CN112759544A - 3-(二甲氨基甲基)哌啶-4-醇衍生物制备方法和药物用途 - Google Patents
3-(二甲氨基甲基)哌啶-4-醇衍生物制备方法和药物用途 Download PDFInfo
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- CN112759544A CN112759544A CN201911076305.XA CN201911076305A CN112759544A CN 112759544 A CN112759544 A CN 112759544A CN 201911076305 A CN201911076305 A CN 201911076305A CN 112759544 A CN112759544 A CN 112759544A
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- Prior art keywords
- methyl
- dimethylamino
- piperidin
- methoxyphenyl
- compound
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- 238000002360 preparation method Methods 0.000 title abstract description 35
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 6
- -1 2,4, 5-trifluorophenyl Chemical group 0.000 claims description 75
- 208000002193 Pain Diseases 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 230000036407 pain Effects 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- NVDIESCTJSWZJX-IFMALSPDSA-N C1=C(CS(=O)(=O)N2CC[C@]([C@@H](C2)CN(C)C)(C2=CC=CC(OC)=C2)O)C=CC=C1 Chemical compound C1=C(CS(=O)(=O)N2CC[C@]([C@@H](C2)CN(C)C)(C2=CC=CC(OC)=C2)O)C=CC=C1 NVDIESCTJSWZJX-IFMALSPDSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 102000003840 Opioid Receptors Human genes 0.000 claims description 6
- 108090000137 Opioid Receptors Proteins 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
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- DZTPAFUHUBRAJF-TZIWHRDSSA-N C1(=CC=CC=C1)CS(=O)(=O)N1CC[C@@](C2=CC(O)=CC=C2)([C@@H](C1)CN(C)C)O Chemical compound C1(=CC=CC=C1)CS(=O)(=O)N1CC[C@@](C2=CC(O)=CC=C2)([C@@H](C1)CN(C)C)O DZTPAFUHUBRAJF-TZIWHRDSSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- NVDIESCTJSWZJX-UNMCSNQZSA-N C1(CS(=O)(=O)N2C[C@@H]([C@](O)(CC2)C2=CC(OC)=CC=C2)CN(C)C)=CC=CC=C1 Chemical compound C1(CS(=O)(=O)N2C[C@@H]([C@](O)(CC2)C2=CC(OC)=CC=C2)CN(C)C)=CC=CC=C1 NVDIESCTJSWZJX-UNMCSNQZSA-N 0.000 claims description 3
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- MVNWQTVWQCWDEW-UHFFFAOYSA-N FC(OC(OC(F)(F)F)OF)F Chemical compound FC(OC(OC(F)(F)F)OF)F MVNWQTVWQCWDEW-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
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- 235000019341 magnesium sulphate Nutrition 0.000 description 12
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- 239000008346 aqueous phase Substances 0.000 description 11
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
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- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 229960004380 tramadol Drugs 0.000 description 7
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Abstract
3‑(二甲氨基甲基)哌啶‑4‑醇衍生物制备方法和药物用途。本发明提供式(I)或式(II)化合物或其药学上可接受的盐，及其制备方法和药物用途，
Description
技术领域
本发明属于制药领域，涉及具有通式(I)和(II)的3-(二甲氨基甲基)哌啶-4-醇哌啶衍生物或其盐类与制备方法，并涉及所述化合物在治疗阿片受体介导的疾病中的用途。
背景技术
疼痛是多种疾病进程中所出现的常见症状，是困扰患者的主要问题之一，已被列为继体温、脉搏、呼吸、血压之后的第五大生命体征。目前，阿片类镇痛药物在疼痛治疗中有着不可替代的作用，如吗啡、芬太尼等。但长期使用会出现耐药性，成瘾性，戒断反应，呼吸抑制等不良反应。曲马多是Grünenthal公司 1977年开发的一种人工合成的阿片类中枢系统镇痛剂，商品名为tramal。它是相对较弱的μ阿片受体激动剂(对μ阿片受体的Ki＝2400nM，EC50＞1000nM)，并且可以抑制5-羟色胺和去甲肾上腺素的再摄取。它主要经肝脏代谢，且几乎完全经肾脏排泄。曲马多作为一种不典型的阿片类药物，不同于其他传统的阿片类药物，有其独特的药理学特点，不仅有较强的镇痛效果，而且不良反应少，现已经被广泛应用于疼痛的治疗。然而，临床上的应用显示，曲马多的镇痛效果略弱于吗啡、芬太尼等镇痛药。此外，曲马多还存在呼吸抑制、成瘾性、恶心、腹泻、头痛、头晕、嗜睡和便秘等副作用。长期服药还可以出现出汗、焦虑、睡眠不良、疼痛和身体颤抖等戒断反应。另外，有研究表明，曲马多的使用与需要住院治疗的低钠血症和低血糖风险增加有关。因此，有必要开发镇痛作用更强、副作用更低的镇痛药。
发明内容
本发明提供了式(I)和(II)所示的化合物，或其药学上可接受的盐，以及制备该化合物的方法：
其中，
R1选自氢、C1-6烷基、氟代烷基、环烷基、链状烯基、环烯基、取代或未取代芳基C1-6烷基；
R2选自取代或未取代芳基、取代或未取代杂芳基，其取代基可选自芳基、卤素、C1-6烷基、氰基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氟、硝基、酚羟基；
X选自羰基、磺酰基：
优选实施方式中，R1选自氢、甲基。
优选实施方式中，R2选自取代或未取代芳基。所述取代或未取代芳基优选为苯基或2,4,5-三氟苯基。
优选实施方式中，式(I)化合物选自：
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇。
优选实施方式中，式(II)化合物选自：
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇。
本发明还提供了式(I)或式(II)化合物药学上可接受的盐类，可是与无机酸或有机酸形成的盐，如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、苯甲酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、乳酸盐、柠檬酸盐、葡糖酸盐、甲磺酸盐、苯磺酸盐或对甲苯磺酸盐，优选盐酸盐。
本发明还提供了式(I)或式(II)化合物药学上可接受的溶剂化物或水合物。
本发明还提供了一种药物组合物，其包括：式(I)或式(II)或其药学上可接受的盐、溶剂化物或水合物；以及药学上可接受的载体。
上述化合物制备的药物可用于治疗或改善与阿片受体有关的疾病。所述疾病可选自但不限于疼痛、胃肠道疾病和抑郁症。例如，疼痛可选自但不限于中枢介导的疼痛、外周介导的疼痛、与结构或软组织损伤有关的疼痛、与炎症有关的疼痛、与进行性疾病有关的疼痛、神经病疼痛、急性疼痛和慢性疼痛。
这种方法可以通过给予对象有效治疗量的式(I)或(II)化合物或其药学上可接受的盐、溶剂化物或其水合物来实现。
本发明还提供了通式(I)或(II)化合物或其药学上可接受的盐、溶剂化物或其水合物的制备方法。当X为羰基时，其制备方法包括Mannich反应、格式试剂亲核加成、拆分剂拆分、脱保护基Boc、缩合、成盐等步骤；化合物6的母液用相反构型的拆分剂拆分可得6的对映体。6的对映体经脱保护基Boc、缩合、成盐等步骤可得式(II)所示化合物。
