CN109575075B - 一种制备喹啉酮生物碱的中间体 - Google Patents
一种制备喹啉酮生物碱的中间体 Download PDFInfo
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- CN109575075B CN109575075B CN201811551667.5A CN201811551667A CN109575075B CN 109575075 B CN109575075 B CN 109575075B CN 201811551667 A CN201811551667 A CN 201811551667A CN 109575075 B CN109575075 B CN 109575075B
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- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 7
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- 238000000034 method Methods 0.000 claims description 61
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- 125000004169 (C1-C6) alkyl group Chemical group 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
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 56
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
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- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 6
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- FYYSQDHBALBGHX-YFKPBYRVSA-N N(alpha)-t-butoxycarbonyl-L-asparagine Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(N)=O FYYSQDHBALBGHX-YFKPBYRVSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical group S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
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- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000007295 Wittig olefination reaction Methods 0.000 description 1
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- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
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- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
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- 238000007865 diluting Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229950010030 dl-alanine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZFGUZIJANHMZBO-UHFFFAOYSA-N ethanone;zinc Chemical compound [Zn].C[C]=O ZFGUZIJANHMZBO-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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- C07D257/04—Five-membered rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/70—Sulfur atoms
- C07D277/76—Sulfur atoms attached to a second hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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Abstract
Description
本发明是中国专利申请号:201610847450.3的分案申请,原申请的申请日为2016年9月25日,优先权日为2015年9月29日,原申请的发明名称为一种海洋真菌来源的抗病毒喹啉酮生物碱类衍生物的制备方法。
技术领域
本发明属于药物合成领域,涉及一种制备喹啉酮生物碱的中间体。
背景技术
文献报道海洋真菌来源的喹啉酮生物碱类化合物具有多种生物活性(Journal ofNatural Products 2014,77,2720-2724;Marine Biotechnology 2015,17,408-415),例如抗病毒活性、抗污损活性等,尤其是中国发明专利(申请号:201510150737.6和201510150071.4)中公开了系列含有氨基酸侧链的喹啉酮生物碱类化合物对RSV具有强的抗病毒活性,其有希望发展为抗RSV先导化合物,甚至是候选药物。
现有技术中(Journal of the American Chemical Society 2015,137,4980-4983),尚未有报道化学合成含有氨基酸侧链的喹啉酮生物碱的方法,单纯靠天然提取或生物合成方法获取该类化合物,极大地限制了其药理活性及其药代动力学的研究。因此,开发一种高效地化学合成该类喹啉酮生物碱的方法,显得尤为重要。
