CN115243764A - 作为trmp8拮抗剂的杂环衍生物 - Google Patents
作为trmp8拮抗剂的杂环衍生物 Download PDFInfo
- Publication number
- CN115243764A CN115243764A CN202180018532.6A CN202180018532A CN115243764A CN 115243764 A CN115243764 A CN 115243764A CN 202180018532 A CN202180018532 A CN 202180018532A CN 115243764 A CN115243764 A CN 115243764A
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- CN
- China
- Prior art keywords
- benzyl
- ethyl
- methylpiperazine
- methyl
- methylphenoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000005557 antagonist Substances 0.000 title description 2
- 125000000623 heterocyclic group Chemical group 0.000 title description 2
- 238000001816 cooling Methods 0.000 claims abstract description 49
- 210000004400 mucous membrane Anatomy 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 218
- -1 CH 2 CN Inorganic materials 0.000 claims description 171
- 150000001875 compounds Chemical class 0.000 claims description 170
- 229910052739 hydrogen Inorganic materials 0.000 claims description 153
- 239000001257 hydrogen Substances 0.000 claims description 141
- 150000002431 hydrogen Chemical class 0.000 claims description 85
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 63
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 55
- 239000012453 solvate Substances 0.000 claims description 48
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 33
- 229910052731 fluorine Inorganic materials 0.000 claims description 31
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 29
- MIROPJRVCZUDEI-UHFFFAOYSA-N 1-[2-(2-benzyl-4-methylphenoxy)ethyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1CCOC1=CC=C(C)C=C1CC1=CC=CC=C1 MIROPJRVCZUDEI-UHFFFAOYSA-N 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical group FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
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- 150000001721 carbon Chemical group 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 229930192474 thiophene Chemical group 0.000 claims description 7
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- 229910019142 PO4 Inorganic materials 0.000 claims description 5
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- QHDVTWUUQWPRSL-UHFFFAOYSA-N 1-[2-(2-benzylphenoxy)ethyl]-4-methylpiperazine;hydrochloride Chemical compound Cl.C1CN(C)CCN1CCOC1=CC=CC=C1CC1=CC=CC=C1 QHDVTWUUQWPRSL-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/20—Synthetic spices, flavouring agents or condiments
- A23L27/205—Heterocyclic compounds
- A23L27/2054—Heterocyclic compounds having nitrogen as the only hetero atom
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/20—Synthetic spices, flavouring agents or condiments
- A23L27/205—Heterocyclic compounds
- A23L27/2056—Heterocyclic compounds having at least two different hetero atoms, at least one being a nitrogen atom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/24—Thermal properties
- A61K2800/244—Endothermic; Cooling; Cooling sensation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Birds (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
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Abstract
公开了由式(I)定义的TRPM8调节剂,用于实现对皮肤和黏膜的清凉效果。
Description
技术领域
本发明涉及能够激活TRPM8离子通道的特定类别的化合物。本发明还涉及所述化合物用于引起冷感的用途以及包含这些化合物的消费品。
背景
TRPM8(瞬时受体电位melastatin成员8,也称为Trp-p8或MCR1)被无害的冷激活并因此作为温度传感器起着重要作用。通道广泛分布于不同组织(例如人体皮肤和黏膜(例如口腔黏膜,咽喉黏膜和鼻黏膜),男性泌尿生殖道,肺上皮细胞和动脉肌细胞)。它们是Ca2+可渗透的非选择性阳离子通道,具有多模式门控机制,被无害的冷至低温,膜去极化和称为清凉剂的分子(包括天然和合成化合物)激活。2002年,该受体在许多出版物中首次被描述为冷感受器。
本发明基于以下发现:当在体外和体内与TRPM8受体接触时,可以使用特定类别的化合物来驱动清凉响应。
长期以来,提供清凉感的化合物在香精香料工业中发挥着重要作用,以产生与新鲜度和清洁度的关联。清凉化合物广泛用于各种产品,例如食品,烟草制品,饮料,洁牙剂,漱口剂,牙膏和洗浴用品。所提供的清凉感有助于消费品的吸引力和可接受性。特别是,口腔护理产品,例如洁牙剂和漱口剂,是用清凉剂配制的,因为它们提供口气清新效果和口腔清洁,清凉,清新的感觉。
已经描述了大量提供清凉感的化合物。最著名的天然化合物是薄荷醇,尤其是L-薄荷醇。在提供清凉感的合成化合物中,许多是薄荷醇的衍生物或在结构上与薄荷醇相关,并衍生有官能团,包括甲酰胺,缩酮,酯,醚和醇。
申请人令人惊奇地发现了一类新的化合物,其在结构方面与迄今已知的TRPM8调节剂显著不同。令人惊奇地发现,本文进一步描述的这类化合物可以在非常低的浓度下对人体皮肤和/或黏膜提供持久的清凉。
概述
在第一方面,提供了一种调节(体外和体内调节)瞬时受体电位melastatin成员8(TRPM8)的方法,所述方法包括使所述受体与式(I)的化合物、或其盐或溶剂合物接触
其中
环A代表苯基环、环己基或环己烯基环;
R1选自氢、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)和C1-C6烷氧基(例如甲氧基、乙氧基、丙氧基),
R2连接至环A的3、4或5位且选自氢、卤素(例如F、Cl、Br、I)、C1-C6烷基(例如甲基、乙基、异丙基、异丁基、异丙基)、C1-C6烷氧基(例如甲氧基、乙氧基)和C(O)O-C1-C3-烷基(例如C(O)OCH3),
R3选自氢、C1-C6烷基(例如甲基、乙基)、C2-C6烯基(例如乙烯基)、OH和=O,且R4选自氢、C1-C6烷基(例如甲基、乙基),C2-C6烯基(例如乙烯基)和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统(即R3和R1为二价残基-CH2-CH2-),且R4为氢,
R5选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
R6选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
m为0或1,
p为0或1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基(例如甲基或异丙基);
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH或CH2OH,
Y连接至环A的2或3位且选自C4-C6烷基(例如异丁基),
其中
环B代表苯基、噻吩、呋喃或吡啶环,
R11选自CN、卤素(例如F、CL、Br、I)、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基(例如甲基或乙基)、C1-C3烷氧基(例如甲氧基或乙氧基),C2-C3烯基(例如乙烯基或烯丙基)和OH,且n为0-5的整数(包括1、2和3),条件是如果n>1,则R11可以相同或不同,并且
X选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH。
根据第二个方面,提供了一种在人或动物中引起清凉感的方法,所述方法包括使所述人或动物与式(I)的化合物或其盐或溶剂合物接触。
在第三个方面,提供了消费品,特别是与人体皮肤和/或黏膜接触的消费品,其包含由式(I)定义的化合物或其盐或溶剂合物。
在第四个方面,提供了一种包含清凉感的组合物,其中所述组合物包含至少一种式(I)的化合物、其盐或溶剂合物和另外的清凉化合物。
在第五个方面,提供了药物组合物,其包含一种或多种由式(I)定义的化合物或其盐或溶剂合物。
在第六个方面,提供了式(I)的化合物或其盐或溶剂合物。
提供的与本发明的任何特定一个或多个所述方面相关的细节、实施例和优选项将在本文中进一步描述并且同样适用于本发明的所有方面。除非本文另有说明或与上下文明显矛盾,否则本文所述的实施方案、实施例和优选项的所有可能变化形式的任何组合都包含在本发明中。
详述
本发明至少部分基于在结构方面与迄今已知的TRPM8调节剂显著不同的一类新化合物的惊人发现,其能够激活TRPM8离子通道,从而导致Ca2+流入冷敏感神经元。结果产生的电信号最终被感知为冷感。申请人惊奇地发现,本文进一步描述的这类化合物可以在非常低的浓度下对人体皮肤和/或黏膜提供持久的清凉。
下文由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)是“TRPM8激动剂”,这意味着它们对TRPM8通道的细胞Ca2+离子渗透性具有激动作用。因此,“TRPM8激动剂”是指任何化合物,当与TRPM8受体接触时,使用如Klein等人(Chem.Senses 36:649-658,2011)所述的FLIPR方法,所述化合物相对于背景产生荧光增加,这在实验部分也有更详细的描述。
因此,在第一方面提供了一种调节(体外和体内调节)瞬时受体电位melastatin成员8(TRPM8)的方法,所述方法包括使所述受体与式(I)的化合物、或其盐或溶剂合物接触
其中
环A代表苯基环、环己基或环己烯基环;
R1选自氢、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)和C1-C6烷氧基(例如甲氧基、乙氧基、丙氧基),
R2连接至环A的3、4或5位且选自氢、卤素(例如F、Cl、Br、I)、C1-C6烷基(例如甲基、乙基、异丙基、异丁基、异丙基)、C1-C6烷氧基(例如甲氧基、乙氧基)和C(O)O-C1-C3-烷基(例如C(O)OCH3),
R3选自氢、C1-C6烷基(例如甲基、乙基)、C2-C6烯基(例如乙烯基)、OH和=O,且R4选自氢、C1-C6烷基(例如甲基、乙基),C2-C6烯基(例如乙烯基)和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统(即R3和R1为二价残基-CH2-CH2-),且R4为氢,
R5选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
R6选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
m为0或1,
p为0或1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基(例如甲基或异丙基);
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH或CH2OH,
Y连接至环A的2或3位且选自C4-C6烷基(例如异丁基),
其中
环B代表苯基、噻吩、呋喃或吡啶环,
R11选自CN、卤素(例如F、CL、Br、I)、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基(例如甲基或乙基)、C1-C3烷氧基(例如甲氧基或乙氧基),C2-C3烯基(例如乙烯基或烯丙基)和OH,且n为0-5的整数(包括1、2和3),条件是如果n>1,则R11可以相同或不同,并且
X选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,其中R11选自CN、卤素(例如F、Cl、Br、I)、CH2CN、NO2、NH2、CF3和甲基。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),且R2选自甲基、乙基和卤素(例如Cl)。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,其中R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,其中R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢,且R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,其中X选自-CH2-和-O-。
此外,非限制性实例是式(I)的化合物、其盐或溶剂合物,R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢,R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢,且X选自-CH2-和-O-。
非限制性实例是式(Ia)的化合物、其盐或溶剂合物,
其中
环A代表苯基环、环己基或环己烯基环;
R1选自氢、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)和C1-C6烷氧基(例如甲氧基、乙氧基、丙氧基),
R2选自氢、卤素(例如F、Cl、Br、I)、C1-C6烷基(例如甲基、乙基、异丙基、异丁基、异丙基)、C1-C6烷氧基(例如甲氧基、乙氧基)和C(O)O-C1-C3-烷基(例如C(O)OCH3),
R3选自氢、C1-C6烷基(例如甲基、乙基)、C2-C6烯基(例如乙烯基)、OH和=O,且R4选自氢、C1-C6烷基(例如甲基、乙基),C2-C6烯基(例如乙烯基)和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统(即R3和R1为二价残基-CH2-CH2-),且R4为氢,
R5选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
R6选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
m为0或1,
p为0或1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基(例如甲基或异丙基);
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH,
环B代表苯基、噻吩、呋喃或吡啶环,
R11选自CN、卤素(例如F、CL、Br、I)、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基(例如甲基或乙基)、C1-C3烷氧基(例如甲氧基或乙氧基),C2-C3烯基(例如乙烯基或烯丙基)和OH,且n为0-5的整数(包括1、2和3),条件是如果n>1,则R11可以相同或不同,并且
X连接至环A的2或3位且选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,其中R11选自CN、卤素(例如F、Cl、Br、I)、CH2CN、NO2、NH2、CF3和甲基。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),且R2选自甲基、乙基和卤素(例如Cl)。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,其中R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,其中R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢,且R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,其中X选自-CH2-和-O-。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢,R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢,且X选自-CH2-和-O-。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物。
其中
R1选自氢、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)和C1-C6烷氧基(例如甲氧基,),
R2选自氢、卤素(例如F、Cl、Br、I)、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)、C1-C6烷氧基(例如甲氧基、乙氧基)和C(O)O-C1-C3-烷基(例如C(O)OCH3),
R3选自氢、C1-C6烷基(例如甲基、乙基、异丙基)、C2-C6烯基(例如乙烯基)、OH和=O,且R4选自氢、C1-C6烷基(例如甲基、乙基、异丙基)、C2-C6烯基(例如乙烯基)和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统(即R3和R1为二价残基-CH2-CH2-),且R4为氢,
R5选自氢、F和C1-C6烷基(例如甲基、乙基),
R6选自氢、F和C1-C6烷基(例如甲基、乙基),
m为0或1,
p为0或1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基(例如甲基或异丙基);
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH或CH2OH,
R11选自CN、卤素(例如F、CL、Br、I)、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基(例如甲基或乙基)、C1-C3烷氧基(例如甲氧基或乙氧基),C2-C3烯基(例如乙烯基或烯丙基)和OH,且n为0-5的整数(包括1、2和3),条件是如果n>1,则R11可以相同或不同,并且
X选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,其中R11选自CN、卤素(例如F、Cl、Br、I)、CH2CN、NO2、NH2、CF3和甲基。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),且R2选自甲基、乙基和卤素(例如Cl)。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,其中R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,其中R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,其中R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢,且R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,其中X选自-CH2-和-O-。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,R1选自H和C1-C3烷基(包括乙基),R2选自甲基、乙基和Cl,R3选自H、甲基、-OH和=O,且R4选自氢和甲基,条件是R3和R4中的至少一个为氢,R5和R6选自氢和甲基,例如R5和R6中的至少一个为氢,或R5=R6为氢,且X选自-CH2-和-O-。
进一步的非限制性实例是式(I)、(Ia)或(Ib)的化合物,其选自
(1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-基)甲醇,
(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲醇,
(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲酮,
(E)-1-(2-((6-亚苄基-2,4-二甲基环己-1-烯-1-基)氧基)乙基)-4-甲基哌嗪,
(E)-1-(3-(2-苄基-4-甲基苯基)烯丙基)-4-甲基哌嗪,
1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪,
(E)-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)亚苄基)环己-1-酮,
(E)-2-(5-甲基-2-(2-吗啉代乙氧基)亚苄基)环己-1-酮,
2-(3,5-二甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-((1-吗啉代丙-2-基)氧基)苄基)苯甲腈,
1-((8-苄基苯并二氢吡喃-2-基)甲基)-4-甲基哌嗪,
1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪,
1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪二盐酸盐,
1-(2-(2-((5-氯噻吩-2-基)甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-碘苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(3-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(3-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(4-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-(呋喃-2-基甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(2-(三氟甲基)苄基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(吡啶-2-基甲基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(吡啶-3-基甲基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(吡啶-4-基甲基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-3,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-3-甲氧基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-3-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-(叔丁基)-6-甲氧基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐,
1-(2-(2-苄基-4-氯苯氧基)乙基)-4-乙基哌嗪盐酸盐,
1-(2-(2-苄基-4-氯苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-4-乙基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-4-异丙基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-乙基哌嗪盐酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2,3-二羟基琥珀酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2-羟基丙烷-1,2,3-三羧酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2,2,2-三氟乙酸盐),
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2-羟基琥珀酸盐),
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(磷酸盐),
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二马来酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二甲磺酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪草酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪硫酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-醇,
1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-6-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐,
1-(2-苄基-4-甲基苯乙基)-4-甲基哌嗪,
1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-醇,
1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-酮,
1-(3-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐,
1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪,
1-甲基-4-(2-(4-甲基-2-(1-苯基乙基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(1-苯基乙烯基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(2-甲基苄基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(3-甲基苄基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(噻吩-2-基甲基)苯氧基)乙基)哌嗪盐酸盐,
2-(2-((1-羟基丙-2-基)氧基)-3,5-二甲基苄基)苯甲腈,
2-(2-(2-羟基-3-吗啉代丙基)-5-甲基苯氧基)苯甲腈,
2-(2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯基)乙腈,
2-(2,4-二甲基-5-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈,
2-(2,6-二氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺,
2-(2,6-二氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺,
2-(2,6-二氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺,
2-(2-氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺,
2-(2-氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺,
2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈盐酸盐,
2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈盐酸盐,
2-(3,5-二甲基-2-(2-(四氢-2H-吡喃-4-基)乙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)-3-氟苯甲腈,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯胺,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈盐酸盐,
2-(3,5-二甲基-2-(3-吗啉代丙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(3-吗啉代丙基)苯氧基)苯甲腈,
2-(3,5-二甲基-2-(甲基(2-吗啉代乙基)氨基)苄基)苯甲腈,
2-(4-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈,
2-(5-甲基-2-(2-(1-甲基哌啶-4-基)乙氧基)苄基)苯甲腈,
2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈,
2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐,
2-(5-甲基-2-(2-吗啉代乙氧基)苄基)环己-1-酮,
2-(5-甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈,
2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈,
2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈盐酸盐,
2-苄基-4-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺,
2-(4-甲基哌嗪-1-基)乙酸2-苄基-4-甲基苯酯,
2-苄基-N,4-二甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺,
2-苄基-N,4-二甲基-N-(2-吗啉代乙基)苯胺,
3-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐,
3-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯胺,
3-溴-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈,
3-氯-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈,
4-(1-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙-2-基)吗啉,
4-(2-(2-(1-(2-氟苯基)乙基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(1-(2-氟苯基)乙烯基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,4-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,6-二氯苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙基)吗啉,
4-(2-(2-(2,6-二氟苄基)-4-甲基苯氧基)乙基)吗啉,
4-(2-(2-(2-氯苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(3,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2,4-二甲基-5-((全氟苯基)甲基)苯氧基)乙基)吗啉,
4-(2-(2,4-二甲基-6-(2,4,5-三氟苄基)苯氧基)乙基)吗啉,
4-(2-(2,4-二甲基-6-(2-硝基苄基)苯氧基)乙基)吗啉,
4-(2-(2-苄基-4-甲基苯氧基)乙基)-1,2,6-三甲基哌嗪,
4-(2-(2-苄基-4-甲基苯氧基)乙基)吗啉盐酸盐,
4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉1-氧化物,
4-(2-(2-乙基-6-(2-氟苄基)-4-甲基苯氧基)乙基)吗啉,
4-(3-(2-(2-氟苯氧基)-4,6-二甲基苯基)丙基)吗啉,
4-甲基-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯酚,
4-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲酸乙酯二盐酸盐,和
3-苄基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯甲酸甲酯。
由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)包含几个手性中心并且因此可以以立体异构体的混合物形式存在,或者它们可以被拆分为异构体纯形式。拆分立体异构体增加了这些化合物的制造和纯化的复杂性,仅仅是因为经济原因,优选以它们的立体异构体的混合物形式使用这些化合物。然而,如果需要制备单独的立体异构体,这可以根据本领域已知的方法来实现,例如制备型HPLC和GC、结晶或立体选择性合成。因此,本文描述的化学结构包括所示化合物的所有可能的立体异构体和互变异构体形式。
应注意,由式(I)定义的一些化合物(其包括式(Ia)和(IB)的化合物)是液体,并因此可以单独或与其他众所周知的溶剂组合使用,以溶解其他化合物,例如清凉化合物(它们中的一些在下文描述,例如申请人的国际专利申请PCT/EP2020/079009和PCT/EP2020/083453中描述的那些清凉化合物,N-(4-(氰基甲基)苯基)-2-异丙基-5-甲基环己烷-1-甲酰胺、2-异丙基-5-甲基-N-(2-(吡啶-2-基)乙基)环己烷-1-甲酰胺、3-(苯并[d][1,3]二氧杂环戊二烯-5-基)-N,N-二苯基丙烯酰胺和N-(吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯氧基)乙酰胺。这是特别优选的,因为液体(包括溶液)的处理有利于所述化合物的计量和/或混合。
还应注意,由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在,和作为N-氧化物。通常,化合物可以是水合的,溶剂化的或N-氧化物。某些化合物可以以多种结晶或无定形形式存在。一般而言,所有物理形式对于本文所设想的用途而言都是等效的并且旨在落入本发明的范围内
“溶剂合物”是指通过溶剂化(溶剂分子与溶质的分子或离子的组合)形成的化合物,或由溶质离子或分子,即由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)与一种或多种溶剂分子组成的聚集体。当水为溶剂时,相应的溶剂合物为“水合物”。其他合适的溶剂可以是但不限于:丙酮,乙腈,苯,环己烷,二氢左旋葡糖烯酮(dihydrolevoglucosenone),甲基-四氢呋喃,戊二醇,乙二醇,石油醚,乳酸乙酯,乳酸甲酯,乳酸丙酯,乳酸丁酯,二乙醚,叔丁基甲基醚,二甲亚砜,N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,二噁烷,乙醇,乙酸乙酯,乙二醇,二甘醇,对薄荷烷(1-异丙基-4-甲基环己烷),丙二醇,庚烷,己烷,甲醇,甲苯和二甲苯。
“盐”是指由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)的盐,其具有母体化合物的所需药理学活性。此类盐包括:(1)酸加成盐,与无机酸如盐酸,氢溴酸,硫酸,硝酸,磷酸等形成;或与有机酸如氨基酸,乙酸,三氟乙酸,丙酸,己酸,环戊烷丙酸,乙醇酸,丙酮酸,乳酸,丙二酸,琥珀酸,苹果酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,3-(4-羟基苯甲酰基)苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,1,2-乙二磺酸,2-羟基乙磺酸,苯磺酸,4-氯苯磺酸,2-萘磺酸,4-甲苯磺酸,樟脑磺酸,4-甲基二环[2.2.2]-辛-2-烯-1-甲酸,葡庚糖酸,3-苯基丙酸,三甲基乙酸,叔丁基乙酸,十二烷基硫酸,葡萄糖酸,谷氨酸,羟基萘酸,水杨酸,硬脂酸,粘康酸等形成;或(2)当母体化合物中存在的酸质子被金属离子例如碱金属离子,碱土离子或铝离子取代;或与有机碱如乙醇胺,二乙醇胺,三乙醇胺,N-甲基葡糖胺等配位时形成的盐。
在第二方面,提供了一种在人或动物中引起清凉感的非医疗方法,所述方法包括使人或动物与式(I)的化合物(其包括式(Ia)和(Ib)的化合物)或其盐或溶剂合物接触。
在某些实施方案中,所述方法是实现对皮肤或黏膜的清凉效果的方法,包括使皮肤或黏膜与包含一种或多种式(I)的化合物(其包括式(Ia)和(Ib)的化合物)或其盐或溶剂合物的产品接触。
式(I)的化合物(其包括式(Ia)和(Ib)的化合物)可直接施用或作为溶液或悬浮液施用,其包含有效量的式(I)的化合物。有效的量尤其取决于人体的目标TRPM8区域,还取决于化合物或化合物混合物的清凉效力。
在第三方面,提供了包含由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)的消费品,特别是与人体皮肤和/或黏膜接触的消费品。
与黏膜接触的消费品包括但不限于食品,饮料,口香糖,烟草和烟草代替产品,牙科护理产品,个人护理产品,包括唇部护理产品,性健康和私密护理产品。
在某些实施方案中,牙科护理产品为口腔护理产品,牙齿护理产品,假牙清洁剂,假牙粘合剂等。
在某些实施方案中,食品是冰镇消费品,例如冰淇淋,冰糕;糖食,例如糖果和巧克力;含有薄荷或薄荷香料的食品,酱汁,乳制品,例如牛奶饮料和酸奶;和小吃。
在某些实施方案中,烟草代替产品是适合通过电子方式消费的液体或固体,例如用于电子烟的液体。
在某些实施方案中,与黏膜接触的个人护理产品是唇膏,鼻喷雾剂和滴眼剂。
与人体皮肤接触的消费品包括但不限于化妆品。在某些实施方案中,化妆品是护肤产品,尤其是沐浴产品,皮肤洗涤和清洁产品,护肤产品,眼妆,指甲护理产品,足部护理产品等。在某些实施方案中,化妆品是具有特定效果的产品,尤其是防晒剂,驱虫产品,美黑产品,去色素产品,除臭剂,止汗剂,脱毛剂和剃须产品。在某些实施方案中,化妆品是护发产品,尤其是洗发香波,护发产品,头发定型产品,美发产品和染发产品以及头皮护理产品,例如头皮清凉洗发香波和乳剂。
消费品可以是任何物理形式,例如固体,半固体,膏药,溶液,悬浮液,洗剂,乳剂,泡沫,凝胶,糊剂或其组合。适合的消费品的物理形式很大程度上取决于这种消费品应该满足的具体作用,例如清洁,软化,护理,清凉等。
在某些实施方案中,与人体皮肤接触的消费品是织物护理产品(例如织物清洁剂,织物调理剂(包括滚筒干衣片)和增香剂(液体或固体),它们在第一步中被应用于织物,例如,当洗涤织物时,所述经处理的织物随后与人体皮肤接触。
本发明的化合物(由式(I)定义的化合物,包括式(Ia)和(Ib)的化合物)的使用水平尤其取决于身体的目标TRPM8区域,还取决于化合物或化合物混合物的清凉效力。例如在本发明化合物的空腔应用例如洁牙剂,牙线,口香糖或美白牙贴(white strip)中,使用水平可以是组合物重量的约0.00001%(0.01ppm)至约0.1%(1000ppm);约0.00005%(0.5ppm)至约0.1%(1000ppm);约0.0001%(1ppm)至约0.05%(500ppm);或约0.001%(10ppm)至约0.01%(100ppm)。当本发明的化合物用于漱口剂中时,使用水平可以是组合物重量的约0.000001%(10ppb)至约0.01%(100ppm)或约0.0001%(1ppm)至约0.001%(10ppm)。当本发明的化合物被局部递送例如在洗发香波和洗剂中时,其水平可以为组合物重量的约0.001%(10ppm)至约0.5%(5000ppm)或组合物重量的约0.01%(100ppm)至约0.4%(4000ppm)。
化合物的清凉效力(强度)由其EC50值定义。EC50(半最大有效浓度)是指在指定的暴露时间后,在基线和最大值中间引起响应的化合物的浓度。它通常用作效力的量度。EC50是浓度的量度,以μM(μmolar)单位表示,其中1μM相当于1μmol/L。
EC50为10μM或更低的化合物被人类感知为清凉。EC50值越低,清凉效力越高。例如,EC50值为约0.1μM的化合物被认为是强清凉化合物。
然而,化合物的清凉特性不仅取决于其强度(效力;EC50),还取决于其持续时间,即感知清凉效果的时间段(以分钟为单位)。持续时间可以从冲洗后的几秒钟到几小时甚至几天不等。在口腔护理产品的情况下,优选的“持久”效果通常在冲洗后20分钟到3小时之间。
式(I)的化合物(其包括式(Ia)和(Ib)的化合物)在相对低浓度下非常有效。因此,优选制备储备溶液,所述储备溶液在与消费品混合之前被进一步稀释。除了水,特别合适的溶剂是甘油三乙酸酯和丙二醇。但也可以使用包含表面活性剂的其他溶剂体系。
为了改进如本文由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)的清凉效果,可以将所述化合物、其盐或溶剂合物与选自钙离子和盐,镁离子和盐,精氨酸或任何能够结合钙或镁的螯合剂的化合物组合。
已知这些化合物能够调节细胞外空间中此类离子的浓度,因此影响TRPM8离子通道的响应,从而导致感知的清凉效果发生变化。
根据Kizilbash等人(WO2019/121193A1),当与具有增强所述效果的特性的试剂组合时,清凉强度和风味强度二者可以得到增强。因此,本文由式(I)定义的化合物可以在一个特定实施方案中与WO2019/121193中公开的增强剂组合,WO2019/121193以引用的方式并入,特别是关于增效剂的内容。
式(I)的化合物(其包括式(Ia)和(Ib)的化合物)可以与本领域已知的其他清凉化合物组合使用。
因此,在第四方面提供了一种包含清凉感的组合物,其中该组合物包含至少一种式(I)的化合物、其盐或溶剂合物和另外的清凉化合物。
在一个具体实施方案中,式(I)的化合物(其包括式(Ia)和(Ib)的化合物)可以与薄荷醇(例如胡椒薄荷油的形式),薄荷酮,对薄荷烷甲酰胺,N-2,3-三甲基-2-异丙基-丁酰胺(WS-23),乳酸薄荷酯(ML),薄荷酮甘油缩醛(MGA),3-(1-薄荷氧基)-丙-1,2-二醇(TK-10),对薄荷烷-3,8-二醇(称为Coolact 38D),异胡薄荷醇(称为Coolact P),琥珀酸单薄荷酯戊二酸单薄荷酯,邻薄荷基甘油,N,N-二甲基琥珀酰胺酸薄荷酯,2-(仲丁基)环己-1-酮(鲜薄荷酮),N-(吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯氧基)乙酰胺,2-(4-乙基苯氧基)-N-(吡唑-3-基)-N-(噻吩-2-基甲基)乙酰胺,3-(苯并[d][1,3]二氧杂环戊二烯-5-基)-N,N-二苯基丙烯酰胺,4-(2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-乙氧基丙基)-2-甲氧基苯酚,4-(2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-((2-异丙基-5-甲基环己基)氧基)丙基)-2-甲氧基苯酚(包括4-(2-(4-烯丙基-2,6-二甲基苯氧基)-1-(((1S,2R,5S)-2-异丙基-5-甲基环己基)氧基)丙基)-2-甲氧基苯酚)和4-(2-(4-烯丙基-2,6-二甲基苯氧基)-1-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)丙基)-2-甲氧基苯酚),N-(2-羟基-2-苯基乙基)-2-异丙基-5,5-二甲基环己烷-1-甲酰胺,N-(4-(氰基甲基)苯基)-2-异丙基-5,5-二甲基环己烷甲酰胺和N-(3-羟基-4-甲氧基苯基)-2-异丙基-5,5-二甲基环己烷甲酰胺。可以与式(I)的化合物组合的其他清凉化合物是申请人的国际专利申请PCT/EP2020/079009和PCT/EP2020/083453中描述的那些。