所述拆分剂可选择L-DBTA、D-DBTA、左旋扁桃酸、右旋扁桃酸、左旋酒石酸、右旋酒石酸、左旋樟脑磺酸、右旋樟脑磺酸中的一种。拆分溶剂可选择甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯中的一种或几种。反应温度可为室温到120℃，优选60～90℃。拆分剂与底物比例可为0.5当量到1.5当量。
当X为磺酰基时，其制备方法包括苯甲酰化、脱保护基Boc、缩合、水解、成盐等步骤；6的对映体经苯甲酰化、脱保护基Boc、缩合、水解、成盐等步骤可得式(II)所示化合物。
各反应路线中的取代基和基团的定义如上所述。
具体实施方式
如本申请全文，包括权利要求书中所使用，除非另外特别表明，否则以下术语具有下文定义的含义如本文中所使用。
术语“C1-C6烷基”指含有1至6个碳原子的饱和的支链或直链烷基，诸如 (但不限于)甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基及正己基。
术语“C1-6单取代或多取代烷基”指如上文所定义的C1-C6烷基中的一个或多个氢原子被选自下列的取代基代替：OH、卤素、烷氧基、二烷基氨基或杂环基，例如吗啉基、哌啶基等。
术语“C1-6单取代或多取代烷基酰基”指上文所定义的“C1-6单取代或多取代烷基”通过羰基与连接于母体分子部分。
术语“环烷基”是指碳原子的环状饱和单价单环或双环碳氢基团，例如环丙基、环丁基、环戊基、环己基，或类似基团。所述环烷基可任选地被一个、两个或三个取代基所取代，所述取代基选自卤原子、羟基、芳基。
术语“链状烯基”指具有至少一个碳-碳双键的脂族烃基，包括具有至少一个碳-碳双键的直链或支链基团。其例如具有2至6个碳原子。代表性实例包括(但不限于)乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1- 丁烯基、2-丁烯基等。当本发明的化合物含有C2-C6链状烯基时，所述化合物可以纯E(entgegen)形式、纯Z(zusammen)形式或其任何混合物形式存在。
术语“环烯基”是指通过在环烷基移除额外的氢原子形成双键基团而得到相应的环烯基。
术语“芳基”指含有6至10个碳原子且具有共轭π电子系统的所有碳单环或稠环多环芳族基团，诸如苯基或萘基。
术语“取代或未取代芳基”是指芳基上的0至3个氢原子被选自下列的取代基代替：芳基、卤素、C1-6烷基、氰基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、硝基、酚羟基。
术语“卤代”或“卤素”指氯、氟、溴或碘原子。
术语“取代或未取代芳基酰基”指上文所定义的“取代或未取代芳基”通过羰基与连接于母体分子部分。
术语“取代或未取代芳基烷基”是指如上文所定义的C1-C6烷基中的一个或多个氢原子被如上文所定义的“取代或未取代芳基”所取代。
术语“杂芳基”指单环或稠环多环芳族杂环基团，其中至少一个环中的一个或多个杂原子环成员(成环原子)各自独立地选自氧(O)、硫(S)及氮(N)。杂芳基的实例包括(但不限于)6元环取代基，诸如吡啶基、吡嗪基、嘧啶基及哒嗪基；5 元杂芳基，诸如三唑基、咪唑基、呋喃基、异噁唑基、异噻唑基、1,2,3-、1,2,4、 1,2,5-或1,3,4-噁二唑基、噁唑基、噻吩基、噻唑基、异噻唑基及吡唑基；6/5 元稠环取代基，诸如吲哚基、吲唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噁二唑基、苯并噻唑基、异苯并噻吩基、苯并噻吩基、苯并异噁唑基、苯并噁唑基、苯并间二氧杂环戊烯基、呋喃并吡啶基、嘌呤基、咪唑并吡啶基、咪唑并嘧啶基、吡咯并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基(例如5,6,7,8-四氢[1,2,4]三唑并[1,5-a]吡啶-2-基)及邻氨基苯甲酰基；及6/6元稠环取代基，诸如喹啉基、异喹啉基、噌啉基、喹唑啉基、氧代色烷基及1,4-苯并噁嗪基。
术语“取代或未取代杂芳基”是指杂芳基上的0至3个氢原子被选自下列的取代基代替：芳基、卤素、C1-6烷基、氰基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氟、硝基、酚羟基。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的异构体，例如互变异构体、对映异构体、非对映异构体、及其混合物形式。
“有效治疗量”指在某种程度上减轻所治疗病症中一种或多种症状的化合物的给药量。
术语“药学上可接受的载体”表示能用于制备药物组合物的载体，它们一般是安全的、无毒性的，不是生物上或其他方面不期待的，且包括能被动物和人类药学上接受的载体。在说明书和权利要求书中使用的“药学上可接受的载体”包括一种或一种以上的这类载体。
本发明所述的药物组合物可以是液体、半液体或固体形式，按照适合于所用的给药途径的方式配制。本发明所述的药物组合物可以按照下列给药方式给药：口服、肠胃外、腹膜内、静脉内、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体等方式。
口服药物组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸；稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙；助流剂的实例包括但不限于二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。
以肠胃外给予本发明药物组合物，一般以注射为主，包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式，如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本发明注射剂的药学上可接受的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液；非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油；抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等；等渗剂的实例包括氯化钠和葡萄糖；缓冲剂包括磷酸盐和柠檬酸盐。
本发明药物组合物还可以制备成无菌的冻干粉针剂，将化合物溶于磷酸钠缓冲溶液，其中含有葡萄糖或其他适合的赋形剂，随后在本领域技术人员已知的标准条件下将溶液无菌过滤，继之以冷冻干燥，得到所需的制剂。
术语“式(I)或式(II)”或“式(I)或式(II)化合物”可称作“本发明的化合物”。这样的术语还被定义为包括本发明的化合物的所有形式，包括水合物、溶剂合物、异构体、结晶及非结晶形式、同晶型体、多晶型物及其代谢物。
本发明的化合物一般按照IUPAC或CAS命名体系命名。可以使用本领域技术人员公知的缩写(例如，“Ph”表示苯基、“Me”表示甲基、“Et”表示乙基、“h”表示小时，“r.t.”表示室温)。
实施例1
氯化N-甲基-N-亚甲基甲铵(中间体2)的制备
伴有氮气气球、温度计和恒压滴液漏斗的1L三口瓶加N,N,N',N'-四甲基甲烷二胺(60g，587.2mmol,1eq.)、甲基叔丁基醚(500ml)，冷却至0℃。30℃下滴加乙酰氯(46.1g，587.2mmol，1eq.)。滴加完毕，搅拌30分钟，抽滤，滤饼加乙腈(100ml)和MTBE(25ml)搅拌10min，抽滤，滤饼减压蒸干(55℃)，得46g类白色固体，收率83.7％。
实施例2
3-((二甲氨基)甲基)-4-氧代哌啶-1-甲酸叔丁酯(中间体3)的制备：
250ml单口瓶加Boc-哌啶酮(10g，50.2mmol，1eq.)、乙腈(100ml)，搅拌下加氯化N-甲基-N-亚甲基甲铵(5.64g，60.24mmol，1.2eq.)，乙酰氯(0.20g， 2.51mmol，0.05eq.)。室温(25～30℃)搅拌2h，TLC(DCM和DCM：MeOH＝10： 1，茚三酮显色)显示原料反应完全。将乙腈减压蒸除(30℃)，加DCM(80ml)、饱和碳酸氢钠(80ml)，混合、静置、分层、分液。水相DCM(80+40ml)萃取。有机相合并，水洗(50ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得11.75g棕黄色粘稠液体，收率91.3％。
实施例3
3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-甲酸叔丁酯(中间体5)的制备：
伴有氮气球、恒压滴液漏斗、冷凝管和温度计的500ml四口瓶加镁屑(2.75g，114.6mmol，2.5eq.)、THF(80ml)、1粒碘，少量间溴苯甲醚(21.4g，114.6mmol， 2.5eq.)的THF(30ml)溶液，升温回流引发，停止加热。缓慢滴加间溴苯甲醚的THF溶液(约20min)。滴加完毕，0℃下滴加Boc-二甲胺甲基哌啶酮(11.75 g，45.84mmol，1eq.)的THF(50ml)溶液。滴加完毕，保温搅拌。将反应液倒入饱和氯化铵的水溶液中(100ml)中，将THF减压蒸除(30～40℃)。乙酸乙酯萃取(100+50ml)。有机相合并，水洗(30ml)，饱和氯化钠洗(30ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得19.9g黄色液体。
实施例4
(3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-甲酸叔丁酯的制备：
实施例3所得黄色油状物加IPA(异丙醇)(100ml)，搅拌下加L-DBTA(L-(-)- 二苯甲酰酒石酸)(13.14g，36.67mmol，0.8eq.)，升温回流溶解。降温搅拌，至室温加晶种(20mg)。搅拌过夜(12h)，析出固体，冰盐浴搅拌(-10～0℃) 1.5h。抽滤，滤饼冷IPA(10ml)淋洗，减压蒸干(60℃)，得8.1g类白色固。取8g加IPA(120ml)，升温回流溶解，降温搅拌，至室温后洗出大量固体。2h 后抽滤，滤饼常温IPA(10ml)淋洗，减压蒸干，得6.06g类白色固体。取5.96 g加IPA(60ml)升温回流溶解，降温搅拌，至室温后，搅拌1h，抽滤，滤饼 IPA淋洗(6ml)，减压蒸干(60℃)，得5.47g类白色固体。所得固体用饱和碳酸氢钠溶液和乙酸乙酯游离，得到目标构型异构体。LC-MS-ESI+：[M+H]+365.3. 