发明内容
本发明的目的在于提供申请人在先申请(申请号:201510150737.6和201510150071.4)中记载的海洋真菌来源的抗病毒喹啉酮生物碱类衍生物的制备方法。在先申请(申请号:201510150737.6和201510150071.4)中的公开内容通过引用完全结合于本发明中。
本发明提供一种式I-1结构的喹啉酮生物碱类化合物或其药学上可接受的盐的制备方法,包括由式A化合物与R1OH反应制备式I-1化合物的步骤:
式A化合物与任选取代的氨基酸R1OH,在有机溶剂中,发生缩合反应,得到式I-1化合物;其中R1为羧基端脱掉羟基的氨基酸残基,R2为H、C1-C4烷基、C3-C6环烷基、C1-C4卤代烷基、C1-C4烷基酰基、C1-C4卤代烷基酰基、C3-C6环烷基酰基、C2-C4烯基、C5-C10芳基烷基,“-----”表示单键或不存在,表示指向纸面里的键或指向纸面外的键所述氨基酸为丙氨酸(Ala)、缬氨酸(Val)、亮氨酸(Leu)、异亮氨酸(Ile)、脯氨酸(Pro)、苯丙氨酸(Phe)、色氨酸(Trp)、蛋氨酸(Met)、甘氨酸(Gly)、丝氨酸(Ser)、苏氨酸(Thr)、半胱氨酸(Cys)、酪氨酸(Tyr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、赖氨酸(Lys)、精氨酸(Arg)、组氨酸(His)、天冬氨酸(Asp)、谷氨酸(Glu)中的一种,其中氨基酸的构型为D型、L型、或DL型,氨基酸(R1OH)中的氨基任选被C1-C4烷基、C3-C6环烷基、C1-C4卤代烷基、C1-C4烷基酰基、C1-C4烷氧基羰基、Boc或Fmoc中的一个或两个取代,氨基酸(R1OH)中的亚烷基或芳基任选被C1-C4烷基、C3-C6环烷基、C1-C4烷氧基、C1-C4卤代烷基或C1-C4烷基酰基、羟基、卤素、硝基、氰基中的一个或多个取代。
上述制备方法的前提条件是R1OH不为Boc-L-缬氨酸、Boc-D-天冬酰胺、L-脯氨酸、Fmoc-N-甲基-D-缬氨酸、Fmoc-L-组氨酸、Boc-DL-苯丙氨酸、Boc-L-组氨酸。
所述缩合反应条件为本领域常规的羟基与羧基缩合(酯化)反应条件,优选在缩合剂和碱的作用下反应,缩合剂选自二环己基碳二亚胺DCC、二异丙基碳二亚胺DIC、1-乙基-(3-二甲基氨基丙基)碳二亚胺EDC中的一种或几种,或者其盐酸盐,优选DCC、DIC;碱选自:二甲氨基吡啶、三乙胺、吡啶中的一种或几种,优选DMAP。
本发明的另一实施方案中提供式I-1化合物的制备方法,其特征在于还包括由式B化合物经还原反应制备式A化合物的步骤:
式B化合物在有机溶剂中与还原剂作用得到式A化合物。上述方法中羰基的还原可以是立体选择性还原或非选择性还原,选择性还原或非选择性还原方法为本领域的技术人员常用的羰基的选择性还原或非选择性还原方法,例如还原剂采用可用作催化剂的主族元素氢化物或过渡金属络合物,转移加氢,用金属或低价金属盐还原,二亚胺还原或加氢。上述羰基还原方法在现有技术中已较为成熟,例如R.L.Larock,Comprehensive OrganicTransformations,Wiley-VCH,New York,1999中有描述。所述还原剂选自选择性还原为β-OH的还原剂,优选硼氢化物(或乙酰基硼氢化物)与金属盐或其水合物的组合;或者选自选择性还原为α-OH的还原剂,优选三仲丁基硼氢化物;或者选自非选择性还原剂,优选硼氢化物(或乙酰基硼氢化物)、氢化铝锂。
选择性还原为β-OH的还原剂,进一步优选(乙酰基)硼氢化钠、(乙酰基)硼氢化锂、(乙酰基)硼氢化钾、(乙酰基)硼氢化锌中的一种或几种与CeCl3·7H2O、CoCl2·6H2O、CdCl2·2.5H2O、CuCl、CuBr中的一种或几种的组合;选择性还原为α-OH的还原剂,优选三仲丁基硼氢化钠、三仲丁基硼氢化锂、三仲丁基硼氢化钾、三仲丁基硼氢化锌中的一种或几种;非选择性还原剂,优选(乙酰基)硼氢化钠、(乙酰基)硼氢化锂、(乙酰基)硼氢化钾、(乙酰基)硼氢化锌、氢化铝锂中的一种或几种。
具体的还原操作可参见现有技术中羰基还原的方法,例如CN101031531A、CN101607895A、CN101089008A、CN104592243A、CN104327143A、CN104231031A等。
本发明的另一实施方案中提供式B化合物的制备方法,其特征在于包括由式C化合物经烃基化或酰基化反应制备式B化合物的步骤:
式C化合物经烃基化反应或酰基化反应得到式B化合物,烃基化反应条件为本领域常规条件:有机溶剂中,在碱、烃基化试剂作用下反应,其中烃基化试剂优选R2X,其中X为卤素,优选氯、溴、碘,R2为C1-C4烷基、C3-C6环烷基、C1-C4卤代烷基、C2-C4烯基、C5-C10芳基烷基;碱优选碱金属碳酸盐(如Na2CO3、K2CO3、Cs2CO3);酰基化反应条件也为本领域常规条件:有机溶剂中,在碱、酰基化试剂作用下反应,其中酰基化试剂优选R′COX(酰卤)、R′COOCOR′(酸酐),其中X为卤素,优选氯、溴、碘,R′为C1-C3烷基、C1-C3卤代烷基、C1-C4烷基、C3-C6环烷基;酰基化试剂的摩尔用量为式M化合物的0.8~1.1倍;反应温度为-20℃至0℃;碱优选碱金属碳酸盐(如Na2CO3、K2CO3、Cs2CO3)、三乙胺、吡啶、醋酸钠、喹啉、咪唑、二甲基苯胺等;其中有机溶剂优选二氯甲烷、乙腈、苯、甲苯、THF、乙醚、乙二醇二甲醚、DMF、二氧六环等。
本发明的另一实施方案中提供式I-1化合物的制备方法,其特征在于还包括如下任一种或几种式B化合物的制备方法:其中当式B化合物中“-----”表示单键时,以式B-1化合物表示式B化合物;当式B化合物中“-----”不存在时,以式B-2化合物表示式B化合物;
方法一:
式D化合物与式E化合物在有机溶剂、有机碱作用下,发生wittig反应得到式B-1化合物;其中,R9为(R8)3P+X-或PO(OR8)2,其中R8选自烷基、芳基,优选C1-C6烷基、苯基,X选自卤素、OTs,优选Cl、Br、I、OTs;有机碱优选LDA、LiHMDS、NaHMDS、KHMDS、n-BuLi、t-BuLi、t-BuOK、t-BuONa、NaH、LiH、KH中的一种或几种;有机溶剂优选THF、乙二醇二甲醚DME、Et2O、异丙醚、甲基叔丁基醚MTBE、DMF或甲苯中的一种或几种;
方法二:
式F化合物与式G化合物在有机溶剂、有机碱作用下,发生wittig反应得到式B-1化合物;其中,R9为(R8)3P+X-或PO(OR8)2,其中R8选自烷基、芳基,优选C1-C6烷基、苯基,X选自卤素、OTs,优选Cl、Br、I、OTs;有机碱优选LDA、LiHMDS、NaHMDS、KHMDS、n-BuLi、t-BuLi、t-BuOK、t-BuONa、NaH、LiH、KH中的一种或几种;有机溶剂优选THF、乙二醇二甲醚DME、Et2O、异丙醚、甲基叔丁基醚MTBE、DMF或甲苯中的一种或几种;
方法三:
式H化合物与式G化合物在有机溶剂、有机碱作用下,发生Julia olefination反应得到式B-1化合物;其中,R10为有机碱优选LDA、LiHMDS、NaHMDS、KHMDS、n-BuLi、t-BuLi、t-BuOK、t-BuONa、NaH、LiH、KH、NaOMe、NaOEt中的一种或几种;有机溶剂优选THF、乙二醇二甲醚DME、Et2O、异丙醚、甲基叔丁基醚MTBE、DMF或甲苯中的一种或几种;
方法四:
式D化合物与式I化合物在有机溶剂、有机碱作用下,发生Julia olefination反应得到式B-1化合物;其中,R10为有机碱优选LDA、LiHMDS、NaHMDS、KHMDS、n-BuLi、t-BuLi、t-BuOK、t-BuONa、NaH、LiH、KH、NaOMe、NaOEt中的一种或几种;有机溶剂优选THF、乙二醇二甲醚DME、Et2O、异丙醚、甲基叔丁基醚MTBE、DMF或甲苯中的一种或几种;
方法一至四中wittig或Julia olefination反应的操作可参见现有技术中的方法,例如CN102731468A、CN102070563A(Julia试剂制备)、CN104844452A、CN104829439A、CN104558013A、CN104529859A、CN103086937A、CN103183680A等;
方法五:
式B-1化合物于有机溶剂中在还原剂作用下反应得到式B-2化合物;还原剂选自本领域常规双键还原剂,优选H2与Pd/C、Pt/C、PtO2、雷尼镍(Raney Nickel)中的一种或几种的组合;
式B化合物包含“-----”表示单键或不存在的两种情形,即式B化合物包含式B-1和式B-2两种化合物,上述式B-1和式B-2的制备方法即为式B化合物的制备方法。
式C化合物也可由Julia olefination或wittig反应制备得到。
本发明中式D化合物可由化合物J(CAS登记号:90612-20-7)经本领域常规选择性还原羧基为醛基的方法制备;选择性还原方法可参见现有技术中的方法,例如Angew.Chem.Int.Edit.,2015,54(17),5196–5200;Chem.Commun.,2002,836-837;Org.Lett.,2013,15(3),496–499;Chemistry Letters,2012,41(3),229-231等文献中记载的还原羧基为醛基的方法。化合物J可通过商业化购买(FCH Group);或由专利US3074831、GB919394中记载的CAS登记号为91267-01-5的化合物氧化制备;或由CAS登记号为870262-55-8的化合物替代其中一种异构体,其它异构体可按照文献Chem.Commun.,2005,4908–4910中记载的方法或类似方法进行制备。
式F化合物由式K化合物经卤代后,再在本领域制备磷叶立德或膦酸酯常用的条件下制备得到;优选在碱作用下与(R8)3P或P(OR8)3反应制备得到;其中卤代反应条件优选式K化合物与I2、Ph3P或者NBS、Ph3P反应得到相应碘代或溴代产物;(R8)3P或P(OR8)3优选Ph3P或P(OEt)3、P(OMe)3。
按照类似式K化合物制备式F化合物的方法,可由式L化合物制备得到式E化合物。式E化合物由式L化合物经卤代后,再在本领域制备磷叶立德或膦酸酯常用的条件下制备得到;优选在碱作用下与(R8)3P或P(OR8)3反应制备得到;其中卤代反应条件优选式L化合物与I2、Ph3P或者NBS、Ph3P得到相应碘代或溴代产物;(R8)3P或P(OR8)3优选Ph3P或P(OEt)3、P(OMe)3。
式H化合物可由式K化合物经卤代后,再在碱作用下与反应后再经氧化制备得到;其中卤代反应条件优选式K化合物与I2、Ph3P,NBS、Ph3P,氯化亚砜或者草酰氯得到相应碘代、溴代、氯代产物;氧化反应条件优选间氯过氧苯甲酸、双氧水或者过氧乙酸。具体氧化反应的操作可参见专利CN103183680A(实施例6-7)中记载的相应氧化方法。
按照类似式K化合物制备式H化合物的方法,可由式L化合物制备得到式I化合物。式I化合物可由式L化合物经卤代后,再在碱作用下与反应后再经氧化制备得到;其中卤代反应条件优选式L化合物与I2、Ph3P,NBS、Ph3P,氯化亚砜或者草酰氯得到相应碘代、溴代、氯代产物;氧化反应条件优选间氯过氧苯甲酸、双氧水或者过氧乙酸。具体氧化反应的操作可参见专利CN103183680A(实施例6-7)中记载的相应氧化方法。
式G化合物可由式L化合物经氧化反应制备,氧化反应条件为本领域常用的氧化羟基为羰基的反应条件,例如Corey-Kim、Jones、Pfitzner-Moffatt、Swern、Dess-Martin等氧化方法(《Strategic Applications of Named Reactions in Organic Synthesis》,László Kürti and Barbara Czakó,2005,Elsevier Academic Press,ISBN:0-12-429785-4),优选利用Dess-Martin试剂进行氧化。
式K化合物可由式D化合物在本领域常用选择性还原醛基为羟甲基的条件下还原得到,选择性还原的条件优选0.5equiv.NaBH4和1.0equiv.2,4-戊二酮,具体操作可参见Organic Letters(2011),13(4),588-591中(制备化合物11)记载的方法。
式L化合物可由现有技术(例如,Tetrahedron Letters,2003,44(22),4271-4273;Tetrahedron,2003,59(37),7301-7306;Chinese Journal of Chemistry,2009,27,1379-1381等)中合成4-苯基-氢化喹啉-2-酮的方法进行合成。
式L化合物优选由路线一(P→O→N→M→L)或路线二(W→V→U→T→S→R→M→L)制备。
路线一:P→O→N→M→L
