CN104080775A - 立体选择性合成1,4-保护的9-羟基-5-氧代-1,4-二氮杂-螺[5.5]十一烷的方法 - Google Patents
立体选择性合成1,4-保护的9-羟基-5-氧代-1,4-二氮杂-螺[5.5]十一烷的方法 Download PDFInfo
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- 238000003786 synthesis reaction Methods 0.000 title description 6
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及立体选择性制备任选为其互变异构体形式的式(5)化合物的方法。
Description
本发明涉及一种立体选择性制备任选为其互变异构体形式的式(5)化合物的方法，
发明背景
式(5)化合物(任选为其互变异构体形式)是立体选择性制备式(I)化合物(任选为其互变异构体形式以及任选为其药理学上可接受的酸加成盐的)的方法中的有价值中间体，
该化合物具有有价值的药理学性质，特别是对由酪氨酸激酶介导的信号转导的抑制效应，以及用于治疗疾病，特别是肿瘤疾病、良性前列腺增生以及肺和呼吸道疾病。
由现有技术已知喹唑啉衍生物为例如用于治疗肿瘤疾病以及肺和呼吸道疾病的活性物质。喹唑啉衍生物的制备方法描述在WO03082290和WO07068552中。WO2009098061和WO2011015526公开了化合物(I)的制备方法。
本发明要解决的问题是提供用于制备式(I)化合物的替代性的立体选择性合成方法或者制备此合成的重要中间体的有利方法。
发明详述
本发明通过下文所述的合成方法解决了上述问题。
本发明涉及立体选择性制备式(5)化合物(任选为其互变异构体形式)的方法，
其中
SG1表示选自三氟乙酰基、乙酰基、苯甲酰基和三甲基乙酰基的保护基，
SG2表示选自叔丁氧羰基、乙氧羰基和甲氧羰基的保护基，
其特征在于所述方法包括反应步骤(C)和(D)，其中
(C)是式(3)化合物形成式(4)化合物的反应
且
(D)是式(4)化合物形成式(5)化合物的还原反应，
其中方法步骤(C)和(D)以所述顺序依次进行。
在优选方法中，所述反应步骤(C)和(D)之前是另外的反应步骤(A)和(B)，
其中
(A)表示式(1)化合物形成式(2)化合物的反应
且
(B)表示式(2)化合物形成式(3)化合物的反应
方法步骤(A)、(B)、(C)和(D)以所述顺序依次进行。
还优选的是用于立体选择性制备式(5)化合物(任选为其互变异构体形式的)的方法
其特征在于
SG1表示三氟乙酰基，且
SG2表示叔丁氧羰基。
本发明进一步涉及式(2)中间体(任选为其互变异构体或盐形式)
其中，
SG1表示选自三氟乙酰基、乙酰基、苯甲酰基和三甲基乙酰基的保护基。
优选的是式(2A)中间体(任选为其互变异构体或盐形式)，
本发明进一步涉及式(4)中间体(任选为其互变异构体或盐形式)，
其中
SG1表示选自三氟乙酰基、乙酰基、苯甲酰基和三甲基乙酰基的保护基，且
SG2表示选自叔丁氧羰基、乙氧羰基和甲氧羰基的保护基。
优选的是式(4A)中间体(任选为其互变异构体或盐形式)。
本发明进一步涉及任选为其互变异构体或盐形式的式(2)或(4)中间体(优选中间体(2A)或(4A))的用途，其用于制备任选为其互变异构体或盐形式的式(I)化合物。
将中间体(2)或(4)(优选中间体(2A)或(4A))用于制备式(I)化合物的新用途，可通过制备式(5)化合物以及WO2012104206中描述的随后合成步骤(G)至(L)来实施。
相比于WO2012104206中描述的合成获得了以下优势，特别是考虑到化合物(I)的大规模工业生产：
a)起始自化合物(1)的化合物(5)总收率显著增加10至20％，例如15％，增加至60％。
b)使用较少量的乙酸用于缩醛分裂并避免了所导致的较大量酸性废物。
c)通过使用较便宜的非均相催化氢化方法，避免了使用硼氢化钠。
在方法步骤(A)、(B)、(C)、(D)中可使用替代的试剂、催化剂和溶剂，优选选自表I.1-I.4中所列的试剂、催化剂和溶剂：
表I.1 供选择的溶剂
表I.2 供选择的碱和酸
表I.3 供选择的试剂
表I.4 供选择的催化剂
| 方法步骤 | 催化剂 | 特别优选催化剂 |
| (C) | 二甲氨基吡啶(DMAP)和吡啶 | DMAP |
| (D) | 雷尼镍、铂/炭、二氧化铂、钌/炭和铑/炭 | 雷尼镍 |
优选在以下温度范围内进行上述方法步骤(A)至(D)：
在方法步骤中：
(A)：优选0至70℃，特别优选10至20℃；
(B)：优选20至70℃，特别优选60至70℃；
(C)：优选0至78℃，特别优选10至30℃；
(D)：优选20至80℃，特别优选40至70℃。
反应方程式1示例性地说明而来本发明的合成。所有化合物以其碱的形式显示。
反应方程式1：化合物(5)的合成
在方法步骤(A)中，在存在2.2至3.2摩尔当量碱的情况下使用2.0至3.0摩尔当量试剂在氨基氮位保护离析物(1)。方法步骤(B)描述了使用2.0至4.0摩尔当量的酸水性-酸性脱保护缩酮(2)以获得对应的酮(3)。在下一步骤(C)中在存在2至10摩尔％催化剂的情况下采用1.0至1.5摩尔当量的试剂保护仍然游离的酰胺氮。在最后的步骤(D)中采用氢发生该酮基的催化立体选择性还原以形成顺式构型醇(4)。
在优选的实施方案中，在方法步骤(A)中在存在2.4摩尔当量N-甲基吗啉(NMM)三氟乙酸盐的情况下使用2.2摩尔当量三氟乙酸酐(TFAA)在氨基氮位保护离析物(1)。方法步骤(B)描述了使用2.8摩尔当量的乙酸(HOAC)水性酸性脱保护缩酮(2)以形成对应的酮(3)。在下一步骤(C)中在存在5摩尔％二甲氨基吡啶的情况下采用1.2摩尔当量的焦碳酸二叔丁酯保护仍然游离的酰胺氮为氨基甲酸酯。在最后的步骤(D)中采用氢进行该酮基的催化立体选择性还原以获得顺式构型醇(4)。