对薄荷烷甲酰胺的实例包括化合物例如N-乙基-对薄荷烷-3-甲酰胺(商业上称为WS-3),N-乙氧基羰基甲基-对薄荷烷-3-甲酰胺(WS-5),N-(4-甲氧基苯基)-对薄荷烷-3-甲酰胺(WS-12)和N-叔丁基-对薄荷烷-3-甲酰胺(WS-14),N-(4-(氰基甲基)苯基)-2-异丙基-5-甲基环己烷-1-甲酰胺(商业上称为Evercool 180),2-异丙基-5-甲基-N-(2-(吡啶-2-基)乙基)环己烷-1-甲酰胺(商业上称为Evercool 190)和(1R,2S,5R)-N-((S)-2-((R)-2-氨基丙酰氨基)-2-苯基乙基)-2-异丙基-5-甲基环己烷-1-甲酰胺。
为了实现不仅仅是清凉效果,式(I)的化合物(其包括式(Ia)和(Ib)的化合物)、其盐或溶剂合物可以与其他活性物质组合,例如香精,香料和甜味剂。
香料成分的实例包括天然香料,人造香料,辛香料,调味品等。示例性香料成分包括合成香料油和调味芳香剂和/或油,油树脂,精油和馏出物以及包含上述至少一种的组合。
香料油包括留兰香油,肉桂油(cinnamon oil),冬青油(水杨酸甲酯),胡椒薄荷油,日本薄荷油,丁香油,月桂油,茴香油,桉叶油,百里香油,柏叶油,肉豆蔻油,多香果,鼠尾草油,肉豆蔻衣,苦杏仁油和肉桂皮油(cassia oil);有用的增香剂包括人造,天然和合成水果香精,例如香荚兰,和柑橘油,包括柠檬,橙子,酸橙,葡萄柚,日本柚子(yuzu),酢橘(sudachi),以及水果精油,包括苹果,梨,桃子,葡萄,覆盆子,黑莓,醋栗,蓝莓,草莓,樱桃,李子,李子干(prune),葡萄干(raisin),可乐(cola),瓜拉那(guarana),橙花,菠萝,杏子,香蕉,甜瓜,杏子,樱桃,热带水果,芒果,山竹果,石榴,番木瓜等。
香料组合物赋予的另外的示例性香精包括牛奶香精,黄油香精,干酪香精,奶油香精和酸奶香精;香荚兰香精;茶或咖啡香精,例如绿茶香精,乌龙茶香精,茶香精,可可香精,巧克力香精和咖啡香精;薄荷香精,例如胡椒薄荷香精,留兰香香精和日本薄荷香精;辛香精,例如阿魏香精,香旱芹(ajowan)香精,茴香(anise)香精,当归属香精,小茴香(fennel)香精,多香果香精,肉桂香精,黄春菊香精,芥茉香精,小豆蔻香精,葛缕子(caraway)香精,枯茗(cumin)香精,丁香香精,胡椒香精,芫荽子香精,黄樟香精,香薄荷(savory)香精,川花椒香精,紫苏香精,杜松子香精,姜香精,八角茴香香精,辣根香精,百里香香精,龙蒿(tarragon)香精,莳萝(dill)香精,辣椒香精,肉豆蔻香精,罗勒香精,欧芹香精,马郁兰(marjoram)香精,迷迭香香精,月桂叶香精和山葵(wasabi)(日本辣根)香精;坚果香精,例如杏仁香精,榛子香精,澳洲坚果香精,花生香精,美洲山核桃香精,开心果(pistachio)香精和胡桃香精;酒香精,例如葡萄酒香精,威士忌香精,白兰地香精,朗姆酒香精,杜松子酒香精和利口酒香精;花香精;和蔬菜香精,例如洋葱香精,大蒜香精,甘蓝香精,胡萝卜香精,芹菜香精,蘑菇香精和蕃茄香精。
通常可以使用任何香精或食品添加剂(包括食用色素),例如由Leatherhead FoodInternational Ltd.提供的“Essential guide to food additives”,2008年第三版,第101-321页(ISBN:978-1-905224-50-0)中所述的那些,该出版物通过引用并入本文。
在一个具体的实施方案中,式(I)的化合物(其包括式(Ia)和(Ib)的化合物)可以与茴香脑,左旋薄荷醇,左旋香芹酮,乙基麦芽酚,香草醛,桉叶油素,丁香酚,外消旋薄荷醇,顺式-3-己烯醇,芳樟醇,薄荷油(例如胡椒薄荷油(peppermint arvensis oil),薄荷胡椒油(peppermint piperita oil),留兰香天然油,留兰香苏格兰油),甲基环戊烯醇酮(corylone),丁酸乙酯,乙酸顺式-3-己烯酯,柠檬醛,桉树油,乙基香草醛,水杨酸甲酯,2’-羟基苯丙酮,乙酸乙酯,二氢茉莉酮酸甲酯,香叶醇,柠檬油,乙酸异戊酯,百里酚,乙位紫罗兰酮,乙酸芳樟酯,癸醛,顺式茉莉酮,己酸乙酯,甜瓜醛(2,6-二甲基庚-5-烯醛),香茅醇,乙酰乙酸乙酯,肉豆蔻油和丁香油或它们的混合物组合。
甜味剂的实例包括但不限于蔗糖,果糖,葡萄糖,高果糖玉米糖浆,玉米糖浆,木糖,阿拉伯糖,鼠李糖,赤藓醇,木糖醇,甘露糖醇,山梨醇,肌醇,丁磺氨钾,阿司帕坦,纽甜,三氯蔗糖(sucralose)和糖精及其混合物;三叶苷,橙皮素二氢查耳酮糖苷,柚苷二氢查耳酮,罗汉果苷V,罗汉果提取物,甜叶悬钩子苷,悬钩子提取物,菝葜苷(glycyphyllin),异罗汉果苷V(isomogroside V),罗汉果苷IV,赛门苷I(siamenoside I),新罗汉果苷,木库罗苷IIb(mukurozioside IIb),(+)-hernandulcin,4β-hydroxyhernandulcin,白元参甙(baiyunoside),糙苏甙I(phlomisoside I),异株泻根甜味甙(bryodulcoside),bryosidebryonoside,相思子三萜苷A-E(abrusosides A-E),青钱柳甙A(cyclocarioside A),青钱柳甙I(cyclocaryoside I),albiziasaponins A-E,甘草皂苷(glycyrrhizin),araboglycyrrhizin,巴西甘草甜素I-V(periandrins I-V),蝶卡苷(pterocaryosides)A和B,奥斯拉津(osladin),polypodosides A和B,telosmoside A8-18,甜茶内酯(phyllodulcin),huangqioside E neoastilbin,莽那亭(monatin),3-乙酰氧基-5,7-二羟基-4’-甲氧基黄烷酮,2R,3R-(+)-3-乙酰氧基-5,7,4’-三羟基黄烷酮,(2R,3R)-二氢槲皮素3-O-乙酸酯,二氢槲皮素3-O-乙酸酯4’-甲醚,甜味蛋白(brazzein),仙茅甜蛋白(curculin),马槟榔甜蛋白(mabinlin),莫尼糖蛋白(monellin),neoculin,潘塔亭(pentadin),非洲竹芋甜素(thaumatin)及其组合。上述举出的一些化合物是已知的甜味增强剂和甜味剂。当用作甜味增强剂时,它们通常以低于其甜味检测阈的量使用。
在某些实施方案中,式(I)的化合物可以与共同涉及口腔可接受的载体材料的另外的成分组合。
在一些方面,口服可接受的载体可以包含一种或多种适合于局部口服给药的相容的固体或液体赋形剂或稀释剂。如本文所用,“相容”是指组合物的组分能够混合,而不会以显著降低稳定性和/或功效的方式相互作用。载体可以包括洁牙剂,非磨蚀性凝胶,龈下凝胶,漱口剂或冲洗剂,口腔喷雾剂,口香糖,锭剂和薄荷糖的常用和常规组分。所用载体的选择基本上取决于将组合物引入口腔的方式。用于牙膏,牙胶等的载体材料包括研磨材料,起泡剂,粘合剂,保湿剂,调味剂和甜味剂等,如在例如授予Benedict的美国专利No.3,988,433中所公开的。用于双相洁牙剂制剂的载体材料公开于均授予Lukacovic等人的美国专利No.5,213,790;5,145,666和5,281,410,以及授予Schaeffer的美国专利4,849,213和4,528,180中。漱口剂,漱口液或口腔喷雾剂载体材料通常包括水,香料和甜味剂等,如在例如授予Benedict的美国专利No.3,988,433中所公开的。锭剂载体材料通常包括糖果基料;口香糖载体材料包括胶基,香料和甜味剂,如在例如授予Grabenstetter等人的美国专利No.4,083,955。小袋载体材料通常包括小袋,调味剂和甜味剂。对于用于将活性物质递送到牙周袋中或牙周袋周围的龈下凝胶,选择“龈下凝胶载体”,如在例如均授予Damani的美国专利No.5,198,220和5,242,910。适用于制备本公开的组合物的载体是本领域众所周知的。它们的选择将取决于次要考虑,例如味道,成本和货架稳定性等。
其他合适类型的口服可接受的载体材料或赋形剂列于WO2010/059289,特别是第17-31页,其通过引用并入。
科学文献指出,TRPM8通道的激活可能有助于治疗大多数TRPM8介导的病理症状(J.Med.Chem.2016,59(22),10006-10029)。因此,可以设想式(I)的化合物也可能适用于治疗前列腺癌,膀胱无力,炎症或疼痛,包括使患者与本文定义的一种或多种式(I)的化合物接触。人们还可以设想本文定义的式(I)的化合物适用于缓解咳嗽和感冒,刺激,喉咙痛或声音嘶哑的症状,以及治疗咽喉吞咽困难(Int.J.Mol.Sci.2018,19,4113)。
因此,在第五方面提供了药物组合物,其包含一种或多种由式(I)定义的化合物(其包括式(Ia)和(Ib)的化合物)或其盐或溶剂合物。
取决于所考虑的具体治疗方案,包含一种或多种式(I)的化合物的药物组合物可以肠胃外,局部,口服或局部给药。药物组合物可以是液体,悬浮液或固体制剂。
在某些实施方案中,药物组合物是鼻喷雾剂,局部乳剂,皮肤喷雾剂,咽喉喷雾剂或滴眼剂。
尽管落入上述式(I)的定义内的一些化合物本身是已知的,但其他化合物是新的。
因此,在本发明的第六方面提供了式(I)的化合物、其盐或溶剂合物
其中
环A代表苯基环、环己基或环己烯基环;
R1选自氢、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)和C1-C6烷氧基(例如甲氧基、乙氧基、丙氧基),
R2连接至环A的3、4或5位且选自C1-C6烷基(例如甲基、乙基、异丙基、异丁基、异丙基)、C1-C6烷氧基(例如甲氧基、乙氧基)和C(O)O-C1-C3-烷基(例如C(O)OCH3),
R3选自氢、C1-C6烷基(例如甲基、乙基)、C2-C6烯基(例如乙烯基)、OH和=O,且R4选自氢、C1-C6烷基(例如甲基、乙基),C2-C6烯基(例如乙烯基)和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统(即R3和R1为二价残基-CH2-CH2-),且R4为氢,
R5选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
R6选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
m为0,
p为1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基(例如甲基或异丙基);
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH或CH2OH,
Y连接至环A的2或3位且选自C4-C6烷基(例如异丁基),
其中
环B代表苯基、噻吩、呋喃或吡啶环,
R11选自CN、卤素、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基、C1-C3烷氧基、C2-C3烯基和OH,且n为0-5的整数,条件是如果n>1,则R11可以相同或不同,
X选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH,
条件是式(I)的化合物不为1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪。
此外,非限制性实例是式(I)的化合物,其中Y连接至2位且R2连接至4位。
此外,非限制性实例是式(Ia)的化合物、其盐或溶剂合物,
其中
环A代表苯基环、环己基或环己烯基环;
R1选自氢、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)和C1-C6烷氧基(例如甲氧基、乙氧基、丙氧基),
R2选自C1-C6烷基(例如甲基、乙基、异丙基、异丁基、异丙基)、C1-C6烷氧基(例如甲氧基、乙氧基)和C(O)O-C1-C3-烷基(例如C(O)OCH3),
R3选自氢、C1-C6烷基(例如甲基、乙基)、C2-C6烯基(例如乙烯基)、OH和=O,且R4选自氢、C1-C6烷基(例如甲基、乙基),C2-C6烯基(例如乙烯基)和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统(即R3和R1为二价残基-CH2-CH2-),且R4为氢,
R5选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
R6选自氢、F和C1-C6烷基(例如甲基、乙基、异丁基),
m为0,
p为1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基(例如甲基或异丙基);
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH,
环B代表苯基、噻吩、呋喃或吡啶环,
R11选自CN、卤素(例如F、CL、Br、I)、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基(例如甲基或乙基)、C1-C3烷氧基(例如甲氧基或乙氧基)、C2-C3烯基(例如乙烯基或烯丙基)和OH,且n为0-5的整数(包括1、2和3),条件是如果n>1,则R11可以相同或不同,并且
X连接至环A的2或3位且选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH,
条件是式(I)的化合物不为1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪。
此外,非限制性实例是式(Ia)的化合物,其中X连接至环A的2位。
此外,非限制性实例是式(Ib)的化合物、其盐或溶剂合物,
其中
R1选自氢、C1-C6烷基(例如甲基、乙基、异丙基、异丁基)和C1-C6烷氧基(例如甲氧基),
R2选自C1-C6烷基(例如甲基、乙基、异丙基、异丁基)、C1-C6烷氧基(例如甲氧基、乙氧基)和C(O)O-C1-C3-烷基(例如C(O)OCH3),
R3选自氢、C1-C6烷基(例如甲基、乙基、异丙基)、C2-C6烯基(例如乙烯基)、OH和=O,且R4选自氢、C1-C6烷基(例如甲基、乙基、异丙基)、C2-C6烯基(例如乙烯基)和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统(即R3和R1为二价残基-CH2-CH2-),且R4为氢,
R5选自氢、F和C1-C6烷基(例如甲基、乙基),
R6选自氢、F和C1-C6烷基(例如甲基、乙基),
m为0,
p为1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基(例如甲基或异丙基);
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH或CH2OH,
R11选自CN、卤素(例如F、CL、Br、I)、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基(例如甲基或乙基)、C1-C3烷氧基(例如甲氧基或乙氧基),C2-C3烯基(例如乙烯基或烯丙基)和OH,且n为0-5的整数(包括1、2和3),条件是如果n>1,则R11可以相同或不同,并且
X选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH,
条件是式(Ib)的化合物不为1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪。
式(I)的化合物是本身已知的化合物或者可以由本领域技术人员使用已知的合成方法制备。
其中W为NR13(R13为C1-C3烷基)的式(I)的化合物可以由其中W为NH的式(I)的化合物与合适的羰基化合物例如甲醛(例如低聚甲醛或福尔马林)、丙酮、乙醛或丙醛在还原剂(例如硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠)的作用下、在适当的溶剂(例如乙酸、THF、乙醇)中、在适当的温度(25℃、40℃)下反应来制备。
式(I)的化合物通常可以通过合适的羰基化合物2(例如醛、酮或羧酸)与胺3在还原剂(例如硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、氢化铝锂、甲酸或氢气在均相或多相金属催化剂例如钯催化剂或钌催化剂存在下)的作用下反应来制备。该反应可以在单一步骤或在两个操作中进行,其中所述胺3首先与所述羰基2反应,然后经受还原剂。该反应在适当的溶剂例如但不限于四氢呋喃(THF)、二氯甲烷(DCM)、乙酸、甲苯、水、乙醇中进行或在无溶剂情况下进行,并且可以受益于碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如氢氧化钠或碳酸钾)的存在。该反应在适当的温度(例如0℃、25℃、80℃或120℃)下进行,所述温度可能因使用的方案(即如果反应是在单一操作中进行或者涉及分离通过2和3之间的反应形成的中间体)而变化。在一些情况下,例如当R4是OH时,可能需要通过使2与活化剂例如亚硫酰氯或草酰氯(任选地在催化N,N-二甲基甲酰胺的存在下)在适当的溶剂例如二氯甲烷中或在无溶剂情况下、在适当的温度(例如0℃、24℃或70℃)下反应来活化2。所得中间体然后可以如上所述与胺3反应。
式(I)的化合物也可以通过使胺3与卤化物4任选地在碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如氢化钠、氢氧化钠、碳酸钾或磷酸钾)的存在下反应来制备。该反应在适当的溶剂例如N,N-二甲基甲酰胺(DMF)、四氢呋喃(THF)或甲苯中、在适当的温度(例如0℃、25℃或100℃)下进行。在一些情况下,使用催化量的添加剂例如碘化钾、碘化钠或四丁基碘化铵可能是有利的。
卤化物4又可以由羰基化合物3通过用合适的还原剂(例如硼氢化钠、三乙酰氧基硼氢化钠、氢化铝锂或氢气在均相或多相金属催化剂例如钯催化剂或钌催化剂的存在下)在适当的溶剂例如四氢呋喃(THF)、二氯甲烷(DCM)、甲苯、水、乙醇或甲醇中、在适当的温度(例如0℃或25℃)下还原3来制备。由该还原得到的醇然后可以通过将其与适当的试剂例如但不限于溴、四溴化碳、四氯化碳、N-溴代琥珀酰亚胺或N-氯代琥珀酰亚胺反应,并在膦例如三苯基膦或三丁基膦的存在下被替换为卤素。这在适当的溶剂例如二氯甲烷、甲苯、四氢呋喃或乙腈中、在适当的温度(例如25℃、40℃、100℃)下进行。
或者,式(I)的化合物可以通过中间体5和卤化物6任选地在碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如氢氧化钠、氢氧化钾或碳酸钾)的存在下、在适当的溶剂(例如DMF、二甲亚砜(DMSO)、乙腈、THF、甲苯、异丙醇或乙醇)中、在适当的温度(例如25℃、80℃、100℃、150℃)下反应来制备。在一些情况下,使用催化量的添加剂例如碘化钾、碘化钠或四丁基碘化铵可能是有利的。
其中W为O或NH的化合物2可以以类似的方式通过使5与卤化物7反应来制备。如上所述,这任选地在碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如氢氧化钠、氢氧化钾、氢化钠或碳酸钾)的存在下、在适当的溶剂(例如DMF、二甲亚砜(DMSO)、乙腈、THF、甲苯、异丙醇或乙醇)中、在适当的温度(例如0℃、25℃、80℃、100℃、150℃)下进行。在一些情况下,使用催化量的添加剂如碘化钾、碘化钠或四丁基碘化铵可能是有利的。
其中W为CH2的化合物2可以通过烯烃8与氢气在适当的压力(例如1bar或10bar)下、在金属催化剂例如钯催化剂(例如钯碳或乙酸钯)或铑催化剂(例如氧化铝上的铑)的存在下、在适当的溶剂(例如THF、乙酸乙酯、乙醇或甲醇)中、在适当的温度(例如25℃)下反应来合成。
化合物8可以通过醛9和化合物10在胺例如哌啶或吡咯烷和碱例如吡啶或三乙胺的存在下、在适当的温度(例如100℃或140℃)下反应来制备。
其中W为CH2的化合物2也可由三氟甲磺酸酯11与烯丙基化试剂例如烯丙基三丁基锡烷或乙酸烯丙酯在金属催化剂例如钯催化剂(例如Pd(Ph3P)4、乙酸钯或三(二亚苄基丙酮)二钯(0))的存在下、任选地在盐例如氯化锂的存在下反应来制备。该反应在适当的溶剂例如DMF或乙腈中、在适当的温度(例如70℃或90℃)下进行。所得中间体可以被官能化,例如通过环氧化,所述环氧化通过在适合的溶剂(例如二氯甲烷或乙醚)中、在适当的温度(0℃或25℃)下将其暴露于环氧化试剂(例如3-氯过苯甲酸(mCPBA)、过乙酸、二甲基二氧杂环丙烷(DMDO)或甲基(三氟甲基)二氧杂环丙烷(TFDO)来进行。所得环氧化物然后可以通过在适当的溶剂(例如EtOH、THF、DMF或MeOH)中、在适当的温度(例如50℃或70℃)下与胺3反应来官能化。
三氟甲磺酸酯11可以通过其中W为O的5与磺化剂例如三氟甲基磺酸酐任选地在碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如碳酸钾)的存在下、在适当的溶剂例如二氯甲烷中、在适当的温度(例如0℃、25℃)下反应来制备。
三氟甲磺酸酯11还可用于制备其中W为NH的5,通过使11与胺源例如苄胺任选地在碱例如胺碱(例如三乙胺、二异丙基乙胺(DIPEA))或无机碱(例如碳酸钾、碳酸铯)的存在下、在金属催化剂例如钯催化剂(例如Pd(Ph3P)4、乙酸钯或三(二亚苄基丙酮)二钯(0))的存在下、并且任选地在配体例如三苯基膦或2,2'-双(二苯基膦基)-1,1'-联萘(其可以是对映体纯的R-或S-对映体或外消旋体)的存在下反应来进行。该反应在适当的溶剂例如甲苯、DMF中或在无溶剂的情况下、并在适当的温度(例如70℃、100℃或120℃)下进行。然后可以将所得苄基保护的苯胺脱保护,通过使其与氢气在适当的压力(例如1bar或10bar)下、在金属催化剂例如钯催化剂(例如钯碳或乙酸钯)的存在下、在适当的溶剂(例如THF、乙酸乙酯、乙醇或甲醇或无溶剂)中、在适当的温度(例如25℃)下反应,得到其中W为NH的5。
其中X为>C=O的化合物12可以通过苯酚13和酰基卤化物14任选地在碱例如胺碱(例如三乙胺、二异丙基乙胺(DIPEA))或无机碱(例如碳酸钾或氢氧化钠)的存在下、在适当的溶剂(例如二氯甲烷、四氢呋喃、水、二噁烷、乙醇、二甲苯、氯苯或无溶剂)中、在适当的温度(例如0℃、25℃)下反应来制备。所得中间体可以通过与路易斯酸例如三氯化铝在适当的溶剂(例如二甲苯、氯苯或无溶剂)中、在适当的温度(例如120℃或150℃)下反应而重排。在一些情况下,上述两种操作可以合并为单一步骤,在该情况下可以抑制碱。
所得的其中X为>C=O的化合物12可以通过与还原剂(例如硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、氢化锂铝或氢气在均相或多相金属催化剂例如钯催化剂(例如钯碳)或钌催化剂的存在下)在适当的溶剂例如四氢呋喃(THF)、二氯甲烷(DCM)、乙酸、甲苯、水或乙醇中、在适当的温度(例如0℃、25℃、40℃)下反应,进一步转化为其中X为>CHOH的12。所得的其中X为>CHOH的化合物12可以通过与氢化物源例如三乙基硅烷、苯基硅烷或聚甲基氢硅氧烷(PMHS)在酸例如三氟乙酸的存在下、在适当的溶剂例如DCM中、在适当的温度(例如0℃或25℃)下反应,进一步转化为其中X为CH2的化合物12。
其中X为>C=CH2的化合物12可以直接由其中X为>C=O的化合物12通过与格氏试剂例如甲基氯化镁、甲基碘化镁或甲基溴化镁在适当的溶剂(例如乙醚、THF或己烷)中、在适当的温度(例如0℃、25℃、40℃)下反应来得到。然后将所得的甲醇(carbinol)通过在适当的溶剂(例如DCM)中、在适当的温度(例如0℃、25℃、40℃)下用酸(例如乙酸、三氟乙酸或盐酸)处理来消除。然后其中X为>C=CH2的化合物12可以通过与氢气在适当的压力(例如1bar或10bar)下、在金属催化剂例如钯催化剂(例如钯碳或乙酸钯)的存在下、在适当的溶剂(例如THF、乙酸乙酯、乙醇或甲醇或无溶剂)中、在适当的温度(例如25℃)下反应来转化为其中X为>CH-CH3的化合物12。
化合物15可以通过苯酚13与苄基卤化物16在氯化锌(II)的存在下、在适当的溶剂(例如氯苯、甲苯或无溶剂)中、在适当的温度(例如120℃或140℃)下反应来制备。或者,苯酚13可以与苄基卤化物16在碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如氢氧化钠、氢氧化钾或碳酸钾)的存在下、在适当的溶剂(例如乙腈、丙酮、THF或DMF)中、在适当的温度(例如25℃、40℃或70℃)下反应。由此获得的中间体然后可以通过与氯化钛(IV)在适当的溶剂(例如DCM)中、在适当的温度(例如-10℃、0℃或25℃)下反应而重排为15。
必须提及的是,某些敏感的官能团可以以保护或掩蔽的形式通过制备顺序,并通过本领域技术人员已知的标准方法在合成顺序的稍后点显露出来。例如,芳基卤化物17可以与氰化物源例如氰化铜(I)在适当的溶剂(例如N-甲基-2-吡咯烷酮(NMP)或DMF)中、在适当的温度(例如140℃或200℃)下反应,得到氰化物18。
溴化物19可与碘化物源例如碘化铜(I)在三氟乙酸钠d存在下、在适当的溶剂(例如DMF和甲苯)中、在适当的温度(120℃或150℃)下反应,得到碘化物20。
硝基化合物21可以与氢气在适当的压力(例如1bar或10bar)下、在金属催化剂例如钯催化剂(例如钯碳或乙酸钯)的存在下、在适当的溶剂(例如THF、乙酸乙酯、乙醇或甲醇或无溶剂)中、在适当的温度(例如25℃)下反应,得到苯胺22。
上述实例绝不是限制性或穷举的,本领域技术人员将认识到官能团操作在制备式(I)的化合物中的一般适用性。
化合物23可以通过化合物24与氧化剂(例如氯铬酸吡啶鎓、重铬酸吡啶鎓、戴斯-马丁氧化剂(三乙酸3-氧代-1,3-二氢-1λ5,2-苯并碘氧杂戊环-1,1,1-三基酯)或DMSO在活化剂例如草酰氯飞存在下)任选地在碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))的存在下、在适当的溶剂(例如DCM、THF)中、在适当的温度(其可以根据所选的氧化剂从-78℃变化到25℃并且进一步高达40℃)下反应进行氧化来制备。化合物24可以通过化合物25与硼烷源(例如硼烷二甲硫醚或9-硼二环[3.3.1]壬烷(9-BBN))在适当的溶剂(例如THF)中、在适当的温度(例如0℃、25℃)下反应,然后用碱水溶液(例如NaOH)和氧化剂例如过氧化氢在适当的温度(例如0℃、25℃)下处理来制备。
化合物25可以通过在适当的溶剂(例如二氯甲烷或乙醚)中、在适当的温度(0℃或25℃)下将其暴露于环氧化试剂(例如3-氯过苯甲酸(mCPBA)、过乙酸、二甲基二氧杂环丙烷(DMDO)或甲基(三氟甲基)二氧杂环丙烷(TFDO))进行环氧化,然后使形成的环氧化物与胺3在适当的溶剂(例如EtOH、THF、DMF或MeOH)中、在适当的温度(例如50℃或70℃)下反应,直接转化为某些式(I)的化合物。
化合物26可以通过醇27与卤化物28在碱例如无机碱(例如磷酸钾)、铜催化剂(例如碘化铜(I))和吡啶甲酸的存在下、在适当的溶剂(例如DMSO、DMF或N-甲基-2-吡咯烷酮(NMP))中、在适当的温度(例如90℃或120℃)下反应来制备。
类似的反应条件和试剂可用于由30和28通过在碱例如无机碱(例如磷酸钾)、铜催化剂(例如碘化铜(I))和吡啶甲酸的存在下、在适当的温度(例如90℃或120℃)下、在适当的溶剂(例如DMSO、DMF或N-甲基-2-吡咯烷酮(NMP))中反应来制备29。
化合物31可以通过将32通过与还原剂(例如氢化铝锂、氢化二异丁基铝或氢气在均相或多相金属催化剂例如钯催化剂(例如钯碳)或钌催化剂的存在下)在适当的溶剂例如四氢呋喃(THF)、二氯甲烷(DCM)、甲苯、水或乙醇中、在适当的温度(例如0℃、25℃、40℃)下反应进行还原来制备。
化合物33可以通过使醇34与烯丙基卤化物35任选地在碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如氢氧化钠、氢化钠、氢氧化钾或碳酸钾)的存在下、在适当的溶剂(例如丙酮、DMF、DMSO、乙腈、THF、甲苯、异丙醇或乙醇、水或无溶剂)中、在适当的温度(例如0℃、25℃或60℃)下反应来制备。所得醚中间体然后可以通过在适当的溶剂(例如DMF、DMSO或无溶剂)中加热到合适的温度(例如150℃或200℃)而进一步转化为33。
化合物36可以通过化合物37与氢气在适当的压力(例如1bar、5bar或10bar)下、在金属催化剂例如钯催化剂(例如钯碳或乙酸钯)或铑催化剂(例如氧化铝上的铑)的存在下、在适当的溶剂(例如THF、乙酸乙酯、乙醇或甲醇或无溶剂)中、在适当的温度(例如25℃或50℃)下反应进行还原来制备。化合物37可以通过醛38与环己酮在碱例如无机碱(例如氢氧化钠或氢氧化钾)的存在下、在适当的溶剂(例如单独的水或水与其他溶剂例如THF或二噁烷的混合物)中、在适当的温度(例如0℃、25℃或40℃)下反应来制备。
必须注意,许多上述涉及胺作为底物的一般方法可以用相应的胺的盐例如盐酸盐、氢溴酸盐、草酸盐、磷酸盐等进行。在那些情况下,可能需要使用额外的碱例如胺碱(例如三乙胺、吡啶或二异丙基乙胺(DIPEA))或无机碱(例如氢化钠、氢氧化钠、碳酸钾或磷酸钾)以使反应发生,这是本领域技术人员将认识到的事实。
还必须注意,与本文所述的用于制备式(I)的化合物的步骤顺序不同的步骤顺序也是可能的并且在一些情况下是有利的。如本领域技术人员将理解的,这可以消除在整个合成过程中保护携带敏感官能团的基团的需要。
现在参考以下非限制性实施例进一步描述本发明。这些实施例仅出于说明的目的,并应当理解,本领域技术人员可以做出变化和修改。
实施例
实施例1:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐
实施例1a:2-(2-苄基-4-甲基苯氧基)乙酸乙酯
将2-苄基-4-甲基苯酚(0.70g,3.53mmol)在DMF(N,N-二甲基甲酰胺)(5mL)中的溶液用碳酸钾(1.46g,10.6mmol,3.0equiv.)处理,然后用2-氯乙酸乙酯(0.45mL,4.24mmol,1.2eq.)处理。将所得混合物在r.t.(室温,即大约25℃)搅拌过夜,然后用MTBE(甲基叔丁基醚)(50mL)稀释并过滤,用另外的MTBE(50mL)洗涤。将滤液用水(2×50mL)、盐水(50mL)洗涤,用MgSO4干燥并减压浓缩,得到2-(2-苄基-4-甲基苯氧基)乙酸乙酯(1.0g,3.51mmol,定量收率),为无色液体,其未经纯化用于下一步。GC/MS(EI,70eV)m/z(%):284(70,[M]+),197(100),196(22),195(99),181(31),166(22),165(71),152(30),91(96),29(35)。
实施例1b:2-(2-苄基-4-甲基苯氧基)乙酸:
向2-(2-苄基-4-甲基苯氧基)乙酸乙酯(1.00g,3.53mmol)在THF(四氢呋喃)(15mL)中的溶液中加入2M NaOH水溶液(10mL)并将混合物加热至回流保持2小时。将混合物冷却,倒入冰冷的1M HCl水溶液(30mL)中,用MTBE(2×50mL)萃取,用盐水(50mL)洗涤,用MgSO4干燥并减压浓缩,得到2-(2-苄基-4-甲基苯氧基)乙酸(0.78g,3.04mmol,86%收率),为白色固体,其未经进一步纯化用于下一步。GC/MS(EI,70eV)m/z(%):256(82,[M]+),197(44),196(26),195(100),181(41),166(23),165(43),91(68),77(19),31(30)。1H NMR(400MHz,CDCl3):δ=7.19-7.34(m,5H),7.01(s,2H),6.71(d,J=8.1Hz,1H),4.61(s,2H),4.04(s,2H),2.29ppm(s,3H)。13C NMR(101MHz,CDCl3):δ=173.0,153.1,140.8,131.8,131.6,129.9,128.7,128.4,127.9,126.0,111.8,65.4,36.3,20.6ppm。
实施例1c:2-(2-苄基-4-甲基苯氧基)乙酰氯:
将2-(2-苄基-4-甲基苯氧基)乙酸(0.68g,2.65mmol)用亚硫酰氯(1.36mL,18.6mmol,7equiv.)处理并将混合物加热至70℃保持1小时。减压蒸发混合物,得到2-(2-苄基-4-甲基苯氧基)乙酰氯(0.73g,2.65mmol,定量收率),为白色固体,其未经进一步纯化用于下一步。1H NMR(400MHz,CDCl3):δ=7.10-7.33(m,5H),6.96-7.03(m,2H),6.66(d,J=8.1Hz,1H),4.89(s,2H),4.02(s,2H),2.28ppm(s,3H)。13C NMR(101MHz,CDCl3):δ=170.3,152.7,140.7,132.1,131.9,130.2,128.9,128.3,127.8,125.9,111.9,73.1,35.9,20.6ppm。
实施例1d:2-(2-苄基-4-甲基苯氧基)-1-(4-甲基哌嗪-1-基)乙酮盐酸盐:
将2-(2-苄基-4-甲基苯氧基)乙酰氯(0.36g,1.30mmol)在DCM(二氯甲烷)(7mL)中的溶液冷却至0℃,然后用1-甲基哌嗪(0.143g,1.43mmol,1.1equiv.)处理并在室温下搅拌40小时。将得到的白色固体过滤并真空干燥,得到2-(2-苄基-4-甲基苯氧基)-1-(4-甲基哌嗪-1-基)乙酮盐酸盐(0.43g,1.15mmol,88%收率),为白色固体,其未经进一步纯化用于下一步。LC-MS(ESI+):339([M+H]+)。13C NMR(101MHz,CDCl3):δ=166.9,153.5,141.1,132.5,131.6,128.6,128.5,128.4,128.1,126.2,111.5,68.6,53.1,52.8,43.4,42.1,36.3,20.5ppm。
实施例1e:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐:
在r.t.(室温)下将LAH(LiAlH4)(26mg,0.680mmol,1.7equiv.)在THF(四氢呋喃)(8mL)中的悬浮液用固体2-(2-苄基-4-甲基苯氧基)-1-(4-甲基哌嗪-1-基)乙酮盐酸盐(0.150g,0.400mmol)分份处理。在最初的气体逸出平息后,将混合物加热至50℃保持1小时。冷却至室温后,将混合物通过加入EtOAc(乙酸乙酯)(1mL)和随后加入饱和酒石酸钾钠水溶液(罗谢尔盐溶液)(10mL)淬灭,并将浆液搅拌过夜。将所得混合物用水(20mL)和饱和碳酸氢钠水溶液(20mL)稀释,用EtOAc(2×50mL)萃取,用MgSO4干燥并减压浓缩。将得到的淡黄色液体吸收在乙醚(10mL)中并用2M HCl的乙醚溶液(0.4mL)处理,导致形成白色沉淀。将沉淀过滤并减压干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐(0.129g,0.357mmol,89%收率),为白色固体。LC-MS(ESI+):325([M+H]+)。13C NMR(101MHz,甲醇-d4):δ=153.5,141.1,131.7,131.0,128.5,128.1,128.1,127.8,125.6,111.7,63.0,56.0,49.7,49.1,41.9,35.7,19.2ppm。
实施例2:4-(2-(2-苄基-4-甲基苯氧基)乙基)吗啉盐酸盐
实施例2a:2-(2-苄基-4-甲基苯氧基)-1-吗啉代乙酮:
在0℃下将2-(2-苄基-4-甲基苯氧基)乙酰氯(0.36g,1.3mmol)在DCM(10mL)中的溶液用吡啶(0.12mL,1.4mmol,1.1equiv.)处理,然后用吗啉(0.125g,1.4mmol,1.1equiv.)处理,并将所得混合物在室温下搅拌40小时。将所得混合物用EtOAc(50mL)稀释,用水(2×20mL)、盐水(20mL)洗涤,用MgSO4干燥并减压浓缩。然后将该物质通过硅胶快速柱色谱法纯化,用己烷中的EtOAc梯度洗脱,得到2-(2-苄基-4-甲基苯氧基)-1-吗啉代乙酮(0.245g,0.75mmol,58%收率),为无色液体。GC/MS(EI,70eV)m/z(%):325(9,[M]+),198(17),197(100),195(14),193(11),165(23),152(11),100(14),91(35),70(10),56(14)。1H NMR(400MHz,CDCl3):δ=7.25-7.31(m,2H),7.16-7.23(m,3H),6.97-7.05(m,2H),6.83(d,J=8.3Hz,1H),4.65(s,2H),3.98(s,2H),3.54-3.68(m,4H),3.27-3.41(m,4H),2.29ppm(s,3H)。13C NMR(101MHz,CDCl3):δ=166.9,153.6,140.9,131.9,130.9,129.0,128.7,128.3,128.0,125.9,111.4,68.4,66.7,66.6,45.7,42.4,36.2,20.5ppm。
实施例2b:4-(2-(2-苄基-4-甲基苯氧基)乙基)吗啉盐酸盐:
在室温下将LAH(13mg,0.34mmol,1.1equiv.)在THF(3mL)中的悬浮液用2-(2-苄基-4-甲基苯氧基)-1-吗啉代乙酮(0.100g,0.31mmol)在THF(3mL)中的溶液逐滴处理。在最初的气体逸出平息后,将混合物加热至50℃保持1小时。冷却至室温后,将混合物通过加入EtOAc(乙酸乙酯)(1mL),然后加入酒石酸钾钠水溶液(罗谢尔盐溶液)(10mL)淬灭,并将浆液搅拌过夜。将所得混合物用水(20mL)和饱和碳酸氢钠水溶液(20mL)稀释,用EtOAc(2×50mL)萃取,用MgSO4干燥并减压浓缩。将得到的淡黄色液体吸收在乙醚(10mL)中并用2MHCl的乙醚溶液(0.4mL)处理,导致形成白色沉淀。将沉淀过滤并减压干燥,得到4-(2-(2-苄基-4-甲基苯氧基)乙基)吗啉盐酸盐(29mg,0.083mmol,27%收率),为白色固体。LC-MS(ESI+):312([M+H]+)。1H NMR(400MHz,甲醇-d4):δ=7.24-7.31(m,2H),7.14-7.21(m,1H),7.07-7.14(m,3H),7.03(d,J=2.0Hz,1H),6.93(d,J=8.3Hz,1H),4.29-4.38(m,2H),4.02(s,2H),3.79-3.95(m,2H),3.58-3.74(m,2H),3.53(dd,J=5.3,4.0Hz,2H),3.21-3.31(m,2H),3.08(br s,2H),2.29ppm(s,3H)。13C NMR(101MHz,甲醇-d4):δ=153.6,141.2,131.9,131.0,128.4,128.0,128.0,127.9,125.6,111.5,63.5,62.7,56.4,52.5,35.7,19.2ppm。
实施例3:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪
将1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐(0.10g,0.28mmol)溶解在2M NaOH水溶液(10mL)中并用MTBE(3×20mL)萃取。将合并的萃取物用盐水(20mL)洗涤,用MgSO4干燥并减压浓缩。将所得物质通过硅胶快速色谱法纯化,用己烷中的三乙胺、乙醇和EtOAc(比例1:9:90)的混合物梯度洗脱,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(70mg,0.22mmol,77%收率),为淡黄色液体。GC/MS(EI,70eV)m/z(%):324(1,[M]+),127(43),126(7),114(7),113(100),91(6),70(31),58(5),56(11),43(9),42(11)。
实施例4:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(磷酸盐)
在室温下将磷酸(85wt%,0.35g,3.1mmol)在乙醇(15mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(1.00g,3.08mmol)在乙醇(15mL)中的溶液并将所得悬浮液搅拌15分钟。将形成的固体过滤并在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(磷酸盐)(0.80g,1.5mmol,50%收率),为白色固体。分析计算值(%),C21H34N2O9P2(520.46g/mol):C 48.46,H 6.58,N 5.38,O27.67,P 11.90,实测值:C48.21,H 6.50,N 5.41。
实施例5:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2,2,2-三氟乙酸盐)
在室温下将TFA(2,2,2-三氟乙酸)(0.35g,3.1mmol,2equiv.)在乙醇(10mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(0.50g,1.54mmol)在乙醇(10mL)中的溶液处理。将得到的混合物蒸发至干,并将得到的固体悬浮在乙醚中并过滤,用冷的乙醚洗涤,然后用己烷洗涤。将固体在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2,2,2-三氟乙酸盐)(0.715g,1.29mmol,84%收率),为白色固体。分析计算值(%),C25H30N2O5F6(552.51g/mol):C 54.35,H 5.47,N 5.07,O 14.48,F 20.63,实测值:C 54.42,H5.44,N 5.07。
实施例6:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2-羟基琥珀酸盐)
在室温下将2-羟基琥珀酸(0.33g,2.47mmol)在乙醇(10mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(0.80g,2.47mmol)在乙醇(10mL)中的溶液处理。将所得固体过滤并用乙醚和己烷洗涤,然后在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2-羟基琥珀酸盐)(0.715g,1.20mmol,48%收率),为白色固体。分析计算值(%),C29H40N2O11(592.64g/mol):C 58.77,H 6.80,N4.73,O 29.70,实测值:C57.87,H 6.64,N 4.71。
实施例7:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2,3-二羟基琥珀酸盐
在室温下将2,3-二羟基琥珀酸(0.46g,3.1mmol)在乙醇(10mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(1.0g,3.1mmol)在乙醇(10mL)中的溶液处理。将所得混合物搅拌30分钟,然后蒸发至干并将所得固体悬浮在己烷中并过滤,用冷己烷洗涤。将固体在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2,3-二羟基琥珀酸盐(1.3g,2.74mmol,89%收率),为白色固体。1H NMR(400MHz,DMSO-d6):δ=7.37-8.54(m,4H),7.19-7.29(m,4H),7.12-7.18(m,1H),6.93-7.01(m,2H),6.85(d,J=9.0Hz,1H),4.13(s,2H),4.02(t,J=5.5Hz,2H),3.86(s,2H),2.53-2.92(m,10H),2.45(s,3H),2.19ppm(s,3H)。13C NMR(101MHz,DMSO-d6):δ=174.5,154.4,141.6,131.4,129.4,128.8,126.1,112.2,72.4,66.4,56.6,53.8,51.6,44.2,35.9,20.6ppm。
实施例8:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二马来酸盐
在室温下将马来酸(0.29g,2.47mmol)在乙醇(10mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(0.80g,2.47mmol)在乙醇(10mL)中的溶液处理。将所得固体过滤并用乙醚和己烷洗涤,然后在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二马来酸盐(0.65g,1.17mmol,47%收率),为白色固体。分析计算值(%),C29H36N2O9(556.61g/mol):C 62.58,H 6.52,N 5.03,O 25.87,实测值:C 62.34,H6.50,N 5.05。
实施例9:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二甲磺酸盐
在室温下将甲磺酸(0.35mL,5.42mmol)在乙醇(10mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(0.88g,2.71mmol)在乙醇(10mL)中的溶液处理。将所得混合物搅拌30分钟,然后蒸发至干,将所得固体悬浮在乙醚中并过滤,用冷乙醚洗涤,然后用己烷洗涤。将固体在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二甲磺酸盐(1.22g,2.36mmol,87%收率),为白色固体。分析计算值(%),C23H36N2O7S2(516.68g/mol):C 53.47,H 7.02,N 5.42,O 21.68,S 12.41,实测值:C 52.72,H 6.95,N5.40。
实施例10:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪硫酸盐
在室温下将硫酸(0.16mL,3.1mmol)在乙醇(10mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(1.0g,3.1mmol)在乙醇(10mL)中的溶液处理。将所得固体过滤并用乙醚和己烷洗涤,然后在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪硫酸盐(1.21g,2.86mmol,93%收率),为白色固体。LC-MS(ESI-):97([HSO4]-)。LC-MS(ESI+):324([M+H]+)。
实施例11:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪柠檬酸盐
在室温下将柠檬酸(0.59g,3.1mmol)在乙醇(10mL)中的溶液用1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪(1.0g,3.1mmol)在乙醇(10mL)中的溶液处理。将所得混合物搅拌30分钟,然后蒸发至干,将所得固体悬浮在乙醚中并过滤,用冷乙醚洗涤,然后用己烷洗涤。将固体在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪柠檬酸盐(1.22g,2.36mmol,77%收率),为白色固体。LC-MS(ESI+):324([M+H]+)。1H NMR(400MHz,DMSO-d6):δ=8.02-13.16(m,4H),7.23-7.29(m,2H),7.18-7.22(m,2H),7.13-7.18(m,1H),6.94-7.00(m,2H),6.86(d,J=8.1Hz,1H),4.03(t,J=5.5Hz,2H),3.86(s,2H),2.81-3.02(区间(range),4H),2.76(t,J=5.4Hz,2H),2.54-2.72(m,10H),2.20ppm(s,3H)。13C NMR(101MHz,DMSO-d6):δ=177.0,171.8,154.4,141.5,131.4,129.5,129.4,129.0,128.6,128.2,126.2,112.2,72.0,66.4,56.4,53.6,51.2,44.5,43.7,35.9,20.6ppm。