按照文献Synthesis(2011),(2),243-250或Green Chem.,2011,13,190-196中记载类似的方法,式P化合物与苯硼酸在碱(优选碱金属碳酸盐,如Na2CO3、K2CO3、Cs2CO3)、催化剂(优选Pd类催化剂,如PS-Pd-NHC或MCM-41-2N-Pd(II))、一氧化碳作用下,制备得到式O化合物;式O化合物经本领域常规的还原羧基为羟甲基的方法(可参见本发明中记载的相应方法或现有技术中其它类似官能团转换方法)得到式N化合物;按照文献TetrahedronLetters,2003,44(22),4271-4273中记载的合成4-苯基-氢化喹啉-2-酮的方法,式N化合物与MeOCH2COOR5(R5为烷基,优选甲基、乙基)、LiHMDS作用后经水解得到式M化合物;式M化合物中的酚羟基经烃基化反应或酰基化反应得到式L化合物,烃基化反应条件为本领域常规条件:有机溶剂中,在碱、烃基化试剂作用下反应,其中烃基化试剂优选R2X,其中X为卤素,优选氯、溴、碘,R2为C1-C4烷基、C3-C6环烷基、C1-C4卤代烷基、C2-C4烯基、C5-C10芳基烷基;碱优选碱金属碳酸盐(如Na2CO3、K2CO3、Cs2CO3);酰基化反应条件也为本领域常规条件:有机溶剂中,在碱、酰基化试剂作用下反应,其中酰基化试剂优选R′COX(酰卤)、R′COOCOR′(酸酐),其中X为卤素,优选氯、溴、碘,R′为C1-C3烷基、C1-C3卤代烷基、C1-C4烷基、C3-C6环烷基;酰基化试剂的摩尔用量为式M化合物的0.8~1.1倍;反应温度为-20℃至0℃;碱优选碱金属碳酸盐(如Na2CO3、K2CO3、Cs2CO3)、三乙胺、吡啶、醋酸钠、喹啉、咪唑、二甲基苯胺等;其中有机溶剂优选二氯甲烷、乙腈、苯、甲苯、THF、乙醚、乙二醇二甲醚、DMF、二氧六环等。
路线二:W→V→U→T→S→R→M→L
按照文献Chinese Journal of Chemistry,2009,27,1379-1381中记载类似的方法,式W化合物与苯甲酰氯在碱(优选碱金属碳酸盐,如Na2CO3、K2CO3、Cs2CO3)作用下,制备得到式V化合物;式V化合物经本领域常规的上硅基保护基的方法(可参见《有机合成中的保护基》(荣国斌译)记载的相应方法或现有技术中其它类似上硅基保护基的方法)得到式U化合物,上硅基保护基的试剂优选TBSCl、TMSCl、TBDPSCl、TESCl等,即R7为硅基保护基,优选TBS、TMS、TBDPS、TES等;接下来按照文献Chinese Journal of Chemistry,2009,27,1379-1381中记载类似的合成4-苯基-氢化喹啉-2-酮的方法,式U化合物与格氏试剂(优选苯基溴化镁)反应后在碱(优选NaOH、KOH)的作用下得到式T化合物,式T化合物与甲氧基乙酸、氯化亚砜作用得到式S化合物,式S化合物在t-BuOK作用下得到式R化合物,式R化合物经本领域常规的脱硅基保护基的方法(例如采用TBAF、HF/pyridine等试剂)得到式M化合物。式M化合物按照路线一中记载的酚羟基经烃基化或酰基化的方法即可得到式L化合物。
其中式W化合物可通过商业定制渠道获得,或者通过下列方法制备:
由式X化合物经本领域常规羧基还原为羟甲基的方法得到式W化合物(由于式X中包含两个羧基,因此该反应选择性较差,收率不足50%)。
式X化合物(CAS登记号:101421-90-3)可通过商业定制或按现有技术(例如Collection of Czechoslovak Chemical Communications(1959),24,857-861;GB808298;Chemicke Listy pro Vedu a Prumysl(1958),52,1474-1478等文献)中的方法制备得到。
本发明的另一实施方案中提供式I-1的制备方法,其特征在于本发明制备的式I-1化合物优选具有如下立体结构:
上述实施方案中相应立体结构的式I-1化合物可由具备相同立体构型的原料进行制备;也可由本领域常用的手性拆分方法(手性柱层析或手性试剂拆分)获得。
本发明的另一实施方案中提供系列中间体化合物,其特征在于上述中间体具有式K、F、G、L、E、H、I、L、O、N、M、W、V、U、T、S、R所示的结构:
其中表示指向纸面里的键或指向纸面外的键R2为H、C1-C4烷基、C3-C6环烷基、C1-C4卤代烷基、C1-C4烷基酰基、C1-C4卤代烷基酰基、C3-C6环烷基酰基、C2-C4烯基、C5-C10芳基烷基;R7为硅基保护基,优选TBS、TMS、TBDPS、TES;R9为(R8)3P+X-或PO(OR8)2,其中R8选自烷基、芳基,优选C1-C6烷基、苯基,X选自卤素、OTs,优选Cl、Br、I、OTs;,R10为
本发明的另一实施方案中提供中间体式K、F、G、L、E、H、I、L、O、N、M、W、V、U、T、S、R化合物的制备方法,其步骤包括上述本发明所述及本发明实施例中所述的方法。
本发明的另一实施方案中提供式I-1化合物药学上可接受的盐的制备方法,其特征在于还包括使式I-1化合物中的碱性基团(如氨基或胺基)与适当的酸(例如盐酸、硫酸、磷酸、草酸、马来酸、甲烷磺酸、琥珀酸、柠檬酸、富马酸、葡萄糖醛酸、甲酸、乙酸、丁二酸等中的一种或几种)反应的步骤。
本发明的另一实施方案中提供式I-1化合物或其药学上可接受的盐的制备方法,其特征在于还包括脱除氨基上保护基的操作,例如酸性条件下(优选TFA)脱除Boc、碱性条件下(优选吗啉)脱除Fmoc。
本文中所述“烷基”优选甲基、乙基、丙基、正丁基、异丁基、叔丁基;“卤代烷基”优选三氟甲基、二氟甲基、五氟乙基、全氟丁基;“烷基酰基”优选乙酰基、丙酰基、正丁酰基、异丁酰基;“卤代烷基酰基”优选氯乙酰基、溴乙酰基;“烯基”优选烯丙基、丙烯基、丁-2-烯基;“环烷基”优选环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基;“环烷基酰基”优选环丙酰基、环丁酰基、环戊酰基、环己酰基;“芳基烷基”优选苄基、苯基乙基;“卤素”优选氟、氯、溴、碘;所述“烷氧基羰基”优选甲氧基羰基、乙氧基羰基、丙氧基羰基、叔丁氧基羰基;基团中涉及的“酰基”均为羰基(C=O)。