以下实施例用于阐释经由式(5)化合物制备实例来实施的方法。这些实施例的目的是示例性性说明本发明而非将其限制至它们的内容。
实施例1
1,4-二氧杂-9-(2,2,2-三氟-乙酰基)-9,12-二氮杂-二螺[4.2.5.2]十五烷-13-酮
方法步骤(A)
在室温(室温对应于20至25℃)，将107.2g的N-甲基吗啉滴加至300ml2-甲基四氢呋喃中的100g的1,4-二氧杂-9,12-二氮杂-二螺[4.2.5.2]十五烷-13-酮中。然后将该混合物冷却至6-10℃并滴加204.2g三氟乙酸酐。在此加入期间温度升高至RT。120min后先后加入200ml水以及450ml甲基环己烷。60min后将该混悬液冷却至0℃。25min后滤出沉淀物并用100ml水以及100ml甲基环己烷先后洗涤。50℃下真空干燥后，获得137.9g产物。
质谱(ESI+)：m/z＝323[M+H]+
M.p.224.8℃
实施例2
1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-5,9-二酮
方法步骤(B)
将195ml水和65ml乙酸加至390ml甲醇中的130g的1,4-二氧杂-9-(2,2,2-三氟-乙酰基)-9,12-二氮杂-二螺[4.2.5.2]十五烷-13-酮中。加热该混合物至68℃并在此温度下搅拌120min。然后蒸除325ml溶剂。将所得混悬液冷却至5℃。30min后滤出沉淀物并用50ml甲基叔丁基醚洗涤残留物。50℃下真空干燥后，获得101.4g产物。
质谱(ESI+)：m/z＝279[M+H]+
M.p.169.0℃
实施例3
5,9-二氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤(C)
在室温75min内，将90ml乙腈中的84.7g焦碳酸二叔丁酯滴加至180ml乙腈中的90g的1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-5,9-二酮和1.98g二甲氨基吡啶的混合物中。60min后加入并灌输990ml水。60min后滤出沉淀物并用180ml水洗涤。50℃下真空干燥后获得113.8g产物。
质谱(ESI+)：m/z＝379[M+H]+
M.p.114.9℃
实施例4
(顺式)-9-羟基-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤(D)
将5.1g雷尼镍加至170ml乙醇中的17g的5,9-二氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯中。在高压处理器中60℃和50bar氢压下氢化反应混合物10小时。然后滤除催化剂并用40ml乙醇洗涤滤饼。蒸除165ml乙醇。往残留物中加入374ml甲苯并进一步蒸除136ml溶剂。60℃下将所得溶液与55m水合并，并分离各相。从剩下的有机相中进一步蒸除195ml溶剂。在120min内将所得混悬液冷却至2℃。30min后滤出沉淀并用20ml甲苯洗涤两次。50℃下真空干燥后，获得12.6g产物，其仍然含有约6％反式产物。
质谱(ESI+)：m/z＝381[M+H]+
M.p.163.0℃
数据编制
使用Waters质谱仪ZQ 2000(电喷雾源)以编制所示质谱数据。
Claims (8)
1.一种立体选择性制备任选为其互变异构体形式的式(5)化合物的方法，
其中
SG1表示选自三氟乙酰基、乙酰基、苯甲酰基和三甲基乙酰基的保护基，
SG2表示选自叔丁氧羰基、乙氧羰基和甲氧羰基的保护基，
其特征在于所述方法包括反应步骤(C)和(D)，其中
(C)是式(3)化合物形成式(4)化合物的反应
且
(D)是式(4)化合物形成式(5)化合物的还原反应，
方法步骤(C)和(D)以所述顺序依次进行。
2.根据权利要求1的方法，其特征在于反应步骤(C)和(D)之前进行另外的反应步骤(A)和(B)，
其中
(A)表示式(1)化合物形成式(2)化合物的反应
且
(B)表示式(2)化合物形成式(3)化合物的反应
方法步骤(A)、(B)、(C)和(D)以所述顺序依次进行。
3.根据权利要求1或2的用于立体选择性制备任选为其互变异构体形式的式(5A)化合物的方法，
其特征在于
SG1表示三氟乙酰基，且
SG2表示叔丁氧羰基。
4.根据权利要求2的式(2)中间体，任选为其互变异构体或盐形式
其中
SG1表示选自三氟乙酰基、乙酰基、苯甲酰基和三甲基乙酰基的保护基。
5.根据权利要求4的式(2A)中间体，任选为其互变异构体或盐形式。
6.根据权利要求1或2的式(4)中间体，任选为其互变异构体或盐形式，
其中
SG1表示选自三氟乙酰基、乙酰基、苯甲酰基和三甲基乙酰基的保护基，且
SG2表示选自叔丁氧羰基、乙氧羰基和甲氧羰基的保护基。
7.根据权利要求6的式(4A)中间体，任选为其互变异构体或盐形式，
8.任选为其互变异构体或盐形式的式(2)或(4)中间体在用于制备任选为其互变异构体或盐形式的式(I)化合物中的用途，
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|---|---|---|---|
| EP12154688.1 | 2012-02-09 | ||
| EP12154688 | 2012-02-09 | ||
| PCT/EP2013/052287 WO2013117568A1 (de) | 2012-02-09 | 2013-02-06 | Verfahren zur stereoselektiven synthese von 1,4-geschützten 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane |
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| EP (1) | EP2812317B1 (zh) |
| JP (1) | JP6105631B2 (zh) |