实施例12:1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪
实施例12a:2-(2-苄基-4-甲基苯氧基)丙酸乙酯:
类似于实施例1a,由2-苄基-4-甲基苯酚(5.0g,25.2mmol)和2-溴丙酸乙酯(5.48g,30.3mmol,1.2equiv.)制备,在硅胶快速柱色谱法,用EtOAc/己烷洗脱后,得到2-(2-苄基-4-甲基苯氧基)丙酸乙酯(5.55g,18.6mmol,74%收率),为无色液体。GC/MS(EI,70eV)m/z(%):298(39,[M]+),198(20),197(100),195(18),166(17),165(43),121(46),120(22),105(40),91(25)。1H NMR(400MHz,CDCl3):δ=7.30-7.36(m,4H),7.20-7.28(m,1H),6.96-7.02(m,2H),6.67-6.72(m,1H),4.76(q,J=6.8Hz,1H),4.26(q,J=7.1Hz,2H),4.10-4.16(m,1H),4.07(s,1H),2.30(s,3H),1.62(d,J=6.8Hz,3H),1.30ppm(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3):δ=172.5,153.4,141.3,131.5,130.6,130.2,129.1,128.2,127.6,125.7,112.0,73.0,61.1,36.1,20.6,18.6,14.2ppm。
实施例12b:1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪
将2-(2-苄基-4-甲基苯氧基)丙酸乙酯(5.50g,18.4mmol)在DCM(40mL)中的溶液冷却至-78℃并用DIBAL-H(二异丁基氢化铝)溶液逐滴处理(1M,在甲苯中,38.7mL,38.7mmol,2.1equiv.)。使所得混合物升温至室温,历时1h,然后冷却至5℃并用EtOAc(3mL)淬灭,用罗谢尔盐溶液(50mL)处理并在室温下搅拌3小时。混合物用DCM(3×100mL)萃取,用水(100mL)洗涤,用MgSO4干燥并减压浓缩,得到粗中间体醇2-(2-苄基-4-甲基苯氧基)丙-1-醇(4.4g,15mmol),将其溶解在DCM(30mL)中并在室温下缓慢加入到硅藻土(3.9g)和PCC(氯铬酸吡啶鎓)(3.88g,18.0mmol)在DCM(20mL)中的悬浮液中。将所得混合物在室温下搅拌5小时,然后通过硅胶塞过滤并浓缩,得到粗中间体醛2-(2-苄基-4-甲基苯氧基)丙醛(3.85g,10.2mmol)。将其溶解在DCM(40mL)中并用1-甲基哌嗪(1.12g,11.2mmol)处理,然后分批加入三乙酰氧基硼氢化钠(2.38g,11.2mmol)。将所得混合物在室温搅拌3小时,然后倒入冰冷的饱和NaHCO3水溶液(100mL)中,用DCM(3×50mL)萃取,用水(100mL)洗涤,用MgSO4干燥并减压浓缩。然后将该物质通过硅胶快速柱色谱法纯化,用己烷中的三乙胺、乙醇和EtOAc(比例1:9:90)的混合物梯度洗脱,得到1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪(1.55g,4.58mmol,25%收率),为无色液体。GC/MS(EI,70eV)m/z(%):338(1,[M]+),141(13),140(9),114(7),113(100),100(6),98(6),70(29),56(6),43(6),42(10)。1H NMR(400MHz,CDCl3):δ=7.21-7.31(m,4H),7.16-7.21(m,1H),6.99(dd,J=8.3,2.0Hz,1H),6.94(d,J=2.0Hz,1H),6.83(d,J=8.3Hz,1H),4.50-4.59(m,1H),3.96(s,2H),2.67(dd,J=13.1,6.2Hz,1H),2.49(dd,J=13.1,4.8Hz,1H),2.33-2.71(m,8H),2.29(s,3H),2.27(s,3H),1.23ppm(d,J=6.4Hz,3H)。13C NMR(101MHz,CDCl3):δ=153.3,141.5,131.5,130.4,129.5,129.0,128.1,127.6,125.6,112.9,72.4,63.7,55.3,53.8,46.1,36.2,20.5,18.6ppm。
实施例13:1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐
在室温下将1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪(0.63g,1.86mmol)在乙醚中的溶液用2M HCl的乙醚溶液(2.5mL,5mmol)处理,将所得固体过滤并用乙醚洗涤,然后用己烷洗涤,然后在真空烘箱中干燥,得到1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐(0.52g,1.39mmol,75%收率),为白色固体。LC-MS(ESI+):339([M+H]+)。13CNMR(101MHz,DMSO-d6):δ=151.8,141.6,131.7,131.1,130.4,129.3,128.6,128.2,126.2,114.5,69.3,49.4-50.1(br),36.1,20.7,17.3ppm。
实施例14:1-(2-(2-苄基-4-乙基苯氧基)乙基)-4-甲基哌嗪盐酸盐
按照与实施例12类似的顺序,由2-苄基-4-乙基苯酚、2-氯乙酸乙酯和1-甲基哌嗪制备,得到1-(2-(2-苄基-4-乙基苯氧基)乙基)-4-甲基哌嗪,将其根据实施例13所述的方法以盐酸盐形式沉淀,得到1-(2-(2-苄基-4-乙基苯氧基)乙基)-4-甲基哌嗪盐酸盐,为白色固体。LC-MS(ESI+):339([M+H]+)。1H NMR(400MHz,DMSO-d6):δ=11.48-13.47(m,1H),7.26-7.34(m,2H),7.15-7.25(m,3H),7.06(dd,J=8.3,2.2Hz,1H),7.00(s,1H),6.93(d,J=8.3Hz,1H),4.40(br s,2H),3.95(s,2H),3.39-3.78(m,10H),2.82(br s,3H),2.46-2.57(m,3H),1.13ppm(t,J=7.6Hz,3H)。13C NMR(101MHz,DMSO-d6):δ=153.9,141.3,136.8,130.4,129.4,129.1,128.8,127.0,126.3,112.3,63.3,49.7-50.6(br),48.9-49.6(br),35.9,27.8,16.4ppm。
实施例15:1-甲基-4-(2-(4-甲基-2-(噻吩-2-基甲基)苯氧基)乙基)哌嗪盐酸盐
实施例15a:4-甲基-2-(噻吩-2-基甲基)苯酚
在室温下将对甲酚(20.8g,192mmol,5equiv.)和三氟甲磺酸(0.404g,2.69mmol,0.07equiv.)的混合物用噻吩-2-甲基乙酸甲酯(6g,38.4mmol)逐滴处理,历时5分钟,并将所得混合物加热至100℃保持1小时。将所得混合物冷却至室温并倾倒在水(200mL)上,用EtOAc(3×100mL)萃取,用水(100mL)、盐水(100mL)洗涤,用MgSO4干燥并减压浓缩。通过硅胶快速柱色谱法纯化粗品,用己烷中的EtOAc梯度洗脱,得到4-甲基-2-(噻吩-2-基甲基)苯酚(1.3g,5.98mmol,16%收率),为无色液体。LC-MS(ESI+):331([M+H]+)。
实施例15b:1-甲基-4-(2-(4-甲基-2-(噻吩-2-基甲基)苯氧基)乙基)哌嗪盐酸盐
按照与实施例12类似的顺序,由4-甲基-2-(噻吩-2-基甲基)苯酚、2-氯乙酸乙酯和1-甲基哌嗪制备,得到1-甲基-4-(2-(4-甲基-2-(噻吩-2-基甲基)苯氧基)乙基)哌嗪,将其根据实施例13所述的方法以盐酸盐形式沉淀,得到1-甲基-4-(2-(4-甲基-2-(噻吩-2-基甲基)苯氧基)乙基)哌嗪盐酸盐,为白色固体。LC-MS(ESI+):331([M+H]+)。13C NMR(101MHz,DMSO-d6):δ=153.5,144.1,131.1,130.3,129.0,128.6,127.3,125.6,124.5,112.3,63.3,48.98-50.57(br),30.2,20.6ppm。
实施例16:4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉1-氧化物
实施例16a:4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉
按照与实施例12类似的顺序,由2-苄基-4-甲基苯酚、2-氯乙酸乙酯和硫代吗啉制备,得到4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉,为无色液体。GC/MS(EI,70eV)m/z(%):327(3,[M]+),165(4),130(6),118(5),117(7),116(100),91(7),88(8),56(7),55(3),42(4)。1H NMR(400MHz,CDCl3):δ=7.12-7.27(m,5H),6.97(dd,J=8.3,1.8Hz,1H),6.91(d,J=2.1Hz,1H),6.73(d,J=8.2Hz,1H),4.01(t,J=5.6Hz,2H),3.93(s,2H),2.73-2.80(m,6H),2.59-2.64(m,4H),2.24ppm(s,3H)。13C NMR(101MHz,CDCl3):δ=154.5,141.3,131.4,129.9,129.4,128.8,128.2,127.7,125.8,111.4,66.4,58.2,55.3,36.2,28.0,20.5ppm。
实施例16b:4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉1-氧化物
在5℃下将4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉(0.66g,2.02mmol)在乙醇(10mL)中的溶液用NaIO4(0.45g,2.1mmol,1.04equiv.)处理,并使其升温至室温。15小时后,将混合物过滤,用EtOAc(50mL)稀释,用水(50mL)、盐水(50mL)洗涤,用MgSO4干燥并减压浓缩。粗品通过硅胶快速柱色谱法纯化,用己烷中的EtOAc梯度洗脱,得到4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉1-氧化物(0.36g,1.05mmol,52%收率),为黄色液体。GC/MS(EI,70eV)m/z(%):343(9,[M]+),326(16),165(12),132(16),116(100),91(18),88(26),77(11),56(32),55(10),42(11)。1H NMR(400MHz,CDCl3):δ=7.12-7.28(m,5H),6.99(dd,J=8.2,1.7Hz,1H),6.93(d,J=2.0Hz,1H),6.74(d,J=8.2Hz,1H),4.03(t,J=5.3Hz,2H),3.94(s,2H),3.07-3.16(m,2H),2.81(t,J=5.3Hz,2H),2.66-2.78(m,6H),2.25ppm(s,3H)。13CNMR(101MHz,CDCl3):δ=154.4,141.2,131.6,130.1,129.1,128.6,128.2,127.8,125.8,111.4,66.7,57.2,46.8,44.9,36.2,20.5ppm。
实施例17:1-(2-(2-(4-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐
按照与实施例12类似的顺序,由2-(4-氯苄基)-4-甲基苯酚、2-氯乙酸乙酯和1-甲基哌嗪制备,得到1-(2-(2-(4-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,将其根据实施例13中所述的方法以盐酸盐形式沉淀,得到1-(2-(2-(4-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐,白色固体。LC-MS(ESI+):359([M+H]+)。13C NMR(101MHz,CDCl3):δ=152.9,139.8,132.6,131.6,131.3,129.8,128.8,128.7,127.3,111.4,62.8,56.4,49.7,49.0,42.9,36.0,20.5ppm。
实施例18:1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-乙基哌嗪盐酸盐
按照与实施例12类似的顺序,由2-苄基-4-甲基苯酚、2-氯乙酸乙酯和1-乙基哌嗪制备,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-乙基哌嗪,将其根据实施例13所述的方法以盐酸盐形式沉淀,得到1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-乙基哌嗪盐酸盐,为白色固体。LC-MS(ESI+):339([M+H]+)。1H NMR(400MHz,DMSO-d6):δ=11.82-12.38(m,1H),7.27-7.36(m,2H),7.15-7.26(m,3H),7.03(dd,J=8.2,1.8Hz,1H),6.96(d,J=1.7Hz,1H),6.91(d,J=8.3Hz,1H),4.39(br s,2H),3.95(s,2H),3.34-3.80(m,10H),3.17(br s,2H),2.21(s,3H),1.28ppm(t,J=7.2Hz,3H)。
实施例19:4-(2-(2-乙基-6-(2-氟苄基)-4-甲基苯氧基)乙基)吗啉
实施例19a:2-氟苯甲酸2-乙基-4-甲基苯酯
在0℃下将2-乙基-4-甲基苯酚(4.16g,30.5mmol)在DCM(30ml)中的溶液用2-氟苯甲酰氯(4.01ml,33.6mmol)处理,然后滴加三乙胺(4.26ml,30.5mmol)。将所得混合物在室温搅拌2小时。然后将混合物倒入冰冷的1M HCl水溶液(100mL)中,用MTBE(2×100mL)萃取,用盐水(50mL)洗涤,用MgSO4干燥并减压浓缩,得到2-氟苯甲酸2-乙基-4-甲基苯酯(7.9g,30.5mmol,定量),为淡黄色液体,其未经进一步纯化用于下一步。GC/MS(EI,70eV)m/z(%):258(6,[M]+),135(2),124(8),123(100),115(2),95(17),91(6),77(3),75(6),65(2)。1HNMR(400MHz,CDCl3):δ=8.14(td,J=7.5,1.8Hz,1H),7.59-7.66(m,1H),7.31(td,J=7.6,1.2Hz,1H),7.24(ddd,J=10.8,8.3,1.0Hz,1H),7.14(d,J=1.2Hz,1H),7.07-7.09(m,2H),2.62(q,J=7.6Hz,2H),2.39(s,3H),1.24ppm(t,J=7.6Hz,3H)。
实施例19b:(3-乙基-2-羟基-5-甲基苯基)(2-氟苯基)甲酮
将2-氟苯甲酸2-乙基-4-甲基苯酯(1.00g,3.87mmol)在氯苯(1ml)中的溶液用三氯化铝(1.03g,7.7mmol)一次性处理并将混合物加热至回流(油浴,在150℃)保持1小时。将所得混合物冷却至室温并倒入冰冷的1M HCl水溶液(20mL)中,用MTBE(3×20mL)萃取,用盐水(30mL)洗涤,用MgSO4干燥并减压浓缩,得到一种物质,将其通过硅胶快速柱色谱法纯化,用己烷中的EtOAc梯度洗脱,得到(3-乙基-2-羟基-5-甲基苯基)(2-氟苯基)甲酮(1.0g,3.87mmol,定量),为淡黄色液体,其未经进一步纯化用于下一步。GC/MS(EI,70eV)m/z(%):258(82,[M]+),257(36),163(37),147(67),135(29),134(83),123(100),95(64),91(45),75(24)。
实施例19c:2-乙基-6-(2-氟苄基)-4-甲基苯酚
在0℃下将(3-乙基-2-羟基-5-甲基苯基)(2-氟苯基)甲酮(1.00g,3.87mmol)在乙醇(12ml)中的溶液用硼氢化钠(0.146g,3.87mmol)处理,并使其达到室温。30分钟后,将混合物倒入饱和NH4Cl水溶液(50mL)中,用MTBE(2×100mL)萃取,用盐水(50mL)洗涤,用MgSO4干燥并减压浓缩。将所得材料溶解在DCM(10ml)中并在0℃下用三乙基硅烷(1.841ml,11.52mmol)处理,然后用TFA(0.888ml,11.52mmol)处理。将所得黄色混合物在室温下搅拌15小时,然后倒入冰冷的饱和NaHCO3水溶液(50mL)中,用MTBE(2×100mL)萃取,用盐水(50mL)洗涤,用MgSO4干燥并减压浓缩。所得粗产物通过硅胶快速柱色谱法纯化,用己烷中的EtOAc梯度洗脱,得到2-乙基-6-(2-氟苄基)-4-甲基苯酚(0.94g,3.84mmol,定量),为黄色液体。GC/MS(EI,70eV)m/z(%):244(100,[M]+),215(25),148(63),135(41),133(98),109(61),105(52),96(48),91(33),77(24)。1H NMR(400MHz,CDCl3):δ=7.03-7.28(m,4H),6.88(d,J=2.0Hz,1H),6.83(s,1H),4.63(d,J=2.2Hz,1H),3.99(s,2H),2.61(q,J=7.6Hz,2H),2.26(s,3H),1.25ppm(t,J=7.6Hz,3H)。
实施例19d:4-(2-(2-乙基-6-(2-氟苄基)-4-甲基苯氧基)乙基)吗啉
在室温下将2-乙基-6-(2-氟苄基)-4-甲基苯酚(0.939g,3.84mmol)在异丙醇(7ml)中的溶液用4-(2-氯乙基)吗啉盐酸盐(1.073g,5.77mmol)处理,然后用KOH(0.647g,11.53mmol)处理。将得到的淡黄色混合物加热回流15小时,然后冷却至室温,倒入稀的NH4Cl水溶液(100mL)中,用MTBE(2×100mL)萃取,用水(50mL)、盐水(50mL)洗涤),经硫酸镁干燥并减压浓缩。将得到的物质进行硅胶快速柱色谱法,用己烷中的EtOAc梯度洗脱,得到4-(2-(2-乙基-6-(2-氟苄基)-4-甲基苯氧基)乙基)吗啉(0.83g,2.33mmol,61%收率),为无色液体。GC/MS(EI,70eV)m/z(%):357(1,[M]+),270(5),114(21),109(10),101(6),100(100),70(3),56(7),55(4),42(5),28(4)。1H NMR(400MHz,CDCl3):δ=7.16-7.24(m,1H),7.02-7.15(m,3H),6.93(d,J=1.7Hz,1H),6.73(d,J=2.0Hz,1H),4.06(s,2H),3.88(t,J=5.7Hz,2H),3.71-3.78(m,4H),2.77(t,J=5.7Hz,2H),2.69(q,J=7.6Hz,2H),2.50-2.60(m,4H),2.26(s,3H),1.26ppm(t,J=7.6Hz,3H)。
实施例20:1-(2-(2-苄基-4-氯苯氧基)乙基)-4-甲基哌嗪盐酸盐
按照与实施例12类似的顺序,由2-苄基-4-氯苯酚、2-氯乙酸乙酯和1-甲基哌嗪制备,得到1-(2-(2-苄基-4-氯苯氧基)乙基)-4-甲基哌嗪,将其根据实施例13所述的方法以盐酸盐形式沉淀,得到1-(2-(2-苄基-4-氯苯氧基)乙基)-4-甲基哌嗪盐酸盐,为白色固体。
实施例21:1-(2-(2-苄基-4-氯苯氧基)乙基)-4-乙基哌嗪盐酸盐
按照与实施例12类似的顺序,由2-苄基-4-氯苯酚、2-氯乙酸乙酯和1-乙基哌嗪制备,得到1-(2-(2-苄基-4-氯苯氧基)乙基)-4-乙基哌嗪,将其根据实施例13所述的方法以盐酸盐形式沉淀,得到1-(2-(2-苄基-4-氯苯氧基)乙基)-4-乙基哌嗪盐酸盐,为白色固体。
实施例22:1-(2-(2-苄基苯氧基)乙基)-4-甲基哌嗪盐酸盐
按照与实施例12类似的顺序,由2-苄基苯酚、2-氯乙酸乙酯和1-甲基哌嗪制备,得到1-(2-(2-苄基苯氧基)乙基)-4-甲基哌嗪,将其根据实施例13所述的方法以盐酸盐形式沉淀,得到1-(2-(2-苄基苯氧基)乙基)-4-甲基哌嗪盐酸盐,为白色固体。
实施例23:4-(2-(2-苄基-4-甲基苯氧基)乙基)-1,2,6-三甲基哌嗪
实施例23a:2-(2-苄基-4-甲基苯氧基)乙酸乙酯
将2-苄基-4-甲基苯酚(3.00g,15.0mmol,1.0equiv.)在35ml DMF(二甲基甲酰胺)中的溶液用碳酸钾(6.22g,45.0mmol,3.0equiv.)处理,然后加入2.0ml 2-氯乙酸乙酯(2.206g,18.0mmol,1.2equiv.)。将黄色悬浮液加热至60℃保持3h。然后将反应混合物倒入冰水中并用MTBE萃取两次。有机层用水洗涤两次,用MgSO4干燥并在真空下除去挥发物。粗产物通过快速柱色谱法使用0-40%EtOAc/己烷的梯度进行纯化,得到2-(2-苄基-4-甲基苯氧基)乙酸乙酯(3.93g,88%收率)。GC/MS(EI):m/z(%):(EI,70eV):284(62,[M]+·),197(100),196(23),195(91),182(16),181(27),166(18),165(56),152(24),91(79)。
实施例23b:2-(2-苄基-4-甲基苯氧基)乙-1-醇
将2-(2-苄基-4-甲基苯氧基)乙酸乙酯(3.9g,13.72mmol,1.0当量)和32ml甲醇装入250ml 2-颈圆底烧瓶中。将混合物冷却至5℃并加入NaBH4(0.315gm,0.5equiv.,8.32mmol)并在环境温度下搅拌1小时。将反应倾倒在50ml饱和NaHCO3上。将水层用H2O稀释,并用MTBE萃取两次。将合并的有机层用MgSO4干燥,过滤,将挥发物蒸发,并将产物在高真空下干燥,得到3.59g的2-(2-苄基-4-甲基苯氧基)乙醇(89%收率)。GC/MS(EI):m/z(%):(EI,70eV):242(24,[M]+·),198(24),165(31),152(18),120(74),92(46),91(100),77(26),65(24),45(41)。
实施例23c:2-苄基-1-(2-溴乙氧基)-4-甲基苯
在250mL 2-颈圆底烧瓶中将CBr4(5.75g,17.33mmol,1.2equiv.)在0-5℃下添加到2-(2-苄基-4-甲基苯氧基)乙醇(3.5g,14.44mmol,1.0equiv.)和PPh3(4.55g,17.33mmol,1.2equiv.)在45ml CH3CN中的溶液中。将反应在环境温度下搅拌3小时。然后除去挥发物并将残余物溶解在庚烷和4:1MeOH/H2O混合物中。将有机层用MeOH/H2O4:1混合物洗涤3次,并将水层用庚烷再萃取。合并的有机层用MgSO4干燥,过滤并减压除去挥发物。然后将产物在高真空下干燥,得到4.88g的2-苄基-1-(2-溴乙氧基)-4-甲基苯(90%纯度,100%收率),将其未经进一步纯化使用。GC/MS(EI):m/z(%):(EI,70eV):306(50),304(51,[M]+·),197(100),165(48),154(36),153(34),152(41),120(88),117(46),91(65)。
实施例23d:4-(2-(2-苄基-4-甲基苯氧基)乙基)-1,2,6-三甲基哌嗪
在3℃下,向NaH(0.15g,3.28mmol,1.2equiv.)在3ml DMF中的悬浮液中加入在1mlDMF中的1,2,6-三甲基哌嗪(0.35g,2.72mmol,1.0equiv.),将溶液在环境温度下搅拌20min。在3℃下加入在2ml DMF中的2-苄基-1-(2-溴乙氧基)-4-甲基苯(1.0g,3.28mmol,1.2当量),并将反应混合物在环境温度下进一步搅拌5小时。然后将混合物冷却至3℃,用饱和NaHCO3稀释,并倒入25ml H2O中。产物用EtOAc萃取两次并用H2O洗涤。有机层用MgSO4干燥,并将挥发物蒸发。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在己烷中的混合物通过快速柱色谱法纯化,得到4-(2-(2-苄基-4-甲基苯氧基)乙基)-1,2,6-三甲基哌嗪(0.37g,32%收率),为淡黄色液体。1H NMR(500MHz,CDCl3)δ(ppm)=7.32-7.22(m,4H),7.21-7.15(m,1H),7.02-6.96(m,1H),6.93(d,J=2.1Hz,1H),6.77(d,J=8.2Hz,1H),4.07(t,J=5.8Hz,2H),3.96(s,2H),2.88-2.81(m,2H),2.72(t,J=5.8Hz,2H),2.31-2.24(m,2H),2.29(s,3H),2.26(s,3H),2.05(t,J=11.0Hz,2H),1.08(d,J=6.4Hz,6H)。13C NMR(101MHz,CDCl3)δ(ppm)=154.5,141.3,131.2,129.8,129.6,128.9,128.2,127.6,125.7,111.6,66.5,61.7,57.9,57.1,37.9,36.0,20.5,18.3。GC/MS(EI):m/z(%):(EI,70eV):352(1,[M]+·),155(66,[M]+·),142(10),141(100),126(18),98(9),91(10),84(27),57(16),56(23),42(18)。
实施例24:三氟甲磺酸2-苄基-4-甲基苯酯
在250ml 3-颈圆底烧瓶中,将2-苄基-4-甲基苯酚(3.20g,16.14mmol,1.0equiv.)和催化量的DMAP(N,N-二甲基-4-氨基吡啶,0.3g,2.421mmol,0.15equiv.)在54ml CH2Cl2中的溶液冷却至0℃。加入3.4ml(24.21mmol,1.5equiv.)Et3N,然后通过注射器滴加4.1ml三氟甲磺酸酐(6.83g,24.21mmol,1.5equiv.),得到深红色溶液。然后移除冰浴,并将反应在环境温度下搅拌2小时。然后,将反应混合物浓缩,再用CH2Cl2稀释,再蒸发挥发物(总共3次)。然后粗物质通过柱色谱法使用0-15%EtOAc/环己烷的梯度进行纯化,得到三氟甲磺酸2-苄基-4-甲基苯酯(4.83,95%纯度,86%收率)。GC/MS(EI):m/z(%):(EI,70eV):330(53,[M]+·),197(100),182(24),181(29),169(56),165(31),154(47),153(32),152(33),91(38)。
实施例25:N,2-二苄基-4-甲基苯胺
将Cs2CO3(1.97g,6.05mmol,2.0equiv.),0.29g(S)-BINAP(0.29g,0.45mmol,0.15equiv.)和Pd(OAc)2(70mg,0.303mmol,0.1equiv.)添加到三氟甲磺酸2-苄基-4-甲基苯酯(1.00g,3.03mmol,1.0equiv.),苄胺(0.97g,9.08mmol,3.0equiv.)在15ml甲苯中的溶液中。然后在环境下用氮气吹扫得到的红色悬浮液,然后在剧烈搅拌下加热至100℃。3小时后,将反应混合物冷却至环境温度。然后将混合物用EtOAc稀释并倾倒在H2O上,用12ml 1MHCl、H2O和盐水洗涤。水层用EtOAc再萃取,有机层用MgSO4干燥,过滤并蒸发挥发物。然后使用0-100%EtOAc/庚烷的梯度通过柱色谱法纯化粗物质,得到0.67g(76%收率)的N,2-二苄基-4-甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):288(10),287(41,[M]+·),197(16),196(100),194(21),181(33),180(37),165(11),91(66),65(16)。
实施例26:2-苄基-4-甲基苯胺
在250ml 3-颈圆底烧瓶中,将150mg Pd/C添加到在25mL THF(四氢呋喃)中的N,2-二苄基-4-甲基苯胺中。所得溶液用氩气吹扫3次,然后用充满H2的气球再吹扫3次。然后将反应在环境温度下、在来自新填充的气球的氢气气氛下搅拌。然后将混合物通过硅藻土过滤并用己烷洗涤。将母液的挥发物蒸发并在高真空下干燥粗产物。使用0-20%EtOAc/庚烷的梯度通过柱色谱法纯化,得到2-苄基-4-甲基苯胺(0.8g,78%收率)。GC/MS(EI):m/z(%):(EI,70eV):198(15),197(100,[M]+·),196(25),182(46),181(17),180(22),165(26),120(34),106(19),91(19)。
实施例27:N-(2-苄基-4-甲基苯基)-2-溴乙酰胺
在5℃下,将在3mL Et2O中的2-溴乙酰溴(0.20g,1.0mmol,1.0equiv.)加入到在3mL Et2O中的2-苄基-4-甲基苯胺(0.20g,1.0mmol,1.0equiv.)中,随后沉淀出白色固体。将反应在环境温度下搅拌2小时。然后,将悬浮液溶解在CH2Cl2中,用盐酸(2M)洗涤两次,再用CH2Cl2萃取。有机层用MgSO4干燥,过滤并在真空下除去挥发物。将粗品悬浮在己烷中,滤出溶剂并用己烷进一步洗涤固体。干燥灰白色固体物质得到0.25g的N-(2-苄基-4-甲基苯基)-2-溴乙酰胺(77%收率)。GC/MS(EI):m/z(%):(EI,70eV):317(38,[M]+·),224(55),196(100),194(63),181(51),180(81),160(83),146(57),142(38),91(77)。
实施例28:N-(2-苄基-4-甲基苯基)-2-吗啉代乙酰胺
在100mL 3-颈圆底烧瓶中,将N-(2-苄基-4-甲基苯基)-2-溴乙酰胺(0.35g,1.163mmol,1.0equiv.),吗啉(1.0mL,1.1013g,11.63mmol,10equiv.)和K2CO3(0.32g,2.325mmol,2.0equiv.)在20mL甲苯中的混合物回流过夜。然后将反应混合物冷却至环境温度,过滤并减压除去挥发物。然后使用10-100%EtOAc/庚烷的梯度通过快速柱色谱法纯化粗产物,得到N-(2-苄基-4-甲基苯基)-2-吗啉代乙酰胺(0.35g,93%收率),为灰白色固体。GC/MS(EI):m/z(%):(EI,70eV):324(2,[M]+·),194(3),180(3),101(7),100(100),91(3),86(3),70(3),56(10),42(5)。
实施例29:2-苄基-4-甲基-N-(2-吗啉代乙基)苯胺
将LiAlH4(0.16g,4.32mmol,4.0equiv.)和4mL THF装入250mL3-颈圆底烧瓶中并冷却至3-8℃。滴加在6ml THF中的N-(2-苄基-4-甲基苯基)-2-吗啉代乙酰胺(0.35g,1.1mmol,1.0equiv.),然后加热至60℃保持3小时。由于反应未完成,在环境温度下加入另外3当量(120mg)LiAlH4,然后再次将反应加热至60℃过夜。将反应冷却至3℃,缓慢加入0.3mL H2O,然后加入0.3mL的NaOH(NaOH),再加入0.9mL的H2O。然后移去冰浴并将混合物在环境温度下搅拌10分钟,然后加入足够的MgSO4并搅拌另外5分钟。过滤混合物并蒸发挥发物。使用40-100%EtOAc/庚烷的梯度通过快速柱色谱法纯化,得到2-苄基-4-甲基-N-(2-吗啉代乙基)苯胺(0.28g,84%收率),为灰白色固体。1H NMR(400MHz,CDCl3)δ(ppm)=7.35-7.28(m,2H),7.27-7.19(m,3H),7.07-7.00(m,1H),6.94(d,J=2.0Hz,1H),6.59(d,J=8.1Hz,1H),4.17(br s,1H),3.92(s,2H),3.55(t,J=4.4Hz,4H),3.11(t,J=5.6Hz,2H),2.57(dd,J=5.3,6.5Hz,2H),2.35(t,J=4.4Hz,4H),2.29(s,3H)。13C NMR(101MHz,CDCl3)δ(ppm)=144.2,139.8,131.6,128.6,128.4,128.1,126.3,126.2,124.8,110.9,66.9,57.0,53.2,40.2,38.0,20.4。GC/MS(EI):m/z(%):(EI,70eV):310(6,[M]+·),211(6),210(33),132(9),117(7),105(4),101(18),100(100),91(8),56(10)。
实施例30:2-苄基-N,4-二甲基-N-(2-吗啉代乙基)苯胺
在环境温度下将低聚甲醛(0.275g,8.7mmol,10equiv.)加入到在6ml AcOH(乙酸)中的2-苄基-4-甲基-N-(2-吗啉代乙基)苯胺(0.27g,0.87mmol,1.0equiv.)中并将混合物在环境温度下搅拌1小时。分批加入氰基硼氢化钠(0.26g,4.17mmol,4.8equiv.)并将反应搅拌过夜。将反应倒入40ml冰冷的NaOH(2M)中并用DCM萃取两次,用40ml pH7磷酸盐缓冲液洗涤,用MgSO4干燥并蒸发挥发物。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在己烷中的混合物通过快速柱色谱法纯化,得到2-苄基-N,4-二甲基-N-(2-吗啉代乙基)苯胺(0.22g,78%收率),为淡黄色液体。1H NMR(400MHz,CDCl3)δ(ppm)=7.22-7.29(m,2H),7.13-7.20(m,3H),7.08(d,J=8.1Hz,1H),7.00(dd,J=8.2,1.8Hz,1H),6.91(d,J=2.0Hz,1H),4.05(s,2H),3.64(m,4H),2.93-3.04(m,2H),2.61(s,3H),2.37-2.41(m,2H),2.33-2.36(m,4H),2.24(s,3H)。13C NMR(101MHz,CDCl3)δ(ppm)=149.6,141.9,136.8,133.5,131.6,129.0,128.2,127.7,125.6,121.3,66.9,56.9,54.4,54.0,43.8,36.6,20.9。GC/MS(EI):m/z(%):(EI,70eV):324(2,[M]+·),225(18),224(100),208(6),165(8),132(12),131(4),117(4),100(24),91(29),56(7)。
实施例31:2-苄基-4-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺
根据实施例29制备:用N-甲基哌嗪代替吗啉。在3-8℃下,将在20ml THF中的N-(2-苄基-4-甲基苯基)-2-(4-甲基哌嗪-1-基)乙酰胺(0.88g,2.61mmol,1.0equiv.)加入到在25ml THF中的LiAlH4(0.44g,11.47mmol,4.4equiv.)中。将反应混合物在环境温度下搅拌2小时,并在60℃下进一步搅拌7小时。然后将反应混合物用冰浴冷却并在5℃下缓慢加入0.5ml H2O,然后加入0.5ml 3M NaOH,然后再次向混合物中加入1.5ml H2O。将混合物在环境温度下搅拌10分钟,然后加入MgSO4并进一步搅拌5分钟。过滤后,减压除去挥发物。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在己烷中的混合物通过快速柱色谱法纯化,得到2-苄基-4-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺(0.7g,87%纯度,72%收率)。1HNMR(400MHz,CDCl3)δ(ppm)=7.32-7.27(m,2H),7.24-7.18(m,3H),7.01(dd,J=1.7,8.1Hz,1H),6.90(d,J=2.0Hz,1H),6.61-6.54(m,1H),4.20(br s,1H),3.92-3.85(m,2H),3.09(t,J=5.9Hz,2H),2.56(t,J=5.9Hz,2H),2.52-2.30(m,8H),2.27(s,3H),2.27(s,3H)。13C NMR(101MHz,CDCl3)δ(ppm)=144.3,139.8,131.4,128.6,128.5,128.1,126.2,126.0,124.9,110.9,56.5,55.0,52.7,46.0,40.6,38.0,20.4。GC/MS(EI):m/z(%):(EI,70eV):323(3,[M]+·),223(14),210(8),132(6),117(5),114(16),113(100),91(8),70(37),43(7),42(10)。
实施例32:2-苄基-N,4-二甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺
根据实施例30制备,用N-甲基哌嗪代替吗啉。向2-苄基-4-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺(0.17g,0.53mmol,1.0equiv.)在4mL AcOH中的溶液中加入低聚甲醛(0.17g,5.26mmol,10.0equiv.)并将混合物在环境温度下搅拌1小时。然后分批加入NaBH3CN(0.16g,2.52mmol,4.8equiv.)并将反应在环境温度下搅拌过夜。然后将反应物倒入40mL冰冷的2M NaOH(pH 14)上并用CH2Cl2萃取两次,然后将有机层用30mL的pH 7磷酸盐缓冲液(K2HPO4缓冲液/KH2PO4缓冲液2:1)洗涤,用MgSO4干燥,过滤并减压除去挥发物。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到2-苄基-N,4-二甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺(0.14g,79%收率),为黄色液体。1H NMR(400MHz,CDCl3)δ(ppm)=7.24-7.31(m,2H),7.16-7.23(m,3H),7.10(d,J=8.1Hz,1H),7.02(dd,J=8.1,2.0Hz,1H),6.93(d,J=2.0Hz,1H),4.08(s,2H),2.97-3.04(m,2H),2.63(s,3H),2.40-2.45(m,2H),2.33-2.51(br m,8H),2.27-2.29(m,3H),2.26-2.27(m,3H)。13C NMR(101MHz,CDCl3)δ(ppm)=149.7,141.9,136.8,133.4,131.5,129.0,128.2,127.6,125.6,121.3,56.5,55.1,54.7,53.4,46.0,43.8,36.6,20.9。GC/MS(EI):m/z(%):(EI,70eV):337(1,[M]+·),237(23),225(17),224(92),165(10),132(14),113(100),91(30),70(45),43(11),42(15)。
实施例33:N-(2,6-二氟苄基)-4-甲基苯胺
在100mL 3-颈圆底烧瓶中,将对甲基苯胺(8.6g,80mmol,4.0equiv.)、NaHCO3(2.11g,25mmol,1.25equiv.)和2mL H2O加热至95℃。在95℃在45分钟内分批加入2,6-二氟苄基氯(3.26g,20mmol,1.0equiv.)。然后将棕色混合物在95℃下搅拌2小时,并随后冷却至50℃。将热混合物过滤并用EtOAc和盐水洗涤。有机层用MgSO4干燥,过滤并蒸发挥发物,并在高真空下进一步干燥。使用0-10%EtOAc/庚烷的梯度通过快速柱色谱法纯化,得到N-(2,6-二氟苄基)-4-甲基苯胺(4.32g,92%收率),为黄色液体。GC/MS(EI):m/z(%):(EI,70eV):233(48,[M]+·),232(21),127(100),120(17),107(9),106(31),101(10),91(10),79(13),77(24)。
实施例34:2-(2,6-二氟苄基)-4-甲基苯胺
在15mL Ace压力管中放置N-(2,6-二氟苄基)-4-甲基苯胺(1.0g,4.29mmol,1.0equiv.)和1.2mL对甲基苯胺。将混合物加热至190℃,然后在190℃下加入AlCl3(0.17g,1.29mmol,0.3当量),此时溶液变为绿黑色。将反应加热至200℃过夜,然后将所得深蓝色混合物冷却至环境温度。将混合物倒入过量的NaOH(2M)中并用EtOAc萃取两次,然后用盐水洗涤。合并的有机层用MgSO4干燥,过滤并蒸发挥发物。使用0-10%EtOAc/庚烷的梯度通过快速柱色谱法纯化,得到2-(2,6-二氟苄基)-4-甲基苯胺(0.31g,20%收率),为红色固体。GC/MS(EI):m/z(%):(EI,70eV):234(15),233(100,[M]+·),232(15),218(12),212(39),198(31),127(27),120(25),106(47),77(18)。
实施例35:2-溴-N-(2-(2,6-二氟苄基)-4-甲基苯基)乙酰胺
根据实施例27制备,用2-(2,6-二氟苄基)-4-甲基苯胺代替2-苄基-4-甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):355(33),353(30,[M]+·),274(24),260(50),212(100),211(25),146(46),127(55),93(21),42(30)。
实施例36:N-(2-(2,6-二氟苄基)-4-甲基苯基)-2-吗啉代乙酰胺
根据实施例28制备,用2-溴-N-(2-(2,6-二氟苄基)-4-甲基苯基)乙酰胺代替N-(2-苄基-4-甲基苯基)-2-溴乙酰胺。GC/MS(EI):m/z(%):(EI,70eV):360(2,[M]+·),212(4),127(4),101(6),100(100),86(3),70(3),56(6),43(2),42(6),28(3)。
实施例37:2-(2,6-二氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺
根据实施例29制备,用N-(2-(2,6-二氟苄基)-4-甲基苯基)-2-吗啉代乙酰胺(0.72g,2.0mmol,1.0equiv.)代替N-(2-苄基-4-甲基苯基)-2-吗啉代乙酰胺,得到0.22g(32%收率)的2-(2,6-二氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺。1H NMR(400MHz,CDCl3)δ(ppm)=7.21(tt,J=6.4,8.4Hz,1H),6.96(dd,J=1.5,8.5Hz,1H),6.90(t,J=7.9Hz,2H),6.80(s,1H),6.57(d,J=8.3Hz,1H),4.53(br s,1H),3.85(s,2H),3.77-3.71(m,4H),3.19(t,J=5.9Hz,2H),2.74-2.66(m,2H),2.56-2.46(m,4H),2.21(s,3H)。13C NMR(101MHz,CDCl3)δ(ppm)=161.7,143.8,141.1,130.0,128.0,126.2,122.9,115.4,111.3,110.9,67.1,57.1,53.4,40.6,23.8,20.5。GC/MS(EI):m/z(%):(EI,70eV):346(5,[M]+·),247(5),246(30),245(4),132(6),127(9),117(6),101(19),100(100),56(5)。
实施例38:2-(2,6-二氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺
根据实施例30制备,用2-(2,6-二氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺(0.21g,0.61mmol,1.0equiv.)代替苄基-4-甲基-N-(2-吗啉代乙基)苯胺,得到0.184g(84%收率)的2-(2,6-二氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺。1H NMR(400MHz,CDCl3)δ(ppm)=7.24-7.15(m,1H),7.09(d,J=8.1Hz,1H),7.00(dd,J=1.7,8.1Hz,1H),6.94-6.84(m,2H),6.71(s,1H),4.12(s,2H),3.76-3.66(m,4H),3.14-3.04(m,2H),2.67(s,3H),2.44(s,6H),2.21(s,3H)。13C NMR(101MHz,CDCl3)δ(ppm)=161.9,149.1,135.2,133.7,129.5,127.7,127.6,121.3,117.0,111.1,66.9,56.9,54.0,44.2,23.2,21.0。GC/MS(EI):m/z(%):(EI,70eV):360(1,[M]+·),261(18),260(100),244(4),201(4),133(4),132(18),128(3),127(43),117(4),100(19)。
实施例39:N-(2,6-二氟苄基)-2,4-二甲基苯胺
根据实施例33制备,用2,4-二甲基苯胺代替对甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):MS(EI,70eV):248(6),247(35,[M]+·),246(7),134(7),127(35),121(9),120(100),118(5),91(12),77(14)。
实施例40:2-(2,6-二氟苄基)-4,6-二甲基苯胺
根据实施例34制备,用N-(2,6-二氟苄基)-2,4-二甲基苯胺代替N-(2,6-二氟苄基)-4-甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):248(16),247(100,[M]+·),246(13),232(20),226(29),212(33),134(20),127(15),120(63),91(14)。
实施例41:2-溴-N-(2-(2,6-二氟苄基)-4,6-二甲基苯基)乙酰胺
根据实施例27制备,用2-(2,6-二氟苄基)-4,6-二甲基苯胺代替2-苄基-4-甲基苯胺。1H NMR(400MHz,CDCl3)δ(ppm)=7.88-7.76(m,1H),7.19(tt,J=6.6,8.3Hz,1H),0.00(d,J=12.7Hz,2H),0.00(t,J=7.8Hz,2H),4.11(s,2H),3.93(s,2H),3.87(s,1H),2.26(s,3H),2.21(s,3H)。
实施例42:N-(2-(2,6-二氟苄基)-4,6-二甲基苯基)-2-吗啉代乙酰胺根据实施例28制备,用2-溴-N-(2-(2,6-二氟苄基)-4,6-二甲基苯基)乙酰胺代替N-(2-苄基-4-甲基苯基)-2-溴乙酰胺。1H NMR(400MHz,CDCl3)δ(ppm)=8.70(s,1H),7.18(tt,J=8.3,6.6Hz,1H),6.93(s,1H),6.84-6.91(m,3H),3.91(s,2H),3.74-3.79(m,4H),3.20-3.27(m,2H),2.68-2.74(m,4H),2.23(s,3H),2.18(s,3H)13C NMR(101MHz,CDCl3)δ(ppm)=168.9,161.4(2),137.3,135.7,135.3,130.4,130.0,128.3,128.0(2),111.3(2),67.1(2),62.1,54.2(2),24.5,21.0,18.8.