1H NMR(400MHz,CD3OD),δ7.252(t,J＝8Hz,1H), 7.043(t,J＝2Hz,1H),6.980(d,J＝7.6Hz,1H),6.792(dd,J1＝8Hz,J2＝2.4Hz,1H), 4.193～4.203(m,1H),3.953～3.992(m,1H),3.791(s,3H),3.344(s,1H),3.193(s,1H), 2.995～3.085(t,1H),2.313～2.370(q,1H),2.045～2.106(m,1H),2.045(s,6H), 1.932～2.012(m,1H),1.808(d,J＝12.8Hz,1H),1.595(d,J＝14Hz,1H),1.494(s,9H).。
实施例5
(3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-甲酸叔丁酯的制备：
500ml单口瓶加实施例4成盐后所得母液用饱和碳酸氢钠溶液游离后，得粗品(13.44g)，IPA(120ml)，搅拌下加D-DBTA(D-(+)-二苯甲酰酒石酸，13.14g， 36.67mmol，0.8eq.)，升温回流溶解。冷却至室温加晶种(20mg)，搅拌过夜(12 h)，析出大量固体，冰水浴冷却1h。抽滤，滤饼冷IPA(10ml)淋洗，减压蒸干，得7.7g类白色固体。取7.6g加IPA(110ml)，升温回流溶解，降温搅拌。至室温搅拌2h后抽滤，滤饼减压蒸干，得6.48g类白色固体。取6.38g加IPA (64ml)，升温回流溶解，降温搅拌。至室温后搅拌4h，抽滤，滤饼IPA淋洗(10ml)，减压蒸干(60℃)，得5.88g类白色固体。所得固体用饱和碳酸氢钠溶液和乙酸乙酯游离，得到目标构型异构体。LC-MS-ESI+：[M+H]+365.3. 
1HNMR(400MHz,CD3OD),δ7.251(t,J＝8Hz, 1H),7.043(t,J＝2Hz,1H),6.979(d,J＝8Hz,1H),6.791(dd,J1＝8Hz,J2＝2.4Hz,1H), 4.192～4.236(m,1H),3.957～3.992(m,1H),3.790(s,3H),3.343(s,1H),3.193(s,1H), 2.995～3.085(t,1H),2.310～2.367(q,1H),2.043～2.105(m,1H),2.043(s,6H), 1.931～2.010(m,1H),1.810(d,J＝12.8Hz,1H),1.593(d,J＝14Hz,1H),1.494(s,9H).。
实施例6
(3R,4S)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐的制备：
100ml单口瓶加(3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-甲酸叔丁酯(2g，5.49mmol，1eq.)、甲醇(10ml)，搅拌溶解，加HCl/Dioxane(3.4 ml，13.72mmol，2.5eq.)，升至50℃搅拌。2h后TLC(DCM：MeOH＝10:1) 显示反应完全。将易挥发物和溶剂减压蒸除，未经纯化，直接用于缩合。
实施例7
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮的制备：
装有实施例6所得盐酸盐的100ml单口瓶加DCM(20ml)、2,4,5-三氟苯乙酸(1.15g，6.04mmol，1,1eq.)、HOBT(1.11g，8.24mmol，1.5eq.)、EDCI-HCl(1.6g， 8.24mmol，1.5eq.)、NMM(2.22g，21.96mmol，4eq.)，25℃搅拌。5.5h后 TLC(DCM：MeOH＝10:1)显示反应完全。加水(50ml)，混合、静置、分层、分液。水相二氯甲烷萃取(50+25ml)。有机相合并，水洗三次(50+50+50ml)，无水硫酸镁干燥，抽滤，滤液减压蒸干，得2.82g浅黄色粘稠物。硅胶柱层析纯化(DCM～DCM：MeOH＝200:1，加5‰TEA)，得2.2g无色粘稠物，收率91.7％。
1H NMR(400MHz,CD3OD),δ7.24～7.29(t,2H), 7.14～7.21(m,1H),7.06(s,1H),6.98～7.02(m,1H),6.81(d,J＝8Hz,1H),4.92(s, 2H),4.59(dd,J1＝92Hz,J2＝16Hz,1H),3.65～4.17(m,5H),3.50(m,J1＝76Hz, J2＝12Hz,1H),3.04(m,J1＝40Hz,J2＝12Hz,1H),2.30～2.40(m,1H),1.98～2.19(m, 7H),1.82(t,J＝12Hz,1H),1.65～1.69(m,1H).13C NMR(150MHz,CD3OD)δ 170.03,169.96,161.28,161.25,151.24,149.87,149.83,130.38,130.35,120.56, 120.43,118.34,118.30,112.98,112.94,112.22,106.48,106.32,106.15,75.09,74.85, 59.04,58.93,55.66,47.49,46.27,46.23,44.88,44.15,43.76,43.58,41.88,41.00, 39.69,33.67.。
实施例8
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮盐酸盐的制备：
100ml单口瓶加1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1- 基)-2-(2,4,5-三氟苯基)乙基-1-酮(0.83g，1.9mmol，1eq.)、甲醇(1ml)，搅拌溶解，加甲基叔丁基醚(15ml)。滴加HCl/Dioxane(0.95ml，3.8mmol，2eq.) 的甲基叔丁基醚(5ml)溶液。。加甲基叔丁基醚(5ml)搅拌。逐渐析出固体。抽滤，滤饼甲基叔丁基醚淋洗，减压蒸干，得0.85g类白色固体，收率94.4％。 m.p.:217.4-220.4℃.1H NMR(400MHz,CD3OD),δ7.26～7.36(m,2H),7.07～7.22 (m,3H),6.88(d,J＝8Hz,1H),4.36～4.64(m,1H),4.01～4.08(m,1H),3.89～3.92(m, 2H),3.51～3.61(m,1H),3.03～3.16(m,2H),2.53～2.82(m,7H),2.26～2.32(m,1H), 2.13～2.24(m,1H),1.72～1.81(m,1H).1C NMR(150MHz,CD3OD),δ168.41, 167.14,159.53,146.58,146.28,145.04(m),128.91,118.53～118.85(m),116.42, 116.27,111.60,111.51,110.51,110.48,104.12～104.45(m),72.42,72.23,56.75, 56.34,53.69,44.78,41.32,40.83,40.65,40.32,38.87,37.86,37.14,31.98,31.50. LC-MS:[M+H]+436.9.HRMS(ESI),calcd for C23H27F3N2O3[M+Na]+,459.1866；found,459.1847.。
实施例9
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮的制备
伴有氮气气球和温度计的100ml三口瓶加1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基 -4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮(1.3g，2.97mmol，1eq.)、DCM(50ml)，冰水浴冷却搅拌，滴加BBr3(1ml，2.65g，10.6mmol，3.6eq.)的DCM(10ml)溶液。滴加完毕，撤冰水浴搅拌(约10～15℃)，22h 后TLC(DCM：MeOH＝10:1)显示反应完全。室温下缓慢加饱和碳酸氢钠溶液 (100ml)，搅拌10min，静置、分层、分液。水相DCM萃取(50+25ml)。有机相合并，水洗(30ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得1.2g粘稠物。纯化后得0.92g泡沫状物质，收率70.8％。