本发明所涉及的酰基化、烃基化、还原、氧化、上保护基、脱保护基、缩合、人名反应等反应的操作都可参见现有技术中相同或类似反应类型的操作进行,其均为本领域的常规实验操作,属于本领域的技术人员应该掌握的普通技术知识。可参考《有机化学实验》、《基础有机化学》、《药物合成反应》、《有机合成中的保护基》(荣国斌译)、《StrategicApplications of Named Reactions in Organic Synthesis》,László Kürti andBarbara Czakó,2005,Elsevier Academic Press,ISBN:0-12-429785-4等教科书或工具书。
本发明中术语“药学上可接受的盐”是指非毒性的无机或有机酸和/或碱的加成盐,可参见“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201–217。无机或有机酸优选盐酸、硫酸、磷酸、草酸、马来酸、甲烷磺酸、琥珀酸、柠檬酸、富马酸、葡萄糖醛酸、甲酸、乙酸、丁二酸等。
应理解,在本发明范围内,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
为了便于对本发明的进一步理解,下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则,本发明的实施方式不限于以下内容。
实施例1
称取N-甲基-L-缬氨酸(289mg,2.2mmol)溶于干燥的甲苯(20mL)中,加入DCC(453mg,2.2mmol)、DMAP(12mg,0.1mmol),室温下搅拌5分钟,加入化合物1(44mg,0.1mmol),加热至65℃反应48小时后,过滤、减压浓缩后,经硅胶柱层析(石油醚/EtOAc=6/1),得到化合物2(27mg,产率49%),ESI-MS(m/z):551.3[M+H]+,573.4[M+Na]+;以及16mg N-甲基-L-缬氨酸与酚羟基酯化的产物(收率约为29%)。
以任选被Boc、Fmoc、Me等常用氨基保护基保护的D、L或DL型丙氨酸(Ala)、缬氨酸(Val)、亮氨酸(Leu)、异亮氨酸(Ile)、脯氨酸(Pro)、苯丙氨酸(Phe)、色氨酸(Trp)、蛋氨酸(Met)、甘氨酸(Gly)、丝氨酸(Ser)、苏氨酸(Thr)、半胱氨酸(Cys)、酪氨酸(Tyr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、赖氨酸(Lys)、精氨酸(Arg)、组氨酸(His)、天冬氨酸(Asp)、谷氨酸(Glu)中的一种替换上述制备例中的N-甲基-L-缬氨酸与化合物1反应,均能以50%左右的收率得到相应的式I-1化合物。
将上述制备例中的化合物1替换为化合物3-8、14,均能以类似的收率得到具有相应立体构型的式I-1化合物,化合物3-8、14结构如下:
实施例2
称取Boc-L-天冬酰胺(100mg,0.43mmol)溶于干燥的甲苯(10mL)中,加入DIC(66mL,0.43mmol)、DMAP(2mg,0.0167mmol),室温下搅拌5分钟,加入化合物9(8mg,0.0167mmol),加热至65℃反应48小时后,过滤、减压浓缩后,经硅胶柱层析(石油醚/EtOAc=8/1至6/1),得到淡黄色固体10mg,即为化合物10,产率86.3%,ESI-MS(m/z):692.3[M+H]+,714.3[M+Na]+。
实施例3
称取DL-脯氨酸(230mg,2mmol)溶于干燥的甲苯(10mL)中,加入DCC(413mg,2mmol)、DMAP(6mg,0.05mmol),室温下搅拌5分钟,加入化合物11(19mg,0.04mmol),加热至60℃反应48小时后,过滤、减压浓缩后,经硅胶柱层析(石油醚/EtOAc=12/1至10/1),得到淡黄色固体21mg,即为化合物12,产率92%,ESI-MS(m/z):577.3[M+H]+,599.3[M+Na]+。
实施例4
称取50mg化合物13(0.095mmol)溶于THF(10mL),于-40℃下加入5.5mg NaBH4(26mg,0.143mmol),保持此温度,搅拌反应40分钟后,加入2mL饱和NH4Cl终止反应,蒸除有机溶剂后,乙酸乙酯萃取,有机相经无水硫酸钠干燥,浓缩后,经硅胶柱层析(洗脱剂为EtOAc/石油醚=10:1~8:1),手性HPLC(TBB手性色谱柱Kromasil,5μm,150×4.6mm)分别得到化合物1(23mg,产率45.8%)和14(21mg,产率41.8%),ESI-MS(m/z):460.3[M+Na]+。
该实施例中,化合物13经非选择性还原剂硼氢化钠作用,以几乎等同的收率得到化合物1和14;若在还原反应中加入1.5倍摩尔量(即0.143mmol)的CeCl3·7H2O、CoCl2·6H2O、CdCl2·2.5H2O、CuCl、CuBr中的一种,则能以超过80%的选择性得到还原为β-OH的产物,即化合物1;若将还原反应中的还原剂硼氢化钠替换为三仲丁基硼氢化钠,则能以超过69%的选择性得到还原为α-OH的产物,即化合物14。
该实施例中,将化合物13替换为式B化合物中任一具体化合物,均能以类似的选择性或收率得到相应的羰基还原为羟基的产物,该还原操作属于本领域常规的羰基还原为羟基的操作。
实施例5
步骤(1):称取化合物J(1.7g,10mmol)、K3PO4(2.1g,10mmol)、NaH2PO2(1.3g,15mmol)溶于THF(50mL)中,氩气保护下,加入Pd(OAc)2(67mg,0.3mmol)和P(Cy)3(196mg,0.7mmol)的THF溶液(10mL)后,加入(t-BuCO)2O(4.65g,25mmol)、H2O(1.0mL),加热至50至60℃反应过夜,TLC检测原料几乎完全消失,蒸除溶剂,经硅胶柱层析(洗脱剂为正己烷)得式D化合物(1.0g,收率约为65.3%),经NMR确证式D化合物的1H NMR中在低场处出现醛基氢信号,13C NMR中羧基碳信号消失,出现醛基碳信号。
步骤(2):称取式D化合物(154mg,1.0mmol)和2,4-戊二酮(100mg,1.0mmol)溶于THF(10mL)中,于冰浴下加入NaBH4(19mg,0.5mmol),自然恢复至室温搅拌反应2小时后,加入饱和NH4Cl终止反应,用乙酸乙酯萃取(30mL×3),合并有机相后经饱和氯化钠洗涤(25mL),无水硫酸钠干燥,过滤,浓缩,经硅胶柱层析(石油醚/乙酸乙酯:6/1)得式K化合物(137mg,88%),经1H NMR确证式K化合物中的醛基氢信号消失,在δH3.6左右出现积分为2H的CH 2OH信号。