实施例43:2-(2,6-二氟苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺
根据实施例29制备,用N-(2-(2,6-二氟苄基)-4,6-二甲基苯基)-2-吗啉代乙酰胺(0.34g,0.91mmol,1.0equiv.)代替苄基-4-甲基-N-(2-吗啉代乙基)苯胺,得到0.143g(43%收率)的2-(2,6-二氟苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺。GC/MS(EI):m/z(%):(EI,70eV):360(6,[M]+·),261(9),260(44),259(16),131(6),127(11),101(14),100(100),56(8),42(7)。
实施例44:2-(2,6-二氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺
根据实施例30制备,用2-(2,6-二氟苄基)-4,6-二甲基苯胺(0.14g,0.39mmol,1.0equiv.)代替2-苄基-4-甲基苯胺,得到0.104g(70%收率)的2-(2,6-二氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺。1H NMR(400MHz,CDCl3)δ(ppm)=7.13-7.26(m,1H),6.91(t,J=7.8Hz,2H),6.83(d,J=1.0Hz,1H),6.53(s,1H),4.04-4.18(m,2H),3.73(t,J=4.7Hz,4H),2.81(s,3H),2.37-2.61(m,8H),2.30(s,3 H),2.18 (s,3 H)。13C NMR (101MHz,CDCl3) δ (ppm)=161.7 (2),146.1,137.1,134.9,134.8,130.5,127.6,127.0,117.3,111.1(2),66.8(2),58.0,53.9(2),53.0,40.8,24.3,20.9,19.2.
GC/MS(EI):m/z(%):(EI,70eV):374(1,[M]+·),275(20),274(100),201(4),146(14),131(5),127(14),100(35),56(7),42(7),28(5)。
实施例45:N-(2-氟苄基)-4-甲基苯胺
根据实施例33制备,用2-氟苄基氯代替2,6-二氟苄基氯。GC/MS(EI):m/z(%):(EI,70eV):215(44,[M]+·),214(19),120(19),110(8),109(100),106(16),91(11),83(14),79(8),77(16)。
实施例46:2-(2-氟苄基)-4-甲基苯胺
根据实施例34制备,用N-(2-氟苄基)-4-甲基苯胺代替N-(2,6-二氟苄基)-4-甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):216(15),215(100,[M]+·),200(17),194(52),183(16),180(29),120(30),109(18),106(30),77(16)。
实施例47:2-溴-N-(2-(2-氟苄基)-4-甲基苯基)乙酰胺
根据实施例27制备,用2-(2-氟苄基)-4-甲基苯胺代替2-苄基-4-甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):337(28),335(28,[M]+·),242(50),198(29),194(100),146(43),123(29),121(32),109(52),42(27)。
实施例48:N-(2-(2-氟苄基)-4-甲基苯基)-2-吗啉代乙酰胺
根据实施例28制备,用2-溴-N-(2-(2-氟苄基)-4-甲基苯基)乙酰胺代替N-(2-苄基-4-甲基苯基)-2-溴乙酰胺。GC/MS(EI):m/z(%):(EI,70eV):342(3,[M]+·),194(4),146(3),109(3),101(6),100(100),70(2),56(6),42(5),28(3)。
实施例49:2-(2-氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺
根据实施例29制备,用N-(2-(2-氟苄基)-4-甲基苯基)-2-吗啉代乙酰胺(0.38g,1.11mmool,0.1equiv.)代替苄基-4-甲基-N-(2-吗啉代乙基)苯胺,得到0.092g(25%收率)的2-(2-氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺。GC/MS(EI):m/z(%):(EI,70eV):328(5,[M]+·),229(5),228(28),132(6),117(6),109(8),105(4),101(18),100(100),56(7)。
实施例50:2-(2-氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺
根据实施例30制备,用2-(2-氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺(0.37g,0.013mmol,1.0equiv.)代替苄基-4-甲基-N-(2-吗啉代乙基)苯胺,得到0.38g(98%收率)的2-(2-氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺。1H NMR(400MHz,CDCl3)δ(ppm)=7.22-7.14(m,1H),7.12-7.09(m,1H),7.08-7.00(m,4H),6.92-6.87(m,1H),4.09(s,2H),3.70-3.64(m,4H),3.04-2.98(m,2H),2.63(s,3H),2.44-2.35(m,6H),2.26(s,3H)13C NMR(101MHz,CDCl3)δ(ppm)=161.2,149.6,135.7,133.6,131.2,131.1,128.7,127.9,127.4,123.8,121.4,115.1,66.9,56.9,54.4,54.0,43.8,29.5,20.9
GC/MS(EI):m/z(%):(EI,70eV):342(2,[M]+·),243(19),242(100),226(5),183(8),132(16),131(4),117(4),109(34),100(25),56(4)。
实施例51:N-(2-氟苄基)-2,4-二甲基苯胺
根据实施例33制备,用2-氟苄基氯代替2,6-二氟苄基氯并用2,4-二甲基苯胺代替对甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):229(54,[M]+·),228(12),134(14),121(10),120(100),118(10),109(96),91(19),83(17),77(20)。
实施例52:2-(2-氟苄基)-4,6-二甲基苯胺
根据实施例34制备,用N-(2-氟苄基)-2,4-二甲基苯胺代替N-(2,6-二氟苄基)-4-甲基苯胺并用2,4-二甲基苯胺代替对甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):230(16),229(100,[M]+·),214(18),208(32),194(32),134(24),120(34),109(24),91(17),77(11)。
实施例53:2-溴-N-(2-(2-氟苄基)-4,6-二甲基苯基)乙酰胺
根据实施例27制备,用2-(2-氟苄基)-4,6-二甲基苯胺代替2-苄基-4-甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):351(38),349(36,[M]+·),256(86),212(31),208(100),160(77),123(38),121(39),109(63),42(32)。
实施例54:N-(2-(2-氟苄基)-4,6-二甲基苯基)-2-吗啉代乙酰胺
根据实施例28制备,用2-溴-N-(2-(2-氟苄基)-4,6-二甲基苯基)乙酰胺代替N-(2-苄基-4-甲基苯基)-2-溴乙酰胺。GC/MS(EI):m/z(%):(EI,70eV):356(3,[M]+·),208(3),109(3),101(6),100(100),86(2),70(3),56(6),42(4),28(2)。
实施例55:2-(2-氟苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺
根据实施例29制备,用N-(2-(2-氟苄基)-4,6-二甲基苯基)-2-吗啉代乙酰胺(1.0g,2.8mmol,1.0equiv.)代替苄基-4-甲基-N-(2-吗啉代乙基)苯胺,得到0.47g(47%收率)的2-(2-氟苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺。GC/MS(EI):m/z(%):(EI,70eV):342(6,[M]+·),243(10),242(58),241(21),183(6),146(7),131(11),109(16),101(14),100(100),56(8)。
实施例56:2-(2-氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺
根据实施例30制备,用2-(2-氟苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺(0.46g,1.34mmol,1.0equiv.)代替苄基-4-甲基-N-(2-吗啉代乙基)苯胺,得到0.38g(79%收率)的2-(2-氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺。1H NMR(400MHz,CDCl3)δ(ppm)=7.21-7.14(m,1H),7.04(d,J=9.0Hz,1H),7.03-6.99(m,2H),6.87(d,J=2.0Hz,1H),6.74(d,J=1.5Hz,1H),4.07(s,2H),3.68(t,J=4.6Hz,4H),3.22-3.02(m,2H),2.69(s,3H),2.50-2.40(m,2H),2.41-2.34(m,4H),2.29(s,4H),2.23(s,3H)。13C NMR(101MHz,CDCl3)δ(ppm)=161.1,146.9,138.9,137.4,134.9,130.9,130.7,129.1,128.9,127.3,123.8,115.0,67.0,58.0,54.0,53.3,40.9,30.7,20.8,19.2。GC/MS(EI):m/z(%):(EI,70eV):356(1,[M]+·),257(19),256(100),240(4),183(8),146(14),131(5),109(15),100(32),56(6),42(4)。
实施例57:N-(2-溴苄基)-2,4-二甲基苯胺
根据实施例33制备,用2-溴苄基氯代替2,6-二氟苄基氯并用2,4-二甲基苯胺代替对甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):291(28),289(28,[M]+·),171(36),169(38),134(26),120(100),91(27),90(22),89(19),77(23)。
实施例58:2-(2-溴苄基)-4,6-二甲基苯胺
根据实施例34制备,用N-(2-溴苄基)-2,4-二甲基苯胺代替N-(2,6-二氟苄基)-4-甲基苯胺并用2,4-二甲基苯胺代替对甲基苯胺。GC/MS(EI):m/z(%):(EI,70eV):291(39),289(38,[M]+·),210(91),208(75),195(47),194(100),180(32),97(21),96(34),91(21)。
实施例59:2-(2-溴苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺
将2-(2-溴苄基)-4,6-二甲基苯胺(2.2g,7.58mmol,1.0equiv.)、4-(2-溴乙基)吗啉(1.471,7.58mmol,1.0equiv.)和四丁基碘化铵(0.56g,1.516mmol,0.2equiv.)在40mLDMF(二甲基甲酰胺)中合并。添加3.2mL的N-乙基二异丙胺(2.45g,18.95mmol,2.5当量)并将反应加热过夜。然后将反应混合物冷却至环境温度,倾倒在饱和NaHCO3水溶液上,并将产物用EtOAc萃取两次。将合并的有机层用水洗涤3次,用MgSO4干燥,过滤并蒸发挥发物。通过快速柱色谱法纯化,使用梯度为0-10%的EtOAc,得到0.55g(17%收率)的2-(2-溴苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺。GC/MS(EI):m/z(%):(EI,70eV):402(4,[M]+·),302(15),222(17),100(100)。
实施例60:2-(2-溴苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺
根据实施例30制备,用2-(2-溴苄基)-4,6-二甲基-N-(2-吗啉代乙基)苯胺(0.54g,1.34mmol,1.0equiv.)代替苄基-4-甲基-N-(2-吗啉代乙基)苯胺,得到0.42g(69%收率)的2-(2-溴苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺。GC/MS(EI):m/z(%):(EI,70eV):416(1,[M]+·),319(17),318(94),317(19),316(100),207(14),179(18),178(17),146(20),100(93),56(15)。
实施例61:2-(3,5-二甲基-2-(甲基(2-吗啉代乙基)氨基)苄基)苯甲腈
在25mL 3-颈圆底烧瓶中,将2-(2-溴苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺(50mg,0.12mmol,1.0equiv.)和氰化铜(I)(13mg,0.14mmol,1.2当量)悬浮在4mL DMF(二甲基甲酰胺)中,并将悬浮液加热至回流过夜。冷却至室温后,混合物用饱和NH4Cl水溶液淬灭并用EtOAc萃取两次。有机层用MgSO4干燥,过滤并减压除去挥发物。使用梯度为0-10%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物进行快速柱色谱法纯化,得到16mg(37%收率)的2-(3,5-二甲基-2-(甲基(2-吗啉代乙基)氨基)苄基)苯甲腈,为橙色粘稠液体。1HNMR(400MHz,CDCl3)δ(ppm)=7.65(dd,J=1.1,7.7Hz,1H),7.43(dt,J=1.5,7.7Hz,1H),7.27(dt,J=1.0,7.6Hz,1H),7.08(d,J=7.8Hz,1H),6.89(d,J=1.7Hz,1H),6.74(d,J=1.5Hz,1H),4.26(d,J=7.6Hz,2H),3.73-3.58(m,4H),3.21-2.92(m,2H),2.63(s,3H),2.33(br s,4H),2.28(s,3H),2.25(s,3H),2.19-2.03(m,2H)。13C NMR(101MHz,CDCl3)δ(ppm)=146.8,146.5,138.3,137.6,135.1,132.6,132.5,131.4,129.7,129.2,126.2,118.4,112.7,66.9,57.9,54.0,53.1,41.0,36.7,20.8,19.3。GC/MS(EI):m/z(%):(EI,70eV):363(0,[M]+·),264(20),263(100),247(4),190(5),146(12),131(5),116(4),100(38),56(6),42(6)。
实施例62:1-烯丙基-2-苄基-4-甲基苯
将Pd(PPh3)4(0.5g,0.30mmol,0.1equiv.)、LiCl(0.22g,1.50mmol,1.5equiv.)和1.2mL烯丙基三丁基锡烷(12g,3.60mmol,1.2equiv.)添加到在30mL DMF中的三氟甲磺酸2-苄基-4-甲基苯酯中,并将所得黄色悬浮液在环境温度下用氮气吹扫。然后将反应混合物加热至90℃过夜。混合物用H2O和EtOAc稀释并经硅藻土过滤,并进一步用庚烷洗涤。将有机层分离并用H2O洗涤,并将水层用庚烷再萃取。将有机层用MgSO4干燥,过滤并减压除去挥发物。使用0-10%EtOAc/庚烷的梯度通过快速柱色谱法纯化,以定量收率得到1-烯丙基-2-苄基-4-甲基苯,为淡黄色液体。GC/MS(EI):m/z(%):(EI,70eV):222(57,[M]+·),193(72),179(44),178(77),165(47),131(55),129(100),128(47),115(47),91(59)。
实施例63:2-(2-苄基-4-甲基苄基)环氧乙烷
在3℃下将3-氯过苯甲酸(1.21g,5.4mmol,1.2equiv.)添加到在22mL CH2Cl2中的1-烯丙基-2-苄基-4-甲基苯中,然后将反应物在环境温度下搅拌2.5小时,然后将混合物用H2O和EtOAc稀释并用硅藻土过滤,然后用庚烷洗涤。将有机层分离并将水层用庚烷再萃取。将有机层用MgSO4干燥,过滤并减压除去挥发物。使用0-10%EtOAc/庚烷的梯度通过快速柱色谱法纯化,以定量收率得到2-(2-苄基-4-甲基苄基)环氧乙烷,为淡黄色液体。GC/MS(EI):m/z(%):(EI,70eV):238(1,[M]+·),220(76,[M]+·),205(75),193(55),192(38),179(91),178(100),165(77),129(54),115(70),91(71)。
实施例64:1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-醇
将2-(2-苄基-4-甲基苄基)环氧乙烷(0.46g,1.93mmol,1.0equiv.)溶解在10mLEtOH中并加入1-甲基哌嗪(0.21g,2.085mmol,1.1equiv.)。将溶液在70℃下(油浴)搅拌20小时。然后将反应冷却至环境温度并除去挥发物。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-醇(0.45g,69%收率),为黄色液体。1H NMR(400MHz,CDCl3)δ(ppm)=7.12-7.18(m,2H),7.03-7.09(m,2H),6.98-7.03(m,2H),6.91(dd,J=7.7,1.3Hz,1H),6.85-6.88(m,1H),3.95(d,J=26.7Hz,1H),3.88(d,J=26.4Hz,1H),3.54-3.65(m,1H),2.66(dd,J=14.2,7.3Hz,1H),2.51(dd,J=14.2,5.4Hz,1H),2.39-2.47(m,2H),2.21-2.38(m,5H),2.20(s,3H),2.15(s,3H),2.12(d,J=6.1Hz,1H),2.10(d,J=1.2Hz,1H)。13CNMR(100MHz,CDCl3)δ(ppm)=141.1,138.6,136.0,133.8,131.6,130.6,128.7,128.4,127.3,125.9,66.8,63.5,55.2,46.0,39.1,37.7,21.0。GC/MS(EI):m/z(%):(EI,70eV):338(0,[M]+·),178(5),165(6),115(5),114(48),113(100),91(8),70(30),56(5),43(7),42(8)。
实施例65:1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-酮
在25mL 3-颈圆底烧瓶中装入在3mL CH2Cl2中的1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-醇(0.15g,044mmol,1.0equiv.)、4-甲基吗啉N-氧化物(80mg,0.665mmol,1.5equiv.)和0.28g的分子筛。向该溶液中加入四丙基过钌酸铵(8mg,0.022mmol,0.05当量)。将所得棕色溶液在环境温度下搅拌40分钟。然后使用短硅胶垫过滤反应混合物并用EtOAc/EtOH/NH4OH 90:9:1的混合物洗涤。将滤液减压浓缩并在高真空下干燥。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到61mg的混合物,其含有1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-醇和起始材料的1:1混合物,为黄色液体。使用制备型RP-HPLC(反相高压液相色谱法)在Kinete×C18柱(5μm粒径,4.6x150mm,配备预柱)上分离3mg标题化合物,洗脱系统由A(CH3CN:H2O,5:95+0.1%三氟乙酸)和B(ACN:H2O,95:5+0.085%三氟乙酸)组成,使用从10%到100%B的梯度,10%B/min。1H NMR(500MHz,DMSO-d6)δ(ppm)=7.27(t,J=7.2Hz,2H),7.19(t,J=7.6Hz,1H),7.10(d,J=7.3Hz,2H),7.04(d,J=7.9Hz,1H),7.01(d,J=7.6Hz,1H),6.96(s,1H),3.86(s,2H),3.73(s,2H),3.30-3.41(m,4H),2.96-3.07(m,2H),2.82-2.91(m,2H),2.77(s,3H),2.39-2.48(m,2H),2.25(s,3H)。
13C NMR(151MHz,DMSO-d6)δppm=205.8,140.8,139.6,136.3,131.6,131.3,130.5,129.1(2),128.9(2),127.5,126.4,65.1,53.0(2),49.6(2),44.3 42.6,38.7,21.1。GC/MS(EI):m/z(%):MS(EI,70eV):336(2,[M]+·),179(3),178(4),165(4),114(7),113(100),98(4),70(27),56(3),43(2),42(5)。
实施例66:(E)-3-(2-苄基-4-甲基苯基)丙烯酸
将在4mL吡啶中的2-苄基-4-甲基苯甲醛(1.0g,3.8mmol,1.0equiv.)、丙二酸(1.0g,9.5mmol,2.5equiv.)和80mL哌啶加热至105℃,直到不再观察到有CO2形成(4小时)。然后在连续搅拌下将反应物倒入40ml冰冷的2M HCl水溶液中。过滤所得悬浮液(pH 1),并将固体(E)-3-(2-苄基-4-甲基苯基)丙烯酸用25ml HCl(2M)洗涤。然后将固体转移到圆底烧瓶中并在环境温度和0.10mbar下干燥过夜。产物(1.2g,62%纯度,78%收率)未经进一步纯化用于下一步。GC/MS(EI):m/z(%):(EI,70eV):252(9,[M]+·),206(29),193(24),192(100),191(37),178(32),161(54),129(22),128(21),115(34),91(22)。
实施例67:(E)-3-(2-苄基-4-甲基苯基)-1-(哌啶-1-基)丙-2-烯-1-酮
将(E)-3-(2-苄基-4-甲基苯基)丙烯酸(0.38g,1.5mmol,1.2equiv.)溶解在0.35mL SOCl2(0.59g,5.0mmol,4.0equiv.)中并在惰性气氛下在室温下搅拌1小时。将反应混合物真空浓缩,残余物用5mL CH2Cl2稀释,并在5℃下加入在10mL CH2Cl2中的1-甲基哌嗪(0.13g,1.25mmol,1.0equiv.)和0.4mL Et3N(2.5mmol,2.0equiv.)。将反应在环境温度下搅拌5分钟,然后将棕色溶液加热回流2小时。冷却至环境温度后,将反应倒入饱和NaHCO3水溶液中并用CH2Cl2萃取两次。合并的有机层用MgSO4干燥,过滤并减压除去挥发物。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到(E)-3-(2-苄基-4-甲基苯基)-1-(4-甲基哌嗪-1-基)丙-2-烯-1-酮(0.32g,38%收率),为粘性黄色液体。
LC/MS(ESI):335(M+H)+,357(M+Na)+,669(2M+H)+。
实施例68:(E)-1-(3-(2-苄基-4-甲基苯基)烯丙基)-4-甲基哌嗪和1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪
将在3mL THF中的(E)-3-(2-苄基-4-甲基苯基)-1-(4-甲基哌嗪-1-基)丙-2-烯-1-酮(0.3g,0.9mmol,1.0equiv.)缓慢加入到LiAlH4(37mg,1.0mmol,1.1equiv.)在5mL THF中的悬浮液中。将反应在环境温度下搅拌45分钟。此后,将反应混合物冷却至3℃,并缓慢加入0.1mL H2O,然后加入0.1mL NaOH(3M),并再加入0.3mL H2O。将白色悬浮液在环境温度下搅拌20分钟,然后加入MgSO4并继续搅拌另外5分钟。然后过滤混合物并蒸发挥发物。使用梯度为20-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到96mg的(E)-1-(3-(2-苄基-4-甲基苯基)烯丙基)-4-甲基哌嗪和1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪的4:1混合物。主要的:GC/MS(EI):m/z(%):(EI,70eV):320(64,[M]+·),179(25),158(29),128(28),99(46),91(100),70(27),56(34),43(23),42(25)次要的:GC/MS(EI):m/z(%):(EI,70eV):322(17,[M]+·),178(10),165(10),127(10),113(100),100(13),91(12),70(25),43(19),42(13)。
实施例69:1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪
通过制备型HPLC分离上述混合物,得到纯的1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪样品。1H NMR(400MHz,氯仿-d)δppm7.38(d,J=7.8Hz,1H),7.24(t,J=7.6Hz,2H),7.06-7.19(m,3H),6.99-7.05(m,1H),6.95(s,1H),6.67(d,J=15.6Hz,1H),6.04(dt,J=15.6,6.8Hz,1H),4.02(s,2H),3.06(dd,J=6.8,1.2Hz,2H),2.52-2.57(m,2H),2.30(s,3H),2.28(s,3H)。13C NMR(101MHz,氯仿-d)δppm 140.8,137.4,137.3,133.5,131.3,130.8,128.6(2),128.37(2),127.4,125.8,61.3,55.2(2),53.1(2),46.1,39.2,21.2。
实施例70:1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪
在环境温度下,将在10ml EtOH中的76mg的(E)-1-(3-(2-苄基-4-甲基苯基)烯丙基)-4-甲基哌嗪和1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪的4:1混合物用40mg Pd/C氢化6h。然后将混合物通过硅藻土过滤并用乙醇彻底洗涤硅藻土垫。滤液在50℃/20mbar下蒸发。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪(36mg,43%收率),为无色液体。1H NMR(400MHz,CDCl3)δ(ppm)=7.25(t,J=7.3Hz,2H),7.16(t,J=7.3Hz,1H),7.11(d,J=7.8Hz,2H),7.06(d,J=7.8Hz,1H),6.99(d,J=7.9Hz,1H),6.92(s,1H),3.99(s,2H),2.54(t,J=8.0Hz,2H),2.18-2.52(m,10H),2.28(s,3H),2.27(s,3H),1.65(br quin,J=7.6Hz,2H)。13C NMR(101MHz,CDCl3)δ(ppm)=141.12,138.09,137.54,135.42,131.28,129.31,128.67(2),128.37(2),127.30,125.88,58.23,55.21(2),53.20(2),46.11,38.87,30.22,28.27,21.01。GC/MS(EI):m/z(%):MS(EI,70eV):322(18,[M]+·),178(10),127(11),113(100),100(13),91(12),70(28),58(10),43(20),42(14)。
实施例71:(E)-2-苄基-1-(2-甲氧基乙烯基)-4-甲基苯
在5-15℃下将5.7mL(5.7mmol,1.2equiv.)的叔丁醇钾(1M的THF溶液)加入到在15mL THF中的甲氧基甲基三苯基氯化鏻(1.96g,5.71mmol,1.2equiv.)中。将所得亮红色混合物在环境温度下搅拌15分钟。然后加入在10mL THF中的2-苄基-4-甲基苯甲醛(1.0g,4.76mmol,1.0equiv.),将反应在环境温度下搅拌45分钟。然后将反应混合物用庚烷稀释并用4:1MeOH/H2O混合物洗涤3次。用庚烷再萃取水层。合并的有机层用硫酸镁干燥,过滤并蒸发挥发物,得到1.0g的(E)-2-苄基-1-(2-甲氧基乙烯基)-4-甲基苯(71%收率,80%纯度),为红色液体,将其未经进一步纯化用于下一步。GC/MS(EI):m/z(%):MS(EI,70eV):238(79,[M]+·),206(100),205(38),193(44),191(63),179(35),178(93),165(50),115(39),91(44)。
实施例72:2-(2-苄基-4-甲基苯基)乙醛
在5℃下将高氯酸(0.3mL,3.3mmol,1.0equiv.)加入到在15mL Et2O中的(E)-2-苄基-1-(2-甲氧基乙烯基)-4-甲基苯(0.79g,3.3mmol,1.0equiv.)中。将反应在5℃下搅拌5分钟。此后,将混合物用MTBE(甲基叔丁基醚)稀释,倾倒在2M NaOH上并用盐水洗涤。水层用MTBE再萃取。合并的有机层用MgSO4干燥,过滤并减压除去挥发物。通过快速柱色谱法纯化,使用梯度为0-10%的EtOAc/庚烷,得到2-(2-苄基-4-甲基苯基)乙醛(0.57g,67%纯度,51%收率),为黄色液体。GC/MS(EI):m/z(%):MS(EI,70eV):224(43,[M]+·),206(38),195(73),181(40),180(46),179(41),178(60),166(35),165(100),91(34)。
实施例73:1-(2-苄基-4-甲基苯乙基)-4-甲基哌嗪
将在20mL CH2Cl2中的2-(2-苄基-4-甲基苯基)乙醛(0.57g,2.54mmol,1.0equiv.)、1-甲基哌嗪(0.28g,2.80mmol,1.1equiv.)装入100mL 3-颈圆底烧瓶中。分批加入三乙酰氧基硼氢化钠(0.60g,2.8mmol,1.1equiv.)以保持内部温度低于30℃。将淡黄色混合物在环境温度下搅拌过夜。然后将反应混合物冷却至5℃并滴加20mL饱和NaHCO3水溶液。混合物用DCM萃取,有机层用水洗涤,用MgSO4干燥并浓缩。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到1-(2-苄基-4-甲基苯乙基)-4-甲基哌嗪(0.29mg,29%收率),为无色液体。1H NMR(400MHz,CDCl3)δ(ppm)=7.25(br t,J=7.8Hz,2H),7.17(br t,J=7.3Hz,1H),7.08-7.12(m,3H),7.00(dd,J=7.8,1.3Hz,1H),6.94(s,1H),3.99(s,2H),2.71-2.76(m,2H),2.30-2.54(m,10H),2.28(s,6H)。13C NMR(101MHz,CDCl3)δ(ppm)=140.98,138.35,135.80,129.83,128.67(2)128.40(2),127.41,128.68,59.85,55.12(2),53.06(2),46.07,38.95,29.87,21.00。GC/MS(EI):m/z(%):MS(EI,70eV):308(1,[M]+·),179(4),178(4),165(5),114(8),113(100),91(5),70(29),56(4),43(4),42(8)。
实施例74:2-氯乙酸2-苄基-4-甲基苯酯
将2-苄基-4-甲基苯酚(2.0g,10.1mmol,1.0equiv.)和催化量的DMAP(0.06g,0.5mmol,0.05equiv.)在7.0mL Et3N(50.4mmol,5equiv.)中的溶液冷却至0℃。滴加2-氯乙酰氯(1.0mL,1.37g,21.1mmol,1.2equiv.),此时颜色变成深棕色。移去冰浴并将反应在环境温度下搅拌过夜。然后将反应混合物用MTBE稀释,倾倒在H2O上并用MTBE萃取两次。合并的有机层用盐水洗涤,用MgSO4干燥,过滤并蒸发挥发物。使用梯度为0-20%的EtOAc/庚烷通过快速柱色谱法纯化,得到2-氯乙酸2-苄基-4-甲基苯酯(0.75g,88%纯度,34%收率),为黄色液体。GC/MS(EI):m/z(%):MS(EI,70eV):274(22,[M]+·),198(93),197(95),183(28),181(23),165(41),153(24),152(29),120(100),91(43),77(33)。
实施例75:2-(4-甲基哌嗪-1-基)乙酸2-苄基-4-甲基苯酯
将在5mL CH3CN中的2-氯乙酸2-苄基-4-甲基苯酯(0.75g,2.73mmol,1.0equiv.)滴加到1-甲基哌嗪(0.55g,5.46mmol,2.0equiv.)、KI(0.91g,5.46mmol,2.0equiv.)、碳酸钾(0.76g,5.46mmol,2.0equiv.)和碳酸氢钠(0.46g,5.46mmol,2.0equiv.)在10mL CH3CN中的混合物中。将淡黄色悬浮液在环境温度下搅拌过夜。然后将反应用EtOAc稀释,过滤并蒸发挥发物。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到2-(4-甲基哌嗪-1-基)乙酸2-苄基-4-甲基苯酯(0.55g,60%收率),为粘性黄色液体。1H NMR(400MHz,CDCl3)δ(ppm)=7.29-7.25(m,2H),7.20(s,1H),7.18-7.12(m,2H),7.10-7.04(m,1H),7.00(d,J=1.7Hz,1H),6.99-6.95(m,1H),3.88(s,2H),3.34(s,2H),2.72-2.56(m,4H),2.56-2.44(m,4H),2.31(s,6H)。13C NMR(101MHz,CDCl3)δ(ppm)=168.7,146.5,139.9,135.8,132.2,131.7,128.7,128.5,128.1,126.2,122.2,59.0,54.8,52.9,46.0,36.4,20.9。GC/MS(EI):m/z(%):MS(EI,70eV):338(4,[M]+·),165(4),114(9),113(100),98(5),91(4),71(4),70(31),56(5),43(5),42(12)。
实施例76:4-甲基苯磺酸(8-苄基苯并二氢吡喃-2-基)甲酯
在250ml 3-颈圆底烧瓶中,在0℃下将2.20g(6.58mmol,1.0equiv.)的4-甲基苯磺酸(8-羟基苯并二氢吡喃-2-基)甲酯和1.6mL(19.74mmol,3.0equiv.)的吡啶在45mL CH2Cl2中的溶液用三氟甲磺酸酐(2.2mL,3.71g,13.16mmol,2.0当量)处理。移除冰浴并将反应在环境温度下搅拌2小时。然后将反应倒入50mL 0.5M HCl中并用CH2Cl2萃取两次。合并的有机层用盐水洗涤,用MgSO4干燥,过滤并蒸发挥发物。在高真空下干燥粗品,得到粗品4-甲基苯磺酸(8-(((三氟甲基)磺酰基)氧基)苯并二氢吡喃-2-基)甲酯(2.55g,83%收率),其未经进一步纯化用于下一步。GC/MS(EI):m/z(%):MS(EI,70eV):466(0,[M]+·),161(17),155(18),133(12),105(13),92(15),91(100),77(13),69(20),65(41),39(13)。
实施例77:4-甲基苯磺酸(8-(((三氟甲基)磺酰基)氧基)苯并二氢吡喃-2-基)甲酯
将苄基硼酸频哪醇酯(0.45g,2.1mmol,3.0equiv.)、4-甲基苯磺酸(8-(((三氟甲基)磺酰基)氧基)苯并二氢吡喃-2-基)甲酯(0.32g,0.67mmol,1.0equiv.)、K3PO4(0.29g,1.37mmol,2.0equiv.)、SPhos(2-二环己基膦基-2',6'-二甲氧基联苯,62mg,0.15mmol,0.22equiv.)和Pd(OAc)2(23mg,0.1mmol,0.15equiv.)在5.5mL甲苯/H2O 10:1中的混合物用氮气吹扫10分钟。然后将反应加热至110℃保持2小时。冷却至室温后,将混合物在EtOAc(20mL)和盐水之间分配。水层用EtOAc再萃取,有机层用MgSO4干燥,过滤并蒸发挥发物。使用梯度为10-100%的EtOAc/庚烷通过快速柱色谱法纯化,得到4-甲基苯磺酸(8-苄基苯并二氢吡喃-2-基)甲酯乙酸酯(0.25g,86%收率),为粘性黄色液体。GC/MS(EI):m/z(%):MS(EI,70eV):408(5,[M]+·),236(20),235(13),223(13),195(19),194(12),178(24),165(19),145(55),91(100),65(17)。
实施例78:1-((8-苄基苯并二氢吡喃-2-基)甲基)-4-甲基哌嗪
在环境温度下,将在1.5mL THF中的1-甲基哌嗪(0.18g,1.76mmol,3.0equiv.)加入到在3.5mL DMSO(二甲基亚砜)中4-甲基苯磺酸(8-苄基苯并二氢吡喃-2-基)甲酯(0.24g,0.59mmol,1.0equiv.)中。将所得混合物在65℃下搅拌过夜。然后,将反应混合物冷却至环境温度,在EtOAc(20mL)和水(3×20mL)之间分配。水层用EtOAc再萃取,有机层用MgSO4干燥,过滤并蒸发挥发物。使用梯度为10-100%的EtOAc/EtOH/NH4OH(90:9:1)在庚烷中的混合物通过快速柱色谱法纯化,得到4-甲基苯磺酸(8-苄基苯并二氢吡喃-2-基)甲酯(125mg,95%纯度,60%收率),为粘性黄色液体。1H NMR(400MHz,CDCl3)δ(ppm)=7.19-7.27(m,4H),7.15(br t,J=6.8Hz,1H),6.86-6.93(m,2H),6.74(t,J=7.5Hz,1H),4.12-4.22(m,1H),3.92(d,J=15.6Hz,1H),3.91(d,J=15.6Hz,1H),2.81-2.92(m,1H),2.33-2.78(m,12H),2.27(s,3H),1.96-2.05(m,1H),1.70-1.82(m,1H)。
13C NMR (101MHz,CDCl3) δ (ppm)=152.5,141.2,128.9 (3),128.8,128.2(2),127.7,125.7,121.7,119.7,74.7,62.9,55.2,53.9,46.1,35.9,26.3,24.8。GC/MS(EI):m/z(%):MS(EI,70eV):336(2,[M]+·),165(4,[M]+·),139(20),114(8),113(100),98(4),91(11),70(28),56(5),43(7),42(9)。
实施例79:2-(2,6-二氟苄基)-4,6-二甲基苯酚
在Ar下向2-(氯甲基)-1,3-二氟苯1(3.0g,18.5mmol)和2,4-二甲基苯酚(6.8g,55.4mmol)的混合物中加入氯化锌(II)(0.5g,3.7mmol)并将所得混合物加热至140℃保持5小时。将反应混合物冷却至室温后,加入水(100mL)以淬灭溶液并使用MTBE(100mL×3)萃取溶液。合并的有机相用水(100mL)洗涤,用MgSO4干燥并通过旋转蒸发浓缩。将得到的液体通过库格尔若蒸馏器(kugelrohr)蒸馏(0.2mbar,120℃)进一步浓缩以除去未消耗的起始原料2,4-二甲基苯酚,并将残余物通过硅胶柱色谱法(PE:MTBE=92:8)纯化,得到标题产物(1.6g,32%收率),为粘性液体。GC/MS(EI):m/z(%):248(11)[M+],233(25),215(10),201(4),183(11),134(50),121(20),106(18),91(20),77(10)。
实施例80:4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉
将2-(2,6-二氟苄基)-4,6-二甲基苯酚(0.37g,1.5mmol)、4-(2-氯乙基)吗啉盐酸盐(0.56g,3.0mmol)、碘化钾(0.025g,0.15mmol)和碳酸钾(2.10g,14.9mmol)在DMF(20mL)中的溶液加热回流3小时。将混合物冷却至室温后,加入水(80mL),用二氯甲烷(50mL×3)萃取溶液,合并的有机相用水(50mL)洗涤并用MgSO4干燥。除去溶剂后,残余物经硅胶柱色谱法(PE:MTBE=3:2)纯化,得到标题产物(0.40g,收率73%),为粘性液体。GC/MS(EI):m/z(%):361(11)[M+],274(20),227(7),201(4),183(4),127(7),114(28),100(100),85(1),70(4)。1H NMR(300MHz,CDCl3)δ7.26-7.14(m,1H),6.95-6.82(m,3H),6.54(s,1H),4.07(s,2H),3.97(t,J=5.8Hz,2H),3.83-3.69(m,4H),2.84(t,J=5.8Hz,2H),2.69-2.53(m,4H),2.29(s,3H),2.17(s,3H)。13C NMR(75MHz,CDCl3)δ163.6(q),163.5(q),160.3(q),160.2(q),153.3(q),133.4(q),131.5(q),130.5(q),130.3(t),128.2(t),128.0(t),127.9(t),127.4(t),116.6(q),116.4(q),116.1(q),111.5(t),111.4(t),111.2(t),111.1(t),69.9(d),67.1(d),58.8(d),54.4(d),22.4(d),22.3(d),22.3(d),20.9(s),16.4(s)。
实施例81:4-(2-(2-(2,6-二氟苄基)-4-甲基苯氧基)乙基)吗啉
按照实施例80的一般方法:使2-(2,6-二氟苄基)-4-甲基苯酚(0.25g,1.1mmol)、4-(2-氯乙基)吗啉盐酸盐(0.40g,2.1mmol)、碳酸钾(1.50g,10.7mmol)和碘化钾(0.035g,0.20mmol)在DMF(13mL)中的混合物反应,得到标题产物(0.30g,收率65%),为粘性液体。GC/MS(EI):m/z(%):347(8)[M+],260(4),213(4),201(4),165(2),127(7),114(8),100(100),85(1),70(4)。1H NMR(300MHz,CDCl3)δ7.23-7.11(m,1H),6.96-6.82(m,3H),6.80-6.71(m,2H),4.11(t,J=5.8Hz,2H),3.99(s,2H),3.73(t,J=5.8Hz,4H),2.82(t,J=5.8Hz,2H),2.59(t,J=5.8Hz,4H),2.21(s,3H)。13C NMR(75MHz,CDCl3)δ163.6(q),163.5(q),160.4(q),160.2(q),154.4(q),130.2(t),129.9(q),127.9(t),127.9(t),127.8(t),127.7(t),127.3(q),116.4(q),111.4(t),111.3(t),111.2(t),111.0(t),67.2(d),66.6(d),57.8(d),54.3(d),22.6(d),20.7(s)。
