CN115403478A - 一种n-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法 - Google Patents
一种n-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法 Download PDFInfo
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- CN115403478A CN115403478A CN202210933120.1A CN202210933120A CN115403478A CN 115403478 A CN115403478 A CN 115403478A CN 202210933120 A CN202210933120 A CN 202210933120A CN 115403478 A CN115403478 A CN 115403478A
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- Prior art keywords
- benzoylphenyl
- trifluoroacetylaminoalkanamide
- nmr
- derivative
- reaction
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- -1 2-benzoylphenyl Chemical group 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006254 arylation reaction Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 7
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 6
- 239000000654 additive Substances 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 5
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims abstract description 3
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims abstract description 3
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical group C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052709 silver Inorganic materials 0.000 claims abstract description 3
- 239000004332 silver Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical group C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
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- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
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- 239000000203 mixture Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 239000000706 filtrate Substances 0.000 description 4
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- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 3
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- 229940079593 drug Drugs 0.000 description 3
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- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical class NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 2
- AITMPVIQUIXEST-FGUNTGOFSA-N (2s)-n-tert-butyl-1-[(2s,4s,5s)-2-hydroxy-4-[[(1s,2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]carbamoyl]-5-phenylhexyl]-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide Chemical compound C([C@@H](O)C[C@@H]([C@H](C)C=1C=CC=CC=1)C(=O)N[C@H]1C2=CC=CC=C2C[C@H]1O)N([C@@H](C1)C(=O)NC(C)(C)C)CCN1CC1=CC=CN=C1 AITMPVIQUIXEST-FGUNTGOFSA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 150000001503 aryl iodides Chemical class 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 239000002904 solvent Substances 0.000 description 2
