CN108929333A - 制备苯并氧氮杂*化合物的方法 - Google Patents
制备苯并氧氮杂*化合物的方法 Download PDFInfo
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- CN108929333A CN108929333A CN201810489045.8A CN201810489045A CN108929333A CN 108929333 A CN108929333 A CN 108929333A CN 201810489045 A CN201810489045 A CN 201810489045A CN 108929333 A CN108929333 A CN 108929333A
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- Prior art keywords
- bromo
- acid
- methyl
- isopropyl
- solution
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- 238000000034 method Methods 0.000 title abstract description 42
- -1 benzo oxygen azepine Chemical compound 0.000 title description 88
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- XCMYPTLLFDFJAE-UHFFFAOYSA-N tert-butyl n-(propan-2-ylideneamino)carbamate Chemical compound CC(C)=NNC(=O)OC(C)(C)C XCMYPTLLFDFJAE-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
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- KLBOFRLEHJAXIU-UHFFFAOYSA-N tributylazanium;chloride Chemical compound Cl.CCCCN(CCCC)CCCC KLBOFRLEHJAXIU-UHFFFAOYSA-N 0.000 description 1
- PYIHTIJNCRKDBV-UHFFFAOYSA-L trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCCCCC[N+](C)(C)C PYIHTIJNCRKDBV-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本申请描述了制备PI3K抑制剂即具有以下结构的式(I)的GDC‑0032的方法及可用于制备式(I)的中间体。
Description
本申请是申请日为2014年3月12日、申请号为201480015055.8(国际申请号为PCT/EP2014/054786)、名称为“制备苯并氧氮杂化合物的方法”的发明专利申请的分案申请。
对相关申请的交叉引用
按照37 CFR §1.53(b)提交的本非临时申请按照35 USC §119(e)要求于2013年3月13日提交的美国临时申请61/799,619的权益且将其整体引入本申请作为参考。
技术领域
本发明涉及制备PI3K抑制剂化合物GDC-0032的方法。
背景技术
磷酸肌醇3-激酶(PI3K)是在肌醇环的3-羟基残基处对脂质进行磷酸化的脂质激酶(Whitman et al(1988)Nature, 332:664)。由PI3-激酶生成的3-磷酸化磷脂(PIP3)充当以下第二信使,所述第二信使募集具有脂质结合结构域(包括锤型同源(PH)区域)的激酶如Akt和磷酸肌醇依赖性激酶-1(PDK1)。Akt与膜PIP3的结合引起Akt向质膜的易位,这使Akt与PDK1接触,而后者负责活化Akt。肿瘤抑制磷酸酶PTEN使PIP3脱磷酸化且由此充当Akt活化的负调节剂。PI3-激酶Akt和PDK1在调节包括细胞周期调节、增殖、存活、凋亡和活动性在内的多种细胞过程中是重要的且是疾病如癌症、糖尿病和免疫炎症的分子机制中的关键组成部分(Vivanco et al(2002)Nature Rev. Cancer 2:489;Phillips et al(1998)Cancer83:41)。
癌症中主要的PI3-激酶亚型是I类PI3-激酶p110 α(alpha)(US 5824492;US5846824;US 6274327)。其它亚型参与心血管疾病和免疫炎性疾病(Workman P(2004)Biochem Soc Trans 32:393-396;Patel et al(2004)Proceedings of the AmericanAssociation of Cancer Research(Abstract LB-247)95th Annual Meeting, March 27-31, Orlando, Florida, USA;Ahmadi K and Waterfield MD(2004)Encyclopedia ofBiological Chemistry(Lennarz W J, Lane M D eds)Elsevier/Academic Press)。PI3激酶/Akt/PTEN途径是癌症药物开发中有吸引力的靶标,这是因为预期这样的调节剂或抑制剂将会抑制增殖、逆转凋亡阻滞及克服癌细胞中对细胞毒性剂的抗性(Folkes et al(2008)J. Med. Chem.51:5522-5532;Yaguchi et al(2006)Jour. of the Nat. CancerInst. 98(8):545-556)。PI3K-PTEN-AKT信号传导途径在很多种癌症中是失调的(SamuelsY, Wang Z,Bardellil A et al. High frequency of mutations of the PIK3CA genein human cancers.(2004)Science; 304(5670):554;Carpten J, Faber AL, Horn C. “Atransforming mutation in the pleckstrin homology domain of AKT1 in cancer”(2007)Nature; 448:439-444)。
GDC-0032,也已知为2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酰胺,具有强效的PI3K活性(WO 2011/036280;US 8242104)且正在具有局部晚期或转移性实体瘤的患者中进行研究。
发明内容
本发明涉及制备被命名为2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酰胺且具有以下结构的PI3K抑制剂I(GDC-0032)及其立体异构体、几何异构体、互变异构体和药用盐的方法:
本发明另一个方面包括可用于制备GDC-0032且具有以下结构的新颖中间体:
本发明还涉及以下方面:
项1.制备具有以下结构的(2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酰胺I及其立体异构体、几何异构体、互变异构体和药用盐的方法:
所述方法包括:
(a)使IV和4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-联(1,3,2-二氧硼杂环戊烷)反应以形成22:
(b)使22、钯催化剂和III反应以形成23:
(c)使23与含水碱性试剂反应以形成II:
和
(d)使II先后与酰基活化试剂和氨反应得到I。
项2.项1的方法,其中IV通过使17与溴化剂反应来制备:
项3.项1或2的方法,其中所述钯催化剂选自PdCl2(PPh3)2、Pd(t-Bu)3、PdCl2 dppfCH2Cl2、Pd(PPh3)4、Pd(OAc)/PPh3、Cl2Pd[(Pet3)]2、Pd(DIPHOS)2、Cl2Pd(Bipy)、[PdCl(Ph2PCH2PPh2)]2、Cl2Pd[P(邻甲苯基)3]2、Pd2(dba)3/P(邻甲苯基)3、Pd2(dba)/P(呋喃基)3、Cl2Pd[P(呋喃基)3]2、Cl2Pd(PMePh2)2、
Cl2Pd[P(4-F-Ph)3]2、Cl2Pd[P(C6F6)3]2、Cl2Pd[P(2-COOH-Ph)(Ph)2]2、
Cl2Pd[P(4-COOH-Ph)(Ph)2]2及封装的催化剂Pd EnCatTM30、Pd EnCatTMTPP30和Pd(II)EnCatTMBINAP30。
项4.项1-3中任一项的方法,其中用固体吸附性钯清除剂由I除去钯。
项5.项4的方法,其中所述固体吸附性钯清除剂选自硅胶、定孔玻璃珠和低交联聚苯乙烯。
项6.项1-5中任一项的方法,其中III如下制备:
(a)使V与2-羟基乙基化试剂反应以形成14:
和
(b)使14与含水碱性试剂反应以形成V。
项7.项1-5中任一项的方法,其中III如下制备:
(a)使28与乙脒反应以形成29:
和
(b)使29与异丙基肼和酸性试剂反应以形成III。
项8.项1-5中任一项的方法,其中III如下制备:使28与N’-异丙基亚肼代乙酰胺6反应以形成III:
项9.项7的方法,其中28如下制备:
(a)使11与羟胺反应以形成24:
(b)使24与丙炔酸乙酯反应以形成25:
(c)加热25以形成26:
(d)使26与2-羟基乙基化试剂反应以形成27:
和
(e)使27与含水碱性试剂反应以形成28。
项10.一种化合物,其选自以下结构:
项11.如本申请所述的本发明。
定义