步骤(3):称取式K化合物(156mg,1.0mmol)、咪唑(177mg,2.6mmol)、Ph3P(341mg,1.3mmol)溶于乙腈-乙醚的混合液(12mL,体积比1:3)中,于冰浴下搅拌分批加入I2(330mg,1.3mmol),自然恢复至室温搅拌反应1小时,蒸除溶剂后,经硅胶柱层析(洗脱剂为正己烷),得到R9为I的式F化合物(240mg,收率为90%),ESI-MS(m/z):289.0[M+Na]+。接下来,取适量的上述碘代产物,以甲苯为溶剂,与0.5倍摩尔量的Ph3P反应后过滤以80%左右的收率(以Ph3P计)得到相应的碘代三苯基磷叶立德化合物33或者以二氯甲烷为溶剂,与0.5倍摩尔量的(EtO)3P反应以约83%的收率(以(EtO)3P计)得到相应的膦酸酯化合物34
步骤(4):称取式K化合物(156mg,1.0mmol)、Ph3P(341mg,1.3mmol)、NBS(231mg,1.3mmol)溶于氯仿(15mL,体积比1:3)中,于室温下搅拌反应过夜,加入正己烷过滤,滤液浓缩后,经硅胶柱层析(洗脱剂为正己烷),得到R9为Br的式F化合物(186mg,收率为85%),ESI-MS(m/z):241.0,243.0[M+Na]+。接下来,取适量的上述溴代产物,以甲苯为溶剂,与Ph3P(0.5equiv.)反应得到相应的溴代三苯基磷叶立德化合物35或者取适量的上述溴代产物,以二氯甲烷为溶剂,与(MeO)3P(0.5equiv.)反应得到相应的膦酸酯或者取适量的上述溴代产物,以丙酮为溶剂,与1.1倍摩尔量的在1.1倍摩尔量的碳酸钠或碳酸钾作用下,回流反应6小时后,蒸干有机溶剂,乙酸乙酯萃取、水洗、饱和氯化钠洗涤、无水硫酸钠干燥、过滤浓缩得粗产品分别为再以氯仿为溶剂,在2.5倍摩尔量的间氯过氧苯甲酸或过氧乙酸的作用下,室温搅拌反应2小时左右,以10%亚硫酸钠淬灭反应,氯仿萃取、水洗、饱和氯化钠洗涤、无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析分别以58%和60%的总收率得到R10为的式H化合物(即)。
注意:化合物J可通过与手性试剂(本领域常用的拆分异构体的手性试剂)反应或经手性柱层析拆分得到4种单一立体构型的化合物: 分别以J-1、J-2、J-3、J-4为原料,按照本实施例中的实验操作,可得到具有相应立体构型的式D、K、F、H化合物。
实施例6
步骤(1):称取式P化合物(279mg,1.0mmol)、苯硼酸(134mg,1.1mmol)、MCM-41-2N-Pd(II)(60mg,0.02mmol Pd)和K2CO3(415mg,3mmol)溶于8mL甲苯中,持续通入1atm CO,加热至75至80℃,反应过夜,加入乙酸乙酯(50mL)稀释、水洗、饱和氯化钠洗涤、无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析(MeOH/CH2Cl2=1/10),以78%的收率得到式O化合物(201mg),ESI-MS(m/z):280.1[M+Na]+。
步骤(2):按照实施例5步骤(1)和(2)中类似的操作,称取式O化合物(1.0mmol)、K3PO4(1.0mmol)、NaH2PO2(1.5mmol)溶于THF(8mL)中,氩气保护下,加入Pd(OAc)2(0.03mmol)和P(Cy)3(0.07mmol)的THF溶液(1.0mL)后,加入(t-BuCO)2O(2.5mmol)、H2O(200μL),加热至50至60℃反应过夜,TLC检测原料几乎完全消失,蒸除溶剂,加入乙酸乙酯(50mL)稀释、水洗、饱和氯化钠洗涤、无水硫酸钠干燥、过滤、浓缩得粗品,将其溶于10mL THF中,加入2,4-戊二酮(100mg,1.0mmol),降温至0℃加入NaBH4(19mg,0.5mmol)后,自然恢复至室温搅拌反应2小时后,加入饱和NH4Cl终止反应,用乙酸乙酯萃取(30mL×3),合并有机相后经饱和氯化钠洗涤(25mL),无水硫酸钠干燥,过滤,浓缩,经硅胶柱层析(MeOH/CH2Cl2=1/15)得式N化合物(151mg,两步总收率为62%),ESI-MS(m/z):266.1[M+Na]+。
步骤(3):称取式N化合物(243mg,1.0mmol)溶于10mL THF中,降温至0℃,加入7mLLiHMDS(1mol/L的THF溶液),保持0℃搅拌反应15min后,加入MeOCH2COOEt(532mg,4.5mmol),自然恢复至室温,继续搅拌反应1h后,加入H2O(1mL)于室温下搅拌反应2h后,用乙酸乙酯(50mL×3)萃取,合并有机相,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=4/1至3/1)得到式M化合物(211mg,收率约为67%),ESI-MS(m/z):338.1[M+Na]+。
实施例7
步骤(1):称取化合物W(183mg,1mmol)溶于THF(15mL)中,冰盐浴下加入Na2CO3(212mg,2mmol)、BzCl(309mg,254μL,2.2mmol)搅拌反应30min后自然恢复至室温继续反应3h后,加入乙酸乙酯(80mL)稀释,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=6/1至4/1)得到式V化合物(140mg,收率约为52%),ESI-MS(m/z):292.1[M+Na]+。
步骤(2):称取式V化合物(269mg,1mmol)溶于THF(15mL)中,加入咪唑(340mg,5.0mmol)、TBSCl(452mg,3.0mmol)于室温下搅拌反应过夜,加入乙酸乙酯(80mL)稀释,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(正己烷)得到式U化合物(458mg,收率约为92%),ESI-MS(m/z):520.2[M+Na]+。
步骤(3):称取式U化合物(269mg,1mmol)溶于CH2Cl2(15mL)中,于-70℃下滴加1mol/L苯基溴化镁的THF溶液(3mL,3mmol),保持-70℃搅拌反应1h后升温至-40℃继续反应1h后,加入饱和氯化铵终止反应,用CH2Cl2(50mL×3)萃取,合并有机相,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后得粗品,将其溶于20mL甲醇中,加入10mol/L的强氧化钠(0.3mL),回流反应过夜,用Et2O(50mL×3)萃取,合并有机相,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=12/1至10/1)得到式T化合物(368mg,两步总收率约为78%),ESI-MS(m/z):494.3[M+Na]+。