实施例82:4-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)吗啉
按照实施例80的一般方法:使2-(2-氟苄基)-4,6-二甲基苯酚(0.40g,1.7mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.60g,3.5mmol)、碳酸钾(2.40g,17.4mmol)和碘化钾(0.060g,0.30mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.40g,64%收率),为粘性液体。GC/MS(EI):m/z(%):343(10)[M+],256(26),227(7),183(5),165(3),133(1),114(22),100(100),87(1),70(3)。1H NMR(300MHz,CDCl3)δ7.21-7.10(m,1H),7.10-6.97(m,3H),6.86(s,1H),6.71(s,1H),4.02(s,2H),3.85(t,J=5.7Hz,2H),3.76-3.67(m,4H),2.73(t,J=5.7Hz,2H),2.57-2.46(m,4H),2.27(s,3H),2.20(s,3H)。13C NMR(75MHz,CDCl3)δ162.7(q),159.4(q),153.6(q),133.4(q),132.1(q),131.1(t),131.0(t),130.7(q),130.4(t),129.0(t),128.2(q),128.0(q),127.7(t),127.7(t),124.1(t),124.1(t),115.3(t),115.0(t),70.0(d),67.0(d),58.8(d),54.3(d),28.6(d),28.6(d),20.9(s),16.5(s)。
实施例83:4-(1-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙-2-基)吗啉和4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙基)吗啉
按照实施例80的一般方法:使2-(2,6-二氟苄基)-4,6-二甲基苯酚(0.4g,1.6mmol)、4-(2-氯丙基)吗啉盐酸盐(0.6g,3.2mmol)、碳酸钾(2.3g,16.1mmol)和碘化钾(0.05g,0.3mmol)在DMF(20mL)中的化合物反应,得到4-(1-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙-2-基)吗啉(0.20g,0.50mmol,收率31%)(为粘性液体)和4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙基)吗啉(0.12g,0.32mmol,收率19%)(为粘性液体)。
4-(1-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙-2-基)吗啉:GC/MS(EI):m/z(%):375(1)[M+],245(1),227(2),201(2),183(2),128(7),114(100),98(1),84(1),70(3)。1H NMR(300MHz,CDCl3)δ7.25-7.15(m,1H),6.94-6.88(m,2H),6.84(s,1H),6.51(s,1H),4.07(s,2H),3.96-3.91(m,1H),3.82-3.66(m,5H),3.12-2.96(m,1H),2.76-2.61(m,4H),2.29(s,3H),2.16(s,3H),1.25(d,J=6.7Hz,3H)。13C NMR(75MHz,CDCl3)δ163.6(q),163.5(q),160.3(q),160.2(q),153.2(q),133.4(q),131.4(q),130.6(q),130.3(t),128.2(t),128.1(t),127.9(t),127.3(t),116.6(q),116.3(q),116.7(q),111.5(t),111.4(t),111.3(t),111.2(t),74.2(d),67.5(d),59.8(t),50.0(d),22.2(d),20.9(s),16.6(s),12.8(s)。
4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙基)吗啉:GC/MS(EI):m/z(%):375(1)[M+],341(1),288(15),227(5),201(5),128(30),100(100),91(1),77(1),56(7)。1HNMR(300MHz,CDCl3)δ7.25-7.13(m,1H),6.94-6.85(m,2H),6.82(s,1H),6.49(s,1H),4.40-4.24(m,1H),4.07(s,2H),3.76-3.61(m,4H),2.87-2.72(m,1H),2.64-2.45(m,5H),2.27(s,3H),2.15(s,3H),1.27(d,J=6.2Hz,3H)。13C NMR(75MHz,CDCl3)δ163.61(q),163.49(q),160.33(q),160.21(q),151.82(q),132.62(q),131.97(q),130.52(q),130.36(t),128.07(t),127.93(t),127.79(t),127.12(t),116.79(q),116.53(q),116.26(q),111.43(t),111.32(t),111.20(t),111.09(t),75.77(t),67.17(d),64.95(d),54.77(d),23.06(d),20.88(s),18.84(s),17.40(s)。
实施例84:4-(2-(2-(2-氯苄基)-4,6-二甲基苯氧基)乙基)吗啉
按照实施例80的一般方法:使2-(2-氯苄基)-4,6-二甲基苯酚(0.38g,1.5mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.57g,3.1mmol)、碳酸钾(2.13g,15.4mmol)和碘化钾(0.050g,0.31mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.20g,收率35%),为粘性液体。GC/MS(EI):m/z(%):359(1)[M+],272(20),209(1),141(30),100(100),87(1),56(5)。1H NMR(300MHz,CDCl3)δ7.44-7.34(m,1H),7.20-7.10(m,2H),7.08-6.98(m,1H),6.89(s,1H),6.65(s,1H),4.11(s,2H),3.84(t,J=5.7Hz,2H),3.72-3.69(m,4H),2.71(t,J=5.7Hz,2H),2.55-2.43(m,4H),2.27(s,3H),2.22(s,3H)。13CNMR(75MHz,CDCl3)δ153.8(q),138.8(q),134.2(q),133.5(q0,131.9(q),130.8(q),130.8(t),130.5(t),129.4(t),129.1(t),127.5(t),126.9(t),69.9(d),67.0(d),58.7(d),54.2(d),33.4(d),20.9(s),16.5(s)。
实施例85:4-(2-(2-(2,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉
按照实施例80的一般方法:使2-(2,5-二氟苄基)-4,6-二甲基苯酚(0.30g,1.2mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.45g,2.4mmol)、碳酸钾(1.67g,12.1mmol)和碘化钾(0.040g,0.24mmol)在DMF(13mL)中的混合物反应,得到标题产物(0.36g,收率80%),为粘性液体。GC/MS(EI):m/z(%):361(1)[M+],346(1),274(20),227(5),201(5),127(7),100(100),87(2),70(5),56(10)。1H NMR(300MHz,CDCl3)δ7.02-6.92(m,1H),6.88(s,1H),6.87-6.78(m,2H),6.75(s,1H),3.99(s,2H),3.85(t,J=5.7Hz,2H),3.77-3.69(m,4H),2.73(t,J=5.7Hz,2H),2.60-2.47(m,4H),2.28(s,3H),2.23(s,3H);13C NMR(75MHz,CDCl3)δ160.4(q),160.4(q),158.6(q),158.5(q),157.2(q),157.2(q),155.4(q),155.3(q),153.7(q),133.6(q),131.4(q),131.0(q),130.9(t),130.3(q),130.2(q),130.1(q),130.0(q),129.1(t),117.6(t),117.5(t),117.3(t),117.2(t),116.2(t),116.1(s),115.9(t),115.8(t),114.2(t),114.1(t),113.9(t),113.7(t),70.1(d),67.0(d),58.8(d),54.3(d),28.8(d),20.9(s),16.5(s)。
实施例86:1-(2-(2-(2-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2-(2-氯苄基)-4-甲基苯酚(0.50g,2.2mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.01g,4.3mmol)、碳酸钾(2.97g,21.5mmol)和碘化钾(0.070g,0.43mmol)在DMF(体积:15mL)中的混合物反应,得到标题产物(0.63g,收率78%),为粘性液体。GC/MS(EI):m/z(%):358(2)[M+],281(2),253(2),207(2),183(10),195(8),165(7),127(40),113(100),70(40)。1H NMR(300MHz,CDCl3)δ7.41-7.31(m,1H),7.16-7.07(m,2H),7.07-6.96(m,2H),6.86(s,1H),6.76(d,J=8.2Hz,1H),4.12-4.00(m,4H),2.73(t,J=5.6Hz,2H),2.53(s,4H),2.40(s,4H),2.27(s,3H),2.23(s,3H)。13C NMR(75MHz,CDCl3)δ154.7(q),138.8(q),134.3(q),131.4(t),130.6(t),129.9(q),129.3(t),128.0(t),127.8(q),127.2(t),126.6(t),111.4(t),66.8(d),57.3(d),55.2(d),53.6(d),46.1(s),33.5(d),20.6(s)。
实施例87:4-(2-(2-(2,4-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉
按照实施例80的一般方法:使2-(2,4-二氟苄基)-4,6-二甲基苯酚(0.28g,1.1mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.41g,2.2mmol)、碳酸钾(1.53g,11.1mmol)和碘化钾(0.040g,0.22mmol)在DMF(13mL)中的混合物反应,得到标题产物(0.30g,收率73%),为粘性液体。GC/MS(EI):m/z(%):361(1)[M+],341(1),274(10),227(5),183(2),127(7),114(20),100(100),87(1),70(3)。1H NMR(300MHz,CDCl3)δ7.11-7.04(m,1H),6.88(s,1H),6.84-6.72(m,2H),6.70(s,1H),3.97(s,2H),3.86(t,J=5.7Hz,2H),3.74-3.71(m,4H),2.75(t,J=5.7Hz,2H),2.60-2.48(m,4H),2.28(s,3H),2.22(s,3H)。13C NMR(75MHz,CDCl3)δ163.2(q),163.1(q),162.5(q),162.4(q),160.0(q),159.8(q),159.2(q),159.1(q),153.6(q),133.6(q),131.9(q),131.7(t),131.7(t),131.6(t),131.5(t),130.9(q),130.6(t),128.9(t),124.1(q),124.1(q),123.9(q),123.9(q),111.3(t),111.2(t),111.0(t),110.9(t),103.9(t),103.6(t),103.2(t),70.0(d),67.0(d),58.8(d),54.3(d),28.1(d),28.1(d),20.9(s),16.5(s)。
实施例88:4-(2-(2-(2,6-二氯苄基)-4,6-二甲基苯氧基)乙基)吗啉
按照实施例80的一般方法:使2-(2,6-二氯苄基)-4,6-二甲基苯酚(0.50g,0.89mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.33g,1.9mmol)、碳酸钾(1.23g,8.9mmol)和碘化钾(0.030g,0.18mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.21g,收率57%),为粘性液体。GC/MS(EI):m/z(%):393(1)[M+],241(1),306(6),243(5),193(5),165(5),114(400),100(100),84(1),70(3)。1H NMR(300MHz,CDCl3)δ7.36(d,J=8.0Hz,2H),7.23-7.12(m,1H),6.85(s,1H),6.17(d,J=7.5Hz,1H),4.35(s,2H),4.02(t,J=5.8Hz,2H),3.83-3.71(m,4H),2.86(t,J=5.8Hz,2H),2.72-2.55(m,4H),2.30(s,3H),2.12(s,3H)。13C NMR(75MHz,CDCl3)δ153.4(q),136.6(q),136.4(q),133.3(q),130.5(q),130.4(q),130.2(t),128.4(t),128.3(t),125.9(t),69.7(d),67.1(d),58.9(d),54.4(d),31.3(d),21.0(s),16.4(s)。
实施例89:4-(2-(2-(3,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉
按照实施例80的一般方法:使2-(3,5-二氟苄基)-4,6-二甲基苯酚(0.27g,1.1mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.41g,2.2mmol)、碳酸钾(1.50g,10.9mmol)和碘化钾(0.040g,0.22mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.33g,收率81%),为粘性液体。GC/MS(EI):m/z(%):361(1)[M+],346(1),274(10),201(5),183(2),127(7),114(15),100(100),87(1),70(3)。1H NMR(300MHz,CDCl3)δ6.90(s,1H),6.79-6.69(m,3H),6.67-6.55(m,1H),3.96(s,2H),3.80(t,J=5.7Hz,2H),3.76-3.69(m,4H),2.72(t,J=5.7Hz,2H),2.58-2.47(m,4H),2.26(d,J=10.2Hz,6H)。13CNMR(75MHz,CDCl3)δ164.8(q),164.6(q),161.5(q),161.4(q),153.6(q),145.7(q),145.6(q),145.5(q),133.7(q),132.0(q),131.1(q),130.9(t),129.2(t),111.8(t),111.7(t),111.6(t),111.5(t),101.8(t),101.5(t),101.2(t),70.2(d),67.0(d),58.8(d),54.3(d),35.9(d),20.8(s),16.5(s)。
实施例90:4-(2-(2,4-二甲基-6-(2,4,5-三氟苄基)苯氧基)乙基)吗啉
按照实施例80的一般方法:使2,4-二甲基-6-(2,4,5-三氟苄基)苯酚(0.30g,1.1mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.42g,2.2mmol)、碳酸钾(1.56g,11.3mmol)和碘化钾(0.040g,0.23mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.36g,收率80%),为粘性液体。GC/MS(EI):m/z(%):379(20)[M+],292(17),245(8),219(6),201(5),145(7),114(14),100(100),85(1),70(3)。1H NMR(300MHz,CDCl3)δ7.04-6.83(m,3H),6.73(s,1H),3.94(s,2H),3.85(t,J=5.6Hz,2H),3.78-3.67(m,4H),2.74(t,J=5.6Hz,2H),2.60-2.49(m,4H),2.26(d,J=7.1Hz,3H),2.23(s,3H)。13C NMR(75MHz,,CDCl3)δ153.6(q),133.7(q),131.3(q),131.1(q),131.0(t),129.0(t),124.9(q),124.9(q),124.8(q),124.7(q),124.6(q),124.6(q),118.8(t),118.7(t),118.6(t),118.5(t),105.4(t),105.2(t),105.1(t),104.8(t),70.1(d),67.0(d),58.79(d),54.3(d),28.3(d),20.8(s),16.5(s)。
实施例91:1-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2-(2-氟苄基)-4,6-二甲基苯酚(0.25g,1.0mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪盐酸盐(0.41g,2.1mmol)、碳酸钾(1.43g,10.3mmol)和碘化钾(0.030g,0.21mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.10g,收率26%),为粘性液体。GC/MS(EI):m/z(%):356(2)[M+],227(2),209(2),183(5),165(3),127(57),113(100),100(17),84(7),70(38)。1H NMR(300MHz,CDCl3)δ7.21-6.98(m,4H),6.86(s,1H),6.71(s,1H),4.00(s,2H),3.83(t,J=5.8Hz,2H),2.76(t,J=5.8Hz,2H),2.54(s,8H),2.36(s,3H),2.26(s,3H),2.20(s,3H)。13C NMR(75MHz,CDCl3)δ162.7(q),159.4(q),153.6(q),133.5(q),132.1(t),131.1(t),131.1(q),130.8(q),130.5(t),129.1(t),128.2(q),128.0(q),127.8(t),127.7(t),124.1(t),124.1(t),115.3(t),115.0(t),70.2(d),58.1(d),54.9(d),53.2(d),45.7(s),28.6(d),28.5(d),20.9(s),16.5(s)。
实施例92:1-(2-(2-(2-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2-(2-溴苄基)-4,6-二甲基苯酚(0.15g,0.52mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.18g,0.77mmol)、碳酸钾(0.57g,4.1mmol)和碘化钾(0.020g,0.10mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.050g,收率23%),为粘性液体。GC/MS(EI):m/z(%):416(2)[M+],360(1),209(10),195(8),179(9),165(7),127(75),113(100),100(20),70(40)。CDCl3)δ7.56-7.51(m,1H),7.23-6.82(m,4H),6.63(s,1H),4.09(s,2H),3.82(s,2H),3.73(s,2H),2.92-2.46(m,8H),2.27(s,3H),2.22(s,3H),2.20(s,3H)。13C NMR(75MHz,CDCl3)δ153.8(q),140.6(q),133.5(q),132.7(t),131.9(q),130.8(t),130.6(t),129.1(t),127.8(t),127.5(t),124.9(q),70.2(d),58.1(d),54.9(d),53.1(d),45.7(s),36.2(d),20.9(s),16.5(s)。
实施例93:1-(2-(2,4-二甲基-6-(2-(三氟甲基)苄基)苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2,4-二甲基-6-(2-(三氟甲基)苄基)苯酚(85mg,0.24mmol,80%纯度)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(114mg,0.49mmol)、碳酸钾(335mg,2.43mmol)和碘化钾(8mg,0.05mmol)在DMF(10mL)中的混合物反应,得到标题产物(14mg,0.03mmol,收率14%),为粘性液体。GC/MS(EI):m/z(%):406(1)[M+],343(4),256(18),227(5),183(4),114(25),100(100),91(1),84(1),70(3)。1H NMR(300MHz,CDCl3)δ7.65(d,J=7.7Hz,1H),7.38(t,J=7.4Hz,1H),7.32-7.24(m,1H),7.06(d,J=7.7Hz,1H),6.89(s,1H),6.60(s,1H),4.19(s,2H),3.81(t,J=5.9Hz,2H),2.69(t,J=5.9Hz,2H),2.75-2.37(m,8H),2.31(s,3H),2.28(s,3H),2.19(s,3H)。13C NMR(75MHz,CDCl3)δ153.8(q),140.0(q),133.6(q),132.2(q),131.9(t),131.2(t),130.9(q),130.7(t),129.5(t),126.1(t),125.9(t),125.8(t),70.3(d),58.0(d),54.9(d),53.3(d),45.8(s),31.9(d),20.9(s),16.6(s)。
实施例94:1-甲基-4-(2-(4-甲基-2-(2-甲基苄基)苯氧基)乙基)哌嗪
向在DMF(20mL)中的氢化钠(1.27g,29.7mmol)中添加4-甲基-2-(2-甲基苄基)苯酚(1.00g,4.2mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.49g,6.4mmol)和碘化钾(0.14g,0.85mmol)。将所得混合物在60℃下搅拌过夜。加入水以淬灭反应,使用EA(乙酸乙酯)萃取溶液,除去溶剂并通过硅胶柱色谱法非常小心地纯化残余物(PE:MTBE=1:1至MTBE至DCM:甲醇=10:1),得到标题产物(0.30mg,收率20%),为粘性液体。GC/MS(EI):m/z(%):338(5)[M+],195(4),165(5),127(55),113(100),98(7),70(55)。1H NMR(300MHz,CDCl3)δ7.20-7.05(m,3H),6.97-6.94(m,2H),6.80-6.69(m,2H),4.08(t,J=5.6Hz,2H),3.90(s,2H),2.77(t,J=5.6Hz,2H),2.59-2.47(m,8H),2.32(s,3H),2.28(s,3H),2.21(s,3H)。13C NMR(75MHz,CDCl3)δ154.5(q),139.1(q),136.6(q),130.9(t),130.0(t),129.9(t),129.4(q),128.7(t),127.6(t),126.0(t),125.9(t),111.3(t),66.7(d),57.2(d),54.9(d),53.2(d),45.8(s),33.3(d),20.6(s),19.7(s)。
实施例95:1-(2-(2-(呋喃-2-基甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:将2-(呋喃-2-基甲基)-4-甲基苯酚(0.83g,4.2mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.18g,5.0mmol)、碳酸钾(2.89g,20.9mmol)和碘化钾(0.14g,0.84mmol)在DMF(20mL)中的混合物加热至100℃保持5小时。加入水淬灭反应,用EA萃取溶液3次,除去溶剂,并将残余物通过硅胶柱色谱法纯化(MTBE至DCM:甲醇=10:1),得到标题产物(0.47g,收率34%),为粘性液体。GC/MS(EI):m/z(%):314(30)[M+],185(2),127(35),113(100),98(7),84(5),70(50)。1HNMR(300MHz,CDCl3)δ7.30(s,1H),6.98(d,J=8.2Hz,1H),6.93(d,J=8.2Hz,1H),6.74(d,J=8.2Hz,1H),6.26(d,J=2.8Hz,1H),5.95(d,J=2.8Hz,1H),4.07(t,J=5.6Hz,2H),3.92(s,2H),2.80(t,J=5.6Hz,2H),2.68-2.60(m,4H),2.56-2.48(m,4H),2.33(s,3H),2.24(s,3H)。13C NMR(75MHz,CDCl3)δ154.7(q),154.4(q),141.1(t),131.1(t),130.1(q),128.2(t),126.7(q),111.7(t),110.3(t),106.0(t),66.9(d),57.3(d),55.1(d),53.3(d),45.9(s),28.7(d),20.6(s)。
实施例96:1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐
将1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪(160mg,0.47mmol)溶解在5mL THF中并加入5mL 3M HCl水溶液。将所得混合物在rt(rt=室温)下搅拌半小时,然后将混合物浓缩,得到标题产物(170mg,21%),为白色固体。GC/MS(EI):m/z(%):338(5)[M+],209(3),178(2),165(5),127(50),113(100),100(20),84(5),70(40)。
实施例97:4-(2-(2,4-二甲基-6-(2-硝基苄基)苯氧基)乙基)吗啉
按照实施例80的一般方法:使4-(2-氯乙基)吗啉盐酸盐(0.21g,1.1mmol)、2,4-二甲基-6-(2-硝基苄基)苯酚(0.15g,0.6mmol)(按照与实施例79类似的方法制备)、碳酸钾(0.77g,5.5mmol)和碘化钾(0.018g,0.11mmol)在DMF(10mL)中反应,得到标题产物(70mg,收率41%),为粘性液体。GC/MS(EI):m/z(%):370(1)[M+],238(2),224(5),111(15),100(100),93(2),84(1),70(3)。1H NMR(300MHz,CDCl3)δ7.80(d,J=8.9Hz,1H),7.58(d,J=9.1Hz,1H),7.39(s,1H),7.35-7.27(m,1H),7.16(s,1H),7.03-6.94(m,1H),3.72-3.64(m,3H),3.63-3.55(m,4H),2.48(t,J=5.6Hz,3H),2.36(s,3H),2.33(s,3H),2.34-2.28(m,4H)。13C NMR(75MHz,CDCl3)δ164.1(q),157.7(q),153.1(q),134.5(t),134.1(t),132.3(t),130.9(q),128.7(q),123.6(t),122.5(t),121.7(q),115.8(q),115.1(t),70.8(d),66.9(d),58.3(d),53.9(d),20.8(s),16.5(s)。
实施例98:1-(2-(2-苄基-3-甲氧基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2-苄基-3-甲氧基苯酚(0.15g,0.70mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.33g,1.4mmol)、碳酸钾(0.97g,7.00mmol)和碘化钾(0.020g,0.14mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.090g,收率37%),为粘性液体。GC/MS(EI):m/z(%):340(3)[M+],249(1),197(3),165(5),152(5),127(50),113(100),100(10),91(15),70(45)。1H NMR(300MHz,CDCl3)δ7.25-7.05(m,6H),6.58-6.51(m,2H),4.07(t,J=5.6Hz,2H),4.01(s,2H),3.80(s,3H),2.78(t,J=5.6Hz,2H),2.70-2.35(m,8H),2.32(s,3H)。13C NMR(75MHz,CDCl3)δ158.4(q),157.4(q),141.8(q),128.6(t),127.9(t),127.4(t),125.3(t),117.7(q),104.6(t),103.9(t),66.7(d),57.2(d),55.8(s),54.9(d),53.2(d),45.8(s),28.8(d)。
实施例99:1-(2-(2-((5-氯噻吩-2-基)甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2-((5-氯噻吩-2-基)甲基)-4-甲基苯酚(1.00g,4.2mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.28g,5.4mmol)、碳酸钾(4.63g,33.5mmol)和碘化钾(0.14g,0.84mmol)在DMF(20mL)中的混合物反应,得到标题产物(0.62g,收率40%),为粘性液体。GC/MS(EI):m/z(%):364(8)[M+],331(4),281(10),253(8),207(80),127(40),113(100),96(5),84(3),70(40)。1H NMR(300MHz,CDCl3)δ7.06-6.93(m,2H),6.75(d,J=8.7Hz,1H),6.66(d,J=3.5Hz,1H),6.54(d,J=3.5Hz,1H),4.07(t,J=11.0,5.4Hz,2H),4.01(s,2H),2.85-2.75(m,2H),2.62-2.51(m,8H),2.33(s,3H),2.24(s,3H)。13C NMR(75MHz,CDCl3)δ154.2(q),143.4(q),130.9(t),130.1(q),128.5(t),128.1(q),125.6(t),124.0(t),111.6(t),66.6(d),57.3(d),55.1(d),53.3(d),45.9(s),31.1(d),20.6(s)。
实施例100:1-(2-(2-苄基-6-甲基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2-苄基-6-甲基苯酚(0.20g,1.0mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.48g,2.0mmol)、碳酸钾(1.39g,10.1mmol)和碘化钾(0.030g,0.20mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.040g,收率11%),为粘性液体。GC/MS(EI):m/z(%):324(5)[M+],268(1),195(5),165(15),127(2),128(55),113(100),100(20),84(5),70(40)。1H NMR(300MHz,CDCl3)δ7.26-6.85(m,8H),4.10-4.00(m,2H),3.90-3.75(m,2H),2.70-2.55(m,10H),2.44-2.24(m,6H)。13C NMR(75MHz,CDCl3)δ155.8(q),141.2(q),133.8(q),131.1(q),129.7(t),128.9(t),128.5(t),126.1(t),124.2(t),70.1(d),57.9(d),54.7(d),52.8(d),45.5(s),35.9(d),16.6(s)。
实施例101:1-(2-(2-苄基-4-(叔丁基)-6-甲氧基苯氧基)乙基)-4-甲基哌嗪
将2-苄基-4-(叔丁基)-6-甲氧基苯酚(0.25g,0.93mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.44g,1.8mmol)、碳酸钾(1.28g,9.2mmol)和碘化钾(0.030g,0.19mmol)在DMF(10mL)中的混合物加热至回流过夜。加入水,用DCM萃取溶液3次,除去溶剂并将残余物通过硅胶柱色谱法纯化(MTBE,然后DCM:甲醇=10:1),得到标题产物(0.28g,收率74%),为粘性液体。GC/MS(EI):m/z(%):396(5)[M+],281(2),255(3),181(2),165(3),127(100),113(92),91(12),84(9),70(37)。1H NMR(300MHz,CDCl3)δ7.25-7.10(m,5H),6.79(d,J=2.1Hz,1H),6.75(d,J=2.0Hz,1H),4.00(s,2H),3.91(t,J=5.9Hz,2H),3.83(s,3H),2.66(t,J=5.9Hz,2H),2.55-2.38(m,8H),2.30(s,3H),1.27(s,9H)。13C NMR(75MHz,CDCl3)δ152.1(q),146.8(q),144.1(q),141.6(q),133.7(q),128.8(t),128.3(t),125.8(t),119.7(t),108.3(t),70.0(d),58.1(d),55.8(s),55.0(d),53.2(d),45.9(s),36.5(d),34.7(q),31.6(s)。
实施例102:1-(2-(2-(3-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪
按照实施例80的一般方法:使2-(3-氯苄基)-4-甲基苯酚(0.80g,3.4mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.62g,6.9mmol)、碳酸钾(4.75g,34.4mmol)和碘化钾(0.11g,0.69mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.67g,52%收率),为粘性液体。GC/MS(EI):m/z(%):358(3)[M+],253(1),229(1),195(4),165(7),127(52),113(100),70(33)。1H NMR(300MHz,CDCl3)δ7.23-7.05(m,4H),6.98(d,J=8.2Hz,1H),6.92(s,1H),6.73(d,J=8.2Hz,1H),4.04(t,J=5.7Hz,2H),3.89(s,2H),2.75(t,J=5.7Hz,2H),2.6-2.54(m,4H),2.52-2.40(m,4H),2.30(s,3H),2.25(s,3H)。13C NMR(75MHz,CDCl3)δ154.5(q),143.5(q),133.9(q),131.4(t),129.9(q),129.5(t),128.9(t),128.6(q),128.1(t),127.1(t),125.9(t),111.6(t),66.5(d),57.3(d),55.1(d),53.5(d),45.9(s),36.1(d),20.6(s)。
实施例103:3-苄基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯甲酸甲酯
将3-苄基-4-羟基苯甲酸甲酯(0.15g,0.62mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.29g,1.2mmol)、碳酸钾(0.86g,6.2mmol)和碘化钾(0.021g,0.12mmol)在DMF(10mL)中的混合物加热至回流保持4小时。加入水,用DCM萃取溶液3次,除去溶剂,并将残余物通过硅胶柱色谱法方法纯化(MTBE至DCM:甲醇=10:1),得到标题产物(0.090g,收率40%),为粘性液体。GC/MS(EI):m/z(%):368(1)[M+],239(2),207(5),181(5),165(10),127(55),113(100),91(53),70(40)。1H NMR(300MHz,CDCl3)δ7.90(d,J=8.6Hz,1H),7.84(s,1H),7.25-7.20(m,2H),7.19-7.11(m,3H),6.83(d,J=8.6Hz,1H),4.11(t,J=5.6Hz,2H),3.96(s,2H),3.85(s,3H),2.78(t,J=5.6Hz,2H),2.70-2.54(m,4H),2.52-2。40(m,4H),2.32(s,3H)。13C NMR(75MHz,CDCl3)δ167.1(q),160.5(q),140.5(q),132.3(t),130.1(t),129.6(q),128.8(t),128.4(t),126.1(t),122.5(q),110.7(t),66.8(d),56.9(d),55.0(d),53.2(d),52.0(s),45.8(s),36.4(d)。
实施例104:1-(2-(2,4-二甲基-6-(吡啶-2-基甲基)苯氧基)乙基)-4-甲基哌嗪
将2,4-二甲基-6-(吡啶-2-基甲基)苯酚盐酸盐(0.35g,0.98mmol)(按照与实施例79类似的方法制备,并按照与实施例96类似的方法分离为盐酸盐)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.46g,2.0mmol)、碳酸钾(2.03g,14.7mmol)和碘化钾(16mg,0.098mmol)在DMF(30mL)中的混合物加热至回流保持3小时。加入水,用DCM萃取溶液3次,除去溶剂,并将残余物通过硅胶柱色谱法纯化(DCM:甲醇=10:1),得到标题产物(0.58g,收率66%),为粘性液体。GC/MS(EI):m/z(%):339(1)[M+],268(4),221(10),181(2),165(5),127(60),113(100),98(10),70(85)。1H NMR(300MHz,CDCl3)δ8.50(d,J=4.7Hz,1H),7.55-7.50(m,1H),7.15-7.00(m,2H),6.85(s,1H),6.80(s,1H),4.16(s,2H),3.83(t,J=5.7Hz,2H),2.72(t,J=5.7Hz,2H),2.67-2.38(m,8H),2.32(s,3H),2.25(s,3H),2.19(s,3H)。13C NMR(75MHz,CDCl3)δ161.4(q),153.6(q),149.2(t),136.5(t),133.5(q),131.9(q),130.8(q),130.6(t),129.4(t),123.1(t),121.1(t),70.3(d),58.1(d),54.9(d),53.2(d),45.8(s),38.8(d),20.8(s),16.5(s)。
实施例105:4-(2-(2,4-二甲基-5-((全氟苯基)甲基)苯氧基)乙基)吗啉
将2,4-二甲基-6-((全氟苯基)甲基)苯酚(1.00g,3.3mmol)(在通过与实施例79类似的方法制备2,4-二甲基-6-((全氟苯基)甲基)苯酚时作为异构体副产物分离)、4-(2-氯乙基)吗啉盐酸盐(1.23g,6.6mmol)、碳酸钾(4.57g,33.1mmol)和碘化钾(0.11g,0.66mmol)在DMF(13mL)中的混合物加热至回流保持3小时。反应溶液的颜色变成很深的颜色。加入水,用DCM萃取溶液3次,除去溶剂,并将残余物通过硅胶柱色谱法纯化(PE:MTBE=1:1),得到标题产物(0.15g,收率10%)。GC/MS(EI):m/z(%):415(1)[M+],237(2),219(2),181(5),114(5),100(100),91(3),70(4)。1H NMR(300MHz,CDCl3)δ6.95(s,1H),6.55-6.44(m,1H),4.07-3.89(m,4H),3.80-3.65(m,4H),2.87-2.69(m,2H),2.66-2.50(m,4H),2.28(s,3H),2.15(s,3H)。13C NMR(75MHz,CDCl3)δ155.3(q),133.7(q),133.4(q),133.0(q),132.9(t),127.9(q),125.7(q),112.0(t),67.1(d),66.7(d),57.8(d),54.3(d),25.8(d),25.8(d),18.6(s),15.8(s)。
实施例106:1-(2-(2-(3-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪
将2-(3-溴苄基)-4,6-二甲基苯酚(0.40g,1.4mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.49g,2.1mmol)、碳酸钾(1.52g,11.0mmol)和碘化钾(0.050g,0.28mmol)在DMF(10mL)中的混合物加热至100℃过夜。加入水,用DCM萃取溶液3次,除去溶剂,并将残余物通过硅胶柱色谱法纯化(MTBE至DCM:甲醇=10:1),得到标题产物(0.25g,收率42%),为粘性液体。GC/MS(EI):m/z(%):416(2)[M+],209(5),195(4),179(4),165(4),127(65),113(100),100(15),84(5),70(40)。1H NMR(300MHz,CDCl3)δ7.35(s,1H),7.34-7.26(m,1H),7.20-7.07(m,2H),6.87(s,1H),6.73(s,1H),3.95(s,2H),3.87-3.72(m,2H),2.81-2.70(m,2H),2.70-2.52(m,8H),2.26(s,3H),2.23(s,3H),2.22(s,3H)。13C NMR(75MHz,CDCl3)δ153.6(q),143.9(q),133.5(q),132.6(q),131.9(t),130.9(q),130.6(t),129.9(t),129.2(t),129.1(t),127.6(t),122.5(q),70.3(d),58.2(d),55.0(d),53.5(d),45.9(s),35.7(d),20.9(s),16.5(s)。
实施例107:1-(2-(2-苄基-3,6-二甲基苯氧基)乙基)-4-甲基哌嗪