术语"手性"是指具有镜像配对体不可重叠性的分子,而术语“非手性”是指可与其镜像配对体重叠的分子。
术语"立体异构体"是指具有相同化学组成但原子或基团具有不同空间排列的化合物。
"非对映异构体"是指具有两个或更多个手性中心且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,例如熔点、沸点、光谱性质和反应活性。非对映异构体的混合物可通过高分辨率分析操作例如电泳和色谱来分离。
"对映异构体"是指化合物的互为不可重叠镜像的两种立体异构体。
本申请使用的立体化学定义和常识大体遵循S.P.Parker,Ed.,
McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill BookCompany,New York;和Eliel, E. and Wilen, S., "Stereochemistry of OrganicCompounds",John Wiley & Sons, Inc., New York, 1994。本发明化合物可含有不对称中心或手性中心,因此以不同立体异构形式存在。所预期的是,本发明化合物的所有立体异构形式,包括但不限于非对映异构体、对映异构体和阻转异构体及它们的混合物例如外消旋混合物,构成本发明一部分。多种有机化合物以光学活性形式存在即它们具有使平面偏振光的平面发生旋转的能力。当描述光学活性化合物时,使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号,其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。就给定的化学结构而言,除这些立体异构体互为镜像外,这些立体异构体是相同的。具体的立体异构体还可称为对映异构体且上述异构体的混合物常常称为对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当化学反应或方法中没有立体选择性或立体特异性时,可出现外消旋混合物或外消旋体。术语"外消旋混合物"和"外消旋体"是指两种对映异构物质的等摩尔混合物,其不具有光学活性。
术语"互变异构体"或"互变异构形式"是指具有不同能量的可通过低能垒相互转化的结构异构体。例如,质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移来进行的相互转化,例如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组来进行的相互转化。
本申请所用的短语“药用盐”是指本发明化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖二酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1’-亚甲基-二-(2-羟基-3-萘甲酸盐))。药用盐可涉及另一种分子诸如乙酸根离子、琥珀酸根离子或其它抗衡离子的包合物。抗衡离子可以是稳定母体化合物电荷的任何有机或无机部分。此外,药用盐可在其结构中具有多于一个带电原子。多个带电原子为药用盐的部分的实例可具有多个抗衡离子。因此,药用盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
如果本发明化合物为碱,则可通过本领域可用的任何适合的方法制备所需的药用盐,例如,使用无机酸如盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等或用有机酸如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、羟乙酸、水杨酸、吡喃糖基酸诸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸诸如柠檬酸或酒石酸、氨基酸诸如天冬氨酸或谷氨酸、芳族酸诸如苯甲酸或肉桂酸、磺酸诸如对甲苯磺酸或乙磺酸等处理游离碱。
如果本发明化合物为酸,则可通过任何适合的方法制备所需的药用盐,例如,用无机或有机碱诸如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等处理游离酸。适当盐的示例性实例包括但不限于衍生自氨基酸诸如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺及环胺诸如哌啶、吗啉和哌嗪的有机盐及衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
"溶剂化物"是指一个或多个溶剂分子与本发明化合物的缔合或复合。形成溶剂化物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语"水合物"是指其中溶剂分子是水的复合物。
本申请所用的短语“药用盐”是指本发明化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖二酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1’-亚甲基-二-(2-羟基-3-萘甲酸盐))。药用盐可涉及另一种分子诸如乙酸根离子、琥珀酸根离子或其它抗衡离子的包合物。抗衡离子可以是稳定母体化合物电荷的任何有机或无机部分。此外,药用盐可在其结构中具有多于一个带电原子。多个带电原子为药用盐的部分的实例可具有多个抗衡离子。因此,药用盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
GDC-0032的制备
本发明包括用于合成式I的GDC-0032即PI3K和mTOR的一种小分子抑制剂(RocheRG7604, CAS登记号1282512-48-4)的途径、方法、试剂和中间体,所述GDC-0032具有以下结构:
且可被命名为2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酰胺(US 8242104;WO2011/036280;其通过引用的方式明确地并入本申请)。本申请使用的GDC-0032包括其所有立体异构体、几何异构体、互变异构体和药用盐。
本发明化合物可含有不对称中心或手性中心,因此以不同立体异构形式存在。所预期的是,本发明化合物的所有立体异构形式,包括但不限于非对映异构体、对映异构体和阻转异构体及它们的混合物例如外消旋混合物,构成本发明一部分。此外,本发明涵盖所有几何和位置异构体。在本申请所示的结构中,当未具体说明任何具体手性原子的立体化学时,则涵盖且包括作为本发明化合物的所有立体异构体。当通过表示具体构型的楔形实线或虚线来具体说明立体化学时,则由此说明和定义立体异构体。
本发明化合物可以非溶剂化形式及具有诸如水、乙醇等的药用溶剂的溶剂化形式存在且本发明意在涵盖溶剂化和非溶剂化形式。
本发明化合物也可以不同的互变异构形式存在且所有此类形式均包括在本发明范围内。术语“互变异构体”或“互变异构形式”指的是可经由低能障互相转化的具有不同能量的结构异构体。例如,质子互变异构体(也称为质子移变互变异构体)包括通过质子迁移进行的互相转化,诸如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组进行的互相转化。
本发明化合物还涵盖同位素标记的化合物,它们与本文所述化合物相同,只是一个或多个原子被具有与自然界通常找到的原子质量或质量数不同的原子质量或质量数的原子替换。规定的任何特定原子或元素的所有同位素涵盖在本发明化合物及其用途的范围内。能掺入本发明化合物的例示性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,诸如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I和125I。某些同位素标记的本发明化合物(例如那些用3H和14C标记的)在化合物和/或底物组织分布测定法中是有用的。氚(3H)和碳-14(14C)同位素因它们易于制备和可检测性而有用。另外,用更重的同位素诸如氘(2H)替代可提供某些治疗优势,其源自更大的代谢稳定性(例如体内半衰期延长或剂量需求降低)并因此在有些情况中是优选的。发射正电子的同位素,诸如15O、13N、11C和18F,可用于正电子发射断层摄影术(PET)研究以检查底物受体占据。同位素标记的本发明化合物一般能通过遵循与下文实施例中公开的规程类似的规程,通过用同位素标记的试剂替代非同位素标记的试剂来制备。
用于制备GDC-0032的起始物质和试剂可通常获自商业来源诸如Sigma-AldrichChemical(Milwaukee,WI),或可使用本领域技术人员熟知的方法容易地制备(例如通过通常描述于以下中的方法制备:Louis F.Fieser and Mary Fieser,Reagents for OrganicSynthesis,v.1-19,Wiley,N.Y.(1967-1999 ed.),或Beilsteins Handbuch derorganischen Chemie,4,Aufl.ed.Springer-Verlag,Berlin,包括附录(也经Beilstein在线数据库获得)。
以下方案1-15示例说明了用于合成式I的GDC-0032的化学反应、途径、方法学及某些中间体和试剂。
方案1:
方案1显示由Boc-肼1合成中间体异丙基肼盐酸盐4。1与丙酮和硫酸镁缩合得到Boc-腙即2-(丙-2-亚基)肼羧酸叔丁酯2(实施例1)。在乙酸和甲醇中将2进行钯催化的氢化得到Boc-异丙基-肼3(实施例2),将其用氯化氢气体原位处理得到4(实施例3)。
可替换地,2的双键可用氢化物试剂诸如氰基硼氢化钠还原(实施例2)。
方案2:
方案2显示由亚氨代乙酸甲酯盐酸盐5和异丙基肼盐酸盐4合成1-异丙基-3-甲基-1H-1,2,4-三唑7。使5和4在三乙胺和甲醇中反应,随后将缩合产物N’-异丙基亚肼代乙酰胺6(实施例4)用原甲酸三乙酯(三乙氧基甲烷)环化得到7(实施例5)。可替换地,4和乙脒可反应得到6。