1H NMR(400MHz,CD3OD),δ7.28～7.30(m,1H),7.14～7.20(m,2H),6.87～6.93(m, 1H),6.86(d,J＝8Hz,1H),4.93(s,2H),4.45～4.70(m,1H),3.89～4.15(m,1H), 3.36～3.62(m,1H),2.93～3.13(m,1H),2.30～2.41(m,1H),1.95～2.13(m,8H),1.87 (d,J＝12Hz,1H),1.65～1.70(m,1H).13C NMR(150MHz,CD3OD)δ170.03, 169.97,158.58,158.54,149.81,149.76,130.35,130.30,120.59,120.45,117.21, 117.15,114.60,113.29,113.25,106.47,106.32,106.15,75.01,74.75,59.02,58.93, 47.51,46.28,46.22,45.00,44.17,43.76,43.60,41.85,40.92,39.71,33.67.LC-MS: [M+H]+422.9.。
实施例10
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮盐酸盐
100ml单口瓶加1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1- 基)-2-(2,4,5-三氟苯基)乙基-1-酮(0.18g，0.43mmol，1eq.)、甲醇(1ml)，搅拌溶解，加MTBE(7ml)，滴加HCl/Dioxane(0.21ml，0.86mmol，2eq.)的 MTBE(3ml)溶液。滴加完毕，析出固体，加MTBE(15ml)搅拌。抽滤，滤饼MTBE淋洗，减压蒸干，得174mg类白色固体，收率88.2％.LC-MS: [M+H]+422.9.1H NMR(400MHz,CD3OD),δ7.13～7.33(m,3H),6.95～7.02(m, 2H),6.73(d,J＝8Hz,1H),4.33～4.64(m,1H),4.01～4.08(t,1H),3.84～3.94(m,2H),3.50～3.65(m,1H),3.21(s,1H),3.01～3.16(m,2H),2.71～2.76(m,4H),2.53～2.60(d,3H),2.10～2.27(m,2H),1.77(t,J＝16Hz,1H),1.19(s,3H).。13C NMR(150MHz, CD3OD)δ170.49,170.20,159.04,148.62,148.34,130.92,120.58～120.92(m), 117.32,117.17,115.34,113.58,113.47,106.19～106.51(m),74.37,74.20,68.17, 58.84,58.44,46.88,45.96,45.78,43.41,43.07,42.76,42.70,42.50,42.46,40.86, 39.78,39.23,34.02,33.57.HRMS(ESI),calcd for C22H25F3N2O3[M+Na]+, 445.1709；found,445.1691.。
实施例11
(3S,4R)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐的制备：
100ml单口瓶加(3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-甲酸叔丁酯(2g，5.49mmol，1eq.)、甲醇(10ml)，搅拌溶解，加HCl/Dioxane(3.4 ml，13.72mmol，2.5eq.)，25℃搅拌。1.5h后TLC(DCM：MeOH＝10:1)显示有少量原料。过夜(11.5h)，TLC显示反应完全。将易挥发物和溶剂减压蒸除，未经纯化，直接用于缩合。
实施例12
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮的制备：
装有(3S,4R)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐的100ml单口瓶加DCM(20ml)、2,4,5-三氟苯乙酸(1.15g，6.04mmol，1,1eq.)、HOBT(1.11 g，8.24mmol，1.5eq.)、EDCI-HCl(1.6g，8.24mmol，1.5eq.)、NMM(2.22g， 21.96mmol，4eq.)，室温搅拌。11.5h后TLC(DCM：MeOH＝10:1)显示反应完全。加水(50ml)，混合、静置、分层、分液。水相二氯甲烷萃取(50+25ml)。有机相合并，水洗三次(50+50+50ml)，无水硫酸镁干燥，抽滤，滤液减压蒸干，得2.82g浅黄色粘稠物。硅胶柱层析纯化(DCM～DCM：MeOH＝200:1，加5‰TEA)，得2.09g无色粘稠物，收率87.1％。
1H NMR(400MHz,CD3OD),δ7.24～7.31(m,2H),7.14～7.20(q,1H),7.06(s,1H), 7.00(t,J＝8Hz,1H),6.81(d,J＝8Hz,1H),4.92(s,2H),4.59(dd,J1＝88Hz,J2＝16 Hz,1H),3.80～4.16(m,5H),3.50(m,J1＝76Hz,J2＝12Hz,1H),3.04(m,J1＝60Hz, J2＝12Hz,1H),2.28～2.40(m,1H),1.97～2.19(m,7H),1.82(t,J＝12Hz,1H), 1.65～1.69(m,1H).13C NMR(150MHz,CD3OD)δ170.03,169.97,161.26,158.52, 151.25,149.87,149.83,149.61,148.70,147.10,130.38,130.35,120.56,120.43, 118.34,118.30,112.98,112.94,112.22,106.49,106.33,106.15,75.10,74.85,59.04, 58.93,55.66,54.84,47.49,46.27,46.23,44.88,44.15,43.76,43.58,41.88,41.00, 39.69,33.67.LC-MS:[M+H]+436.8.。
实施例13
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮盐酸盐的制备：
100ml单口瓶加1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1- 基)-2-(2,4,5-三氟苯基)乙基-1-酮(0.8g，1.83mmol，1eq.)、甲醇(1ml)，搅拌溶解，加甲基叔丁基醚(15ml)。滴加HCl/Dioxane(0.92ml，3.67mmol，2eq.) 的甲基叔丁基醚(5ml)溶液。析出固体，加甲基叔丁基醚(5ml)搅拌。抽滤，滤饼甲基叔丁基醚淋洗，减压蒸干，得0.79g类白色固体，收率91.9％。LC-MS: [M+H]+436.9.m.p.:216.0-218.9℃.1H NMR(400MHz,CD3OD),δ7.26～7.36(m, 2H),7.06～7.22(m,3H),6.88(m,J1＝8Hz,J2＝4Hz,1H),4.36～4.65(m,1H), 4.01～4.08(m,1H),3.85～3.96(m,2H),3.82(m,3H),3.02～3.06(m,2H),2.53～2.82 (m,7H),2.27～2.35(m,1H),2.11～2.24(m,1H),1.72～1.80(m,1H).13C NMR(150 MHz,CD3OD)δ170.48,170.21,161.60,148.67,148.36,130.98,130.95,120.57～120.92,118.49,118.34,113.67,113.58,112.58,112.55,106.19～106.52,74.50,74.31,58.82,58.41,55.77,46.86,43.39,42.92,42.72,42.40,40.95,39.94,39.22,34.06,33.57.HRMS(ESI),calcd for C23H27F3N2O3[M+Na]+,459.1866； found,459.1850.。
实施例14
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮的制备