- 238000005583 trifluoroacetylation reaction Methods 0.000 description 2
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- AKBHYCHPWZPGAH-UHFFFAOYSA-N 2-[3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one Chemical compound CC1=C(Cl)C=C(COC2CN(C2)C(=O)C2CC3(C2)COC(=O)N3)C=C1 AKBHYCHPWZPGAH-UHFFFAOYSA-N 0.000 description 1
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 description 1
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- IVUAAOBNUNMJQC-UHFFFAOYSA-N 5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC=CC=C2NC(=O)CN=C1C1=CC=CC=C1 IVUAAOBNUNMJQC-UHFFFAOYSA-N 0.000 description 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了N‑(2‑苯甲酰基苯基)‑2‑三氟乙酰氨基烷酰胺衍生物的制备方法，包括以下步骤：在钯催化剂和银添加剂的存在下，含有N‑三氟乙酰基氨基酸衍生物与碘苯化合物进行芳基化氧化反应，得到苯酰基苯取代的N‑三氟乙酰基氨基酸衍生物；该合成方法采用的原料和试剂价廉易得，并且反应收率较高。
Description
技术领域
本发明属于有机合成领域，具体涉及一种N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法。
背景技术
苯二氮卓骨架在药物化学中是一种重要的结构，在苯二氮卓家族中，5-芳基-1,4-苯二氮杂卓-2-酮骨架在商业药物中普遍存在，如沙那克(阿普唑仑)、安定(地西泮)和克洛宁(氯硝西泮)。
这些药物主要作为GABA受体激动剂用于中枢神经系统临床适应症，如焦虑、失眠、肌肉痉挛、癫痫和惊厥。除了这些经典的适应症外，5-芳基-1,4-苯二氮卓-2-酮骨架还被广泛用于其他生物活性化合物，如胆囊收缩素拮抗剂和γ-分泌酶抑制剂。由于其在药物发现中的广泛应用，开发新的高效合成方法来制备这些药物是非常有意义的。
(1)制备5-芳基-1,4-苯二氮杂-2-酮类化合物常用的路线包括以下三步((a)K.Hirai,T.Ishiba,H.Sugimoto,T.Fujishita,Y.Tsukinoki and K.Hirose,J.Med.Chem.1981,24,20-27；(b)R.Reddy,F.Ballante,N.J.Zhou and G.R.Marshall,EurJ Med Chem 2017,127,531-553.)：官能化2-氨基二芳基甲酮与N-保护氨基酸的缩合反应、脱保护和通过亚胺形成环化，其中缩合反应的反应式如下：
该路线涉及到一个关键中间体N-(2-苯甲酰基苯基)-2-氨基烷酰胺衍生物的制备，需要使用到官能化2-氨基二苯甲酮作为起始材料，但是官能化2-氨基二苯甲酮不能直接购买得到，不易获得，限制了该方法的使用。
为此，如果能提供一种新的N-(2-苯甲酰基苯基)-2-氨基烷酰胺衍生物的制备方法具有重要的意义。
发明内容
本发明提供了一种N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，该制备方法可以采用价廉易得的原料方便地合成N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物。
一种N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，包括以下步骤：
在钯催化剂和银添加剂的存在下，含有N-三氟乙酰基氨基酸衍生物与碘苯化合物进行芳基化氧化反应，得到苯酰基苯取代的N-三氟乙酰基氨基酸衍生物；
其中，R2选自H、C1～C6烷基、C1～C6烷氧基或卤素；
R1选自H、C1～C6烷基、C1～C6烷氧基、C1～C6烷氧羰基、氰基、硝基或卤素；
R为H、C1～C6烷基或者甲硫基取代的C1～C6烷基。
作为优选，R2选自H、甲基、甲氧基、F、Cl或Br；
R1选自H、甲基、甲氧基、甲氧羰基、乙氧羰基、氰基、硝基、F、Cl或Br；
R为H、甲基、1,1环乙基或者甲硫基取代的乙基。
作为优选，所述的钯催化剂为醋酸钯；
所述的添加剂为碳酸银。
作为优选，所述的芳基化氧化反应的溶剂为DMAC，反应时还添加
分子筛。
作为优选，所述的芳基化氧化反应的温度为110～140℃，反应时间为20～30小时
本发明中，所述的含有N-三氟乙酰基氨基酸衍生物的制备方法如下：
(1)邻甲苯胺衍生物与N-Boc-L-氨基酸衍生物在N,N'-二环己基碳二亚胺和4-(二甲氨基)吡啶的作用下在二氯甲烷中进行酰胺化反应，得到含N-Boc-L-氨基酸类酰胺化合物；
(2)含N-Boc-L-氨基酸类酰胺化合物经过脱保护和三氟乙酰化，得到含有N-三氟乙酰基氨基酸衍生物；
所述脱保护在三氟乙酸的作用下进行；
所述的三氟乙酰化所用的试剂为三氟乙酸酐。