将2-苄基-3,6-二甲基苯酚(0.22g,1.0mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.49g,2.1mmol)、碳酸钾(1.43g,10.4mmol)和碘化钾(0.030g,0.21mmol)在DMF(10mL)中的全部混合物加热至100℃保持3小时。加入水,用DCM萃取溶液3次,除去溶剂,将残余物通过硅胶柱色谱法纯化(MTBE至DCM:甲醇=10:1)得到标题产物(0.15g,收率42%),为粘性液体。GC/MS(EI):m/z(%):338(3)[M+],209(5),195(4),178(45),165(10),127(45),113(100),100(35),84(10),70(40)。1H NMR(300MHz,CDCl3)δ7.25-7.18(m,2H),7.16-7.04(m,3H),7.00(d,J=7.6Hz,1H),6.87(d,J=7.7Hz,1H),4.10(s,2H),3.75(t,J=5.9Hz,2H),2.67(t,J=5.9Hz,2H),2.62-2.40(m,8H),2.31(s,3H),2.29(s,3H),2.14(s,3H)。13C NMR(75MHz,CDCl3)δ156.3(q),140.9(q),136.6(q),131.7(q),129.3(t),128.4(t),128.4(t),128.2(t),126.0(t),125.7(t),70.4(d),58.1(d),55.0(d),53.4(d),45.9(s),32.5(d),19.8(s),16.6(s)。
实施例108:1-(2-(2-苄基-4-异丙基苯氧基)乙基)-4-甲基哌嗪
将2-苄基-4-异丙基苯酚(0.25g,1.1mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.52g,2.2mmol)、碳酸钾(1.53g,11.1mmol)和碘化钾(0.040g,0.22mmol)在DMF(10mL)中的全部混合物加热至回流保持4小时。加入水,用DCM萃取溶液3次,除去溶剂,将残余物通过硅胶柱色谱法纯化(MTBE至DCM:甲醇=10:1)得到标题产物(0.16g,收率41%),为粘性液体。GC/MS(EI):m/z(%):352(2)[M+],207(4),195(1),178(2),165(4),127(45),113(100),100(5),91(10),70(45)。1H NMR(300MHz,CDCl3)δ7.29-7.11(m,5H),7.10-6.94(m,2H),6.84-6.71(m,1H),4.07(s,2H),3.96(s,2H),2.90-2.71(m,3H),2.70-2.36(m,8H),2.33(s,3H),1.21(d,J=3.7,6H)。13C NMR(75MHz,CDCl3)δ154.7(q),141.3(q),141.1(q),129.2(q),129.1(t),128.8(t),128.2(t),125.7(t),124.9(t),111.3(t),66.6(d),57.3(d),54.9(d),53.3(d),45.8(s),36.5(d),33.3(t),24.3(s)。
实施例109:1-(2-((6-苄基苯并[d][1,3]二氧杂环戊二烯-5-基)氧基)乙基)-4-甲基哌嗪
将6-苄基苯并[d][1,3]二氧杂环戊二烯-5-醇(0.10g,0.44mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.21g,0.88mmol)、碳酸钾(0.61g,4.4mmol)和碘化钾(0.020g,0.090mmol)在DMF(10mL)中的混合物加热至回流保持4小时。加入水,用DCM萃取溶液3次,除去溶剂,将残余物通过硅胶柱色谱法纯化(MTBE至DCM:甲醇=10:1)得到标题产物(0.09g,0.24mmol,收率54.3%),为粘性液体。GC/MS(EI):m/z(%):354(15)[M+],254(5),225(5),169(4),152(5),127(100),113(85),98(10),84(12),70(45)。1H NMR(300MHz,CDCl3)δ7.26-7.20(m,2H),7.18-7.11(m,3H),6.58(s,1H),6.50(s,1H),5.86(s,2H),3.98(t,J=5.6Hz,2H),3.86(s,2H),2.72(t,J=5.6Hz,2H),2.70-3.38(m,8H),2.32(s,3H)。13C NMR(75MHz,CDCl3)δ151.4(q),146.5(q),141.4(q),128.8(t),128.4(t),125.9(t),122.2(q),110.4(t),101.1(d),96.1(t),67.8(d),57.3(d),54.9(d),53.3(d),45.8(s),35.9(d)。
实施例110:1-(2-((6-苄基-2,3-二氢-1H-茚-5-基)氧基)乙基)-4-甲基哌嗪
将6-苄基-2,3-二氢-1H-茚-5-醇(0.22g,0.98mmol)(按照与实施例79类似的方法制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.46g,2.0mmol)、碳酸钾(1.36g,9.8mmol)和碘化钾(0.030g,0.20mmol)在DMF(10mL)中的混合物加热至100℃(在150℃的位置加热)过夜。加入水,用DCM萃取溶液3次,除去溶剂,将残余物通过硅胶柱色谱法纯化(MTBE至DCM:甲醇=10:1)得到标题产物(0.11g,收率30%),为粘性液体。GC/MS(EI):m/z(%):350(10)[M+],221(4),207(4),178(5),165(4),127(55),113(100),100(5),91(10),70(435)。1H NMR(300MHz,CDCl3)δ7.35-7.14(m,5H),6.95(s,1H),6.75(s,1H),4.18-3.87(m,4H),2.92-2.75(m,6H),2.66-2.42(m,8H),2.39-2.28(m,3H),2.05(m,2H)。13C NMR(75MHz,CDCl3)δ155.4(q),143.4(q),141.7(q),136.0(q),128.9(t),128.3(t),127.5(q),126.3(t),125.7(t),108.0(t),66.7(d),57.3(d),54.9(d),53.3(d),45.8(s),36.3(d),33.3(d),32.2(d),25.8(d)。
实施例111:1-(2-(2,4-二甲基-6-(吡啶-3-基甲基)苯氧基)乙基)-4-甲基哌嗪
将2,4-二甲基-6-(吡啶-3-基甲基)苯酚盐酸盐(0.35g,1.1mmol)(按照与实施例79类似的方法制备并按照与实施例96类似的方法分离为盐酸盐)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.53g,2.2mmol)、碳酸钾(2.32g,16.8mmol)和碘化钾(0.020g,0.11mmol)在DMF(30mL)中的混合物加热至回流保持5小时。加入水,用DCM萃取溶液3次,除去溶剂并通过硅胶柱色谱法纯化残余物(DCM:甲醇:TEA=10:1),得到标题产物(0.22g,收率56%),为粘性液体。GC/MS(EI):m/z(%):339(30)[M+],324(5),296(15),283(20),269(85),127(60),113(100),98(15),84(20),70(90)。1H NMR(300MHz,CDCl3)δ8.49(s,1H),8.41(d,J=4.7,1H),7.46(d,J=7.8Hz,1H),7.16(dd,J=7.8,4.7Hz,1H),6.85(s,1H),6.70(s,1H),3.96(s,2H),3.81(t,J=5.7Hz,2H),2.74(t,J=5.7Hz,2H),2.70-2.44(m,8H),2.35(s,3H),2.24(s,3H),2.19(s,3H)。13C NMR(75MHz,CDCl3)δ153.5(q),150.3(t),147.5(t),136.8(q),136.3(t),133.6(q),132.3(q),130.9(q),130.7(t),129.0(t),123.4(t),70.4(d),58.1(d),54.9(d),53.1(d),45.6(s),33.3(d),20.8(s),16.5(s)。
实施例112:1-(2-(2-苄基-3-甲基苯氧基)乙基)-4-甲基哌嗪
将2-苄基-3-甲基苯酚(0.15g,0.76mmol)(按照与实施例79类似的方法制备并通过色谱小心地与其他区域异构体分离)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.36g,1.5mmol)、碳酸钾(1.05g,7.6mmol)和碘化钾(0.030g,0.15mmol)在DMF(10mL)中的混合物加热至回流保持4小时。加入水,用DCM萃取溶液3次,除去溶剂,将残余物通过硅胶柱色谱法纯化(MTBE至DCM:甲醇=10:1)得到标题产物(0.10g,收率40%),为粘性液体。GC/MS(EI):m/z(%):324(5)[M+],209(4),195(4),178(4),165(10),127(75),113(100),100(15),91(13),70(80)。1H NMR(300MHz,CDCl3)δ7.25-7.17(m,2H),7.16-7.05(m,4H),6.85-6.71(m,2H),4.12-4.01(m,4H),2.75(t,J=5.5Hz,2H),2.70-2.33(m,8H),2.29(s,3H),2.25(s,3H)。13C NMR(75MHz,CDCl3)δ156.9(q),140.9(q),138.6(q),128.2(t),127.6(q),127.1(t),125.6(t),122.9(t),109.2(t),66.8(d),57.2(d),54.9(d),53.3(d),45.8(s),31.9(d),19.9(s)。
实施例113:4-甲基-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯酚
向氢化钠(56wt%,0.95g,22.2mmol)在DMF(10mL)中的悬浮液中添加2,2'-亚甲基二(4-甲基苯酚)(1.27g,5.6mmol),并随后添加1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.7g,7.2mmol),并将所得混合物在室温下搅拌2天。加入水,用EA萃取溶液,除去溶剂,将残余物通过柱色谱法纯化(DCM:包含EA=10:1)得到150mg棕色固体。将得到的物质与稀盐酸混合,然后将整个混合物浓缩以除去水,得到标题产物(0.11g,收率6%),为白色固体。GC/MS(EI):m/z(%):354(26)[M+],339(3),209(4),165(4),127(30),113(100),98(5),84(3),70(25)。
实施例114:1-(2-(2,4-二甲基-6-(吡啶-4-基甲基)苯氧基)乙基)-4-甲基哌嗪
将2,4-二甲基-6-(吡啶-4-基甲基)苯酚盐酸盐(0.19g,0.46mmol)(按照与实施例79类似的方法制备并按照与实施例96类似的方法分离为盐酸盐)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.22g,0.91mmol)、碳酸钾(0.95g,6.8mmol)和碘化钾(7.6mg,0.050mmol)在DMF(体积:30mL)中的混合物加热至回流过夜。加入水,用DCM萃取溶液3次,除去溶剂并通过硅胶柱色谱法纯化残余物(DCM:甲醇:TEA=10:1),得到标题产物(0.060g,收率38%),为粘性液体。GC/MS(EI):m/z(%):339(10)[M+],324(53),283(5),260(8),240(4),213(75),127(40),113(100),98(8),84(8),70(50)。1H NMR(300MHz,CDCl3)δ8.43(d,J=5.7Hz,2H),7.08(d,J=5.7Hz,2H),6.82(s,1H),6.69(s,1H),3.93(s,2H),3.76(t,J=5.5Hz,2H),3.07(q,J=7.3Hz,1H),2.86-2.68(m,9H),2.52(s,3H),2.22(s,3H),2.18(s,3H)。13C NMR(75MHz,CDCl3)δ153.4(q),150.5(q),149.7(t),133.8(q),131.2(q),130.9(t),130.9(q),129.3(t),124.1(t),70.2(d),57.6(d),54.3(d),51.8(d),44.7(s),35.5(d),20.7(s),16.5(s),8.7(s)。
实施例115:1-((2-溴苄基)氧基)-2,4-二甲基苯
将碳酸钾(42.4g,307mmol)、1-溴-2-(溴甲基)苯(48.6g,194mmol)和2,4-二甲基苯酚(25.0g,205mmol)在丙酮(300mL)中的悬浮液在回流下加热14小时。然后通过旋转蒸发除去溶剂,加入水(200mL),用MTBE(100mL×3)萃取溶液,有机相用Na2SO4干燥,并除去溶剂,得到标题产物(56.0g,收率89%),为白色固体,将其直接用于下一步。GC/MS(EI):m/z(%):292(98)[M+],290(100)[M+],211(5),171(24),121(5),90(45),77(25)。
实施例116:2-(2-溴苄基)-4,6-二甲基苯酚
在0℃下向1-((2-溴苄基)氧基)-2,4-二甲苯在二氯甲烷(200mL)中的溶液中滴加氯化钛(IV)(39.1g,206mmol),并将混合物在0℃下搅拌10分钟。加入水(150mL)淬灭反应,用二氯甲烷(100mL×3)萃取溶液,有机相用MgSO4干燥并除去溶剂。残余液体经硅胶柱色谱法纯化(PE:MTBE=95:5),得到标题产物(11.5g,收率17%),为无色液体。GC/MS(EI):m/z(%):292(95)[M+],290(98)[M+],211(90),196(80),181(40),165(50),134(100),91(40)。
实施例117:2-(2-羟基-3,5-二甲基苄基)苯甲腈
将2-(2-溴苄基)-4,6-二甲基苯酚(1.0g,3.4mmol)和氰化铜(I)(0.33g,3.7mmol)在N-甲基-2-吡咯烷酮(10mL)中的混合物加热至回流保持1小时。冷却的反应混合物用水(20mL)稀释,用MTBE(50mL×3)萃取,用Na2SO4干燥并减压浓缩。残余物经硅胶柱色谱法纯化(PE:MTBE=85:15),得到标题产物(0.46g,收率56%),为淡红色固体。GC/MS(EI):m/z(%):237(100)[M+],222(158),208(55),194(50),182(35),165(15),121(40),91(20),77(15)。
实施例118:2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈
按照实施例80的一般方法:使2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.65g,2.74mmol)、4-(2-氯乙基)吗啉(0.82g,5.48mmol)、碳酸钾(3.79g,27.4mmol)和碘化钾(0.09g,0.55mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.83g,收率84%),为粘性液体。GC/MS(EI):m/z(%):350(7)[M+],263(23),234(5),208(3),190(4),165(3),140(1),100(100),56(14)。1H NMR(300MHz,CDCl3)δ7.64(d,J=7.7Hz,1H),7.45(t,J=7.3Hz,1H),7.32-7.19(m,2H),6.90(s,1H),6.71(s,1H),4.23(s,2H),3.88(t,J=5.7Hz,2H),3.77-3.63(m,4H),2.74(t,J=5.7Hz,2H),2.62-2.46(m,4H),2.28(s,3H),),2.22(s,3H)。13C NMR(75MHz,CDCl3)δ153.7(q),145.3(q),133.7(q),132.9(t),132.8(t),131.5(q),131.1(t),131.0(q),130.1(t),129.2(t),126.7(t),118.5(q),112.6(q),70.2(d),67.1(d),58.8(d),54.3(d),34.4(d),20.9(s),16.5(s)。
实施例119:2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈盐酸盐
向2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈(40mg,0.11mmol)在甲醇(15mL)中的溶液中加入氯化氢(224mg,1.1mmol),并将所得混合物在室温下搅拌30分钟。除去溶剂,残余物在90℃减压干燥,得到标题产物(40mg,收率89%),为粘性液体。GC/MS(EI):m/z(%):350(3)[M+],263(14),234(4),190(3),165(2),140(1),114(15),100(100),87(1),70(3)。
实施例120:2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈
按照实施例80的一般方法:使2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.2g,0.843mmol)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.298g,1.264mmol)、碳酸钾(0.93g,6.7mmol)和碘化钾(0.028g,0.17mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.10g,收率31%),为粘性液体。GC/MS(EI):m/z(%):363(1)[M+],234(1),208(4),190(4),165(3),127(69),113(100),100(9),84(6),70(37)。1H NMR(300MHz,CDCl3)δ7.63(d,J=7.7,1H),7.49-7.38(m,1H),7.32-7.17(m,2H),6.88(s,1H),6.71(s,1H),4.22(s,2H),3.86(t,J=5.8Hz,2H),2.74(t,J=5.8Hz,2H),2.70-2.34(m,8H),2.28(s,3H),2.27(s,3H),2.21(s,3H)。13C NMR(75MHz,CDCl3)δ153.7(q),145.4(q),133.6(q),132.9(t),132.7(t),131.5(q),131.0(t),130.1(t),129.1(t),126.6(t),118.5(q),112.5(q),70.4(d),58.2(d),55.1(d),53.7(d),46。1(s),34.3(d),20.9(s),16.5(s)。
实施例121:2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈盐酸盐
向在甲醇(10mL)中的2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈(0.60g,1.6mmol)中加入氯化氢(0.50g,4.8mmol)并将所得混合物静置半小时。然后通过旋转蒸发除去溶剂并将残余物在库格尔若蒸馏器上干燥(90℃,0.1mbar),得到标题产物(0.65g,收率96%),为浅棕色固体。GC/MS(EI):m/z(%):363(1)[M+],248(1),208(4),190(4),165(3),127(69),113(100),100(9),84(6),70(37)。
实施例122:2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈
按照实施例80的一般方法:使2-(2-羟基-5-甲基苄基)苯甲腈(0.50g,2.2mmol)(按照实施例115、实施例116和实施例117所述的类似顺序制备)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.06g,4.5mmol)、碳酸钾(3.10g,22.4mmol)和碘化钾(0.070g,0.45mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.48g,收率58%),为棕色粘性液体。GC/MS(EI):m/z(%):349(1)[M+],248(1),220(2),190(6),165(3),127(58),113(100),98(5),84(4),70(34)。1H NMR(300MHz,CDCl3)δ7.62(d,J=7.6Hz,1H),7.44(t,J=7.6Hz,1H),7.30-7.20(m,2H),7.02(d,J=8.2Hz,1H),6.99(s,1H),6.76(d,J=8.2Hz,1H),4.17(s,2H),4.06(t,J=5.7Hz,2H),2.75(t,J=5.7Hz,2H),2.66-2.42(m,8H),2.32(s,3H),2.27(s,3H)。13CNMR(75MHz,CDCl3)δ154.5(q),145.3(q),132.7(t),131.7(t),130.1(q),129.8(t),128.6(t),127.2(q),126.4(t),118.5(q),112.6(q),111.6(t),66.4(d),57.2(d),55.0(d),53.3(d),45.9(s),34.7(d),20.6(s)。
实施例123:2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)-3-氟苯甲腈
按照实施例80的一般方法:3-氟-2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.15g,0.59mmol)(按照实施例115、实施例116和实施例117所述的类似顺序制备)、4-(2-氯乙基)吗啉盐酸盐(0.22g,1.2mmol)、碳酸钾(0.81g,5.9mmol)和碘化钾(0.020g,0.12mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.060g,收率26%),为棕色粘性液体。GC/MS(EI):m/z(%):368(2)[M+],281(11),208(2),183(2),158(1),134(3),114(19),100(100),85(1),70(4)。1H NMR(300MHz,CDCl3)δ7.50(d,J=7.2Hz,1H),7.41-7.27(m,2H),6.86(s,1H),6.37(s,1H),4.27(s,2H),3.99(t,J=5.8Hz,2H),3.82-3.67(m,4H),2.83(t,J=5.8Hz,2H),2.68-2.53(m,4H),2.28(s,3H),2.15(s,3H)。13C NMR(75MHz,CDCl3)δ153.4(q),133.4(q),132.1(q),131.8(q),130.8(t),130.7(q),130.4(q),129.1(t),129.0(t),128.9(t),128.9(t),127.1(t),120.7(t),120.4(t),115.6(q),115.5(q),70.0(d),67.1(d),58.8(d),54.4(d),28.1(d),20.9(s),16.5(s)。
实施例124:2-(3,5-二甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈和2-(3,5-二甲基-2-((1-吗啉代丙-2-基)氧基)苄基)苯甲腈
按照实施例80的一般方法:使4-(2-氯丙基)吗啉盐酸盐(0.40g,2.0mmol)、2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.240g,0.99mmol)、碳酸钾(1.37g,9.9mmol)和碘化钾(0.033g,0.20mmol)在DMF(10mL)中反应,得到2-(3,5-二甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈(0.080g,收率22%)(为棕色粘性液体)和2-(3,5-二甲基-2-((1-吗啉代丙-2-基)氧基)苄基)苯甲腈(0.040g,收率11%)(为棕色粘性液体)。
2-(3,5-二甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈:GC/MS(EI):m/z(%):364(1)[M+],277(1),234(2),190(2),165(1),128(5),114(100),98(1),84(1),70(3)。1H NMR(300MHz,CDCl3)δ7.64(d,J=7.7Hz,1H),7.46(t,J=7.2Hz,1H),7.32-7.24(m,1H),7.20(d,J=7.9Hz,1H),6.90(s,1H),6.70(s,1H),4.23(s,2H),3.88-3.78(m,1H),3.73-3.58(m,5H),3.01-2.88(m,1H),2.66-2.52(m,4H),2.28(s,3H),2.22(s,3H),1.13(d,J=6.7Hz,3H)。13C NMR(75MHz,CDCl3)δ153.6(q),145.3(q),133.7(q),132.9(t),132.7(t),131.3(q),131.1(t),131.0(q),130.0(t),129.2(t),126.6(t),118.4(q),112.6(q),74.5(d),67.4(d),59.6(t),49.8(d),34.4(d),20.9(s),16.6(s),12.5(s)。
2-(3,5-二甲基-2-((1-吗啉代丙-2-基)氧基)苄基)苯甲腈:GC/MS(EI):m/z(%):364(1)[M+],349(2),277(3),234(10),190(10),165(1),128(5),114(100),98(1),84(1),70(5)。
实施例125:2-(3,5-二甲基-2-(2-(四氢-2H-吡喃-4-基)乙氧基)苄基)苯甲腈
按照实施例80的一般方法:使2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.15g,0.63mmol)、4-(2-溴乙基)四氢-2H-吡喃(0.24g,1.3mmol)、碳酸钾(0.87g,6.3mmol)和碘化钾(0.020g,0.13mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.18g,收率79%),为粘性液体。GC/MS(EI):m/z(%):349(1)[M+],236(18),222(5),208(18),182(13),165(4),130(2),118(100),83(7),69(7)。1H NMR(300MHz,1H NMR(300MHz,CDCl3)δ7.64(d,J=7.7,1H),7.48-7.44(m,1H),7.36-7.23(m,1H),7.16(d,J=7.8Hz,1H),6.91(s,1H),6.72(s,1H),4.19(s,2H),3.98-3.92(m,2H),3.77(t,J=6.4Hz,2H),3.40-3.30(m,2H),2.30(s,3H),2.20(s,3H),1.72(t,J=5.4Hz,3H),1.67-1.50(m,2H),1.47-1.10(m,2H)。13C NMR(75MHz,CDCl3)δ153.7(s),145.2(s),133.5(s),132.9(d),132.6(d),131.2(s),131.0(d),129.8(d),129.1(d),126.5(d),118.3(s),112.5(s),70.4(t),68.0(t),37.3(t),34.3(t),33.2(t),31.9(d),20.8(q),16.4(q)。
实施例126:2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐
向2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈(0.62g,1.7mmol)在甲醇(10mL)中的溶液中滴加氯化氢(0.52g,5.2mmol),并将所得混合物在室温下静置1小时。然后溶剂通过旋转蒸发在减压下除去并将所得固体在真空下通过库格尔若蒸馏器在80℃下干燥1小时。得到目标产物(0.67g,收率89%),为浅棕色固体。GC/MS(EI):m/z(%):349(4)[M+],279(1),220(2),190(5),165(3),127(55),113(100),98(5),84(4),70(35)。
实施例127:2-(2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯基)乙腈按照实施例80的一般方法:使2-(2-(2-羟基-3,5-二甲基苄基)苯基)乙腈(0.18g,0.72mmol)(按照与实施例79类似的方法制备)、4-(2-氯乙基)吗啉盐酸盐(0.27g,1.4mmol)、碳酸钾(0.99g,7.2mmol)和碘化钾(0.020g,0.14mmol)在DMF(15mL)中的混合物反应,得到标题产物(0.050g,收率11%),为粘性液体。GC/MS(EI):m/z(%):364(2)[M+],277(15),234(8),209(5),191(1),165(3),130(2),100(100),77(1),56(6)。
实施例128:3-溴-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈
按照实施例80的一般方法:将3-溴-2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.25g,0.79mmol)(按照与实施例115、实施例116和实施例117中描述的类似顺序制备),从1,3-二溴-2-(溴甲基)苯开始,代替1-溴-2-(溴甲基)苯)、4-(2-氯乙基)吗啉盐酸盐(0.29g,1.58mmol)、碳酸钾(1.09g,7.91mmol)和碘化钾(0.03g,0.16mmol)在DMF(15mL)中的混合物加热至回流保持3小时。加入水,用DCM萃取溶液3次,除去溶剂并通过硅胶柱色谱法纯化残余物(PE(石油醚):MTBE=1:1),得到标题产物(0.22g,0.48mmol,收率60%),为粘性液体。GC/MS(EI):m/z(%):430(2)[M+],428(2)[M+],345(10),343(10),234(8),204(8),234(8),114(25),100(100),88(3),79(2),70(10),56(15)。
实施例129:2-(5-甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈
按照实施例80的一般方法:使2-(2-羟基-5-甲基苄基)苯甲腈(0.30g,1.3mmol)、4-(2-氯丙基)吗啉盐酸盐(0.52g,2.6mmol)、碳酸钾(1.8g,13mmol)和碘化钾(0.043g,0.26mmol)在DMF(13mL)中反应,得到标题产物(0.010g,收率2%),为粘性液体。GC/MS(EI):m/z(%):350(2)[M+],263(52),220(4),204(2),190(10),178(5),128(10),1146(5),100(100),91(3),77(2),70(5),56(10)。1H NMR(300MHz,CDCl3)δ7.63(d,J=7.6Hz,1H),7.42(t,J=7.2Hz,1H),7.29-7.22(m,2H),7.17(d,J=7.8Hz,1H),7.03(d,J=8.2Hz,1H),6.97(s,1H),6.76(d,J=8.3Hz,1H),4.18(s,2H),4.05-3.94(m,1H),3.88-3.78(m,1H),3.70-3.60(m,4H),2.97-2.80(m,1H),2.60-2.46(m,4H),2.27(s,3H),1.67(s,1H),1.05(d,J=6.7Hz,3H)。13C NMR(75MHz,CDCl3)δ154.6(q),145.4(q),132.7(t),131.8(t),130.1(q),129.7(t),128.6(t),127.0(q),126.5(t),118.4(q),112.6(q),111.4(t),70.2(d),67.5(d),58.8(t),49.9(d),34.8(d),20.6(s),13.1(s)。
实施例130:3-氯-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈
按照实施例80的一般方法:使3-氯-2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.080g,0.28mmol)(按照实施例115、实施例116和实施例117所述的类似顺序制备)、4-(2-氯乙基)吗啉盐酸盐(0.10g,0.55mmol)、碳酸钾(0.38g,2.8mmol)和碘化钾(9.2mg,0.06mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.070g,收率64%),为粘性液体。GC/MS(EI):m/z(%):384(1)[M+],297(10),234(5),204(2),190(2),128(7),114(20),100(100),88(1),70(3)。1H NMR(300MHz,CDCl3)δ7.64(d,J=7.9Hz,2H),7.35(t,J=7.9Hz,1H),6.85(s,1H),6.10(s,1H),4.41(s,2H),4.01(t,J=5.7Hz,2H),3.82-3.69(m,4H),2.85(t,J=5.7Hz,2H),2.69-2.55(m,4H),2.30(s,3H),2.12(s,3H)。13C NMR(75MHz,CDCl3)δ153.4(q),142.1(q),136.6(q),134.4(t),133.4(q),131.7(t),130.6(t),129.9(q),128.4(t),126.2(t),117.5(q),116.0(q),70.0(d),67.1(d),58.9(d),54.4(d),32.5(d),21.0(s),16.4(s)。
实施例131:2-(3,5-二甲基-2-(3-吗啉代丙氧基)苄基)苯甲腈
按照实施例80的一般方法:将2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.13g,0.55mmol)、4-(3-氯丙基)吗啉(0.13g,0.82mmol)、碳酸钾(0.76g,5.5mmol)和碘化钾(0.020g,0.11mmol)在DMF(10mL)中的混合物加热至回流保持3小时。加入水(50mL),用DCM(3×30mL)萃取溶液3次,除去溶剂,并将残余物用硅胶柱色谱法纯化(PE:MTBE=1:1),得到标题产物(0.15g,收率71%),为无色液体。GC/MS(EI):m/z(%):364(1)[M+],349(1),234(2),208(5),128(25),116(5),100(100),86(3),70(10)。1H NMR(300MHz,CDCl3)δ7.63(s,1H),7.43(s,1H),7.26(s,1H),7.18(s,1H),6.89(s,1H),6.70(s,1H),4.19(s,2H),3.78(d,J=3.7Hz,2H),3.68(s,4H),2.59-2.35(m,6H),2.26(s,2H),2.21(s,2H),1.95(s,2H)。13CNMR(75MHz,CDCl3)δ153.6(q),145.4(q),133.6(q),132.9(t),132.7(t),131.5(q),131.2(q),131.0(t),130.0(t),129.1(t),126.6(t),118.4(q),112.5(q),70.9(d),67.1(d),55.4(d),53.8(d),34.4(d),27.4(d),20.9(s),16.4(s)。
实施例132:4-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲酸乙酯二盐酸盐
将1-(2-(2-(4-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪(0.30g,0.72mmol)(按照与实施例79和实施例80中所述的类似步骤顺序制备)在无水THF(20mL)中的溶液冷却至-78℃,并在氩气下滴加正丁基锂(0.5ml,1.6N的己烷溶液,0.79mmol)并将溶液在相同温度下搅拌1小时,之后加入氯甲酸乙酯(0.31g,2.9mmol)。再过4小时后加入饱和NH4Cl水溶液并将混合物温热至室温。将THF在旋转蒸发仪上蒸发。残余物用CH2Cl2(20mL×3)萃取,合并的有机层用Na2SO4干燥,过滤并真空浓缩,得到粗液体。将粗产物添加到Biotage,得到标题产物(0.15g,收率50%),为白色固体。GC/MS(EI):m/z(%):410(4)[M+],365(5),209(5),195(3),127(55),113(100),100(15),84(5),70(25)。
实施例133:3-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐
向在甲醇(10mL)中的3-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈(55mg,0.15mmol)(按照与实施例115、实施例116和实施例117,然后是实施例80中所述类似的顺序制备)中加入氯化氢(153mg,1.47mmol)并将所得混合物静置半小时。然后通过旋转蒸发除去溶剂,得到标题产物(55mg,0.14mmol,收率91%),为浅棕色固体。GC/MS(EI):m/z(%):363(1)[M+],248(1),204(3),190(5),165(2),127(65),113(100),100(7),84(6),70(34)。
实施例134:2-(2,4-二甲基-5-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈
按照实施例80的一般方法:使2-(5-羟基-2,4-二甲基苄基)苯甲腈(0.16g,0.66mmol)(在根据实施例115、实施例116和实施例117中描述的顺序制备2-(2-羟基-3,5-二甲基苄基)苯甲腈中作为异构体副产物分离)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.31,1.3mmol)、碳酸钾(0.91g,6.6mmol)和碘化钾(0.022g,0.13mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.13g,收率52%),为粘性液体。GC/MS(EI):m/z(%):361(1)[M+],294(1),204(2),190(2),165(2),127(40),113(100),98(5),84(3),70(32)。1H NMR(300MHz,CDCl3)δ7.65(d,J=7.0Hz,1H),7.44(t,J=7.7Hz,1H),7.29(d,J=7.5Hz,1H),7.01(d,J=7.8Hz,1H),6.95(s,1H),6.55(s,1H),4.14(s,2H),4.02(t,J=5.6Hz,2H),2.82(t,J=5.7Hz,2H),2.78-2.64(m,4H),2.63-2.46(m,4H),2.35(s,3H),2.17(s,3H),2.13(s,3H)。13C NMR(75MHz,CDCl3)δ155.3(q),144.7(q),134.7(q),133.1(t),133.0(t),132.9(t),129.4(t),128.5(q),126.7(t),125.5(q),118。2(q),113.5(t),112.7(q),66.8(d),57.3(d),55.1(d),53.3(d),45.8(s),37.8(d),18.7(s),15.9(s)。
实施例135:2-(5-甲基-2-(2-(1-甲基哌啶-4-基)乙氧基)苄基)苯甲腈
将亚硫酰氯(2.99g,25mmol)加入到在CDCl3(10mL)中的2-(1-甲基哌啶-4-基)乙-1-醇(0.20g,1.3mmol)中,并将所得混合物加热至回流保持5小时。通过旋转蒸发除去溶剂,得到粗氯化物。将该中间体与在DMF(10mL)中的2-(2-羟基-5-甲基苄基)苯甲腈(0.15g,0.63mmol)、碳酸钾(1.74g,12mmol)和碘化钾(0.020g,0.13mmol)混合,然后加热至回流保持2小时。冷却至室温后,加入水稀释溶液,用DCM萃取溶液,除去包括DMF在内的溶剂,并将残余物通过硅胶柱色谱法纯化(DCM:甲醇=10:1),得到标题产物(0.050g,收率22%),为深色液体。GC/MS(EI):m/z(%):348(60)[M+],333(5),222(5),190(10),142(10),126(100),112(20),96(20),70(15)。1H NMR(300MHz,CDCl3)δ7.57(d,J=7.6Hz,1H),7.40(t,J=7.3Hz,1H),7.25-7.17(m,1H),7.10(d,J=7.8Hz,1H),6.98(d,J=8.2Hz,1H),6.91(s,1H),6.68(d,J=8.3Hz,1H),4.07(s,2H),3.86(t,J=5.5Hz,2H),3.26(d,J=11.4Hz,2H),2.60(s,3H),2.55-2.49(m,1H),2.22(s,3H),1.88-1.45(m,8H)。13C NMR(75MHz,CDCl3)δ154.4(q),145.3(q),132.9(t),132.6(t),131.7(q),129.9(t),129.6(t),128.7(q),126.8(t),126.6(q),118.6(q),111.2(t),64.5(d),54.8(d),44.3(s),34.9(d),30.2(t),29.4(d),20.6(s)。
实施例136:2-(3,5-二甲基-2-(3-吗啉代丙基)苯氧基)苯甲腈
实施例136a:1-(烯丙基氧基)-3,5-二甲基苯
将3,5-二甲基苯酚(25.0g,205mmol)、3-溴丙-1-烯(32.2g,266mmol)和碳酸钾(56.6g,409mmol)在丙酮(400mL)中的混合物加热至回流过夜。旋转蒸发除去溶剂,加入水(200mL),用MTBE(100mL×3)萃取混合物,合并的有机相用MgSO4干燥,旋转蒸发除去溶剂,得到标题产物(33.0g,收率96%),为无色液体。GC/MS(EI):m/z(%):162(100)[M+],147(98),119(60),107(30),91(75),77(50),65(15)。
实施例136b:1-(烯丙基氧基)-3,5-二甲基苯
在Ar下将纯净的1-(烯丙基氧基)-3,5-二甲基苯(5.0g,29.3mmol)加热至200℃保持半小时。将反应冷却至室温后,通过硅胶柱色谱法纯化(PE:MTBE=92:8),得到标题产物(3.6g,收率72%),为无色液体。GC/MS(EI):m/z(%):162(85)[M+],147(100),135(25),119(50),91(55),77(35),65(20)。
实施例136c:2-(2-烯丙基-3,5-二甲基苯氧基)苯甲腈
在Ar下向2-烯丙基-3,5-二甲基苯酚(2.0g,11.7mmol)、2-碘苯甲腈(4.0g,17.5mmol)、磷酸钾(5.0g,23.4mmol)和吡啶甲酸(0.4g,3.5mmol)在DMSO(40mL)中的混合物中加入碘化铜(I)(0.34g,1.8mmol)。将混合物抽真空并用Ar冲洗3次,并将所得混合物加热至90℃过夜。将反应混合物冷却至室温后,加入稀NaCl溶液(100mL),用MTBE(100mL×3)萃取溶液,合并的有机相用MgSO4干燥,除去溶剂并通过硅胶柱色谱法纯化残余物(PE:MTBE=9:1),得到标题产物(2.5g,收率77%),为无色液体。GC/MS(EI):m/z(%):263(75)[M+],248(100),231(40),220(25),128(40),115(35),91(25)。
实施例136d:2-(2-(3-羟基丙基)-3,5-二甲基苯氧基)苯甲腈在Ar下在0℃下向2-(2-烯丙基-3,5-二甲基苯氧基)苯甲腈(0.5g,1.9mmol)在四氢呋喃(20mL)中的溶液中滴加BH3·Me2S(2M THF溶液,2.4mL,4.8mmol)。将混合物在室温下搅拌2小时后,将其冷却至0℃并用NaOH溶液(3M,3mL,6.6mmol)小心处理,然后加入H2O2(30%溶液,2.6g,22.8mmol)。将溶液在室温搅拌15分钟,然后加热回流2小时。将溶液冷却至室温后,加入水(30mL),用乙酸乙酯(40mL×3)萃取溶液,合并的有机相用MgSO4干燥,旋转蒸发除去溶剂,将残余物通过硅胶柱色谱法纯化(PE:MTBE=3:2),得到标题产物(0.19g,收率36%),为白色固体。GC/MS(EI):m/z(%):281(1)[M+],250(5),236(100),220(15),208(65),193(15),165(10),115(10),103(5),91(20)。