伴有氮气气球和温度计的100ml三口瓶加1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基 -4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮(1.33g，3.05mmol，1eq.)、DCM(50ml)，冰水浴冷却搅拌，滴加BBr3(1ml，2.65g，10.6mmol， 3.5eq.)的DCM(10ml)溶液。滴加完毕，撤冰水浴搅拌(约10～15℃)，6.5h 后TLC(DCM：MeOH＝10:1)显示有少量原料。升至25℃搅拌，39h后TLC 显示反应完全。室温下缓慢加饱和碳酸氢钠溶液(100ml)，搅拌10min，静置、分层、分液。水相DCM萃取(50+50ml)。有机相合并，水洗(30ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得1.08g粘稠物。硅胶柱层析纯化(DCM～DCM： MeOH＝100:1)，得0.9g泡沫状物质，收率70％。
1H NMR(400MHz,CD3OD),δ7.24～7.30(q,1H),7.14～7.20(m,2H),6.88～6.93(m, 1H),6.67(dd,J1＝8Hz,J2＝4Hz,1H),4.93(s,2H),4.44～4.69(m,1H),3.89～4.16(m, 1H),3.36～3.62(m,1H),2.93～3.14(m,1H),2.31～2.45(m,1H),1.85～2.14(m,9H), 1.68(t,J1＝12Hz,1H).13C NMR(150MHz,CD3OD)δ170.02,158.60,158.55, 149.74,147.18,130.38,130.31,120.59,120.46,117.21,117.15,114.64,114.61, 113.29,113.26,106.47,106.32,106.14,74.97,74.74,59.02,58.90,47.71,47.50, 46.25,46.10,44.98,44.08,43.70,43.59,41.80,40.91,39.70,33.67.LC-MS:[M+H] +422.9.。
实施例15
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮盐酸盐的制备
100ml单口瓶加1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1- 基)-2-(2,4,5-三氟苯基)乙基-1-酮(0.24g，0.57mmol，1eq.)、甲醇(1ml)，搅拌溶解，加MTBE(7ml)，滴加HCl/Dioxane(0.3ml，1.14mmol，2eq.)的 MTBE(3ml)溶液。滴加完毕，析出固体，加MTBE(15ml)搅拌。抽滤，滤饼MTBE淋洗，减压蒸干，得190mg类白色固体，收率73％.LC-MS:[M+H]+422.9. 1H NMR(400MHz,CD3OD),δ7.16～7.33(m,3H),6.95～7.02(m,2H),6.73(d,J＝8 Hz,1H),4.32～4.62(m,1H),4.00～4.07(m,1H),3.84～3.94(m,2H),3.50～3.66(m, 1H),3.22(s,1H),3.02～3.13(m,2H),2.71～2.76(m,4H),2.53～2.60(d,3H),2.10～2.27(m,2H),1.77(t,J＝16Hz,1H),1.19(s,2H).13C NMR(150MHz,CD3OD) δ170.49,170.19,159.04,148.34,130.92,120.59～120.91(m),117.32,117.17,115.34, 113.58,113.46,106.18～106.52(m),74.20,68.17,58.84,58.45,47.95,46.86,45.96, 45.78,43.41,43.07,42.76,42.50,42.46,40.86,39.78,39.24,34.00,33.57.HRMS (ESI),calcdfor C22H25F3N2O3[M+Na]+,445.1709；found,445.1689.。
实施例16
(3R,4S)-4-(苯甲酰氧基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-1-基甲酸叔丁酯的制备
伴有温度计、氮气球的100ml单口瓶加(3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3- 甲氧基苯基)哌啶-1-甲酸叔丁酯(4.4g，12.07mmol，1eq.)、二氯甲烷(44ml)、三乙胺(2.44g，24.14mmol，2eq.)，冰水浴冷却。20℃下滴加苯甲酰氯(2.55g， 18.11mmol，1.5eq.)。滴加完毕，撤冰水浴搅拌。8.5h后TLC(DCM：MeOH＝10:1) 显示有少量原料游离碱。补加苯甲酰氯(0.85g，0.5eq.)。过夜(15.5h)，TLC 显示反应完全。加水(50ml)，搅拌10min，混合、静置、分层、分液。水相二氯甲烷萃取(50ml)。有机相合并，饱和氯化钠洗(20ml)，无水硫酸镁干燥，抽滤，滤液减压蒸干，得7.45g黄色液体。硅胶柱层析纯化 (DCM～DCM:MeOH＝200:1，加0.5‰三乙胺)，得5.36g无色液体，收率93.8％。1H NMR(400MHz,CD3OD),δ8.086(d,J＝8Hz,2H),7.675(t,J＝7.6Hz,1H), 7.554(t,J＝8Hz,2H),7.261(t,J＝8Hz,1H),6.813～6.864(m,2H),6.766(s,1H), 4.392(d,J＝13.6Hz,1H),4.075(d,J＝13.6Hz,1H),3.739(s,3H),3.121(d,J＝14.4Hz, 2H),2.889(s,1H),2.537～2.594(q,1H),2.346～2.425(m,1H),1.989～2.061(m,8H), 1.484(s,9H).
实施例17
(3S,4S)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-基苯甲酸盐酸盐的制备
100ml单口瓶加(3R,4S)-4-(苯甲酰氧基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-1-基甲酸叔丁酯(5.2g，11.1mmol，1eq.)、甲醇(26ml)、HCl/Dioxane(8.33 ml，33.3mmol，3eq.)，室温搅拌。12h后TLC(DCM:MeOH＝10:1)显示反应完全。将溶剂减压蒸干，加DCM(20ml)，减压蒸干，得粘稠物。未经纯化，直接用于下一步。
实施例18
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-基苯甲酸酯的制备
装有(3S,4S)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-基苯甲酸盐酸盐的 100ml三口瓶加二氯甲烷(45ml)、苄磺酰氯(3.17g，16.7mmol，1.5eq.)，滴加三乙胺(5.62g，55.5mmol，5eq.)，DMAP(68mg，0.56mmmol，0.05eq.)，四丁基溴化铵(358mg，1.11mmol，0.1eq.)，室温搅拌。24h后TLC (DCM:MeOH＝10:1)基本反应完全。加水(50ml)、二氯甲烷(20ml)，混合、静置、分层、分液。水相二氯甲烷萃取(50+25ml)。有机相合并，水洗(25ml)，饱和碳酸氢钠洗(25ml)，饱和氯化钠溶液洗(25ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得7g黄色粘稠物。硅胶柱层析纯化(DCM，加5‰三乙胺)，得4.06g无色粘稠物，2步收率70％。1H NMR(400MHz,CD3OD),δ 8.081～8.105(m,2H),7.728～7.772(m,1H),7.63(t,J＝7.6Hz,2H),7.380(d,J＝8Hz, 2H),7.254(t,J＝8Hz,1H),7.202(t,J＝7.6Hz,1H),7.031(t,J＝8Hz,2H),6.849(dd, J1＝8.4Hz,J2＝2.4Hz,1H),6.764～6.789(m,1H),6.711～6.712(m,1H),4.419(q, J＝21.2Hz,2H),3.993(dd,J1＝12.8Hz,J2＝4.4Hz,1H),3.735(s,3H),3.538(d,J＝12.4 Hz,1H),3.038～3.106(m,2H),2.490～2.557(m,2H),2.297～2.374(m,1H), 1.925～2.087(m,8H).LC-MS-ESI+:[M+H]+523.2.