| KR (1) | KR20140128318A (zh) |
| CN (1) | CN104080775A (zh) |
| AU (1) | AU2013218119A1 (zh) |
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| CA (1) | CA2862520A1 (zh) |
| CL (1) | CL2014001823A1 (zh) |
| EA (1) | EA201400882A1 (zh) |
| IL (1) | IL233370A (zh) |
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| US4575507A (en) * | 1985-05-29 | 1986-03-11 | Pfizer Inc. | Spiro-imidazolidines as aldose reductase inhibitors and their pharmaceutical use |
| US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
| WO2003082290A1 (de) | 2002-03-30 | 2003-10-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 4- ( n-phenylamino ) -chinazoline/chinoline als tyrosinkinaseinhibitoren |
| CA2631813A1 (en) | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof |
| AU2009211523B2 (en) | 2008-02-07 | 2014-03-13 | Boehringer Ingelheim International Gmbh | Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production |
| EP2289881A1 (de) * | 2009-08-06 | 2011-03-02 | Boehringer Ingelheim International GmbH | Verfahren zur stereoselektiven Synthese bicyclischer Heterocyclen |
| SG192216A1 (en) | 2011-02-01 | 2013-09-30 | Boehringer Ingelheim Int | 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof |
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- 2013-02-06 EA EA201400882A patent/EA201400882A1/ru unknown
- 2013-02-06 JP JP2014556029A patent/JP6105631B2/ja active Active
- 2013-02-06 WO PCT/EP2013/052287 patent/WO2013117568A1/de active Application Filing
- 2013-02-06 CN CN201380006918.0A patent/CN104080775A/zh active Pending
- 2013-02-06 MX MX2014009033A patent/MX2014009033A/es not_active Application Discontinuation
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| Publication number | Publication date |
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| WO2013117568A1 (de) | 2013-08-15 |
| CL2014001823A1 (es) | 2015-03-06 |
| BR112014019196A8 (pt) | 2017-07-11 |
| US20130211081A1 (en) | 2013-08-15 |
| KR20140128318A (ko) | 2014-11-05 |
| MX2014009033A (es) | 2014-10-17 |
| JP6105631B2 (ja) | 2017-03-29 |
| US8629146B2 (en) | 2014-01-14 |
| JP2015506966A (ja) | 2015-03-05 |
| IL233370A0 (en) | 2014-08-31 |
| IL233370A (en) | 2015-04-30 |
| AU2013218119A1 (en) | 2014-07-17 |
| EP2812317A1 (de) | 2014-12-17 |
| CA2862520A1 (en) | 2013-08-15 |
| EA201400882A1 (ru) | 2015-01-30 |
| PH12014501760B1 (en) | 2014-11-10 |
| EP2812317B1 (de) | 2016-02-03 |
| PH12014501760A1 (en) | 2014-11-10 |
| BR112014019196A2 (zh) | 2017-06-20 |
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