本发明还提供了一种所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的应用，包括：
在碳酸铯的作用下，N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物在甲醇和水的混合溶剂中进行环合反应，得到所述的5-芳基-1,4-苯二氮杂-2-酮类化合物；
反应温度为60～70℃，反应时间为10～15小时。
反应式如下：
同现有技术相比，本发明的有益效果体现在：
该制备方法可以方便地合成N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物，所采用的原料可以通过便宜易得的邻甲苯胺衍生物制备，来源广泛。
附图说明
图1为实施例1得到的化合物1a的核磁图谱；
图2为实施例1得到的化合物1m的核磁图谱；
图3为实施例2得到的化合物3b的核磁图谱；
图4为实施例2得到的化合物3m的核磁图谱；
图5为实施例3得到的化合物4b的核磁图谱；
图6为实施例3得到的化合物4f的核磁图谱。
具体实施方式
实施例1
底物1的合成步骤：
(1)在100mL的三口烧瓶中加入邻甲苯胺衍生物(10mmol)、N,N'-二环己基碳二亚胺(DCC)(2.48g，12mmol)、4-(二甲氨基)吡啶(DMAP)(0.317g，2.6mmol)和二氯甲烷(30mL)，搅拌溶解。随后，在0℃下将含有N-Boc-L-氨基酸衍生物(11mmol)的二氯甲烷(10mL)溶液滴加到上述混合液中。反应混合物在室温下搅拌大约12小时直到邻甲苯胺衍生物完全消耗。反应完成后，过滤沉淀的二环己基脲(DCU)。真空浓缩滤液，得到粗产物。
(2)在冰水浴条件下，缓慢向上述粗品中滴加11mL三氟乙酸，滴加完毕后，继续搅拌大约1小时，在真空下去除多余的三氟乙酸，添加20mL二氯甲烷进行稀释，然后添加三乙胺直到溶液的pH值为微碱性。随后，在冰水浴条件下将含有4.0mL三氟乙酸酐的20mL二氯甲烷溶液缓慢滴加至上述系统并搅拌1小时。减压浓缩，在浓缩物中添加水(20mL)并搅拌。用乙酸乙酯(3×20ml)萃取该水溶液，合并有机相，用20mL水洗涤一次，并使用无水硫酸钠进行干燥。过滤，减压蒸馏。使用乙酸乙酯/石油醚作为洗脱液经硅胶柱层析分离纯化浓缩物，得到目标产物1(1a、1m、1n、1o、1p、1q、1r、1s、1t、1u、1v、1w、1x、1y或1z)。
反应式如下：
得到的产物的结构和表征数据如下：
3-methyl-N-(o-tolyl)-2-(2,2,2-trifluoroacetamido)butanamide(1a,CASno.1808766-08-6).2.48g,82％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 197–205℃；1H NMR(400MHz,DMSO)δ9.68(s,1H),9.67(s,1H),7.33(d,J＝7.6Hz,1H),7.22(d,J＝7.4Hz,1H),7.17(t,J＝7.1Hz,1H),7.11(t,J＝6.9Hz,1H),4.38(t,J＝8.6Hz,1H),2.24–2.17(m,4H),1.01(d,J＝6.8Hz,3H),0.96(d,J＝6.7Hz,3H).13C NMR(100MHz,DMSO)δ169.1,157.0(q,J＝36.6Hz),136.1,132.5,130.8,126.4,126.1,125.8,116.4(q,J＝288.1Hz),60.1,30.1,19.5,19.2,18.2.HRMS(ESI)calcd for C14H17F3N2O2[M+H]+303.1315,found303.1324.
2,2,2-trifluoro-N-(2-oxo-2-(o-tolylamino)ethyl)acetamide(1m，CASno.357158-15-7).1.04g,40％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 146–148℃；δ1H NMR(500MHz,DMSO)δ9.78(s,1H),9.53(s,1H),7.40(d,J＝7.8Hz,1H),7.22(d,J＝7.4Hz,1H),7.17(t,J＝7.5Hz,1H),7.09(t,J＝7.3Hz,1H),4.07(d,J＝5.6Hz,2H),2.21(s,3H).13C NMR(125MHz,DMSO)δ165.9,156.8(q,J＝36.4Hz),135.8,131.7,130.3,126.0,125.3,124.9,115.9(q,J＝287.9Hz),42.3,17.7.HRMS(ESI)calcd for C11H11F3N2O2[M+H]+261.0845,found 261.0846.
N-(o-tolyl)-2-(2,2,2-trifluoroacetamido)propanamide(1n，CASno.2210945-86-9).1.62g,59％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 162–164℃；1HNMR(400MHz,DMSO)δ9.72(s,1H),9.56(s,1H),7.32(d,J＝7.6Hz,1H),7.22(d,J＝7.3Hz,1H),7.17(t,J＝7.3Hz,1H),7.11(t,J＝7.2Hz,1H),4.57(q,J＝7.0Hz,1H),2.19(s,3H),1.45(d,J＝7.1Hz,3H).13C NMR(100MHz,DMSO)δ171.1,156.7(q,J＝36.5Hz),136.2,132.7,130.8,126.4,126.0,125.8,116.3(q,J＝287.9Hz),49.9,18.1,17.9.HRMS(ESI)calcd forC12H13F3N2O2[M+H]+275.1002,found 275.1001.