步骤(4):称取咪唑(272mg,4mmol)溶于CH2Cl2(15mL),于-10℃下加入SOCl2(73μL,1mmol),自然恢复至室温,继续搅拌反应15min后过滤除去沉淀,于-40℃下向滤液中加入式T化合物(472mg,1mmol)后,自然恢复至室温,继续反应0.5h得反应液备用;
称取CH3OCH2COOH(90mg,77μL,1mmol)、Et3N(152mg,208μL,1.5mmol)溶于CH2Cl2(8mL)中,室温下搅拌直至溶液澄清后降温至0℃,加入上述备用反应液,保持0℃继续搅拌反应4h后,蒸除CH2Cl2后,加入乙酸乙酯(100mL)稀释,依次用1M HCl、饱和NaHCO3、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=30/1)得到式S化合物(343mg,收率约63%),ESI-MS(m/z):571.3[M+Na]+。
步骤(5):称取式S化合物(544mg,1mmol)溶于THF(25mL)中,加入t-BuOK(1.1g,10mmol)于室温下搅拌反应2h后,加入饱和氯化铵终止反应,用乙酸乙酯(50mL×3)萃取,合并有机相,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=12/1至10/1)得到式R化合物(462mg,收率约为85%),ESI-MS(m/z):566.3[M+Na]+。
步骤(6):称取式R化合物(544mg,1mmol)溶于THF(25mL)中,加入TBAF(392mg,1.5mmol)于室温下搅拌反应4h后,加入饱和氯化铵终止反应,浓缩蒸除有机溶剂,用乙酸乙酯(50mL×3)萃取,合并有机相,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=4/1至3/1)得到式M化合物(296mg,收率约为94%),ESI-MS(m/z):338.1[M+Na]+。
注意:该方法得到的式M化合物同样为R,R构型和S,S构型的外消旋体,也需进行手性拆分才能得到的S,S构型的异构体。
实施例8
按照实施例5步骤(1)和(2)中类似的操作,称取式X化合物(197mg,1.0mmol)、K3PO4(212mg,1.0mmol)、NaH2PO2(132mg,1.5mmol)溶于THF(8mL)中,氩气保护下,加入Pd(OAc)2(7mg,0.03mmol)和P(Cy)3(20mg,0.07mmol)的THF溶液(1.0mL)后,加入(t-BuCO)2O(465mg,2.5mmol)、H2O(200μL),加热至50至60℃反应过夜,TLC检测原料几乎完全消失,蒸除溶剂,加入乙酸乙酯(50mL)稀释、水洗、饱和氯化钠洗涤、无水硫酸钠干燥、过滤、浓缩得粗品,将其溶于10mL THF中,加入2,4-戊二酮(100mg,1.0mmol),降温至0℃加入NaBH4(19mg,0.5mmol)后,自然恢复至室温搅拌反应2小时后,加入饱和NH4Cl终止反应,用乙酸乙酯萃取(30mL×3),合并有机相后经饱和氯化钠洗涤(25mL),无水硫酸钠干燥,过滤,浓缩得粗品,经乙醇重结晶后,得式W化合物(77mg,两步总收率为42%),熔点:282-284℃。
实施例9
(1):称取式M化合物(315mg,1mmol)溶于20mL丙酮中,加入Na2CO3(212mg,2mmol),室温下搅拌半小时后,加入1.0mL MeI,30℃下反应4h后,TLC检测反应原料几乎完全消失,乙酸乙酯萃取两次,无水硫酸钠干燥有机层,浓缩后,经硅胶柱层析(洗脱剂为EtOAc/石油醚=8/1~6/1),得到R2为甲基的式L化合物(即化合物15:280mg,收率约为85%),ESI-MS m/z:330.1[M+H]+,352.1[M+Na]+。
按照上述操作方法,采用其它烃基化试剂(如R2X,其中X为卤素,优选氯、溴、碘,R2为C1-C4烷基、C3-C6环烷基、C1-C4卤代烷基、C2-C4烯基、C5-C10芳基烷基)替换上述反应中的MeI,均能以超过75%的收率得到相应的烃基化产物L。
(2):称取式M化合物(315mg,1mmol)溶于20mL二氯甲烷中,于冰盐浴下加入Ac2O(104μL,1.1mmol)、Et3N(300μL),保持冰盐浴的条件反应20min,TLC检测反应原料几乎完全消失,加入二氯甲烷(30mL)稀释,依次用水、饱和氯化钠洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(洗脱剂为EtOAc/石油醚=1/6),得到R2为乙酰基的式L化合物(即化合物16:279mg,收率约为78%),ESI-MS m/z:358.1[M+H]+,380.1[M+Na]+。
按照上述操作方法,采用其它酰基化试剂(优选R′COX(酰卤)、R′COOCOR′(酸酐),其中X为卤素,优选氯、溴、碘,R′为C1-C3烷基、C1-C3卤代烷基、C1-C4烷基、C3-C6环烷基)替换上述反应中的Ac2O,均能以超过50%的收率得到相应的酰基化产物L。
实施例10
称取化合物15(329mg,1mmol)溶于CH2Cl2(15mL)后,加入Dess-Martin氧化剂(CAS登记号:87413-09-0,636mg,1.5mmol)室温下搅拌反应3h后,加入5%Na2S2O3溶液终止反应,用CH2Cl2萃取两次,合并有机相,用饱和氯化钠洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(洗脱剂为EtOAc/石油醚=1/10),得到R2为甲基的式G化合物(即化合物17:295mg,收率约为90%),ESI-MS m/z:328.1[M+H]+,350.1[M+Na]+。
实施例11
按照实施例5步骤(3)的操作,称取化合物15(329mg,1.0mmol)、咪唑(177mg,2.6mmol)、Ph3P(341mg,1.3mmol)溶于乙腈-乙醚的混合液(12mL,体积比1:3)中,于冰浴下搅拌分批加入I2(330mg,1.3mmol),自然恢复至室温搅拌反应1小时,蒸除溶剂后,经硅胶柱层析(洗脱剂为EtOAc/石油醚=1/10),得到R2为Me,R9为I的式E化合物(400mg,收率为91%),ESI-MS(m/z):462.0[M+Na]+。接下来,取适量的上述碘代产物,以甲苯为溶剂,与0.5倍摩尔量的Ph3P反应后过滤以80%左右的收率(以Ph3P计)得到相应的碘代三苯基磷叶立德化合物19或者以二氯甲烷为溶剂,与0.5倍摩尔量的(EtO)3P反应以约83%的收率(以(EtO)3P计)得到相应的膦酸酯化合物20
