
Figure 327448DEST_PATH_IMAGE007
VII。
6.根据权利要求5所述的方法，其中使所述式VII化合物与卤化镁或卤化锂接触以形成式VIII化合物：
VIII。
7.方法，其包括用选择性水解剂来选择性地水解式III的吡啶酮：
III
以形成式IV的吡啶酮羧酸：
Figure 860695DEST_PATH_IMAGE004
IV
其中R为烷基、芳基或苄基，
选择性大于90%。
8.根据权利要求7所述的方法，其中所述水解剂为LiOH。
9.方法，其包括使式VII化合物：
Figure 615024DEST_PATH_IMAGE007
VII
与路易斯酸接触以形成式VIII化合物：
Figure 555299DEST_PATH_IMAGE009
VIII。
10.根据权利要求9所述的方法，其中所述路易斯酸为卤化镁或卤化锂。
11.方法，其包括下列步骤：
a) 在适当条件下使4-甲氧基乙酰乙酸甲酯与N,N-二甲基-1,1-双(甲氧基)甲胺接触以形成3-(二甲基氨基)-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯；
b) 使所述3-(二甲基氨基)-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯与2,2-双(甲氧基)乙胺接触以形成3-{[2,2-双(甲氧基)乙基]氨基}-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯；
c) 在甲醇锂的存在下使所述3-{[2,2-双(甲氧基)乙基]氨基}-2-[(甲氧基)乙酰基]-2-丙烯酸甲酯与乙二酸二甲酯接触以形成1-[2,2-双(甲氧基)乙基]-3-(甲氧基)-4-氧代-1,4-二氢-2,5-吡啶二羧酸二甲酯；
d) 在氢氧化锂的存在下水解所述1-[2,2-双(甲氧基)乙基]-3-(甲氧基)-4-氧代-1,4-二氢-2,5-吡啶二羧酸二甲酯以形成1-[2,2-双(甲氧基)乙基]-5-(甲氧基)-6-[(甲氧基)羰基]-4-氧代-1,4-二氢-3-吡啶羧酸：
e) 在乙酸和催化量的甲磺酸的存在下使所述1-[2,2-双(甲氧基)乙基]-5-(甲氧基)-6-[(甲氧基)羰基]-4-氧代-1,4-二氢-3-吡啶羧酸与(2S)-2-氨基-1-丙醇接触以形成式VI化合物：
Figure 78684DEST_PATH_IMAGE006
VI
f) 在耦合条件下使所述式VI化合物与2,4-二氟苄胺接触以形成式 VII化合物：
Figure 508528DEST_PATH_IMAGE007
VII；以及
g) 使所述式VII化合物与溴化镁接触以形成式VIII化合物：
Figure 422257DEST_PATH_IMAGE009
VIII。
12.根据权利要求3所述的方法，其中使所述式V的吡啶酮羧酸醛与 (3R)-3-氨基-1-丁醇接触以形成式VIa化合物：
Figure 697381DEST_PATH_IMAGE010
VIa。
13.根据权利要求12所述的方法，其中在耦合条件下使所述 VIa化合物与2,4-二氟苄胺接触以形成式VIIa化合物：
Figure 340852DEST_PATH_IMAGE011
VIIa。
14.根据权利要求13所述的方法，其中使所述式VIIa化合物与路易斯酸接触以形成式 VIIIa化合物：
VIIIa。
15.根据权利要求14所述的方法，其中所述路易斯酸为卤化镁或卤化锂。
16.化合物，其选自：
。
17.根据权利要求16所述的化合物，其具有式：
Figure 421438DEST_PATH_IMAGE014
。
18.根据权利要求16 所述的化合物，其具有式：
Figure 919415DEST_PATH_IMAGE015
。
19.方法，其包括使式IV化合物：
Figure 894324DEST_PATH_IMAGE004
IV
其中R为烷基、芳基或苄基，
与乙酸和催化量的强质子酸接触以形成式V的吡啶酮羧酸醛：
Figure 844963DEST_PATH_IMAGE005
V
其中R选自烷基、芳基和苄基。
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CN107428778A (zh) * 2015-01-16 2017-12-01 斯洛文尼亚莱柯制药股份有限公司 制备度鲁特韦和卡波特韦及其类似物的方法
CN106565747A (zh) * 2016-11-10 2017-04-19 顾世海 一种制备度鲁特韦的新方法
CN110582504A (zh) * 2017-02-16 2019-12-17 桑多斯股份公司 卡博特韦钠的晶形
CN109438334A (zh) * 2018-10-29 2019-03-08 南京杰运医药科技有限公司 一种度鲁特韦中间体的合成方法
CN109293675A (zh) * 2018-11-19 2019-02-01 遵义医学院 一种改进的度鲁特韦制备工艺
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CN115572257B (zh) * 2021-06-21 2024-07-09 江西帝劢药业有限公司 一种吡啶酮类化合物的合成方法
CN116003435A (zh) * 2021-09-10 2023-04-25 河南师范大学 一种度鲁特韦的高效绿色制备方法
CN113816972A (zh) * 2021-11-17 2021-12-21 奥锐特药业(天津)有限公司 一种hiv抑制剂的制备方法及其中间体晶型
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CN114605437A (zh) * 2022-04-01 2022-06-10 遵义医科大学 连续一锅法制备三个替拉韦药物的合成工艺

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