实施例19
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇的制备
250ml单口瓶加(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶 -4-基苯甲酸酯(4.12g，7.9mmol，1eq.)、乙醇(40ml)、氢氧化钠(0.63g，15.8mmol，2eq.)，升温回流。2h后TLC(DCM:MeOH＝50:1)显示反应完全。将乙醇减压蒸除，加水(80ml)。乙酸乙酯萃取(50+50ml)。有机相合并，饱和碳酸氢钠溶液洗(30ml)，水洗(30ml)，饱和氯化钠溶液洗(30ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得3.82g黄色粘稠物。硅胶柱层析纯化(DCM， 0.5‰TEA)，得3.1g无色粘稠物，收率93.7％。
1HNMR(400MHz,CD3OD),δ7.469～7.499(m,2H),7.353～7.429(m,3H),7.854(t,J＝8 Hz,1H),7.012(t,J＝2.4Hz,1H),6.962(d,J＝8Hz,8H),6.779～6.808(m,1H),4.399(s, 2H),3.790(s,3H),3.758～3.804(m,1H),3.491～3.534(m,1H),3.121(m,J1＝12.4Hz, J2＝2.4Hz,1H),3.001(t,J＝12Hz,1H),2.282(q,J＝12.8Hz,1H),2.074～2.127(m,1H), 1.960～2.039(m,7H),1.739(dd,J1＝12.8Hz,J2＝2.4Hz,1H),1.579(m,J1＝14Hz, J2＝2.4Hz,1H).LC-MS-ESI+:[M+H]+419.3.。
实施例20
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐
250ml单口瓶加(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶 -4-醇(1g，2..9mmol，1eq.)、二氯甲烷(10ml)、MeOH(0.5ml)，搅拌溶解，滴加HCl/Dioxane(0.72ml，2.87mmol，1.2eq.)。加MTBE(44ml)，室温搅拌过夜(12h)，抽滤，滤饼MTBE淋洗，减压蒸干(60℃)，得1.07g类白色固体，收率98％。1H NMR(400MHz,CD3OD),δ7.484～7.505(m,2H),7.388～7.422(m, 3H),7.332(t,J＝8Hz,1H),7.077(s,1H),7.039(d,J＝7.6Hz,1H),6.868(d,J＝8.4Hz, 1H),4.448(s,2H),3.795～3.814(m,1H),3.555(d,J＝12.8Hz,1H),3.129～3.211(m, 2H),3.295～3.010(t,1H),2.665～2.693(m,4H),2.516(s,3H),2.319(s,1H),2.188(t, J＝12.8Hz,1H),1.682(d,J＝14Hz,1H).13C NMR(150MHz,CD3OD)δ161.59, 148.39,132.16,131.00,130.83,129.78,118.35,113.56,112.58,73.81,68.17,58.33, 57.40,55.76,46.43,45.73,43.29,42.95,42.53,40.47,27.24.LC-MS-ESI+: [M+H]+419.1.。
实施例21
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇的制备
伴有氮气球、温度计的100ml三口瓶加(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇(1.5g，3.6mmol，1eq.)、二氯甲烷(40ml)。冷却至-15℃，-5℃下滴加BBr3(1.98g，7.92mmol，2.2eq.)的二氯甲烷(10ml) 溶液。滴毕，保温搅拌。1.5h后TLC(DCM：MeOH＝10:1)显示反应完全。将反应液缓慢倒入饱和碳酸氢钠溶液(80ml)，搅拌10min，静置、分层、分液。水相二氯甲烷萃取(50ml)。有机相合并，水洗(30ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得1.5g泡沫状物。硅胶柱层析纯化(DCM～DCM： MeOH＝100:1)，得0.96g粘稠物。甲醇(5ml)结晶，得0.35g类白色固体。母液减压蒸干，制备板纯化，(DCM:MeOH＝10:1)，得0.27g类白色固体，合并收率42.5％。1H NMR(400MHz,CD3OD),δ7.47～7.49(m,2H),7.37～7.43(m,3H), 7.15(t,J＝8Hz,1H),6.865(d,J＝12Hz,2H),6.65(d,J＝8Hz,1H),4.39(s,2H), 7.35～7.38(m,1H),3.505(d,J＝12Hz,1H),3.11(t,J＝12Hz,1H),2.99(t,J＝12Hz,1H), 2.28(t,J＝12Hz,1H),1.91～2.09(m,8H),1.77(d,J＝16Hz,1H),1.58(d,J＝16Hz,1H). LC-MS-ESI+:[M+H]+405.0.
实施例22
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇盐酸盐
50ml单口瓶加(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4- 醇(0.12g，0.3mmol，1eq.)、二氯甲烷(3ml)、甲醇(0.5ml)，搅拌溶解。加氯化氢的1,4,-二氧六环溶液(0.113ml，0.45mmol，1.5eq.)。室温搅拌，加甲基叔丁基醚(10.5ml)，缓慢析出固体。搅拌1h，抽滤，滤饼减压蒸干，得 83mg类白色固体，收率63％。1H NMR(400MHz,CD3OD),δ7.48～7.50(m,2H), 7.39～7.44(m,3H),7.22(t,J＝8Hz,1H),6.92～6.94(d,2H),6.71(d,J＝8Hz,1H),4.44(s, 2H),3.74～3.77(m,1H),7.545(d,J＝6Hz,1H),3.11～3.17(m,2H),2.94～2.99(m,1H), 2.69～2.73(m,4H),2.51(s,3H),2.13～2.26(m,2H),1.685(d,J＝12Hz,1H).13C NMR (150MHz,CD3OD)δ159.04,148.38,132.17,130.94,130.83,129.78,129.76, 117.19,115.38,113.43,73.71,68.17,58.36,57.44,46.46,45.71,43.31,43.06,42.56, 40.35,27.24.LC-MS-ESI+:[M+H]+405.0.。
实施例23
(3S,4R)-4-(苯甲酰氧基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-1-基甲酸叔丁酯的制备
伴有温度计、氮气球的100ml单口瓶加(3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3- 甲氧基苯基)哌啶-1-甲酸叔丁酯(4.7g，12.9mmol，1eq.)、二氯甲烷(45ml)、三乙胺(2.61g，25.8mmol，2eq.)，冰水浴冷却。20℃下滴加苯甲酰氯(2.72g， 19.35mmol，1.5eq.)。滴加完毕，撤冰水浴搅拌。1h后TLC(DCM：MeOH＝10:1) 显示反应完全。加水(50ml)，混合、静置、分层、分液。水相二氯甲烷萃取(50 ml)。有机相合并，饱和氯化钠洗(20ml)，无水硫酸镁干燥，抽滤，滤液减压蒸干，得7.3g黄色液体。硅胶柱层析纯化(DCM～DCM:MeOH＝200:1，加0.5‰三乙胺)，得5.66g无色液体，收率93.6％。
1H NMR(400MHz,CD3OD),δ8.09(d,J＝8Hz,2H),7.68(t,J＝8Hz 1H),7.56(t,J＝7.6Hz, 2H),7.261(t,J＝8Hz,1H),6.811～6.864(m,2H),6.758～6.769(m,1H),4.394(d, J＝13.6Hz,1H),4.078(d,J＝13.6Hz,1H),3.738(s,3H),3.122(d,J＝14.4Hz,1H), 2.884(s,1H),2.543～2.600(m,1H),2.347～2.425(m,1H),1.984～2.025(m,8H), 1.484(s,9H).。
实施例24
(3R,4R)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-基苯甲酸盐酸盐的制备
100ml单口瓶加(3S,4R)-4-(苯甲酰氧基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-1-基甲酸叔丁酯(3.2g，6.83mmol，1eq.)、甲醇(15ml)、HCl/Dioxane(5.1 ml，20.5mmol，3eq.)，25℃搅拌。3h后TLC(DCM:MeOH＝10:1)显示反应完全。减压蒸干，得粘稠物。未经纯化，直接用于下一步。
实施例25
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-基苯甲酸酯的制备