或者,4可与乙腈和酸反应以形成6的相应的盐。
方案3:
方案3显示合成中间体2-氯-N-甲氧基-N-甲基乙酰胺10。使2-氯乙酰氯8和N,O-二甲基羟胺盐酸盐9在碳酸钾水溶液和甲基叔丁基醚(MTBE)中反应得到10(实施例6)。
方案4:
方案4显示合成中间体4-溴-2-氟亚氨代苯甲酰胺盐酸盐12,其通过使4-溴-2-氟苯甲腈11与二(三甲基甲硅烷基)氨基锂(LiHMDS)在四氢呋喃中反应而形成(实施例7)。可替换地,将11用氯化氢在醇诸如乙醇中处理以形成亚氨酸酯即4-溴-2-氟亚氨代苯甲酸乙酯盐酸盐,随后用氨(ammonia)在醇诸如乙醇中处理以形成12(实施例7)。
方案5:
方案5显示由1-异丙基-3-甲基-1H-1,2,4-三唑7合成5-(2-(4-溴-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑V。将7用正丁基锂去质子化并用2-氯-N-甲氧基-N-甲基乙酰胺10酰化得到中间体2-氯-1-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)乙酮13(实施例8)。将13用4-溴-2-氟亚氨代苯甲酰胺盐酸盐12和碳酸氢钾在水和THF(四氢呋喃)中环化形成咪唑V(实施例9)。
方案6:
方案6显示由V合成9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III。将V的咪唑氮用2-羟基乙基化试剂诸如1,3-二氧杂环戊烷-2-酮进行烷基化得到2-(2-(4-溴-2-氟苯基)-4-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-1H-咪唑-1-基)乙醇14(实施例10)。将14用含水碱性试剂诸如甲基三丁基氯化铵在氢氧化钾水溶液中环化得到III,其可由乙醇和水结晶(实施例11)。
方案7:
方案7显示起始于2-溴-2-甲基丙酸15合成2-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯IV。将吡唑用15烷基化得到2-甲基-2-(1H-吡唑-1-基)丙酸16(实施例12)。将16用硫酸在乙醇中酯化得到2-甲基-2-(1H-吡唑-1-基)丙酸乙酯17(实施例13)。将17用N-溴琥珀酰亚胺(NBS)进行区域专一性溴化得到IV(实施例14)。可替换地,将16用溴化剂诸如1,3-二溴-5,5-二甲基乙内酰脲(DBDMH)原位处理得到2-(4-溴-1H-吡唑-1-基)-2-甲基丙酸,将其酯化得到IV,其中R为乙基。也可制备其它酯诸如甲酯、异丙酯或任何烷基酯、苄基酯或芳基酯。
方案8:
方案8显示可替换地起始于2-溴-2-甲基丙酸乙酯18合成2-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯IV。将吡唑用18在碱诸如叔丁醇钠或碳酸铯的存在下烷基化得到2-甲基-2-(1H-吡唑-1-基)丙酸乙酯17和2-甲基-3-(1H-吡唑-1-基)丙酸乙酯19的混合物。将混合物用1,3-二溴-5,5-二甲基咪唑烷-2,4-二酮(DBDMH)溴化得到含有IV、3-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯20和4-溴-1H-吡唑21的混合物,将其用强碱在无水条件下诸如二(三甲基甲硅烷基)氨基锂在四氢呋喃中处理。用盐酸酸化得到IV。
方案9:
方案9显示由2-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯IV(CAS登记号:1040377-17-0,WO 2008/088881)和9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III(CAS登记号:1282514-63-9,US 2012/0245144, US8242104)合成2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酰胺即式I的GDC-0032。也可使用除了乙酯之外的其它可用含水碱水解的酯诸如甲酯、异丙酯或任何烷基酯、苄基酯或芳基酯。在一锅法Miyaura Borylation/Suzuki,Buchwald系统中使2-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯IV与4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-联(1,3,2-二氧硼杂环戊烷)(CAS登记号73183-34-3,也称为B2Pin2)和钯催化剂诸如XPhos(2-二环己基膦基-2’,4’,6’-三异丙基联苯(CAS登记号564483-18-7)及盐诸如乙酸钾在溶剂诸如乙醇中在约75℃反应以形成中间体2-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙酸乙酯22(实施例15,CAS登记号:1201657-32-0,US 8242104,US 8263633,WO 2009/150240)。
中间体22可分离或与III原位反应(一锅法)以形成23。
在Suzuki偶联步骤中也可使用多种低价的Pd(II)和Pd(0)钯催化剂以由22和III形成23(实施例16),所述钯催化剂包括PdCl2(PPh3)2、Pd(t-Bu)3、PdCl2dppf CH2Cl2、Pd(PPh3)4、Pd(OAc)/PPh3、Cl2Pd[(Pet3)]2、Pd(DIPHOS)2、Cl2Pd(Bipy)、[PdCl(Ph2PCH2PPh2)]2、Cl2Pd[P(邻甲苯基)3]2、Pd2(dba)3/P(邻甲苯基)3、Pd2(dba)/P(呋喃基)3、Cl2Pd[P(呋喃基)3]2、Cl2Pd(PMePh2)2、Cl2Pd[P(4-F-Ph)3]2、Cl2Pd[P(C6F6)3]2、Cl2Pd[P(2-COOH-Ph)(Ph)2]2、Cl2Pd[P(4-COOH-Ph)(Ph)2]2及封装的催化剂Pd EnCatTM30、Pd EnCatTMTPP30和Pd(II)EnCatTMBINAP30(US 2004/0254066)。
将23的酯基用含水碱性试剂诸如氢氧化锂皂化得到2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酸II(实施例17)。中间体23可分离或进一步与含水碱性试剂原位反应以形成II。将II的羧酸基团用酰基活化试剂诸如二(1H-咪唑-1-基)甲酮(羰基二咪唑,CDI)或N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)脲鎓六氟磷酸盐(HATU)活化,然后与含醇氨试剂诸如溶于甲醇、乙醇或异丙醇的氨、含水氢氧化铵、含水氯化铵或溶于THF的氨反应得到I(实施例18)。
在Suzuki偶联步骤以形成化合物I后可使用多种固体吸附性钯清除剂以除去钯。钯清除剂的示例性实施方案包括Thiol和Thiourea。其它钯清除剂包括硅胶、定孔玻璃珠(TosoHaas)和衍生的低交联聚苯乙烯QuadraPureTMAEA、QuadraPureTMIMDAZ、QuadraPureTMMPA、QuadraPureTMTU(Reaxa Ltd.,Sigma-Aldrich Chemical Co.)。
方案10:
方案10显示由4-溴-2-氟苯甲腈11合成9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III。将羟胺加到11的腈中得到4-溴-2-氟-N-羟基亚氨代苯甲酰胺24。将24与丙炔酸乙酯进行迈克尔加成得到3-(4-溴-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯25。将25在高沸点溶剂诸如甲苯、二甲苯、乙基苯或二苯基氧中加热得到环化的咪唑即2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸乙酯26及副产物嘧啶即2-(4-溴-2-氟苯基)嘧啶-4-醇。可替换地,可将25用催化性路易斯酸诸如Cu(I)盐或Cu(II)盐环化为26。将26用2-羟基乙基化试剂诸如1,3-二氧杂环戊烷-2-酮在碱诸如N-甲基咪唑或碳酸铯中烷基化得到2-(4-溴-2-氟苯基)-1-(2-羟基乙基)-1H-咪唑-4-羧酸乙酯27。将27用含水碱性试剂诸如氢氧化钾、氢氧化锂和甲基三丁基氯化铵环化得到9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-羧酸28。将乙脒加入至28和三苯基膦中得到9-溴-N-(1-亚氨基乙基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-甲酰胺29。将29用异丙基肼盐酸盐4在乙酸中环化得到9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III。
可替换地,28可与N’-异丙基亚肼代乙酰胺6反应得到III(方案12)。
方案11:
方案11显示由4-溴-2-氟亚氨代苯甲酰胺盐酸盐12合成5-(2-(4-溴-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑V。使3-氯-2-氧代丙酸和12与碱反应得到2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸30。可替换地,3-溴-2-氧代丙酸可与12反应得到30。使30与N’-异丙基亚肼代乙酰胺6和偶联剂HBTU(N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲鎓六氟磷酸盐,O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐,CAS登记号94790-37-1)在DMF中反应得到中间体2-(4-溴-2-氟苯基)-N-(1-(2-异丙基肼基)亚乙基)-1H-咪唑-4-甲酰胺31,其不需要分离且在加热后环化得到V。