(o-tolyl)-1-(2,2,2-trifluoroacetamido)cyclopropane-1-carboxamide(1p).1.94g,68％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 208–211℃；1H NMR(400MHz,DMSO)δ9.97(s,1H),9.46(s,1H),7.23(d,J＝6.9Hz,1H),7.18–7.13(m,3H),2.14(s,3H),1.44(dd,J＝7.7,4.5Hz,2H),1.07(dd,J＝7.7,4.5Hz,2H).13C NMR(100MHz,DMSO)δ169.1,158.4(q,J＝36.7Hz),136.5,134.4,130.7,127.1,126.5,126.4,116.2(q,J＝287.7Hz),35.1,18.0,16.6.HRMS(ESI)calcd for C13H13F3N2O2[M+H]+287.1002,found 287.1009.
3-phenyl-N-(o-tolyl)-2-(2,2,2-trifluoroacetamido)propanamide(1r，CASno.2210438-10-9).2.73 g,78％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 189–191℃；1H NMR(400MHz,DMSO)δ9.87(d,J＝8.1Hz,1H),9.73(s,1H),7.37(d,J＝7.1Hz,2H),7.31(t,J＝7.4Hz,3H),7.25–7.16(m,3H),7.1(t,J＝7.3Hz,1H),4.88–4.82(m,1H),3.23(dd,J＝13.6,5.0Hz,1H),3.09(dd,J＝13.5,10.3Hz,1H),2.14(s,3H).13C NMR(100MHz,DMSO)δ169.0,156.8(q,J＝36.6Hz),137.6,136.0,132.8,130.8,129.7,128.6,127.1,126.4,126.2,125.9,116.2(q,J＝288.0Hz),55.6,37.4,18.1.HRMS(ESI)calcd for C18H17F3N2O2[M+H]+351.1315,found 351.1315.
4-(methylthio)-N-(o-tolyl)-2-(2,2,2-trifluoroacetamido)butanamide(1s).1.37g,41％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 150–153℃；1H NMR(400MHz,DMSO)δ9.76(d,J＝7.5Hz,1H),9.65(s,1H),7.35–7.28(m,1H),7.22(d,J＝7.4Hz,1H),7.18(dd,J＝10.6,4.4Hz,1H),7.12(td,J＝7.3,1.2Hz,1H),4.69–4.58(m,1H),2.63–2.54(m,1H),2.53–2.49(m,1H),2.19(s,3H),2.16–2.10(m,2H),2.09(s,3H).13C NMR(100MHz,DMSO)δ169.2,157.1(q,J＝36.5Hz),136.1,132.9,130.8,126.5,126.2,126.0,115.7(q,J＝287.9Hz),53.6,31.1,30.2,18.2,15.0.HRMS(ESI)calcd for C14H17F3N2O2S[M+H]+335.1036,found 335.1038.
3-(1H-indol-3-yl)-N-(o-tolyl)-2-(2,2,2-trifluoroacetamido)propanamide(1t).1.95g,49％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 192–193℃；1NMR(400MHz,)δ10.88(s,1H),9.81(d,J＝7.7Hz,1H),9.74(s,1H),7.72(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.27(d,J＝7.2,1H),7.25–7.18(m,2H),7.18–7.15(m,1H),7.12–7.06(m,2H),7.00(t,J＝7.4Hz,1H),4.96–4.68(m,1H),3.35–3.27(m,1H),3.21(dd,J＝14.5,9.6Hz,1H),2.12(s,3H).13NMR(100MHz,)δ169.5,156.8(q,J＝42.4Hz),136.5,136.1,133.0,130.8,127.5,126.4,126.2,126.1,124.4,121.5,119.0,118.8,116.3(q,J＝288.0Hz),111.8,109.9,55.1,27.7,18.1.HRMS(ESI)calcd for C20H18F3N3O2[M+H]+390.1424,found390.1424.