实施例136e:2-(3,5-二甲基-2-(3-氧代丙基)苯氧基)苯甲腈
在0℃下向2-(2-(3-羟基丙基)-3,5-二甲基苯氧基)苯甲腈(0.18g,0.6mmol)、乙酸钠(0.10g,1.2mmol)和硅胶(0.5g)在二氯甲烷(25mL)中的悬浮液中分批加入氯铬酸吡啶鎓(0.26g,1.2mmol)。然后将所得混合物在室温下搅拌2小时。使用MTBE(60mL)稀释反应溶液,将混合物通过小硅胶垫过滤,通过旋转蒸发除去溶剂并通过硅胶柱色谱法纯化残余物(PE:MTBE=4:1),得到标题产物(0.12g,收率67%),为无色液体。GC/MS(EI):m/z(%):279(10)[M+],260(25),236(30),222(100),208(45),193(15),165(10),115(25),103(10),91(35)。
实施例136f:2-(3,5-二甲基-2-(3-吗啉代丙基)苯氧基)苯甲腈
在0℃下和在氩气下向2-(3,5-二甲基-2-(3-氧代丙基)苯氧基)苯甲腈(0.11g,0.38mmol)和吗啉(0.040g,0.4mmol)在二氯甲烷(10mL)中的溶液中加入三乙酰氧基硼氢化钠(0.11g,0.5mmol)。然后将所得混合物在室温下搅拌过夜。将反应混合物冷却至5℃后,滴加稀NaHCO3溶液(20mL),用MTBE(30mL×3)萃取溶液,合并的有机相用MgSO4干燥,旋转蒸发浓缩,然后通过硅胶柱色谱法纯化残余物(PE:MTBE=7:3),得到标题产物(0.06g,收率42%),为液体。GC/MS(EI):m/z(%):350(8)[M+],207(15),193(3),127(11),115(15),100(100),91(10),56(10)。1H NMR(300MHz,CDCl3)δ7.64(d,J=7.6Hz,1H),7.42(t,J=7.5Hz,1H),7.08(t,J=7.5Hz,1H),6.87(s,1H),6.73(d,J=8.5Hz,1H),6.63(s,1H),3.83-3.50(m,4H),2.74-2.49(m,2H),2.45-2.35(m,6H),2.33(s,3H),2.26(s,3H),1.77-1.58(m,2H)。13CNMR(75MHz,13C NMR(75MHz,CDCl3)δ160.4(s),152.5(s),138.5(s),136.8(s),134.2(d),133.8(d),129.8(s),128.3(d),122.1(d),118.7(d),116.1(s),115.7(d),102.7(s),67.0(t),58.8(t),53.6(t),29.8(s),26.3(d),24.4(d),20.9(q),19.4(q)。
实施例137:4-(3-(2-(2-氟苯氧基)-4,6-二甲基苯基)丙基)吗啉
按照实施例136中所述的类似顺序制备:使3-(2-(2-氟苯氧基)-4,6-二甲基苯基)丙醛(0.17g,0.59mmol)、NaBH(AcO)3(0.19g,0.89mmol)和吗啉(0.070g,0.77mmol)在二氯甲烷(10mL)中反应,得到标题产物(0.17g,收率79%),为棕色粘性液体。GC/MS(EI):m/z(%):343(20)[M+],256(5),227(5),165(4),127(8),100(100),91(5),56(6)。1H NMR(300MHz,CDCl3)δ7.21-7.10(m,1H),7.08-7.00(m,2H),6.96-6.88(m,1H),6.76(s,1H),6.45(s,1H),3.85-3.50(m,4H),2.87-2.57(m,2H),2.40(s,6H),2.32(s,3H),2.20(s,3H),1.88-1.60(m,2H)。13C NMR(75MHz,CDCl3)δ155.3(s),154.6(s),152.1(s),145.1(s),144.8(s),137.9(s),136.3(s),128.3(s),126.5(d),124.5(d),124.0(d),123.7(d),123.6(d),120.3(d),117.0(d),116.8(d),115.8(d),67.0(t),58.9(t),53.7(t),26.3(t),24.2(t),21.0(q),19.4(q)。
实施例138:2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈
实施例138a:2-(3-羟基丙基)-5-甲基苯酚
在0℃下向LiAlH4(3.8g,100mmol)在四氢呋喃(150mL)中的悬浮液中小心地滴加7-甲基-2H-苯并吡喃-2-酮(10.0g,62.4mmol)在四氢呋喃(30mL)中的溶液。添加后,将所得混合物在室温下搅拌2小时。加入稀HCl溶液(100mL)小心淬灭反应,用乙酸乙酯(100mL×2)萃取溶液,合并的有机相用Na2SO4干燥,除去溶剂并通过硅胶柱色谱法纯化残余物(PE:MTBE=1:1),得到标题产物(2.8g,收率26%),为白色固体。GC/MS(EI):m/z(%):166(40)[M+],148(25),133(45),121(100),105(15),91(50),77(35),65(10)。
实施例138b:2-(2-(3-羟基丙基)-5-甲基苯氧基)苯甲腈
将2-(3-羟基丙基)-5-甲基苯酚(0.8g,4.67mmol)、2-碘苯甲腈(1.6g,7.0mmol)、磷酸钾(1.98g,9.3mmol)、碘化铜(I)(0.13g,0.7mmol)和吡啶甲酸(0.17g,1.4mmol)在DMSO(25mL)中的全部混合物抽空并用Ar冲洗3次。然后使其在90℃下搅拌过夜。加入水(100mL),用EA(100mL×3)萃取溶液,有机相用MgSO4干燥,除去溶剂并通过硅胶柱色谱法纯化残余物(PE:MTBE=2:3),得到标题产物(0.70g,收率56%),为白色固体。GC/MS(EI):m/z(%):267(4)[M+],249(100),234(90),222(30),206(40),194(35),115(20),91(35),77(20),65(10)。
实施例138c:2-(5-甲基-2-(3-氧代丙基)苯氧基)苯甲腈
在0℃下向氯铬酸吡啶鎓(0.39g,1.8mmol)、乙酸钠(0.15g,1.8mmol)和1.0g硅胶在二氯甲烷(25mL)中的悬浮液中分批加入2-(2-(3-羟基丙基)-5-甲基苯氧基)苯甲腈(0.25g,0.91mmol)并将所得混合物在室温下搅拌3小时。加入MTBE(60mL),混合物通过硅胶小垫过滤,用MTBE(50mL)冲洗垫,并除去溶剂,得到标题产物(0.26g,收率65%),为粘性液体,将其直接用于下一步。GC/MS(EI):m/z(%):265(45)[M+],236(100),222(75),208(100),194(40),121(50),115(20),91(35),77(20),65(10)。
实施例138d:2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈
将在二氯甲烷(15mL)中的2-(5-甲基-2-(3-氧代丙基)苯氧基)苯甲腈(0.22g,0.50mmol)和1-甲基哌嗪(0.05g,0.5mmol)装入烧瓶。并加入三乙酰氧基硼氢化钠(0.13g,0.60mmol)并将所得混合物在环境温度下搅拌过夜。将反应混合物冷却至5℃,滴加稀释的NaHCO3溶液(30mL),将混合物用二氯甲烷(30mL×3)萃取,浓缩有机相并将残余物通过硅胶柱色谱法纯化(DCM:甲醇=10:1),得到标题产物(0.14g,收率78%),为粘性液体。GC/MS(EI):m/z(%):349(7)[M+],293(6),248(2),194(5),160(6),127(45),113(100),98(5),85(8),70(40)。1H NMR(300MHz,CDCl3)δ7.63(dd,J=7.7,1.5Hz,1H),7.46-7.38(m,1H),7.16(d,J=7.7Hz,1H),7.07(t,J=7.5Hz,1H),6.97(d,J=7.8Hz,1H),6.76(s,1H),6.69(d,J=8.5Hz,1H),2.67-2.34(m,12H),2.30(d,J=5.9Hz,6H),1.86-1.69(m,2H)。13C NMR(75MHz,CDCl3)δ160.3(q),152.3(q),137.9(q),134.3(t),133.9(t),130.9(q),130.9(t),126.5(t),122.3(t),121.2(t),116.2(q),115.8(t),102.8(q),57.7(d),54.6(d),52.5(d),45.6(s),27.6(d),27.1(d),21.1(s)。
实施例139:2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈盐酸盐
向2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈(0.53g,1.44mmol)在甲醇(25mL)中的溶液中加入氯化氢(0.75g,7.20mmol)并将所得混合物在室温下搅拌半小时。然后除去溶剂,混合物在90℃下减压干燥,得到标题产物(550mg,1.35mmol,收率94%),为白色固体。GC/MS(EI):m/z(%):349(10)[M+],293(8),235(5),194(6),160(7),127(42),113(100),98(5),85(8),70(39)。
实施例140:2-(4-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈
按照实施例138中所述类似的顺序制备(从6-甲基-2H-苯并吡喃-2-酮开始,而不是从7-甲基-2H-苯并吡喃-2-酮开始):在最后一步中,向烧瓶中装入在二氯甲烷(15mL)中的2-(4-甲基-2-(3-氧代丙基)苯氧基)苯甲腈(0.18g,0.54mmol)和1-甲基哌嗪(0.050g,0.54mmol)。加入三乙酰氧基硼氢化钠(0.14g,0.65mmol)并将所得混合物在环境温度下搅拌过夜。将反应混合物冷却至5℃,滴加NaHCO3溶液,将混合物用DCM萃取,浓缩有机相并将残余物通过硅胶柱色谱法纯化(DCM:甲醇=10:1),得到标题产物(0.14g,收率72%),为粘性液体。GC/MS(EI):m/z(%):GC/MS(EI):m/z(%):349(25)[M+],293(11),194(5),160(15),127(60),113(100),85(10),70(40)。1H NMR(300MHz,CDCl3)δ7.63(d,J=7.7,1H),7.45-7.36(m,1H),7.13-6.99(m,3H),6.86(d,J=8.2Hz,1H),6.68(d,J=8.5Hz,1H),2.73-2.36(m,12H),2.34(s,6H),1.88-1.72(m,2H)。13C NMR(75MHz,CDCl3)δ160.5(q),150.1(q),135.5(q),134.4(q),133.9(t),133.9(t),131.7(t),128.4(t),122.2(t),120.7(t),116.3(q),115.4(t),102.7(q),57.7(d),54.6(d),52.5(d),45.7(s),27.9(d),27.1(d),21.0(s)。
实施例141:2-(2-(2-羟基-3-吗啉代丙基)-5-甲基苯氧基)苯甲腈
将2-(5-甲基-2-(环氧乙烷-2-基甲基)苯氧基)苯甲腈(0.20g,0.72mmol)(通过按照实施例136a-c中所述的类似顺序制备2-(2-烯丙基-5-甲基苯氧基)苯甲腈,然后按照实施例63中所述进行环氧化而得到)和吗啉(0.19g,2.15mmol)在乙醇(20mL)中的混合物加热至回流过夜。然后除去溶剂,加入水,用DCM萃取溶液,除去溶剂,将残余物通过硅胶柱色谱法纯化(PE:MTBE=3:7),得到标题产物(0.20g,0.57mmol,收率71%),为粘性液体。GC/MS(EI):m/z(%):352(1)[M+],281(1),223(1),207(4),194(1),152(1),130(4),100(100),77(2),56(5)。1H NMR(300MHz,CDCl3)δ7.65(s,1H),7.44(s,1H),7.27(s,1H),7.18-7.05(m,2H),6.92-6.62(m,2H),3.95(d,J=23.6Hz,1H),3.67(s,4H),3.50(s,1H),2.85(d,J=13.6Hz,1H),2.69(d,J=4.3Hz,1H),2.59(s,2H),2.47(d,J=13.8Hz,3H),2.35(d,J=11.7Hz,4H),1.26(s,2H),0.87(s,1H)。13C NMR(75MHz,CDCl3)δ159.8(s),152.9(s),140.2(s),134.2(d),133.9(d),132.1(d),129.1(s),127.5(d),126.4(d),122.4(d),121.0(d),118.0(d),115.9(d),102.9(s),67.1(t),66.2(d),64.2(t),53.5(t),35.2(s),32.1(t),21.1(q)。
实施例142:2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈
实施例142a:2-(2-(2-氰基苄基)-4,6-二甲基苯氧基)丙酸乙酯
将2-(2-羟基-3,5-二甲基苄基)苯甲腈(0.50g,2.1mmol)在DMF(10mL)中的溶液用碳酸钾(0.87g,6.3mmol)处理,然后加入2-溴丙酸乙酯(0.57g,3.2mmol)。将悬浮液在室温搅拌过夜。加入水(50mL),用MTBE(30mL×3)萃取溶液,除去溶剂并通过硅胶柱色谱法纯化残余物(PE:MTBE=8:1),得到标题产物(0.65g,收率90%),为粘性液体。GC/MS(EI):m/z(%):337(30)[M+],291(5),264(25),236(100),220(10),208(75),182(55),121(10),91(5),77(4)。
实施例142b:2-(2-((1-羟基丙-2-基)氧基)-3,5-二甲基苄基)苯甲腈
在0℃下将硼氢化钠(0.20g,5.3mmol)分批加入2-(2-(2-氰基苄基)-4,6-二甲基苯氧基)丙酸乙酯(0.60g,1.9mmol)在甲醇(10mL)中的溶液中并将所得混合物在室温下搅拌过夜。除去溶剂,加入水(50mL),用EA(40mL×3)萃取溶液,浓缩混合物并将残余物通过硅胶柱色谱法纯化(PE:MTBE=1:1),得到标题产物(0.52g,收率94%),为粘性液体。GC/MS(EI):m/z(%):295(10)[M+],264(8),237(100),222(15),208(55),194(30),182(55),121(25)。1H NMR(300MHz,CDCl3)δ7.63(d,J=7.7Hz,1H),7.50-7.41(m,1H),7.33-7.24(m,1H),7.18(d,J=7.8Hz,1H),6.89(s,1H),6.68(s,1H),4.35-4.10(m,3H),3.77(s,2H),2.28(s,3H),2.21(s,3H),1.19(d,J=6.4Hz,3H)。13C NMR(75MHz,CDCl3)δ151.3(q),145.4(q),133.4(q),132.9(t),132.8(t),132.1(q),131.3(t),131.2(q),130.1(t),129.1(t),126.7(t),118.6(q),112.6(q),78.5(t),66.9(d),34.8(d),20.8(s),17.5(s),16.2(s)。
实施例142c:2-(3,5-二甲基-2-((1-氧代丙-2-基)氧基)苄基)苯甲腈
在-78℃下向草酰氯(0.50g,3.94mmol)在二氯甲烷(体积:15mL)中的溶液中滴加(甲基亚磺酰基)甲烷(0.513g,6.6mmol)。然后在反应5分钟后通过注射器逐滴加入2-(2-((1-羟基丙-2-基)氧基)-3,5-二甲基苄基)苯甲腈(0.17g,0.55mmol)在二氯甲烷(5mL)中的溶液。将溶液在-78℃下搅拌30分钟。将三乙胺(1.33g,13mmol)加入到反应混合物中。将所得混合物在室温搅拌30分钟。加入水(25mL)并用二氯甲烷(3×25mL)萃取溶液。将合并的有机相用0.1M HCl水溶液(100mL)、H2O(100mL)洗涤,然后用饱和NaHCO3水溶液(100mL)和盐水(100mL)洗涤。有机相用MgSO4干燥并通过小硅胶垫过滤。除去溶剂,得到标题产物(0.18g,收率95%),为无色液体。GC/MS(EI):m/z(%):293(65)[M+],264(98),236(45),221(20),208(100),190(35),165(24),116(20)。
实施例142d:2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈
在烧瓶中加入在二氯甲烷(10mL)中的2-(3,5-二甲基-2-((1-氧代丙-2-基)氧基)苄基)苯甲腈(0.17g,0.49mmol)和1-甲基哌嗪(0.060g,0.64mmol)。添加三乙酰氧基硼氢化钠(0.13g,0.59mmol)并将所得混合物在环境温度下搅拌过夜。将反应混合物冷却至5℃,滴加NaHCO3溶液(30mL),将混合物用DCM(30mL×3)萃取,浓缩有机相并将残余物通过硅胶柱色谱法纯化(DCM:甲醇:TEA=95:5:1),得到标题产物(0.12g,收率61%),为粘性液体。GC/MS(EI):m/z(%):377(1)[M+],261(1),208(3),190(3),165(2),141(26),113(100),98(6),84(1),70(28)。1H NMR(300MHz,CDCl3)δ7.62(d,J=7.7Hz,1H),7.45-7.41(m,1H),7.29-7.22(m,1H),7.16(d,J=7.9Hz,1H),6.86(s,1H),6.69(s,1H),4.25(s,2H),2.78-2.66(m,1H),2.62-2.34(m,8H),2.27(s,3H),2.24(s,3H),2.20(s,3H),1.19(d,J=6.2Hz,3H)。13CNMR(75MHz,CDCl3)δ152.2(q),145.7(q),132.9(t),132.6(t),132.1(q),131.0(q),131.0(t),130.1(t),129.1(t),126.5(t),118.6(q),112.5(q),76.2(t),64.4(d),55.2(d),54.1(d),46.1(s),34.8(d),20.8(s),18.9(s),17.5(s)。
实施例143:2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈盐酸盐
向在甲醇(10mL)中的2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈(0.050g,0.13mmol)中加入氯化氢(0.065g,0.63mmol)并将所得混合物静置半小时。然后通过旋转蒸发除去溶剂并将残余物在库格尔若蒸馏器上干燥(90℃,0.1mbar),得到标题产物(0.050mg,收率91%),为固体。GC/MS(EI):m/z(%):377(1)[M+],237(2),208(5),141(35),113(100),98(8),84(1),70(30)。
实施例144:(1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-基)甲醇
向烧瓶中装入在二氯甲烷(10mL)中的2-(2-苄基-4-甲基苯氧基)乙醛(0.4g,1.17mmol)和哌啶-4-基-甲醇(0.17g,1.52mmol)。加入三乙酰氧基硼氢化钠(0.37g,1.75mmol)并将所得混合物在环境温度下搅拌过夜。将反应混合物冷却至5℃,滴加NaHCO3溶液,将混合物用DCM萃取,浓缩有机相并将残余物通过硅胶柱色谱法纯化(DCM:甲醇=90:10),得到标题产物(0.24g,0.64mmol,收率54.6%),为粘性液体。GC/MS(EI):m/z(%):339(15)[M+],224(5),195(5),165(5),142(4),128(100),115(4),91(10),67(4)。1H NMR(300MHz,CDCl3)δ7.25-7.10(m,5H),6.95(d,J=8.2Hz,1H),6.89(s,1H),6.73(d,J=8.2Hz,1H),4.05(t,J=5.9Hz,2H),3.92(s,2H),3.45(d,J=6.4Hz,2H),2.96(d,J=11.6Hz,2H),2.75(t,J=5.8Hz,2H),2.22(s,3H),2.12-2.00(m,2H),1.97(s,1H),1.68(d,J=13.1Hz,2H),1.54-1.36(m,1H),1.35-1.20(m,2H)。13C NMR(75MHz,CDCl3)δ154.5(q),141.4(q),131.4(t),129.9(q),129.6(q),128.9(t),128.3(t),127.8(t),125.8(t),111.6(t),67.9(d),66.6(d),57.7(d),54.0(d),38.4(t),36.2(d),28.9(d),20.6(s)。
实施例145:1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-醇
向烧瓶中装入在二氯甲烷(10mL)中的2-(2-苄基-4-甲基苯氧基)乙醛(0.50g,1.5mmol)和哌啶-4-醇(0.19g,1.9mmol)。加入三乙酰氧基硼氢化钠(0.46g,2.2mmol)并将所得混合物在环境温度下搅拌过夜。将反应混合物冷却至5℃,滴加NaHCO3溶液,将混合物用DCM萃取,浓缩有机相并通过硅胶柱色谱法纯化残余物(DCM:甲醇=90:10),得到标题产物(0.43g,收率82%),为粘性液体。GC/MS(EI):m/z(%):325(10)[M+],224(10),195(10),165(11),128(8),114(100),91(13),70(2)。1H NMR(300MHz,CDCl3)δ7.26-7.19(m,2H),7.14(t,J=8.6Hz,3H),6.98(d,J=8.2Hz,1H),6.92(s,1H),6.73(d,J=8.2Hz,1H),5.41(s,1H),4.16(t,J=5.0Hz,2H),3.92(s,2H),3.10-2.84(m,4H),2.66-2.46(m,2H),2.24(s,3H),2.03-1.92(m,3H),1.72-1.55(m,2H)。13C NMR(75MHz,CDCl3)δ154.0(q),141.3(q),131.9(t),130.4(q),128.9(q),128.7(t),128.4(t),128.1(t),125.9(t),111.4(t),64.9(d),56.5(d),50.1(d),36.3(d),32.5(d),20.6(s)。
实施例146:1-(2-(2-苄基-4-甲基苯氧基)乙基)哌嗪
向烧瓶中装入在二氯甲烷(体积:10mL)中的2-(2-苄基-4-甲基苯氧基)乙醛(0.33g,0.96mmol)和哌嗪(0.17g,1.92mmol)。添加三乙酰氧基硼氢化钠(0.27g,1.25mmol)并将所得混合物在环境温度下搅拌过夜。将反应混合物冷却至5℃,滴加NaHCO3溶液,将混合物用DCM萃取,浓缩有机相并通过硅胶柱色谱法纯化残余物(DCM:甲醇=80:20),得到标题产物(0.10g,0.31mmol,收率31.8%),为粘性无色液体。GC/MS(EI):m/z(%):310(25)[M+],268(10),195(10),165(20),152(10),113(30),99(100),86(20),70(30),56(50)。
实施例147:1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪
在室温下,向氢化钠(1.34g,31.3mmol,56%纯度)在DMF(20mL)中的混合物中加入2-苄基-4,6-二甲基苯酚(1.00g,4.5mmol)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.58g,6.7mmol)和碘化钾(0.15g,0.89mmol),然后将混合物在70℃下搅拌过夜。然后将混合物加热至100℃保持1小时。加入水(60mL)淬灭反应,用EA(50mL×3)萃取溶液3次,小心地除去溶剂并通过硅胶柱色谱法纯化残余物(DCM:甲醇=10:1),得到标题产物(0.32g,收率21%),为粘性液体。GC/MS(EI):m/z(%):338(4)[M+],295(1),209(5),178(4),165(7),127(52),113(100),100(19),84(7),70(41)。1H NMR(300MHz,CDCl3)δ7.25-7.10(m,5H),6.83(s,1H),6.71(s,1H),3.97(s,2H),3.77(t,J=5.9Hz,2H),2.70(t,J=5.9Hz,2H),2.56(s,8H),2.28(s,3H),2.24(s,3H),2.18(s,3H)。13C NMR(75MHz,CDCl3)δ153.6(q),141.4(q),133.4(q),133.3(q),130.7(q),130.2(t),129.3(t),128.9(t),128.4(t),125.9(t),70.2(d),58.1(d),55.0(d),53.5(d),45.9(s),35.8(d),20.8(s),16.5(s)。
实施例148:1-甲基-4-(2-(4-甲基-2-(3-甲基苄基)苯氧基)乙基)哌嗪
在室温下,向氢化钠(1.20g,28.0mmol)在DMF(20mL)中的混合物中加入4-甲基-2-(3-甲基苄基)苯酚(1.00g,4.0mmol)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.41g,6.0mmol)和碘化钾(0.13g,0.80mmol)。将所得混合物在40℃下搅拌两天。将其加热至100℃保持1小时。加水淬灭反应,用EA萃取溶液3次,除去溶剂,将残余物通过硅胶柱色谱法纯化(PE:MTBE=1:1至MTBE至DCM:甲醇=10:1),得到标题产物(0.28g,收率20%),为淡黄色粘性液体。GC/MS(EI):m/z(%):338(3)[M+],295(1),209(2),178(3),165(6),127(43),113(100),100(6),84(4),70(37)。1H NMR(300MHz,CDCl3)δ7.20-7.10(m,1H),7.06-6.87(m,5H),6.74(d,J=8.2Hz,1H),4.06(t,J=5.7Hz,2H),3.90(s,2H),2.77(t,J=5.7Hz,2H),2.75-2.41(m,8H),2.32(s,3H),2.30(s,3H),2.24(s,3H)。13C NMR(75MHz,CDCl3)δ154.5(q),141.2(q),137.7(q),131.4(t),129.9(q),129.7(t),129.6(t),128.2(t),127.7(t),126.5(t),125.9(t),111.6(t),66.7(d),57.3(d),55.0(d),53.3(d),45.8(s),36.1(d),21.5(s),20.6(s)。
实施例149:1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪
在0℃下向氢化钠(0.22g,9.1mmol)在DMF(10mL)中的悬浮液中加入2-异丁基-4-甲基苯酚(0.30g,1.8mmol)和1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.45g,1.8mmol)并将反应混合物在室温下搅拌过夜。然后将其倒入冰水中,混合物用EA萃取,除去溶剂,将残余物通过硅胶柱色谱法纯化(DCM:甲醇=3:1),得到标题产物(0.13g,收率23%),为粘性棕色液体。GC/MS(EI):m/z(%):290(1)[M+],275(1),207(2),176(1),147(1),127(38),113(100),98(5),84(4),70(31)。1H NMR(300MHz,CDCl3)δ6.94-6.84(m,2H),6.69(d,J=8.1Hz,1H),4.05(t,J=5.7Hz,2H),2.80(t,J=5.7Hz,2H),2.68-2.55(m,8H),2.52(s,4H),2.42(d,J=7.1Hz,2H),2.32(s,3H),2.24(s,3H),1.95-1.80(m,1H),0.87(d,J=6.6Hz,6H)。13C NMR(75MHz,CDCl3)δ154.8(q),131.8(t),130.2(q),129.4(q),127.1(t),111.3(t),66.6(d),57.4(d),55.1(d),53.5(d),45.9(s),39.7(d),29.9(s),28.9(t),22.7(s),20.6(s)。
实施例150:1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐
在0℃下向氢化钠(0.22g,9.1mmol)在DMF(10mL)中的悬浮液中加入2-异丁基-4-甲基苯酚(0.30g,1.8mmol)和1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.45g,1.8mmol)并将反应混合物在室温下搅拌过夜。然后将其倒入冰水中,混合物用EA萃取,除去溶剂,将残余物通过硅胶柱色谱法纯化(DCM:甲醇=3:1),得到标题产物(0.13g,收率23%),为粘性棕色液体。GC/MS(EI):m/z(%):331(5)[M+],244(8),207(10),171(2),145(3),114(15),100(100),91(3),70(4)。GC/MS(EI):m/z(%):290(1)[M+],275(1),147(1),127(40),113(100),98(5),84(5),70(35)。
实施例151:1-(2-(2-(2-碘苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪
将1-(2-(2-(2-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪(0.15g,0.36mmol)、2,2,2-三氟乙酸钠(0.29g,2.2mmol)和碘化铜(I)(0.41g,2.16mmol)在DMF(10mL)和甲苯(3mL)中的溶液加热至回流保持6小时。然后将混合物在150℃保持两天。加入水(50mL),用DCM(50mL×3)萃取溶液,除去溶剂并通过硅胶柱色谱法纯化残余物(DCM:甲醇=10:1),得到标题产物(0.089g,收率27%),为粘性液体。GC/MS(EI):m/z(%):464(5)[M+],209(10),195(8),179(11),165(10),152(5),127(74),113(100),100(20)。1H NMR(300MHz,CDCl3)δ7.88-7.50(m,1H),7.23-7.18(m,1H),7.11-6.85(m,3H),6.64(d,J=5.7Hz,1H),4.04(d,J=12.8Hz,2H),3.79(t,J=5.3Hz,2H),2.99-2.66(m,10H),2.54(s,3H),2.26(s,3H),2.20(s,3H)。13C NMR(75MHz,CDCl3)δ153.5(q),143.7(q),140.5(q),139.3(t),133.7(q),132.6(t),131.9(q),131.6(q),130.8(q),130.7(t),130.7(t),130.6(t),129.9(t),129.3(t),128.5(t),128.1(t),127.9(t),127.6(t),124.8(q),101.5(q),70.0(d),57.7(d),54.4(d),51.6(d),44.8(s),41.4(d),36.2(d),20.9(s),16.5(s)。
实施例152:2-(2-羟基-5-甲基亚苄基)环己-1-酮
在搅拌下将2-羟基-5-甲基苯甲醛(5.00g,36.7mmol)在4%氢氧化钠水溶液(5.88g,147mmol)中的溶液滴加到4%氢氧化钠水溶液(1.47g,36.7mmol)和环己酮(18.02g,184mmol)的混合物中。将反应混合物在室温搅拌40小时,然后用HCl 6N(40mL)中和。滴加HCl溶液以避免加热。将产物萃取到CHCl3(100mL)中,用水(4×100mL)洗涤并用Na2SO4干燥。蒸发氯仿,所得深棕色液体用热石油醚萃取。粗品经Biotage纯化,得到标题产物(3.60g,收率45%)。GC/MS(EI):m/z(%):210(1)[M+],197(100),183(40),168(10),152(10),91(10),76(8)。
实施例153:2-(2-羟基-5-甲基苄基)环己-1-酮
在搅拌下向Pd-C(钯碳)(0.050g,0.46mmol)在MeOH(50mL)中的悬浮液中加入(E)-2-(2-羟基-5-甲基亚苄基)环己-1-酮(1.00g,4.6mmol),并将混合物置于氢气气氛(5bar)下。将反应混合物在室温搅拌40小时。将产物萃取到CHCl3(100mL)中,用水(4×100mL)洗涤并用Na2SO4干燥。蒸发氯仿,并将所得棕色液体通过硅胶柱纯化,得到标题产物(0.84g,收率82%)。GC/MS(EI):m/z(%):218(40)[M+],199(20),171(40),121(100),108(40),91(20),77(20)。
实施例154:(E)-2-(5-甲基-2-(2-吗啉代乙氧基)亚苄基)环己-1-酮
按照实施例80的一般方法:使(E)-2-(2-羟基-5-甲基亚苄基)环己-1-酮(0.30g,1.4mmol)、4-(2-氯乙基)吗啉二盐酸盐(0.62g,2.8mmol)、碳酸钾(0.58g,4.2mmol)和碘化钾(0.046g,0.28mmol)在DMF(20mL)中的混合物反应,得到标题产物(0.21g,收率46%),为粘性液体。GC/MS(EI):m/z(%):329(10)[M+],242(2),199(5),171(3),145(5),114(5),100(100),91(4),70(5)。1H NMR(300MHz,CDCl3)δ7.61(s,1H),7.13-7.00(m,2H),6.79(d,J=8.2Hz,1H),4.09(t,J=5.9Hz,2H),3.75-3.69(m,4H),2.83-2.70(m,4H),2.59-2.48(m,6H),2.29(s,3H),1.94-1.84(m,2H),1.79-1.68(m,2H)。13C NMR(75MHz,CDCl3)δ201.9(q),155.6(q),136.8(q),131.4(t),130.9(t),130.5(t),129.5(q),124.9(q),112.1(t),67.1(d),57.7(d),54.3(d),40.6(d),29.3(d),24.2(d),23.8(d),20.7(s)。
实施例155:(E)-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)亚苄基)-环己-1-酮
将(E)-2-(2-羟基-5-甲基亚苄基)环己-1-酮(0.30g,1.4mmol)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.65g,2.8mmol)、碳酸钾(0.58g,4.2mmol)和碘化钾(0.046g,0.28mmol)在DMF(20mL)中的混合物加热至100℃保持4小时。然后用水(50mL)稀释,然后用CH2Cl2(50mL×2)萃取。合并的有机层用Na2SO4干燥。过滤混合物,浓缩滤液,得到粗产物。粗产物通过硅胶柱色谱法纯化,用(己烷:MTBE=20:1→10:1)洗脱,得到标题产物(0.13g,0.38mmol,收率27.1%),为无色液体。GC/MS(EI):m/z(%):365(8)[M+],350(5),319(3),290(11),262(100),235(11),207(24),75(9)。1H NMR(300MHz,CDCl3)δ6.91(d,J=9.0Hz,2H),6.68(d,J=8.0Hz,1H),4.11-3.95(m,2H),3.15(dd,J=13.5,4.6Hz,1H),2.76(t,J=5.7Hz,2H),2.70-2.44(m,8H),2.39-2.28(m,5H),2.22(s,3H),2.09-1.86(m,2H),1.82-1.45(m,3H),1.40-1.21(m,1H)。13C NMR(75MHz,CDCl3)δ213.2(q),154.6(q),132.0(t),129.6(q),128.7(q),127.5(t),111.3(t),66.3(d),57.3(d),55.0(d),53.4(d),50.8(t),45.9(s),42.2(d),33.6(d),30.3(d),28.2(d),25.1(d),20.5(s)。
实施例156:2-(5-甲基-2-(2-吗啉代乙氧基)苄基)环己-1-酮
按照实施例80的一般方法:使2-(2-羟基-5-甲基苄基)环己-1-酮(0.30g,1.4mmol)、4-(2-氯乙基)吗啉二盐酸盐(0.61g,2.8mmol)、碳酸钾(0.95g,6.9mmol)和碘化钾(0.046g,0.28mmol)在DMF(20mL)中的混合物反应,得到标题产物(0.24g,收率53%),为粘性液体。GC/MS(EI):m/z(%):331(5)[M+],244(8),207(10),171(2),145(3),114(15),100(100),91(3),70(4)。1H NMR(300MHz,CDCl3)δ6.92(d,J=8.0Hz,1H),6.90(s,1H),6.69(d,J=8.0Hz,1H),4.12-3.95(m,2H),3.74-3.64(m,4H),3.20-3.15(m,1H),2.75(t,J=5.6Hz,2H),2.67-2.48(m,5H),2.45-2.17(m,6H),2.10-1.91(m,2H),1.84-1.46(m,3H),1.41-1.30(m,1H)。13C NMR(75MHz,CDCl3)δ212.9(q),154.6(q),132.0(t),129.6(q),128.6(q),127.5(t),111.2(t),67.0(d),66.1(d),57.9(d),54.1(d),50.8(t),42.2(d),33.6(d),30.3(d),28.1(d),25.1(d),20.5(s)。
实施例157:(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲醇
向LiAlH4(0.17g,4.4mmol)在THF(20mL)中的悬浮液中加入(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲酮(0.15g,0.44mmol)并将所得混合物在室温下搅拌1小时。加入水淬灭反应,用DCM萃取溶液,去除溶剂,将残余物通过硅胶柱色谱法纯化(DCM:甲醇=10:1),得到标题产物(0.10g,收率63%),为粘性液体。GC/MS(EI):m/z(%):340(30)[M+],296(5),252(4),195(8),127(4),127(55),113(100),100(15),84(10),70(55)。1H NMR(300MHz,CDCl3)δ7.42-7.35(m,2H),7.32-7.28(m,2H),7.25-7.17(m,1H),7.02(d,J=8.1Hz,1H),6.93(s,1H),6.78(d,J=8.2Hz,1H),5.87(s,1H),4.16-3.98(m,2H),2.73-2.41(m,10H),2.32(s,3H),2.25(s,3H)。13C NMR(75MHz,CDCl3)δ154.5(q),144.1(q),133.8(q),130.6(q),129.7(t),129.0(t),128.0(t),126.7(t),126.3(t),113.5(t),73.4(t),65.4(d),57.3(d),54.6(d),52.9(d),45.8(s),20.7(s)。
实施例158:1-甲基-4-(2-(4-甲基-2-(1-苯基乙烯基)苯氧基)乙基)哌嗪
实施例158a:苯甲酸对甲苯酯
在0℃下向对甲酚(200g,1.85mol)在DCM(体积:150mL)中的溶液中加入三乙胺(387mL,2774mmol)和DMAP(0.23g,1.85mmol),然后加入苯甲酰氯(312g,2.22mol)。将反应混合物升温至室温并搅拌3小时。此时,反应混合物用DCM 500mL稀释并用NH4Cl 500mL水溶液淬灭。水层用DCM(2×100)萃取,合并的有机层随后用水和盐水洗涤,并真空浓缩。将所得残余物在300mL PE中重结晶,得到标题产物(347g,收率87%),为白色粉末。GC/MS(EI):m/z(%):212(15)[M+],105(100),77(35),51(5)。
实施例158b:(2-羟基-5-甲基苯基)(苯基)甲酮
将苯甲酸对甲苯酯(300g,1.41mol)和氯化铝(283g,2.12mol)的混合物在氯苯(体积:200mL)中缓慢(约0.5小时)加热至120-125℃。将该混合物在该温度下搅拌20小时,然后在0℃加入HCl(172mL,5.65mol)2M HCl。产物用3×200mL DCM萃取,合并的萃取物用Na2SO4干燥,然后蒸发至干。这一方法得到标题产物(240g,1.07mol,收率76%),将其未经额外纯化进一步使用。GC/MS(EI):m/z(%):212(75)[M+],211(100),135(40),105(25),77(35)。
实施例158c:2-(1-羟基-1-苯基乙基)-4-甲基苯酚
在0℃下向在THF(体积:10mL)中的甲基溴化镁(3M乙醚溶液,14.2mmol,4.7mL)中加入(2-羟基-5-甲基苯基)(苯基)甲酮(1.00g,4.7mmol)并将所得混合物在室温下搅拌1小时。用饱和NH4Cl溶液(50mL)淬灭反应,用MTBE(30mL×3)萃取溶液,除去溶剂,残余物直接作为标题产物(1.10g,收率87%)。GC/MS(EI):m/z(%):211(100)[M+],210(100),195(95),165(55),152(20),77(20)。
实施例158d:4-甲基-2-(1-苯基乙烯基)苯酚
向2-(1-羟基-1-苯乙基)-4-甲基苯酚(1.10g,4.8mmol)和MgSO4在DCM(30mL)中的搅拌溶液中加入乙酸(0.060g,0.96mmol)。然后将所得混合物在室温下搅拌过夜。完成后,将反应混合物过滤并用DCM洗涤。将滤液浓缩,残余物通过硅胶色谱法纯化(PE:MTBE=10:1),得到标题产物(1.00g,收率96%),为粘性液体。GC/MS(EI):m/z(%):210(100)[M+],209(100),195(95),178(15),165(50),152(20),115(13),103(10),77(20)。
实施例158e:1-甲基-4-(2-(4-甲基-2-(1-苯基乙烯基)苯氧基)乙基)哌嗪
按照实施例80的一般方法:使4-甲基-2-(1-苯基乙烯基)苯酚(0.25g,1.2mmol)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.56g,2.4mmol)、碳酸钾(1.64g,12mmol)和碘化钾(0.040g,0.24mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.20g,收率47%),为粘性液体。GC/MS(EI):m/z(%):336(98)[M+],209(10),195(5),178(12),165(20),127(35),113(100),98(20),70(85)。1H NMR(300MHz,CDCl3)δ7.31-7.20(m,5H),7.13-7.06(m,2H),6.79-6.72(m,1H),5.62(s,1H),5.29(s,1H),3.89(t,J=5.7Hz,2H),2.45-2.32(m,13H),2.25(s,3H)。13C NMR(75MHz,CDCl3)δ154.3(q),147.8(q),141.8(q),132.0(t),131.4(q),130.2(q),129.4(t),128.1(t),127.3(t),126.5(t),115.3(d),112.6(t),67.3(d),57.0(d),55.1(d),53.4(d),46.1(s),20.6(s)。