可替换地,5-(2-(4-氯-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑44即V的含氯版本可由4-氯-2-氟苯甲腈38制备(方案15)。
方案12:
方案12显示可替换地由4-溴-2-氟苯甲腈11合成9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III。将11用2-羟基乙基氨基甲酸叔丁酯进行烷基化得到2-(5-溴-2-氰基苯氧基)乙基氨基甲酸叔丁酯32。将32在酸性条件下诸如盐酸在乙醇中环化得到8-溴-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-亚胺33。应当注意的是,33具有可替换的互变异构形式,其中双键位于氧氮杂环的内侧。通过使3-溴-2-氧代丙酸(X=Br,R=OH)或其它3-卤代-2-氧代丙酸或酯(R=烷基)和33反应可形成咪唑环得到9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-羧酸28。将28与N’-异丙基亚肼代乙酰胺6和偶联剂诸如HBTU、HATU或CDI在DMF中偶联得到中间体9-溴-N-(1-(2-异丙基肼基)亚乙基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-甲酰胺34,其不需要分离且在加热后形成9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III。
可替换地,N’-异丙基亚肼代乙酰胺6以单盐酸盐形式使用,其需要在反应条件下用适当的碱诸如K2CO3转化成游离形式。
方案13:
方案13显示可替换地由4-溴-2-氟苯甲腈11合成8-溴-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-亚胺33。使11与甲醇钠在甲醇中反应得到4-溴-2-氟亚氨代苯甲酸甲酯35。将35用2-氨基乙醇进行烷基化得到4-溴-2-氟-N-(2-羟基乙基)亚氨代苯甲酰胺36,随后环化为33。
方案14:
方案14显示可替换地由4-溴-2-氟苯甲腈11合成8-溴-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-亚胺33。使11与2-氨基乙醇和叔丁醇钾反应置换氟得到2-(2-氨基乙氧基)-4-溴苯甲腈盐酸盐37。将37用三甲基铝进行环合得到33。可替换地,也可使用其它三烷基铝试剂或镁烷氧化物试剂诸如乙醇镁(二乙醇镁,CAS登记号2414-98-4)以环化37为33。
方案15:
方案15显示由4-氯-2-氟苯甲腈38合成5-(2-(4-氯-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑44。将羟胺加到38的腈中得到4-氯-2-氟-N-羟基亚氨代苯甲酰胺39。使39与丙炔酸乙酯进行迈克尔加成得到3-(4-氯-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯40。将40在二苯基氧中加热得到环化的咪唑即2-(4-氯-2-氟苯基)-1H-咪唑-4-羧酸乙酯41。将41的酯用含水氢氧化钠在四氢呋喃中皂化得到2-(4-氯-2-氟苯基)-1H-咪唑-4-羧酸42。使42与N’-异丙基亚肼代乙酰胺6和偶联剂HBTU在DMF中反应得到中间体2-(4-氯-2-氟苯基)-N-(1-(2-异丙基肼基)亚乙基)-1H-咪唑-4-甲酰胺43,其加热环化得到44。
制剂
根据标准制药规范配制的式I的GDC-0032用于治疗性治疗(包括预防性治疗)哺乳动物(包括人)的过度增生性病症的治疗性组合中。本发明提供药物组合物,其包含GDC-0032和一种或多种药用载体、助流剂、稀释剂、添加剂或赋形剂。
合适的载体、稀释剂、助流剂和赋形剂是本领域熟练技术人员公知的,而且包括下述物质,诸如碳水化合物、蜡、水溶性和/或可膨胀聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等等。
可以使用常规溶解和混合规程来制备配制剂。本发明化合物通常配制成药学剂量形式,以提供可容易控制剂量的药物和使患者顺从处方方案。
可以以多种方式包装供应用的药物组合物(或配制剂),这取决于用于施用药物的方法。一般而言,分发的物品包括容器,其中沉积有适宜形式的药物配制剂。合适的容器是本领域技术人员公知的,而且包括诸如瓶(塑料的和玻璃的)、囊、安瓿、塑料袋、金属筒等材料。容器还可以包括防干扰装置以防止不慎接触到包装的内容物。另外,容器上可贴有描述容器中所含内容物的标签。标签还可以包括适宜的警告。
可以制备本发明化合物的药物制剂,供各种途径和类型的以冻干制剂、碾碎的粉末、或水溶液的形式与药用稀释剂、载体、赋形剂或稳定剂一同施用(Remington’sPharmaceutical Sciences(1995)18th edition,Mack Publ.Co.,Easton,PA)。可以通过于环境温度与适宜的pH及于期望的纯度,与生理学可接受载体(即在所采用的剂量和浓度对接受者无毒的载体)混合来进行配制。制剂的pH主要取决于具体用途和化合物的浓度,但是范围可以是约3至约8。
药物制剂优选是无菌的。具体而言,用于体内施用的制剂必须是无菌的。这种无菌易于通过无菌滤膜过滤来实现。
药物制剂通常能作为固体组合物、片剂、丸剂、胶囊、冻干制剂或作为水溶液来贮存。
本发明药物制剂会以与优良医学实践一致的方式即量、浓度、时间表、疗程、媒介物和施用途径来进行剂量给药和施用。在此语境中要考虑的因素包括所治疗的具体病症、患者个体的临床状况、病症的起因、药物的递送部位、施用方法、施用时间表、和医学从业人员已知的其它因素。
可接受的稀释剂、载体、赋形剂和稳定剂在所采用的剂量和浓度对接受者是无毒的并且包括:缓冲剂,诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如氯化十八烷基二甲基苄基铵;氯己双铵;苯扎氯铵,苄索氯铵;酚,丁醇、乙醇或苄醇;对羟基苯甲酸烃基酯,诸如对羟基苯甲酸甲酯或丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(低于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖类,二糖类和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖类,诸如乳糖、蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子,诸如钠;金属复合物(例如Zn-蛋白质复合物);和/或非离子表面活性剂,诸如TWEENTM,包括Tween80、PLURONICSTM或聚乙二醇(PEG)包括PEG400。活性药物组分还可包载于例如通过凝聚技术或通过界面聚合制备的微胶囊中(例如分别是羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊)、在胶状药物递送系统中(例如脂质体、白蛋白微球体、微乳剂、纳米颗粒和纳米胶囊)、或在粗滴乳状液中。此类技术披露于Remington’s Pharmaceutical Sciences18th edition,(1995)Mack Publ.Co.,Easton,PA。药物制剂的其它实例可在Liberman,H.A.and Lachman,L.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker, Vol 3,2ndEd.,New York,NY中找到。
药用助流剂可选自二氧化硅、粉状纤维素、微晶纤维素、硬脂酸金属盐、铝硅酸钠、苯甲酸钠、碳酸钙、硅酸钙、玉米淀粉、碳酸镁、无石棉滑石、Stearowet C、淀粉、淀粉1500、月桂基硫酸镁、氧化镁和其组合。
药物制剂包括那些适合于本文详述的施用途径的。制剂可以方便地以单位剂量形式存在,而且可以通过药学领域公知的任何方法来制备。技术和配方一般见Remington’sPharmaceutical Sciences 18th Ed.(1995)Mack Publishing Co.,Easton,PA。此类方法包括使活性组分与构成一种或多种辅助组分的载体联合的步骤。一般而言,通过均匀且紧密地使活性组分与液体载体或粉碎的固体载体或二者联合,然后在必要时使产物定形来制备配制剂。
药物组合物可呈无菌注射剂诸如无菌注射用水性或油性混悬剂形式。所述混悬剂可根据本领域已知的方法使用上述那些合适的分散剂或润湿剂和助悬剂来配制。无菌注射剂可为在无毒的胃肠外可接受的稀释剂或溶剂中的溶液剂或混悬剂,诸如在1,3-丁二醇中的溶液或制备自冻干粉末剂。可使用的可接受的媒介物和溶剂包括水、林格溶液和等渗氯化钠溶液。另外,无菌不挥发性油通常可用作溶剂或助悬介质。出于所述目的,可使用任何温和的不挥发性油,包括合成的甘油一酯或甘油二酯。另外,脂肪酸诸如油酸也可用于制备注射剂。
实施例
实施例1 2-(丙-2-亚基)肼羧酸叔丁酯2
向肼羧酸叔丁酯1(CAS登记号870-46-2)(25.1g,0.190mol)在丙酮(185mL)中的溶液中加入硫酸镁(6g)和12滴乙酸(Wu et al(2012)Jour.Med.Chem.55(6):2724-2736;WO2007/056170;Zawadzki et al(2003)Polish Jour.Chem.77(3):315-319)。将混合物加热回流2.5小时并冷却至室温并过滤。将滤液浓缩得到2-(丙-2-亚基)肼羧酸叔丁酯2(CAS登记号16689-34-2),其为灰白色固体(32g,98%)(无需进一步纯化即在下一步中使用)。LC-MS[M+H]+=172.9,RT=2.11分钟。1H NMR 300MHz(CDCl3)δ 7.35(br s,1H,NH),2.04(s,3H),1.82(s,3H),1.54(s,9H);13C NMR 300MHz(CDCl3)δ 152.9,149.7,80.7,28.1,25.3,15.9。