实施例12
按照实施例5步骤(4)的操作,称取化合物16(357mg,1.0mmol)、Ph3P(341mg,1.3mmol)、NBS(231mg,1.3mmol)溶于氯仿(15mL,体积比1:3)中,于室温下搅拌反应过夜,加入正己烷过滤,滤液浓缩后,经硅胶柱层析(EtOAc/石油醚=1/10),得到R2为Ac,R9为Br的式E化合物(340mg,收率为81%),ESI-MS(m/z):442.0,444.0[M+Na]+。接下来,取适量的上述溴代产物,以甲苯为溶剂,与Ph3P(0.5equiv.)反应得到相应的溴代三苯基磷叶立德化合物23或者取适量的上述溴代产物,以二氯甲烷为溶剂,与(MeO)3P(0.5equiv.)反应得到相应的膦酸酯化合物24或者取适量的上述溴代产物,以丙酮为溶剂,与1.1倍摩尔量的在1.1倍摩尔量的碳酸钠或碳酸钾作用下,回流反应6小时后,蒸干有机溶剂,乙酸乙酯萃取、水洗、饱和氯化钠洗涤、无水硫酸钠干燥、过滤浓缩得粗产品分别为 再以氯仿为溶剂,在2.5倍摩尔量的间氯过氧苯甲酸或过氧乙酸的作用下,室温搅拌反应2小时左右,以10%亚硫酸钠淬灭反应,氯仿萃取、水洗、饱和氯化钠洗涤、无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析分别以62%和65%的总收率得到R2为Ac,R10为的式I化合物(即 )。
按照上述实验操作,以化合物15替代化合物16,能以类似的收率得到化合物:
同样地,式L通式范围的任一化合物,通过上述实验操作,均能以类似的收率得到相应磷叶立德、膦酸酯产物E或者相应的式I化合物。
实施例13
方法一:
称取化合物19(1.05g,1.5mmol)、t-BuOK(168mg,1.5mmol)溶于THF(50mL)中,室温下搅拌反应40min后,加入式D化合物(154mg,1.0mmol),加热至回流温度反应3h后,加入饱和NH4Cl终止反应,蒸除有机溶剂,乙酸乙酯萃取(50mL×3)萃取,合并有机相,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=10/1至8/1)得到化合物41(369mg,收率约为82%),ESI-MS(m/z):450.2[M+H]+、472.2[M+Na]+。
方法二:
称取化合物32(626mg,1.2mmol)溶于DME(25mL)中,于-78℃下缓慢滴加1.2mLLiHMDS(1M THF溶液,1.2mmol)后,再滴加式D化合物(154mg,1.0mmol)的DME溶液(5mL)自然升温至-40℃反应3h后,加入饱和NH4Cl终止反应,蒸除有机溶剂,乙醚萃取(50mL×3)萃取,合并有机相,依次用水、饱和NaCl洗涤,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(石油醚/乙酸乙酯=10/1至8/1)得到化合物41(382mg,收率约为85%),ESI-MS(m/z):450.2[M+H]+、472.2[M+Na]+。
同样地,按照本实施例方法一、二中记载的方法,化合物33、34、35、36、37、38、39或40与化合物17或18均可反应制备得到化合物41、42;若采用单一立体构型的原料进行反应则产物具有相应的立体构型。
实施例14
称取450mg化合物41-4(1mmol)溶于THF-CH3OH(体积比5:2,10mL),于-70℃下加入559mg CeCl3·7H2O(1.5mmol)和57mg NaBH4(1.5mmol),保持此温度,搅拌反应40分钟后,加入2mL饱和NH4Cl终止反应,蒸除有机溶剂后,乙酸乙酯萃取,有机相经无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析(洗脱剂为EtOAc/石油醚=1/6至1/4),化合物43(370mg,收率约为82%),ESI-MS(m/z):474.2[M+Na]+。
实施例15
称取Fmoc-D-组氨酸(755mg,2mmol)溶于干燥的甲苯(15mL)中,加入DCC(413mg,2mmol)、DMAP(6mg,0.05mmol),室温下搅拌5分钟,加入化合物43(19mg,0.042mmol),加热至60℃反应48小时后,过滤、减压浓缩后,经乙酸乙酯萃取,有机相经无水硫酸钠干燥,过滤,浓缩后得到的粗品溶于8mL吗啉中,室温搅拌1小时后,浓缩,经硅胶柱层析(洗脱剂为EtOAc/石油醚=1/5~1/3),得到化合物44(25mg,收率约为75%),ESI-MS(m/z):589.3[M+H]+,611.3[M+Na]+。
实施例16
称取45mg化合物43(0.1mmol)溶于5mLCH3OH-CH2Cl2中(体积比1:1),加入催化量的Pd-C,室温下于1atm H2作用下反应4h后,过滤除去Pd-C,浓缩得淡黄色固体44mg,即为化合物45,收率约为97%,ESI-MS(m/z):454.3[M+H]+,476.3[M+Na]+。
实施例17
称取Boc-DL-缬氨酸(300mg,1.38mmol)溶于干燥的甲苯(10mL)中,加入DCC(285mg,1.38mmol)、DMAP(7mg,0.06mmol),室温下搅拌5分钟,加入化合物45(27mg,0.06mmol),加热至65℃反应48小时后,过滤、减压浓缩后,经硅胶柱层析(石油醚/EtOAc=12/1),得到淡黄色固体35mg,即为化合物46,收率约为90%,ESI-MS(m/z):653.4[M+H]+,675.4[M+Na]+。
通式I-1范围内的化合物或其药学上可接受的盐,均能通过本发明实施例记载的方法或在此基础上进行常规改进的方法或现有技术中类似的方法或本发明引用文献中的类似方法或中国发明专利(申请号:201510150737.6和201510150071.4)记载的方法进行制备得到,这是本领域的技术人员在本发明说明书及权利要求书记载的内容基础上可以得到或概括得出的。
在本发明提及的所有文献都在本申请中引用作为参考文献,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述内容之后,本领域的技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
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