装有(3R,4R)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-基苯甲酸盐酸盐的100 ml单口瓶加DCM(20ml)、苄磺酰氯(1.95g，10.25mmol，1.5eq.)、水(20ml)、碳酸钾(3.8g，27.32mmol，4eq.)，室温搅拌。待TLC显示反应完全。加水(30 ml)、DCM(30ml)，混合、静置、分层、分液。水相DCM萃取(30ml)。有机相合并，饱和碳酸氢钠溶液洗(20ml)，无水硫酸镁干燥，抽滤，滤液减压蒸干，得4.5g粘稠物。硅胶柱层析纯化(DCM～DCM：MeOH＝500:1，加0.5‰)，得1.65g类白色固体，收率46％。
1H NMR(400MHz,CD3OD),δ8.098(d,J＝7.2Hz,2H),7.755(t,J＝7.2Hz,1H),7.634(t,J＝7.2Hz,2H), 7.379(d,J＝7.6Hz,2H),7.253(t,J＝8.4Hz,1H),7.196(t,J＝7.6Hz,1H),7.017(t, J＝7.6Hz,2H),6.849(t,J＝4.2Hz,1H),6.774(t,J＝7.2Hz,1H),6.713(s,1H),4.422(q, J1＝22Hz,J2＝14Hz,2H),3.980～4.017(m,1H),3.734(s,3H),3.534(d,J＝12.8Hz, 1H),3.039～3.109(m,2H),2.476～2.544(m,2H),2.297～2.374(m,1H),1.906～2.051(m, 2H),1.986(s,6H).。
实施例26
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇的制备
250ml单口瓶加(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶 -4-基苯甲酸酯(3.7g，7.1mmol，1eq.)、乙醇(40ml)、氢氧化钠(0.57g，14.2 mmol，2eq.)，升温回流。2h后TLC(DCM:MeOH＝25:1)显示反应完全。将乙醇减压蒸除，加水(80ml)。乙酸乙酯萃取(50+50ml)。有机相合并，饱和碳酸氢钠溶液洗(30ml)，水洗(30ml)，饱和氯化钠溶液洗(30ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得3g黄色粘稠物。硅胶柱层析纯化(DCM，0.5‰ TEA)，得2.83g无色液体，收率95.3％。
1H NMR(400MHz,CD3OD),δ7.48～7.50(m,2H),7.35～7.43(m,3H),7.25(t,J＝8Hz,1H),7.01(s, 1H),6.96(d,J＝8Hz,1H),6.795(dd,J1＝8Hz,J2＝4Hz,1H),4.40(s,2H), 3.76～3.80(m,4H),3.49～3.53(m,1H),3.115(m,J1＝12Hz,J2＝4Hz,1H),3.00(t,J＝12 Hz,1H),2.25～2.31(m,1H),2.07～2.13(m,1H),1.98～2.04(m,7H),1.725(d,J＝12Hz, 1H),1.575(d,J＝12Hz,1H).LC-MS-ESI+:[M+H]+419.1.。
实施例27
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐的制备
250ml单口瓶加(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶 -4-醇(1g，2..9mmol，1eq.)、二氯甲烷(10ml)、MeOH(0.5ml)，搅拌溶解，滴加HCl/Dioxane(0.72ml，2.87mmol，1.2eq.)，未析出固体。加MTBE(50ml)，析出固体，抽滤，滤饼MTBE淋洗，减压蒸干(60℃)，得1.03g类白色固体，收率94.5％。1H NMR(400MHz,CD3OD),δ7.489～7.505(m,2H),7.396～7.440(m, 3H),7.310～7.351(m,1H),7.075(s,1H),7.037(d,J＝7.6Hz,1H),6.865(d,J＝4.2Hz, 1H),4.451(s,2H),3.779～3.815(m,4H),3.551(d,J＝12.8Hz,1H),3.131～3.232(m, 3H),3.982(t,J＝12Hz,1H),2.663～2.700(m,4H),2.515(s,3H),2.322(s,1H),2.180(t, J＝13.6Hz,1H),1.678(d,J＝14.4Hz,1H).13C NMR(150MHz,CD3OD)δ161.58, 148.40,132.17,131.00,130.83,129.77,118.35,113.57,112.57,73.80,68.17,58.32, 57.40,55.76,46.45,45.74,43.28,42.93,42.52,40.48,27.24.LC-MS-ESI+: [M+H]+419.1.。
实施例28
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇的制备
伴有氮气气球、温度计的50ml三口瓶加(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇(0.6g，1.434mmol，1eq.)、DCM(15ml)，冷却至-15℃，-5℃下滴加三溴化硼(0.79g，3.154mmol，2.2eq.)的二氯甲烷(2 ml)溶液。加毕，保温搅拌，1.5h后TLC(DCM：MeOH＝10:1)显示反应完全。加饱和碳酸氢钠溶液(50ml)，DCM(50ml)。混合、静置、分层、分液。水相 DCM萃取(30ml)。有机相合并，水洗(15ml)，无水硫酸镁干燥，抽滤，滤液减压蒸干，得0.58g泡沫状物质。制备板纯化(EA:MeOH＝80:1)，得0.22g 类白色固体，收率38％。
LC-MS-ESI+: [M+H]+405.1.1H NMR(400MHz,CD3OD),δ7.47～7.49(m,2H),7.37～7.43(m,3H), 7.15(d,J＝8Hz,1H),6.85～6.88(m,2H),6.65(d,J＝8Hz,1H),4.40(s,2H), 3.75～3.78(m,1H),3.49～3.52(m,1H),3.08～3.14(m,1H),2.99(t,J＝12Hz,1H), 2.27～2.33(m,1H),1.94～2.07(m,8H),1.795(d,J＝12Hz,1H),1.585(d,J＝12Hz, 1H).。
实施例29
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇盐酸盐
50ml单口瓶加(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4- 醇(0.1g，0.25mmol，1eq.)、二氯甲烷(3ml)、甲醇(0.5ml)，搅拌溶解。加氯化氢的1,4,-二氧六环溶液(0.1ml，0.375mmol，1.5eq.)。室温搅拌，加甲基叔丁基醚(7ml)，缓慢析出固体。搅拌1h，抽滤，滤饼减压蒸干，得50mg 类白色固体，收率45％。1H NMR(400MHz,CD3OD),δ7.48～7.50(m,2H), 7.39～7.45(m,3H),7.22(t,J＝8Hz,1H),6.92～6.94(m,1H),6.715(d,J＝4Hz,1H), 4.44(s,2H),3.74～3.77(m,1H),3.545(d,J＝12Hz,1H),3.12～3.17(m,1H), 2.94～3.00(m,1H),2.69～2.74(m,4H),2.51(s,3H),2.13～2.26(m,2H),1.685(d,J＝12 Hz,1H).13C NMR(150MHz,CD3OD)δ159.04,148.38,132.17,130.93,130.84,129.78,129.76,117.19,115.38,113.43,73.71,58.36,57.44,46.47,45.71,43.31,43.06,42.56,40.35.LC-MS-ESI+:[M+H]+405.1.。
实施例30
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇的结构解析
1、仪器型号：Bruker SMART APEX-II单晶X射线衍射仪
2、测试条件：CuKα辐射，石墨单色器，单导管直径Φ＝0.50mm，晶体与CCD
探测器距离d＝60.3mm，管压40kV，管流30mA，扫描方式：
扫描。
3、采用直接法(Shelxs97)解析晶体结构，HHM9-18A晶体属单斜晶系，空间群为P21,晶胞参数：a＝6.1179(12),b＝19.316(3),
α＝γ＝90.00°，β＝96.18(3)°,晶胞体积
晶胞内不对称单位数Z＝2。使用最小二乘法修正结构参数和判别原子种类，使用几何计算法和差值Fourier法获得全部氢原子位置，最终可靠因子R1＝0.0327，wR2＝0.0849(w＝1/σ|F|2)，S＝1.139。最终确定化学计量式为C21H28N2O4S，计算分子量为404.51，计算晶体密度为 1.305g/cm3。
Table 1.Crystal data and structure refinement
Table 2.Atomic coordinates(x 10^4)and equivalent isotropicdisplacement parameters(A^2 x 10^3)
Table 3.Bond lengths[A]
Table 5.Bond angles[deg]
Table 5.Torsion angles[deg]
Table 6.Hydrogen bonds[A and deg.]