实施例2 2-异丙基肼羧酸叔丁酯3
将2-(丙-2-亚基)肼羧酸叔丁酯2用钯催化剂/炭在氢气下在乙酸和甲醇中还原得到2-异丙基肼羧酸叔丁酯3(CAS登记号16689-35-3)。
可替换地,将2-(丙-2-亚基)肼羧酸叔丁酯2(0.51g,3.0mmol)溶于20mL THF中,用NaBH3CN(0.19g,3.0mmol)和几mg溴甲酚绿处理,随后历时约1小时逐滴加入对甲苯磺酸(0.57g,3.0mmol)在1.5mL THF中的溶液以保持反应混合物的pH介于3.5-5.0。在室温再搅拌1小时后,将溶剂经旋转蒸发除去并将残留物在EtOAc(30mL)和盐水之间分配。将有机相用20mL饱和NaHCO3和盐水萃取,蒸发得到残留物并溶于10mL乙醇中。将乙醇溶液用3.6mL1M NaOH溶液(3.6mmol)处理并在室温搅拌30分钟。将溶剂经旋转蒸发除去并将残留物吸收于乙酸乙酯中并用水萃取。将有机层减压蒸发并将残留物经柱色谱纯化(使用5%MeOH在DCM中的溶液作为洗脱剂),收集到2-异丙基肼羧酸叔丁酯3(0.4g,77%收率):mp=47-49℃;Rf=0.44(5%MeOH在DCM中的溶液);1H NMR 300MHz(CDCl3)δ 6.03(s,N-H,1H),3.92(s,N-H,1H),3.14(m,1H),1.46(s,9H),1.02(d,6H,J=6 Hz);13C NMR 300MHz(CDCl3)δ157.2,80.8,51.2,28.7,21.0。
实施例3异丙基肼盐酸盐4
将2-异丙基肼羧酸叔丁酯3用盐酸处理以除去Boc保护基并得到4(CAS登记号16726-41-3)。
实施例4 N’-异丙基亚肼代乙酰胺6
使亚氨代乙酸甲酯盐酸盐5(CAS登记号14777-27-6)、异丙基肼盐酸盐4和三乙胺在甲醇中反应得到6(CAS登记号73479-06-8)。
实施例5 1-异丙基-3-甲基-1H-1,2,4-三唑7
将N’-异丙基亚肼代乙酰胺6用原甲酸三乙酯在乙醇中处理,随后用三乙胺和四氢呋喃处理得到7(CAS登记号1401305-30-3)。
实施例6 2-氯-N-甲氧基-N-甲基乙酰胺10
在15~20℃向21.2kg碳酸钾(K2CO3)(153.7mol,3.0当量)在30L H2O中的溶液中加入N,O-二甲基羟胺9(CAS登记号1117-97-1)(5.0kg,51.3mol,1.0当量)。将反应混合物在室温搅拌30分钟并加入30L甲基叔丁基醚(TBME)。搅拌30分钟后,将混合物冷却至5℃并缓慢加入11.6kg 2-氯乙酰氯8(CAS登记号79-04-9(102.7mol,2.0当量)。将反应混合物在室温搅拌过夜。将有机相与水相分离并将水相用TBME(30L)萃取。将合并的有机相用H2O(50L)和盐水(50L)洗涤并经Na2SO4干燥。过滤并真空浓缩得到5.1kg 2-氯-N-甲氧基-N-甲基乙酰胺10(CAS登记号67442-07-3),其为白色固体。
实施例7 4-溴-2-氟亚氨代苯甲酰胺盐酸盐12
在氮气下在10℃向35.0L二(三甲基甲硅烷基)氨基锂(LiHMDS)(35.0mol,1.4当量,1.0M在THF中)加入4-溴-2-氟苯甲腈11(CAS登记号105942-08-3)的THF溶液(5.0kg在10L THF中),将混合物在室温搅拌3小时。冷却至-20℃并加入8.3L HCl-EtOH(6.6M)。将混合物在-10℃再搅拌1小时,过滤。将湿的滤饼用EA(10L)和H2O(6L)洗涤。真空干燥得到5.8kg 4-溴-2-氟亚氨代苯甲酰胺盐酸盐12(CAS登记号1187927-25-8),其为灰白色固体。
可替换地,向200L容器中加入4-溴-2-氟苯甲腈11(10kg,50.00mol,1.00当量)和乙醇(100L),随后用40kg氯化氢(g)在-10℃在搅拌下净化(方案4)。将所得的溶液在10℃再反应36小时。反应进程经TLC监测直到11完全消耗。将所得的混合物真空浓缩同时保持温度低于60℃。将体积浓缩为10~15L,然后加入60L MTBE以将产物沉淀。经过滤收集沉淀物得到12kg 4-溴-2-氟亚氨代苯甲酸乙酯盐酸盐12,其为白色固体(收率:85%)。1H NMR δ7.88-7.67(m),4.89(br s),4.68(q),3.33(m),1.61(t)。MS M+1:245.9,248.0。
向200L容器中加入4-溴-2-氟亚氨代苯甲酸乙酯盐酸盐(12.5kg,44mol,1.00当量,99%)和乙醇(125L),随后用NH3(g)在-5℃净化12小时。将所得的溶液在30℃再搅拌24小时。反应进程经TLC监测直到原料完全消耗。将沉淀物过滤并将滤液真空浓缩。将产物沉淀并经过滤收集得到6.1kg(54.5%)4-溴-2-氟苯甲脒盐酸盐12,其为白色固体。1H NMR δ9.60(br),7.91-7.64(m),3.40(s),2.50(m)。MS M+1:216.9,219.9。
实施例8 2-氯-1-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)乙酮13
向10L四颈烧瓶中加入1-异丙基-3-甲基-1H-1,2,4-三唑7(400g)在THF(2.5L)中的溶液。将所得的溶液冷却至-40℃并加入2.5M正丁基锂(BuLi)在正己烷(1.41L)中的溶液同时保持内部温度低于-20℃。将所得的黄色混悬液在-40℃搅拌1小时,然后转移。向20L烧瓶中加入2-氯-N-甲氧基-N-甲基乙酰胺10(485g)在THF(4L)中的溶液。将所得的溶液冷却至-40℃,此时获得白色混悬液并向其中加入锂化的三唑7的溶液同时保持内部温度低于-20℃。此时获得黄橙色溶液,将其在-30℃搅拌1小时。加入丙酸(520mL)同时保持内部温度低于-20℃。历时30分钟将所得的灰白色至黄色混悬液温热至-5℃。加入柠檬酸(200g)在水(0.8L)中的溶液并在搅拌5分钟后,获得澄清的二相混合物。此时停止搅拌并移去底部的水层。将有机相用20w%K3PO4溶液(1L)、20w%K2HPO4溶液(2L)和20w%NaCl溶液(1L)洗涤。经真空蒸馏将有机相减少为约4L得到2-氯-1-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)乙酮13,其为深琥珀色液体,将其如原样在下一步中使用。
实施例9 5-(2-(4-溴-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑V
向10L四颈烧瓶中加入THF(5.6L)、4-溴-2-氟亚氨代苯甲酰胺盐酸盐12(567g)、KHCO3(567g)和水(1.15L)。经2小时将所得的白色混悬液加热至60℃。此时获得混浊溶液,向其中加入2-氯-1-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)乙酮13在THF(2L)中的溶液。将溶液在60-65℃搅拌24小时。然后移去底部水层。将有机层真空浓缩。将残留物在MIBK(1.25L)和甲苯(0.7L)的混合物中浆化并将析出的产物过滤,得到552g 5-(2-(4-溴-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑V(98.0%纯度,254nm),其为棕色固体。
实施例10 2-(2-(4-溴-2-氟苯基)-4-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-1H-咪唑-1-基)乙醇14
在50℃将5-(2-(4-溴-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑V(2.75kg,7.55mol)加入至1,3-二氧杂环戊烷-2-酮(碳酸亚乙酯,3.99kg,45.3mol)在N-甲基咪唑(12L)中的溶液中。将混悬液在80℃加热7小时直到经HPLC判断反应完成。将14的溶液冷却至35℃并直接在随后的环化中使用。
实施例11 9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III
在35℃向2-(2-(4-溴-2-氟苯基)-4-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-1H-咪唑-1-基)乙醇14(7.55mmol)在N-甲基咪唑(12L)中的溶液中加入甲基三丁基氯化铵(115g,0.453mol)、甲苯(27.5L)和35%氢氧化钾溶液(10.6kg,25mol在22L水中)。当经HPLC判断反应完成时,将二相溶液在65℃剧烈搅拌18小时。停止搅拌,但继续加热并且移去底部水层。加入乙酸异丙酯(13.8L)并将有机相用水(13.8L和27.5L)洗涤两次。将溶剂经真空蒸馏除去且在除去30L后,加入异丙醇(67.6L)。继续真空蒸馏直到再除去30L溶剂。再加入异丙醇(28.8L)并继续真空蒸馏直到将体积减小42L。加入异丙醇(4L)并且将温度升至>50℃。加入水(28L)以使内部温度保持高于50℃,然后加热至75℃得到澄清溶液。将混合物缓慢冷却且产物由溶液结晶。将所得的混悬液冷却至0℃,保持1小时,然后过滤并将滤饼用水(5.5L)洗涤。将滤饼在45℃在氮气吹扫下干燥得到III,其为褐色固体(3.30kg,71.6wt%,80.6%收率)。
实施例12 2-甲基-2-(1H-吡唑-1-基)丙酸16
使2-溴-2-甲基丙酸15和吡唑在三乙胺和2-甲基四氢呋喃中反应得到16。