实施例159:1-甲基-4-(2-(4-甲基-2-(1-苯基乙基)苯氧基)乙基)哌嗪
实施例159a:4-甲基-2-(1-苯基乙基)苯酚
将在MeOH(30mL)中的4-甲基-2-(1-苯基乙烯基)苯酚(0.40g,1.9mmol)和10%Pd/C(0.15g)的混合物在H2下搅拌过夜。将混合物通过硅胶小垫过滤,除去溶剂,得到标题产物(0.40g,收率94%),为粘性液体,将其直接用于下一步。GC/MS(EI):m/z(%):212(98)[M+],197(100),182(50),165(20),134(30),91(40),77(40),65(15)。
实施例159b:1-甲基-4-(2-(4-甲基-2-(1-苯基乙基)苯氧基)乙基)哌嗪
按照实施例80的一般方法:使4-甲基-2-(1-苯基乙基)苯酚(0.25g,1.2mmol)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.56g,2.4mmol)、碳酸钾(1.63g,11mmol)和碘化钾(0.040g,0.24mmol)在DMF(10mL)中的混合物反应,得到标题产物(0.20g,收率48%),为粘性液体。GC/MS(EI):m/z(%):338(25)[M+],209(5),195(10),165(12),127(90),113(100),100(20),84(10),70(80)。1H NMR(300MHz,CDCl3)δ7.25-7.17(m,4H),7.16-7.09(m,1H),7.00(s,1H),6.95(d,J=8.2Hz,1H),6.70(d,J=8.2Hz,1H),4.50(q,J=7.3Hz,1H),4.10-3.88(m,2H),2.76-2.65(m,2H),2.59-2.55(m,4H),2.54-2.45(m,4H),2.30(s,3H),2.26(s,3H),1.56(d,J=7.3Hz,3H)。13C NMR(75MHz,CDCl3)δ154.1(q),146.8(q),134.5(q),129.8(q),128.6(t),128.1(t),127.7(t),127.4(t),125.7(t),111.7(t),66.7(d),57.3(d),55.1(d),53.4(d),46.0(s),37.8(t),21.2(s),20.9(s)。
实施例160:4-(2-(2-(1-(2-氟苯基)乙基)-4,6-二甲基苯氧基)乙基)吗啉
将2-(1-(2-氟苯基)乙基)-4,6-二甲基苯酚(0.37g,1.51mmol)(按照实施例158和实施例159a所述的类似顺序制备)、4-(2-氯乙基)吗啉盐酸盐(0.85g,4.54mmol)、碳酸钾(1.26g,9.09mmol)和碘化钾(0.03g,0.15mmol)在DMF(20mL)中的混合物加热至回流保持3小时。向冷却的溶液中加入水,用DCM萃取溶液,除去溶剂并通过硅胶柱色谱法纯化残余物(PE:MTBE=1:1),得到标题产物(0.46g,1.25mmol,收率82%),为淡黄色液体。GC/MS(EI):m/z(%):357(10)[M+],270(30),255(15),241(5),227(5),114(30),100(100),91(3),70(10),56(15)。
实施例161:4-(2-(2-(1-(2-氟苯基)乙烯基)-4,6-二甲基苯氧基)乙基)吗啉
将2-(1-(2-氟苯基)乙烯基)-4,6-二甲基苯酚(0.5g,2.06mmol)(按照实施例158所述的类似顺序制备)、4-(2-氯乙基)吗啉盐酸盐(1.15g,6.19mmol)、碳酸钾(1.71g,12.38mmol)和碘化钾(0.03g,0.21mmol)在DMF(20mL)中的混合物加热至回流保持3小时。GCMS显示起始材料完全消耗,并且在GCMS中观察到=7:3的混合物。将水加入冷却的溶液中,使用DCM萃取混合物,除去溶剂并通过硅胶柱色谱法纯化残余物(PE:MTBE=5:1),得到标题产物(0.43g,1.25mmol,收率57%),为淡黄色液体。GC/MS(EI):m/z(%):355(20)[M+],270(30),255(35),241(10),183(10),114(20),100(100),85(3),70(10),56(15)。
实施例162:(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲酮
将(2-羟基-5-甲基苯基)(苯基)甲酮(0.50g,2.4mmol)、1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(1.11g,4.7mmol)、碳酸钾(3.26g,23mmol)和碘化钾(0.080g,0.47mmol)在DMF(体积:10mL)中的混合物加热至回流保持3小时。加入水,用DCM萃取溶液3次,除去溶剂并通过硅胶柱色谱法纯化残余物(DCM:甲醇=10:1),得到标题产物(0.58g,1.54mmol,收率65.5%),为粘性液体。GC/MS(EI):m/z(%):338(3)[M+],282(3),268(5),211(10),165(5),127(55),113(100),98(10),70(85)。1H NMR(300MHz,CDCl3)δ7.79-7.71(m,2H),7.55-7.50(m,1H),7.44-7.35(m,2H),7.24-7.15(m,2H),6.81(d,J=6.3Hz,1H),3.97(t,J=5.6Hz,2H),2.39(t,J=5.6Hz,2H),2.35-2.24(m,11H),2.21(s,3H)。13C NMR(75MHz,CDCl3)δ197.1(q),154.6(q),138.4(q),132.8(t),132.5(t),130.4(q),130.1(t),129.7(t),129.1(q),128.2(t),112.6(t),67.5(d),56.8(d),55.0(d),53.4(d),46.0(s),20.5(s)。
实施例163:1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪
在冰浴中历时2小时将氢化钠(489mg,12.24mmol)加入到在DMF(15mL)中的2-苄基-4-甲基环己醇(0.50mg,2.5mmol)中,将1-(2-氯乙基)-4-甲基哌嗪二盐酸盐(0.87g,3.7mmol)滴加到上述溶液中。滴加结束后,在室温下反应12小时。反应完成后,用水洗涤两次。有机相用无水硫酸钠干燥,蒸发至干,得到标题产物(0.20g,收率25%)。GC/MS(EI):m/z(%):330(3)[M+],127(35),113(100),98(50),84(4),70(20),56(5)。
实施例164:1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪二盐酸盐
根据实施例96中描述的方法,由1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪制备,得到标题产物(0.15g,收率18%),为棕色固体。GC/MS(EI):m/z(%):330(2)[M+],127(40),113(100),98(50),84(4),70(20),56(5)。
实施例165:2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯胺
将4-(2-(2,4-二甲基-6-(2-硝基苄基)苯氧基)乙基)吗啉(0.45g,0.85mmol)和10%Pd/C(150mg)在甲醇(15mL)中的混合物在H2下搅拌过夜。过滤混合物,除去溶剂并通过硅胶柱色谱法纯化残余物(DCM:甲醇=95:5),得到标题产物(0.21g,0.06mmol,收率36.3%),为粘性液体。GC/MS(EI):m/z(%):340(3)[M+],253(13),227(29),210(14),194(4),165(2),114(26),100(100),87(1),70(5)。
实施例166:TRPM8调节剂测定
根据Klein等人(Chem.Senses 36:649-658,2011)生成了稳定表达hTRPM8的HEK293细胞系,并通过Flexstation中的钙成像监测受体激活。对于TRPM8通道激活的Ca成像测定,细胞在第0天以每孔12000个细胞的密度接种在涂有0.001%聚乙烯亚胺(分子量=60000,Acros Organics)的黑色透明底部96孔板中的Dulbecco改良Eagle培养基(DMEM)中,该培养基含有9%胎牛血清。在第2天,使用Fluo-4通过钙成像评估激动剂。简要地,弃去生长培养基,并将细胞在50μL加样缓冲液中于37℃在黑暗中孵育1h,该缓冲液由DMEM(不含血清)中的2.7μM Fluo-4 AM(Invitrogen)和2.5μM丙磺舒(Sigma-Aldrich)组成。孵育后,用100μL的检测缓冲液(单位:mM:130NaCl,5KCl,10HEPES,2CaCl2和10葡萄糖,pH 7.4)洗涤板5次,然后在室温下黑暗中进一步孵育30分钟。然后用100μL测定缓冲液洗涤细胞五次,然后在Flexstation 3(Molecular Devices)中测量本发明化合物的系列稀释液的钙流入量。在加入20μl的10倍浓缩配体储备溶液后引发受体激活,该配体储备溶液也在测定缓冲液中制备。在添加配体之前持续监测荧光15秒,并在添加配体之后持续监测荧光105秒,总共120秒。确定了与溶剂对照相关和相对于31.6μM薄荷醇的最大受体激活。使用KNIME工作流程处理来自系列稀释液的数据,以拟合S型剂量-响应曲线并推断EC50值。
表现出低于35μM的EC50值的TRPM8激动剂列于下表1中。
表1:
++++EC50值在0.05μM及以下范围内
+++EC50值在0.05-0.3μM范围内
++EC50值在0.3-1.00μM范围内
+EC50值在1.00-35μM范围内
实施例167:水溶液中的感官研究
下表2中列出的化合物以1wt-%的浓度溶解在丙二醇中。然后将这些溶液以适当的量分配到含有0.5wt-%Poloxamer 407(它是一种亲水性非离子表面活性剂,例如,购自SigmaAldrich)和0.25wt-%RH40(从BASF获得)作为增溶剂的去离子水中,以获得相应化合物的40ppm(百万分之几)的所需最终浓度。
训练有素的小组成员通过将20mL溶液在口中啜饮60秒,然后吐出,随后在评估期间不漱口,对含有测试化合物的水溶液进行了评估。小组成员在两小时内的不同时间点评估并记录清凉性能以及其他感觉和感官属性。清凉性能以0到10的等级评定,0表示没有效果,10表示极冷。对所有小组成员将得分进行平均,并且将清凉强度分为“N”,表示“无”(得分为0),“L”,表示“低”(得分高于0,最高为1),“M”,表示“中等”(得分高于1,最高为4),“S”,表示“强”(得分高于4,最高为8)和“E”,表示“极端”(得分高于8),其提供在表2中。所测试的化合物均未显示出任何统计学上显著的苦味或负面的感官特征。
表2:
A列:最大清凉
B列:最大清凉的时间,单位分钟
C列:1小时后的清凉
实施例168:在模型洁牙剂中的感官研究
将表3中列出的化合物以1wt-%的浓度溶解在丙二醇中。然后将这些溶液以获得所需100ppm(百万分之几)的测试化合物的最终浓度的适当的量分散到模型未加香洁牙剂中,其配方如下所示(括号中分别标明从供应商获得的成分)。
训练有素的小组成员通过使用牙刷用1g洁牙剂刷牙60秒,随后吐出,之后在评价期间不漱口来评价含有式(I)的化合物的洁牙剂。小组成员在两小时内的不同时间点评估并记录清凉性能以及其他感觉和感官属性。清凉性能以0到10的等级评定,0表示没有效果,10表示极冷。对所有小组成员将得分进行平均,并且将清凉强度分为“N”,表示“无”(得分为0),“L”,表示“低”(得分高于0,最高为1),“M”,表示“中等”(得分高于1,最高为4),“S”,表示“强”(得分高于4,最高为8)和“E”,表示“极端”(得分高于8),其总结在以下表3中。所测试的化合物均未显示出任何统计学上显著的苦味或负面的感官特征。
表3:
A列:最大清凉
B列:最大清凉的时间,单位分钟
C列:1小时后的清凉
Claims (11)
1.调节瞬时受体电位通道melastatin成员8(TRPM8)的方法,包括使所述受体与式(I)的化合物或其盐或溶剂合物接触
其中
环A代表苯基环、环己基或环己烯基环;
R1选自氢、C1-C6烷基和C1-C6烷氧基,
R2连接至环A的3、4或5位且选自氢、卤素、C1-C6烷基、C1-C6烷氧基和C(O)O-C1-C3-烷基,
R3选自氢、C1-C6烷基、C2-C6烯基、OH和=O,且R4选自氢、C1-C6烷基、C2-C6烯基和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统,且R4为氢,
R5选自氢、F和C1-C6烷基,
R6选自氢、F和C1-C6烷基,
m为0或1,
p为0或1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基,
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH或CH2OH,
Y连接至环A的2或3位且选自C4-C6烷基(例如异丁基),
其中
环B代表苯基、噻吩、呋喃或吡啶环,
R11选自CN、卤素、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基、C1-C3烷氧基、C2-C3烯基和OH,且n为0-5的整数,条件是如果n>1,则R11可以相同或不同,
X选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH。
2.根据权利要求1的方法,其中式(I)的化合物选自下组:
(1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-基)甲醇;
(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲醇;
(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲酮;
(E)-1-(2-((6-亚苄基-2,4-二甲基环己-1-烯-1-基)氧基)乙基)-4-甲基哌嗪;
(E)-1-(3-(2-苄基-4-甲基苯基)烯丙基)-4-甲基哌嗪;
1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪;
(E)-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)亚苄基)环己-1-酮;
(E)-2-(5-甲基-2-(2-吗啉代乙氧基)亚苄基)环己-1-酮;
2-(3,5-二甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈;
2-(3,5-二甲基-2-((1-吗啉代丙-2-基)氧基)苄基)苯甲腈;
1-((8-苄基苯并二氢吡喃-2-基)甲基)-4-甲基哌嗪;
1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪;
1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪二盐酸盐;
1-(2-(2-((5-氯噻吩-2-基)甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-(2-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-(2-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-(2-碘苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-(3-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-(3-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-(4-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐;
1-(2-(2-(呋喃-2-基甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2,4-二甲基-6-(2-(三氟甲基)苄基)苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2,4-二甲基-6-(吡啶-2-基甲基)苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2,4-二甲基-6-(吡啶-3-基甲基)苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2,4-二甲基-6-(吡啶-4-基甲基)苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-3,6-二甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-3-甲氧基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-3-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-4-(叔丁基)-6-甲氧基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐;
1-(2-(2-苄基-4-氯苯氧基)乙基)-4-乙基哌嗪盐酸盐;
1-(2-(2-苄基-4-氯苯氧基)乙基)-4-甲基哌嗪盐酸盐;
1-(2-(2-苄基-4-乙基苯氧基)乙基)-4-甲基哌嗪盐酸盐;
1-(2-(2-苄基-4-异丙基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-乙基哌嗪盐酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2,3-二羟基琥珀酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2-羟基丙烷-1,2,3-三羧酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2,2,2-三氟乙酸盐);
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2-羟基琥珀酸盐);
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(磷酸盐);
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二马来酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二甲磺酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪草酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪硫酸盐;
1-(2-(2-苄基-4-甲基苯氧基)乙基)哌嗪;
1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-醇;
1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪;
1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐;
1-(2-(2-苄基-6-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-苄基苯氧基)乙基)-4-甲基哌嗪盐酸盐;
1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪;
1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐;
1-(2-苄基-4-甲基苯乙基)-4-甲基哌嗪;
1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-醇;
1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-酮;
1-(3-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐;
1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪;
1-甲基-4-(2-(4-甲基-2-(1-苯基乙基)苯氧基)乙基)哌嗪;
1-甲基-4-(2-(4-甲基-2-(1-苯基乙烯基)苯氧基)乙基)哌嗪;
1-甲基-4-(2-(4-甲基-2-(2-甲基苄基)苯氧基)乙基)哌嗪;
1-甲基-4-(2-(4-甲基-2-(3-甲基苄基)苯氧基)乙基)哌嗪;
1-甲基-4-(2-(4-甲基-2-(噻吩-2-基甲基)苯氧基)乙基)哌嗪盐酸盐;
2-(2-((1-羟基丙-2-基)氧基)-3,5-二甲基苄基)苯甲腈;
2-(2-(2-羟基-3-吗啉代丙基)-5-甲基苯氧基)苯甲腈;
2-(2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯基)乙腈;
2-(2,4-二甲基-5-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈;
2-(2,6-二氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺;
2-(2,6-二氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺;
2-(2,6-二氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺;
2-(2-氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺;
2-(2-氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺;
2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈;
2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈盐酸盐;
2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈;
2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈盐酸盐;
2-(3,5-二甲基-2-(2-(四氢-2H-吡喃-4-基)乙氧基)苄基)苯甲腈;
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)-3-氟苯甲腈;
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯胺;
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈;
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈盐酸盐;
2-(3,5-二甲基-2-(3-吗啉代丙氧基)苄基)苯甲腈;
2-(3,5-二甲基-2-(3-吗啉代丙基)苯氧基)苯甲腈;
2-(3,5-二甲基-2-(甲基(2-吗啉代乙基)氨基)苄基)苯甲腈;
2-(4-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈;
2-(5-甲基-2-(2-(1-甲基哌啶-4-基)乙氧基)苄基)苯甲腈;
2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈;
2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐;
2-(5-甲基-2-(2-吗啉代乙氧基)苄基)环己-1-酮;
2-(5-甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈;
2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈;
2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈盐酸盐;
2-苄基-4-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺;
2-(4-甲基哌嗪-1-基)乙酸2-苄基-4-甲基苯酯;
2-苄基-N,4-二甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺;
2-苄基-N,4-二甲基-N-(2-吗啉代乙基)苯胺;
3-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐;
3-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯胺;
3-溴-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈;
3-氯-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈;
4-(1-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙-2-基)吗啉;
4-(2-(2-(1-(2-氟苯基)乙基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(1-(2-氟苯基)乙烯基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(2,4-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(2,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(2,6-二氯苄基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙基)吗啉;
4-(2-(2-(2,6-二氟苄基)-4-甲基苯氧基)乙基)吗啉;
4-(2-(2-(2-氯苄基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2-(3,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉;
4-(2-(2,4-二甲基-5-((全氟苯基)甲基)苯氧基)乙基)吗啉;
4-(2-(2,4-二甲基-6-(2,4,5-三氟苄基)苯氧基)乙基)吗啉;
4-(2-(2,4-二甲基-6-(2-硝基苄基)苯氧基)乙基)吗啉;
4-(2-(2-苄基-4-甲基苯氧基)乙基)-1,2,6-三甲基哌嗪;
4-(2-(2-苄基-4-甲基苯氧基)乙基)吗啉盐酸盐;
4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉1-氧化物;
4-(2-(2-乙基-6-(2-氟苄基)-4-甲基苯氧基)乙基)吗啉;
4-(3-(2-(2-氟苯氧基)-4,6-二甲基苯基)丙基)吗啉;
4-甲基-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯酚;
4-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲酸乙酯二盐酸盐;和
3-苄基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯甲酸甲酯。
3.在人或动物中引起清凉感的非医疗方法,包括使人或动物与如在权利要求1中所定义的式(I)的化合物或其盐或溶剂合物接触。
4.实现对皮肤或黏膜的清凉效果的方法,包括使皮肤或黏膜与包含一种或多种如在权利要求1中所定义的式(I)的化合物的产品接触。
5.消费品,包含一种或多种如在权利要求1中所定义的式(I)的化合物。
6.如在权利要求1中所定义的式(I)的化合物,用于提供清凉感。
7.包含清凉感的组合物,其中所述组合物包含如在权利要求1中所定义的式(I)的化合物。
8.式(I)的化合物、其盐或溶剂合物
其中
环A代表苯基环、环己基或环己烯基环;
R1选自氢、C1-C6烷基和C1-C6烷氧基,
R2连接至环A的3、4或5位且选自C1-C6烷基、C1-C6烷氧基和C(O)O-C1-C3-烷基,
R3选自氢、C1-C6烷基、C2-C6烯基、OH和=O,且R4选自氢、C1-C6烷基、C2-C6烯基和OH,条件是R3和R4中的至少一个为氢,或
R3和R1与它们所连接的碳原子一起形成六元环系统,且R4为氢,
R5选自氢、F和C1-C6烷基,
R6选自氢、F和C1-C6烷基,
m为0,
p为1,
W选自-CH2-、-O-、>C=O、-CH=和>NR13,其中R13选自氢和C1-C3烷基,
V选自>CH-和>N-,
Z选自-O-、>S=O、>CHR12、>NR12,其中R12为氢、C1-C3烷基、OH或CH2OH,
Y连接至环A的2或3位且选自C4-C6烷基(例如异丁基),
其中
环B代表苯基、噻吩、呋喃或吡啶环,
R11选自CN、卤素、CH2CN、NO2、NH2、CF3、C(O)OC2H5、C1-C3烷基、C1-C3烷氧基、C2-C3烯基和OH,且n为0-5的整数,条件是如果n>1,则R11可以相同或不同,
X选自-CH2-、-O-、>CH-CH3、>CH=CH2、>C=O和>CHOH,
条件是式(I)的化合物不为1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪。
9.根据权利要求9的式(I)的化合物、其盐或溶剂合物,选自
(1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-基)甲醇,
(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲醇,
(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)(苯基)甲酮,
(E)-1-(2-((6-亚苄基-2,4-二甲基环己-1-烯-1-基)氧基)乙基)-4-甲基哌嗪,
(E)-1-(3-(2-苄基-4-甲基苯基)烯丙基)-4-甲基哌嗪,
(E)-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)亚苄基)环己-1-酮,
(E)-2-(5-甲基-2-(2-吗啉代乙氧基)亚苄基)环己-1-酮,
2-(3,5-二甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-((1-吗啉代丙-2-基)氧基)苄基)苯甲腈,
1-((8-苄基苯并二氢吡喃-2-基)甲基)-4-甲基哌嗪,
1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪,
1-(2-((2-苄基-4-甲基环己基)氧基)乙基)-4-甲基哌嗪二盐酸盐,
1-(2-(2-((5-氯噻吩-2-基)甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(2-碘苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(3-溴苄基)-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(3-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-(4-氯苄基)-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-(呋喃-2-基甲基)-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(2-(三氟甲基)苄基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(吡啶-2-基甲基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(吡啶-3-基甲基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2,4-二甲基-6-(吡啶-4-基甲基)苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-3,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-3-甲氧基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-3-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-(叔丁基)-6-甲氧基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4,6-二甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐,
1-(2-(2-苄基-4-氯苯氧基)乙基)-4-乙基哌嗪盐酸盐,
1-(2-(2-苄基-4-氯苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-4-乙基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-4-异丙基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-乙基哌嗪盐酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2,3-二羟基琥珀酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪2-羟基丙烷-1,2,3-三羧酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2,2,2-三氟乙酸盐),
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(2-羟基琥珀酸盐),
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二(磷酸盐),
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二马来酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪二甲磺酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪草酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)-4-甲基哌嗪硫酸盐,
1-(2-(2-苄基-4-甲基苯氧基)乙基)哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)乙基)哌啶-4-醇,
1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪,
1-(2-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-苄基-6-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-苄基苯氧基)乙基)-4-甲基哌嗪盐酸盐,
1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪,
1-(2-(2-异丁基-4-甲基苯氧基)乙基)-4-甲基哌嗪二盐酸盐,
1-(2-苄基-4-甲基苯乙基)-4-甲基哌嗪,
1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-醇,
1-(2-苄基-4-甲基苯基)-3-(4-甲基哌嗪-1-基)丙-2-酮,
1-(3-(2-苄基-4-甲基苯氧基)丙基)-4-甲基哌嗪盐酸盐,
1-(3-(2-苄基-4-甲基苯基)丙基)-4-甲基哌嗪,
1-甲基-4-(2-(4-甲基-2-(1-苯基乙基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(1-苯基乙烯基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(2-甲基苄基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(3-甲基苄基)苯氧基)乙基)哌嗪,
1-甲基-4-(2-(4-甲基-2-(噻吩-2-基甲基)苯氧基)乙基)哌嗪盐酸盐,
2-(2-((1-羟基丙-2-基)氧基)-3,5-二甲基苄基)苯甲腈,
2-(2-(2-羟基-3-吗啉代丙基)-5-甲基苯氧基)苯甲腈,
2-(2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯基)乙腈,
2-(2,4-二甲基-5-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈,
2-(2,6-二氟苄基)-4-甲基-N-(2-吗啉代乙基)苯胺,
2-(2,6-二氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺,
2-(2,6-二氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺,
2-(2-氟苄基)-N,4,6-三甲基-N-(2-吗啉代乙基)苯胺,
2-(2-氟苄基)-N,4-二甲基-N-(2-吗啉代乙基)苯胺,
2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-((1-(4-甲基哌嗪-1-基)丙-2-基)氧基)苄基)苯甲腈盐酸盐,
2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈盐酸盐,
2-(3,5-二甲基-2-(2-(四氢-2H-吡喃-4-基)乙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)-3-氟苯甲腈,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯胺,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈盐酸盐,
2-(3,5-二甲基-2-(3-吗啉代丙氧基)苄基)苯甲腈,
2-(3,5-二甲基-2-(3-吗啉代丙基)苯氧基)苯甲腈,
2-(3,5-二甲基-2-(甲基(2-吗啉代乙基)氨基)苄基)苯甲腈,
2-(4-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈,
2-(5-甲基-2-(2-(1-甲基哌啶-4-基)乙氧基)苄基)苯甲腈,
2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈,
2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐,
2-(5-甲基-2-(2-吗啉代乙氧基)苄基)环己-1-酮,
2-(5-甲基-2-(2-吗啉代丙氧基)苄基)苯甲腈,
2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈,
2-(5-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)苯氧基)苯甲腈盐酸盐,
2-苄基-4-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺,
2-(4-甲基哌嗪-1-基)乙酸2-苄基-4-甲基苯酯,
2-苄基-N,4-二甲基-N-(2-(4-甲基哌嗪-1-基)乙基)苯胺,
2-苄基-N,4-二甲基-N-(2-吗啉代乙基)苯胺,
3-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲腈二盐酸盐,
3-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯胺,
3-溴-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈,
3-氯-2-(3,5-二甲基-2-(2-吗啉代乙氧基)苄基)苯甲腈,
4-(1-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙-2-基)吗啉,
4-(2-(2-(1-(2-氟苯基)乙基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(1-(2-氟苯基)乙烯基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,4-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,6-二氯苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2,6-二氟苄基)-4,6-二甲基苯氧基)丙基)吗啉,
4-(2-(2-(2,6-二氟苄基)-4-甲基苯氧基)乙基)吗啉,
4-(2-(2-(2-氯苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(2-氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2-(3,5-二氟苄基)-4,6-二甲基苯氧基)乙基)吗啉,
4-(2-(2,4-二甲基-5-((全氟苯基)甲基)苯氧基)乙基)吗啉,
4-(2-(2,4-二甲基-6-(2,4,5-三氟苄基)苯氧基)乙基)吗啉,
4-(2-(2,4-二甲基-6-(2-硝基苄基)苯氧基)乙基)吗啉,
4-(2-(2-苄基-4-甲基苯氧基)乙基)-1,2,6-三甲基哌嗪,
4-(2-(2-苄基-4-甲基苯氧基)乙基)吗啉盐酸盐,
4-(2-(2-苄基-4-甲基苯氧基)乙基)硫代吗啉1-氧化物,
4-(2-(2-乙基-6-(2-氟苄基)-4-甲基苯氧基)乙基)吗啉,
4-(3-(2-(2-氟苯氧基)-4,6-二甲基苯基)丙基)吗啉,
4-甲基-2-(5-甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯酚,
4-(3,5-二甲基-2-(2-(4-甲基哌嗪-1-基)乙氧基)苄基)苯甲酸乙酯二盐酸盐,和
3-苄基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯甲酸甲酯。
10.药物组合物,其包含一种或多种如在权利要求8中所定义的式(I)的化合物。
11.如在权利要求8中所定义的式(I)的化合物,用作药物。
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PCT/CN2020/077896 WO2021174475A1 (en) | 2020-03-05 | 2020-03-05 | Organic compounds |
PCT/EP2021/055420 WO2021175971A1 (en) | 2020-03-05 | 2021-03-04 | Heterocyclic derivatives as trmp8 antagonists |
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JP2023516730A (ja) | 2023-04-20 |
US20230098332A1 (en) | 2023-03-30 |
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