Symmetry transformations used to generate equivalent atoms:#1x-1,y,z#2 x,y,z+1。
实施例31
膜受体的制备
分别表达μ阿片受体、δ阿片受体或κ阿片受体的CHO细胞种于10cm2培养皿中培养(F-12培养基+10％新生牛血清)数天，细胞长满皿底后吸去培养液；加PBS/EDTA溶液(0.1MNaCl，0.01M NaH2PO4,0.04％EDTA)3ml消化3-5min, 用吸管吹打，使细胞完全脱落，收集细胞于40ml离心管，5000rpm离心5min, 去上清液；加入冰冷的匀浆液(50mM HEPES PH 7.4，3mM MgCl,1mM EGTA) 于离心管，将溶液和沉淀转移到匀浆器中匀浆；然后将匀浆液转移到离心管中， 18000rpm离心15min，共离心2次；得到的沉淀加入适量的50mM Tris-HCl， pH7.4的缓冲液匀浆并分装于离心管，-70℃冰箱保存待用。
竞争结合试验
总结合管加相当于20-30μg的表达的膜受体蛋白和[3H]标记的配体(1-2 nM)，相对应的非特异性结合管另加1μM的相应配体，样品管加不同浓度的各种筛选的阿片配体类药物，终体积为100μl,30℃孵育30min，置冰水中终止反应。在Millipore样品收集器上经GF/C(whatman)玻璃纤维滤纸负压抽滤。用 4ml 50mM Tris-HCl(pH 7.4)冲洗三次，滤纸烘干后，置于0.5ml Eppendorf 管，加0.5ml亲脂闪烁液，PERKIN ELMER PRI-CARB 2910液体闪烁计数仪测定放射性强度，计算抑制率，实验重复三次以上，每组三复管。
抑制率(或称结合率)＝(总结合率dpm－样品管dpm)/(总结合管dpm －非特异性结合管dpm)×100％
用Graphpad Prism 5.0软件计算IC50。按下式计算Ki值，Ki＝IC50/(1+[L]/Kd)，[L]为所加标记配体的浓度，Kd为标记配体的平衡解离参数
表1为代表性化合物对阿片受体的亲和常数Ki值，采用三次独立的测量平均值±标准偏差表示。
表1化合物1μM浓度下阿片受体结合率或Ki
a.0.1μM的抑制率
表1的“结合率(％)或Ki(nM)”一栏中，用百分比表示的数值是指结合率，以 nM为单位的数值是指Ki。
从表1可以看出，所有的化合物对μ阿片受体亲和力均强于曲马多，对δ阿片受体和κ阿片受体的亲和力强于曲马多或与曲马多相当。
实施例32
体内热板法镇痛试验
将体重20g左右雌性小鼠放在预热至55℃热板仪上，以小鼠舔后足反应的潜伏期为痛阈指标。实验前筛选动物，将反应潜伏期小于5s或大于30s的动物剔除。为防止足部烫伤，最长观察时间设为60s。基础痛阈为2次测量值的平均值，两次测量之间相隔5min。各组小鼠痛阈值分别在腹腔给药后15分钟、30分钟、60分钟和120分钟进行测定。镇痛有效百分率(％MPE)根据以下公式计算：镇痛有效百分率(％MPE)。根据镇痛有效百分率用软件Graphpad prism 5.0计算 ED50值。
表2 10mg/kg剂量下化合物热板最大镇痛有效百分比或ED50值
表2的“％MPE或ED50”一栏中，用百分比表示的数值是指％MPE，以mg/kg 为单位的数值是指ED50。
从表2可以看出，本发明化合物的镇痛作用强于曲马多。
Claims (9)
1.式(I)或(II)所示的化合物，或其药学上可接受的盐：
其中，
R1选自氢、C1-6烷基、氟代烷基、环烷基、链状烯基、环烯基、取代或未取代芳基C1-6烷基；
R2选自取代或未取代芳基、取代或未取代杂芳基，其取代基可选自芳基、卤素、C1-6烷基、氰基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氟、硝基、酚羟基；
X选自
2.根据权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R1选自氢、甲基。
3.根据权利要求1或2所述的化合物，或其药学上可接受的盐，其特征在于，R2选自取代或未取代芳基，优选自苯基或2,4,5-三氟苯基。
4.根据权利要求1至3中任一项所述的化合物，或其药学上可接受的盐，其特征在于，式(I)化合物选自：
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
(3R,4S)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇。
5.根据权利要求1至3中任一项所述的化合物，或其药学上可接受的盐，其特征在于，式(II)化合物选自：
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
1-((3S,4R)-3-((二甲氨基)甲基)-4-羟基-4-(3-羟基苯基)哌啶-1-基)-2-(2,4,5-三氟苯基)乙基-1-酮；
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
(3S,4R)-1-(苄磺酰基)-3-((二甲氨基)甲基)-4-(3-羟基苯基)哌啶-4-醇。
6.一种药物组合物，其特征在于，包括：权利要求1至5中任一项所述的化合物或其药学上可接受的盐、溶剂化物或水合物；以及药学上可接受的载体。
7.权利要求1-5中任一项所述的化合物或者其药学上可接受的盐类、溶剂化合物或水合物在制备治疗与阿片受体相关适应症的药物中的用途。
8.如权利要求7所述的用途，其特征在于，所述与阿片受体相关适应症为疼痛、肠易激综合征、瘙痒、成瘾、抑郁症。
9.如权利要求8所述的用途，其特征在于，所述的疼痛包括治疗或缓解手术期间的疼痛、慢性疼痛、神经性疼痛、癌性疼痛。
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| PCT/CN2020/125799 WO2021088758A1 (zh) | 2019-11-06 | 2020-11-02 | 一类阿片受体激动剂及其制备方法和药物用途 |
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| CN117447388B (zh) * | 2022-12-15 | 2024-05-10 | 南昌双天使生物科技开发有限公司 | 氘代的4-苯基哌啶-4-醇类化合物的制备及其用途 |
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