实施例13 2-甲基-2-(1H-吡唑-1-基)丙酸乙酯17
将2-甲基-2-(1H-吡唑-1-基)丙酸16用硫酸在乙醇中处理得到17。
可替换地,在室温将吡唑(10g,147mmol,1.0当量)溶于DMF(500ml)中。将2-溴异丁酸乙酯18(22ml,147mmol,1.0当量)、碳酸铯(Cs2CO3)(53g,162mmol,1.1当量)和催化性碘化钠(NaI)(2.2g,15mmol,0.1,当量)加入至混合物中,然后加热至60℃且保持24小时。随后经1H NMR监测反应且在24小时后未检测到吡唑。将反应混合物用饱和NaHCO3溶液(200ml)淬灭并加入乙酸乙酯(EtOAc)(150ml)且将有机相与水相分离。将有机相经Na2SO4干燥,过滤并真空浓缩得到油状物,将其经快速色谱法纯化得到17。
实施例14 2-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯IV
方法A:使2-甲基-2-(1H-吡唑-1-基)丙酸乙酯17与N-溴琥珀酰亚胺(NBS)在2-甲基四氢呋喃中反应得到IV(CAS登记号1040377-17-0)。
方法B:使2-溴-2-甲基丙酸乙酯18和吡唑与叔丁醇钠在二甲基甲酰胺(DMF)中反应得到2-甲基-2-(1H-吡唑-1-基)丙酸乙酯17和2-甲基-3-(1H-吡唑-1-基)丙酸乙酯19的混合物,将其用1,3-二溴-5,5-二甲基咪唑烷-2,4-二酮处理得到IV、3-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯20和4-溴-1H-吡唑21的混合物。将混合物用催化量的二(三甲基甲硅烷基)氨基锂在四氢呋喃中处理,随后用盐酸酸化得到IV。
实施例15 2-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙酸乙酯22
向50L玻璃反应器中加入2-(4-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯IV(1.00kg,3.85mol,1.00当量)、乙酸钾(KOAc)(0.47kg,4.79mol 1.25当量)、4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-联(1,3,2-二氧硼杂环戊烷)即二(频哪醇合)二硼(B2Pin2)(1.22kg,4.79mol,1.25当量)和乙醇(10L,10体积)并将混合物搅拌直到获得澄清的溶液。将溶液用氮气真空/脱气3次。向该混合物中加入XPhos配体(0.023kg,0.048mol,1.0mol%)和Pd预催化剂(0.018kg,0.022mol,0.5mol%),得到均匀的橙色溶液。将溶液用氮气真空/脱气一次。将反应混合物的内部温度设定为75℃且一旦达到设定温度,就将反应混合物每30分钟取样一次且经LC监测(IPC方法:XTerra MS Boronic)。5小时后,几乎完全转化为22(CAS登记号1201657-32-0),其中剩余1.3%IV。
实施例16 2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酸乙酯23
使2-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙酸乙酯22和9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III在Suzuki条件下与钯催化剂在异丙醇和磷酸盐缓冲水溶液中反应得到23。
将1M K3PO4溶液(1.60kg在7.6L水中,7.54mol,2.00当量)加入至实施例15的上述反应混合物中,随后历时2分钟加入III在THF中的溶液(1.33kg,5.0L,3.43mol,0.90当量)。历时45分钟将反应混合物温热至75℃(内部温度)并在75℃搅拌13小时,然后经HPLC分析(未检测到III)显示形成23。
实施例17 2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酸II
将2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酸乙酯23用氢氧化锂水溶液处理到II。
酯皂化反应通过将3.5M LiOH水溶液(0.74kg在5.0L中,17.64mol,5当量)加入至实施例16的反应混合物中并温热至75℃开始。每30分钟取样一次混合物(IPC方法:XTerraMS Boronic)并且在4.5小时后皂化完成(剩余小于0.3%的23)。将反应混合物蒸馏浓缩为约一半的体积(起始体积=37L;最终体积=19L)以除去EtOH和THF,得到棕褐色浆液。将水(5L,5体积)加入至混合物中,然后蒸馏(起始体积=25L;最终体积=21L)。将温度设定在60℃(夹套控制),然后加入乙酸异丙酯(IPAc)(4L,4体积)。将二相混合物在最少5分钟内搅拌,然后在最少5分钟内分离各层。将底部水层移至干净的酸瓶中并将有机层收集在第二个酸瓶中。萃取操作重复总计四次直到有机层变得明显澄清。将水性混合物转移回到反应器中,然后冷却至15℃。缓慢加入HCl的6M溶液(6.4L,38.40mol,10当量)直到获得最终的pH=1。然后将不均匀的混合物过滤。将所得的固体用5L水(2×5体积)洗涤两次。然后将滤液加热至80℃并将真空设定为-10Psi(通过放出氮气)并将固体干燥24小时(KF=2.0%H2O)得到1.54kg(95%校正收率)II,其为白色固体。98%wt,97.3%纯度。
实施例18 2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酰胺I(GDC-0032)
将2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酸II用二(1H-咪唑-1-基)甲酮(羰基二咪唑,CDI)在四氢呋喃中处理,随后用含甲醇的氨处理得到粗I。
将固体II(1.44kg,3.12mol,1.00当量)转移至20L瓶中,然后加入THF(10L,7体积)。将浆液在减压下转移至第二个50L反应器中并再加入THF(5L,3体积)以用于淋洗。将浆液的内部温度设定为22℃并将1,1-羰基二咪唑(CDI)(0.76Kg,5.12mol,1.50当量)加入至混合物中并在5分钟后观察到澄清的溶液。每30分钟取样一次反应混合物并经HPLC分析(IPC:XTerra MS Boronic方法),其显示在30分钟后几乎完全转化为酰基-咪唑中间体和1.2%的剩余的II。加入另一份CDI(0.07kg,0.15mol,0.14当量)并将反应混合物搅拌1小时,然后经HPLC分析(IPC:XTerra MS Boronic方法),其显示剩余0.8%II。
向第二个50L反应器中加入NH3/MeOH(1.5L,10.5mol,3.37当量)和THF(5L,3体积)。将酰基-咪唑中间体在减压下转移至第二个反应器中(转移时间~10分钟)。然后将内部温度设定为45℃并将溶剂的体积由35L蒸馏至12L。然后将水(6L,4体积)加入至混合物中,其进一步由18L蒸馏至11L。最后加入另一份水(6L,4体积)并最后一次将溶剂由17L蒸馏至14L直到THF不再出来。然后将反应混合物冷却至10℃(内部温度)。将白色浆液过滤并将滤饼用水(2×6L,2×4体积)洗涤。然后将固体在Aurora过滤器中在80℃(夹套温度)真空干燥24小时(KF=1.5%H2O)得到1.25kg粗I即GDC-0032(84%校正收率,96%wt,经HPLC测定97.3%纯度),其为白色固体。
制备粗I(1.15kg,2.50摩尔)在MeOH(6L,5体积)中的浆液,然后加入至50L玻璃反应器中。将另外的MeOH(24L,21体积)加入至混合物中,然后将其加热至65℃。获得均匀的混合物。经加入口将Si-thiol(Silicycle,Inc.,0.23kg,20%wt)加入至溶液中并将混合物搅拌3小时。然后将其经Aurora过滤器温热过滤(夹套温度=60℃),精细过滤并在减压下直接转移至第二个50L反应器中。然后将溶液加热回到65℃的内部温度(IT)。将均匀的溶液冷却至54℃并加入I的晶种(12g,1%wt)/MeOH(50mL),其中将减压施用至反应器。然后历时16小时将混合物冷却至20℃。然后将固体经Aurora过滤器过滤并在80℃干燥72小时得到I(921g,80%收率),其为甲醇溶剂化物(经XRPD测定为形式A)并转移至预先称重的Charge-Point袋中。
在隔离器中将固体在IPAc(8L,7体积)中浆化并转移至干净的10L反应器中。将混合物在60℃(IT)搅拌1小时。然后将固体经Aurora系统过滤并在80℃(夹套)干燥96小时。取出I的样品并经GC分析(IPAc=1%)。为了达到更有效的干燥,将API转移至隔离器中的两个玻璃托盘中并用干燥袋密封,然后在设定为100℃的真空烘箱中干燥16小时。GC(IPC:Q12690V2)显示仍然存在1%溶剂。该方法得到760g(68%校正收率,68%wt,经LC测定99.9%纯度)白色固体(经XRPD测定为形式B)。
将粗I(340.7g)加入至2L HDPE瓶中并用0.8L异戊醇(IAA)浆化。将浆液转移至20L反应器中并用6.7L圆底烧瓶(总计22体积)稀释。加热白色浆液直到观察到溶液(内部温度升至118℃且然后冷却至109℃)。将溶液精细过滤(0.2μM过滤器)。烧瓶配备有顶部搅拌器并将滤液在异戊醇(344mL,21体积)中浆化。将混合物温热至95℃(内部温度)直到固体溶解。加入炭(10wt%,0.16g)和Silicycle硫醇(10wt%,0.16g)在异戊醇(1体积,16mL)中的浆液并将混合物在90-95℃搅拌1小时,然后过滤(经填料)。将澄清的琥珀色溶液冷却至73℃(种晶温度范围=70±5℃)并加入GDC-0032即I的晶种(10wt%,0.16g)。将加热套关闭并在搅拌(200rpm)下将混合物冷却至室温过夜。17小时后,由缓慢重力过滤开始将白色固体过滤,然后施用真空。在混合下将固体抽吸干燥20分钟直到获得可自由流动的粉末。将粗物质称重,然后烘箱干燥=16g。将固体在100℃烘箱干燥24小时,然后取样以进行测试。在100℃再继续干燥24小时。1H NMR(DMSO d6)δ 8.38(t),8.01(s),7.87(s),7.44,7.46(d),7.36(s),7.18(br s),6.81(br s),5.82(m),3.99(s),2.50(s),2.26(s),1.75(s),1.48,1.46(d)。
将纯化的2-(4-(2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-1H-吡唑-1-基)-2-甲基丙酰胺I(GDC-0032)经辗压法(He et al(2007)Jour.of Pharm.Sci.,96(5):1342-1355)干法制粒为片剂形式,其中赋形剂包括乳糖、微晶纤维素(PH 01,FMC BioPolymer,50μm颗粒)、交联羧甲基纤维素钠(Ac-Di-FMC BioPolymer)和硬脂酸镁。
实施例19 4-溴-2-氟-N-羟基亚氨代苯甲酰胺24
向4-溴-2-氟苯甲腈11(800g,4mol,1当量)和羟胺盐酸盐(695g,10mol,2.5当量)在MeOH(2L,2.5体积)中的溶液中加入Et3N(485g,4.8mol,1.2当量),然后将混合物在60℃搅拌40分钟并经HPLC监测(无腈剩余)。然后将反应混合物经H2O(30L)淬灭并将大量灰白色固体分离出来,然后过滤,将滤饼用水(10L×2)洗涤并获得1350g湿的4-溴-2-氟-N-羟基亚氨代苯甲酰胺24,其具有96%纯度。
实施例20 3-(4-溴-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯25
在10℃向4-溴-2-氟-N-羟基亚氨代苯甲酰胺24(800g,3.43mol,1当量)和A21(20wt%,160g)在PhMe(12L,15体积)中的溶液中加入丙炔酸乙酯(471g,4.8mol,1.4当量)。将反应混合物在50℃搅拌过夜并经LC-MS监测(剩余约14A%起始物质24)。然后将反应混合物过滤并将滤液真空浓缩且获得1015g 3-(4-溴-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯25,其为黄色油状物且具有84.9%的LC纯度(收率:89%)。
实施例21 2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸乙酯26
将3-(4-溴-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯25(300g,0.91mol,1当量)在二苯基氧(900mL,3体积)中的溶液在190℃在氮气下搅拌1小时并经LC-MS监测(无25剩余)。将混合物冷却至室温并加入TBME(600mL,2体积于25),然后逐滴加入PE(1.8L,6体积于25)以分离出固体。将混合物在室温搅拌20分钟并过滤得到160g湿的滤饼。将湿的滤饼用PE(1L)洗涤且干燥得到120g 2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸乙酯26,其具有92%的LC纯度且为棕色固体。
实施例22 2-(4-溴-2-氟苯基)-1-(2-羟基乙基)-1H-咪唑-4-羧酸乙酯27
使2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸乙酯26与1,3-二氧杂环戊烷-2-酮和N-甲基咪唑反应得到27。
实施例23 9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-羧酸28
使2-(4-溴-2-氟苯基)-1-(2-羟基乙基)-1H-咪唑-4-羧酸乙酯27、氢氧化钾和甲基三丁基氯化铵在65℃反应,冷却并浓缩。将混合物溶于乙醇和水中以使28结晶。
实施例24 9-溴-N-(1-亚氨基乙基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-甲酰胺29
使9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-羧酸28、三苯基膦和乙脒反应得到29。
实施例25 9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III
使9-溴-N-(1-亚氨基乙基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-甲酰胺29与异丙基肼盐酸盐4在乙酸中反应得到III。
实施例26 2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸30
使3-氯-2-氧代丙酸和4-溴-2-氟亚氨代苯甲酰胺盐酸盐12与碱反应得到2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸30。
可替换地,向2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸乙酯26(1350g,4.3mol)在THF(8.1L,6体积)和H2O(4L,3体积)中的溶液中加入NaOH(520g,13mol,3当量)并将反应混合物在65℃搅拌48小时直到反应完成(经LC-MS监测)。将混合物用2M HCl调节为pH=5并将产物分离出来,其为黄色固体,过滤得到2.2kg湿的滤饼,将湿的滤饼用H2O(1.5L)、DCM(1.5L×3)和PE(1L)洗涤并干燥得到970g纯的2-(4-溴-2-氟苯基)-1H-咪唑-4-羧酸30(方案10)。
实施例27 5-(2-(4-溴-2-氟苯基)-1H-咪唑-4-基)-1-异丙基-3-甲基-1H-1,2,4-三唑V
使30与N’-异丙基亚肼代乙酰胺6和偶联剂HBTU在DMF中反应得到中间体2-(4-溴-2-氟苯基)-N-(1-(2-异丙基肼基)亚乙基)-1H-咪唑-4-甲酰胺31,其在加热后环化得到V。
实施例28 2-羟基乙基氨基甲酸叔丁酯得到2-(5-溴-2-氰基苯氧基)乙基氨基甲酸叔丁酯32
将4-溴-2-氟苯甲腈11用2-羟基乙基氨基甲酸叔丁酯烷基化得到32。
实施例29 8-溴-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-亚胺33
将2-(5-溴-2-氰基苯氧基)乙基氨基甲酸叔丁酯32在酸性条件下诸如盐酸在乙醇中环化得到33。
实施例30 9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-羧酸28
使3-溴-2-氧代丙酸和8-溴-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-亚胺33反应得到28(CAS登记号1282516-74-8)。
实施例31 9-溴-2-(1-异丙基-3-甲基-1H-1,2,4-三唑-5-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂III
使28与N’-异丙基亚肼代乙酰胺6和偶联剂HBTU在DMF中偶联得到中间体9-溴-N-(1-(2-异丙基肼基)亚乙基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-2-甲酰胺34,其在加热后形成III。
实施例32 4-溴-2-氟亚氨代苯甲酸甲酯35
使4-溴-2-氟苯甲腈11与甲醇钠在甲醇中反应得到35。
实施例33 8-溴-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-亚胺33
将4-溴-2-氟亚氨代苯甲酸甲酯35用2-氨基乙醇烷基化得到4-溴-2-氟-N-(2-羟基乙基)亚氨代苯甲酰胺36,随后环化为33(方案13)。
可替换地,使11与2-氨基乙醇和叔丁醇钾反应以置换氟,得到2-(2-氨基乙氧基)-4-溴苯甲腈盐酸盐37。将37用三甲基铝环合得到33(方案14)。将11(10g,50mmol)和2-氨基乙醇(3.1mL,50.8mmol)在2-甲基四氢呋喃(80mL)中的溶液冷却至0℃并缓慢加入1M叔丁醇钾在四氢呋喃中的溶液(55mL,55mmol)同时保持溶液温度低于5℃。将反应混合物在0℃搅拌30分钟直到经HPLC判断反应完成,此时将其温热至25℃。加入0.5M HCl在异丙醇中的溶液(100mL,50mmol)并将预期的盐酸盐3直接由溶液结晶。将固体经过滤收集并通过放出氮气真空干燥得到2-(2-氨基乙氧基)-4-溴苯甲腈盐酸盐37,其为白色固体(12.1g,87%收率)。
向烧瓶中加入37(9.00g,32.4mmol)和甲苯(90.0ml)。将混悬液冷却至0℃并历时30分钟逐滴加入三甲基铝(1.8当量,58.4mmol,2M在甲苯中)。然后将混悬液在室温搅拌1小时,然后温热至100℃。5小时后,将溶液冷却至0℃并用NaOH水溶液(2N,90.0ml)淬灭。将混悬液用EtOAc(4×90ml)萃取并将合并的萃取物干燥,然后经过滤。将溶液浓缩并将残留物用EtOAc研磨得到8-溴-3,4-二氢苯并[f][1,4]氧氮杂-5(2H)-亚胺33(6.26g,26.0mmol,80%收率),其为白色结晶固体。
实施例34 4-氯-2-氟-N-羟基亚氨代苯甲酰胺39
向4-氯-2-氟苯甲腈38(400g,2.58mol,1.0当量)和羟胺盐酸盐(448g,6.45mol,2.5当量)在MeOH(1L,2.5体积)中的溶液中加入Et3N(313g,3.1mol,1.2当量),然后将混合物在60℃搅拌40分钟并经HPLC监测(无腈剩余)。然后将反应混合物经H2O(10L)淬灭并将大量灰白色固体分离出来,然后过滤,将滤饼用水(10L×2)洗涤并得到378g 4-氯-2-氟-N-羟基亚氨代苯甲酰胺39,其具有93%纯度(方案15)。
实施例35 3-(4-氯-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯40
在30℃向4-氯-2-氟-N-羟基亚氨代苯甲酰胺39(378g,2mol,1.0当量)和A21(20wt%,75.6g)在甲苯(PhMe)(5.6L,15体积)中的溶液中加入丙炔酸乙酯(275g,2.8mol,1.4当量)。将反应混合物在30℃搅拌过夜并经LC-MS监测。然后将反应混合物过滤并将滤液真空浓缩且得到550g 3-(4-氯-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯40,其为黄色油状物且具有83%的LC纯度(方案15)。
实施例36 2-(4-氯-2-氟苯基)-1H-咪唑-4-羧酸乙酯41
将3-(4-氯-2-氟亚氨代苯甲酰氨基氧基)丙烯酸乙酯40(550g,1.9mol,1.0当量,83%的LC纯度)在二苯基氧(1.65L,3体积)中的溶液在190℃在氮气下搅拌1小时并经LC-MS监测(无40剩余)。将混合物冷却至室温并逐滴加入PE(10L)。将混合物在室温搅拌20分钟并过滤得到400g湿的滤饼,经硅胶色谱纯化(PE/EA=1/5)后得到175g纯的2-(4-氯-2-氟苯基)-1H-咪唑-4-羧酸乙酯41,其具有98%的LC纯度(方案15)。
实施例37 2-(4-氯-2-氟苯基)-1H-咪唑-4-羧酸42
向2-(4-氯-2-氟苯基)-1H-咪唑-4-羧酸乙酯41(175g,4.3mol)在THF(1L,6体积)和H2O(500mL,3体积)中的溶液中加入NaOH(78g,1.95mol,3.0当量)并将反应混合物在65℃搅拌48小时直到其完成(经LC-MS监测)。将混合物用2N HCl调节为pH=5并将产物分离出来,其为黄色固体,过滤得到210g湿的滤饼,将湿的滤饼用H2O(300mL)、DCM(3×300mL)和PE(500mL)洗涤并干燥得到110g纯的2-(4-氯-2-氟苯基)-1H-咪唑-4-羧酸42(CAS登记号1260649-87-3)(方案15)。1H NMR(DMSO d6)δ:12.8(br s),8.0,7.9(br s),7.46,7.4(m)。
尽管为了清楚地理解,已通过解释和实施例在一定程度上详述了前述发明,但说明书和实施例不应当解释为限制本发明范围。因此,所有合适的变化和等价形式都可视为落入由随后的权利要求书定义的本发明范围内。本文所引用的所有专利和科学文献的公开内容均明确地整体引入作为参考。
Claims (2)
1.一种化合物,其选自以下结构:
2.如本申请所述的本发明。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000024720A1 (en) * | 1998-10-23 | 2000-05-04 | Dow Agrosciences Llc | 3-(substituted phenyl)-5-(substituted cyclopropyl)-1,2,4-triazole compounds |
CN102762576A (zh) * | 2009-09-28 | 2012-10-31 | 霍夫曼-拉罗奇有限公司 | 苯并氧杂氮杂*pi3k抑制剂化合物和使用方法 |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9208135D0 (en) | 1992-04-13 | 1992-05-27 | Ludwig Inst Cancer Res | Polypeptides having kinase activity,their preparation and use |
US5846824A (en) | 1994-02-07 | 1998-12-08 | Ludwig Institute For Cancer Research | Polypeptides having kinase activity, their preparation and use |
US6274327B1 (en) | 1992-04-13 | 2001-08-14 | Ludwig Institute For Cancer Research | Polypeptides having kinase activity, their preparation and use |
KR20040024564A (ko) | 2001-07-12 | 2004-03-20 | 아베시아 리미티드 | 마이크로캡슐화된 촉매, 이의 제조 방법 및 이의 사용 방법 |
DE60208815T2 (de) * | 2001-10-12 | 2006-07-20 | Bayer Pharmaceuticals Corp., West Haven | Phenyl substituierte 5-gliedrige stickstoff enthaltende heterocyclen zur behandlung von fettleibigkeit |
WO2007056170A2 (en) | 2005-11-02 | 2007-05-18 | Bayer Healthcare Ag | Pyrrolo[2,1-f] [1,2,4] triazin-4-ylamines igf-1r kinase inhibitors for the treatment of cancer and other hyperproliferative diseases |
KR101083177B1 (ko) | 2006-10-23 | 2011-11-11 | 에스지엑스 파마슈티컬스, 인코포레이티드 | 트리아졸로-피리다진 단백질 키나제 조정제 |
DK2084162T3 (da) * | 2006-10-23 | 2012-10-01 | Sgx Pharmaceuticals Inc | Bicykliske triazoler som proteinkinasemodulatorer |
EP2120578B1 (en) | 2007-01-19 | 2014-11-19 | Xcovery, INC. | Kinase inhibitor compounds |
US8354528B2 (en) * | 2007-10-25 | 2013-01-15 | Genentech, Inc. | Process for making thienopyrimidine compounds |
JP5276676B2 (ja) * | 2008-02-21 | 2013-08-28 | メルク・シャープ・アンド・ドーム・コーポレーション | Erk阻害剤である化合物 |
KR101626996B1 (ko) | 2008-03-31 | 2016-06-02 | 제넨테크, 인크. | 벤조피란 및 벤족세핀 pi3k 저해제 화합물 및 이의 사용 방법 |
GB0810902D0 (en) | 2008-06-13 | 2008-07-23 | Astex Therapeutics Ltd | New compounds |
US8263633B2 (en) | 2009-09-28 | 2012-09-11 | F. Hoffman-La Roche Ag | Benzoxepin PI3K inhibitor compounds and methods of use |
AU2010313469A1 (en) * | 2009-10-29 | 2012-06-07 | Merck Sharp & Dohme Corp. | Bridged Bicyclic Piperidine Derivatives and methods of use thereof |
CN102558167A (zh) * | 2010-12-29 | 2012-07-11 | 中国医学科学院药物研究所 | Gk和ppar双重激动活性的噻唑烷二酮衍生物 |
EP2688891B1 (en) * | 2011-03-21 | 2017-11-15 | F. Hoffmann-La Roche AG | Benzoxazepin compounds selective for pi3k p110 delta and methods of use |
NO3175985T3 (zh) * | 2011-07-01 | 2018-04-28 | ||
NZ702244A (en) * | 2012-06-08 | 2017-06-30 | Hoffmann La Roche | Mutant selectivity and combinations of a phosphoinositide 3 kinase inhibitor compound and chemotherapeutic agents for the treatment of cancer |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000024720A1 (en) * | 1998-10-23 | 2000-05-04 | Dow Agrosciences Llc | 3-(substituted phenyl)-5-(substituted cyclopropyl)-1,2,4-triazole compounds |
CN102762576A (zh) * | 2009-09-28 | 2012-10-31 | 霍夫曼-拉罗奇有限公司 | 苯并氧杂氮杂*pi3k抑制剂化合物和使用方法 |
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