N-(2,4-dimethylphenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(1u).2.34g,74％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 219–221℃；1H NMR(400MHz,DMSO)δ9.65(d,1H),9.59(s,1H),7.18(d,J＝8.0Hz,1H),7.03(s,1H),6.97(d,J＝8.0Hz,1H),4.36(t,J＝8.8Hz,1H),2.25(s,3H),2.23–2.17(m,1H),2.15(s,3H),1.00(d,J＝6.7Hz,3H),0.96(d,J＝6.6Hz,3H).13C NMR(100MHz,DMSO)δ169.0,157.0(q,J＝36.6),135.2,133.5,132.5,131.3,126.9,125.8,116.3(q,J＝288.1Hz),60.1,30.1,20.90,19.5,19.2,18.2.HRMS(ESI)calcd for C15H19F3N2O2[M+H]+317.1472,found317.1472.
N-(4-methoxy-2-methylphenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(1v).2.09g,63％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 219–221℃；1H NMR(400MHz,DMSO)δ9.64(d,J＝8.3Hz,1H),9.56(s,1H),7.15(d,J＝8.7Hz,1H),6.80(d,J＝2.8Hz,1H),6.74(dd,J＝8.7,2.9Hz,1H),4.32(t,J＝8.5Hz,1H),3.72(s,3H),2.24–2.18(m,1H),2.16(s,3H),1.00(d,J＝6.8Hz,3H),0.95(d,J＝6.7Hz,3H).13C NMR(100MHz,DMSO)δ169.1,157.5,157.0(q,J＝36.6Hz),134.6,129.0,127.4,116.4(q,J＝286.3Hz),115.8,111.7,60.0,55.6,30.1,19.5,19.2,18.4.HRMS(ESI)calcd for C15H19F3N2O3[M+H]+333.1421,found 333.1421.
N-(4-fluoro-2-methylphenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(1w).2.27g,71％yeild；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 214–219℃；1H NMR(400MHz,DMSO)δ9.71(s,1H),9.68(s,1H),7.30(dd,J＝8.7,5.6Hz,1H),7.10(dd,J＝9.7,2.8Hz,1H),7.01(td,J＝8.6,2.9Hz,1H),4.34(t,J＝8.4Hz,1H),2.25–2.16(m,4H),1.01(d,J＝6.8Hz,3H),0.96(d,J＝6.7Hz,3H).13C NMR(100MHz,DMSO)δ169.2,160.1(d,J＝241.8Hz),157.1(q,J＝36.8Hz),135.6(d,J＝8.3Hz),132.3,127.8(d,J＝8.7Hz),117.1(d,J＝22.2Hz),116.4(q,J＝286.3),113.0(d,J＝22.2Hz),60.1,30.0,19.5,19.2,18.2.HRMS(ESI)calcd for C14H16F4N2O2[M+H]+321.1221,found 321.1224.
N-(4-chloro-2-methylphenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(1x).2.42g,72％yeild；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 230–232℃；1H NMR(400MHz,DMSO)δ9.73(s,1H),9.70(d,J＝8.0Hz,1H),7.37(d,J＝8.5Hz,1H),7.32(d,J＝2.1Hz,1H),7.23(dd,J＝8.5,2.3Hz,1H),4.36(t,J＝8.4Hz,1H),2.22–2.17(m,4H),0.99(d,J＝6.7Hz,3H),0.95(d,J＝6.7Hz,3H).13C NMR(100MHz,DMSO)δ169.3,157.1(q,J＝36.7Hz),135.1,134.9,130.4,129.9,127.3,126.3,116.4(q,J＝288.1Hz),60.1,30.0,19.5,19.2,18.0.HRMS(ESI)calcd for C14H16ClF3N2O2[M+H]+337.0925,found 337.0926.
N-(2,3-dimethylphenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(1y).2.18g,69％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 219–222℃；1H NMR(400MHz,DMSO)δ9.72(s,1H),9.67(d,J＝8.1Hz,1H),7.11–7.07(m,1H),7.06–7.01(m,2H),4.37(t,J＝8.4Hz,1H),2.25(s,3H),2.22–2.19(m,1H),2.07(s,3H),1.01(d,J＝6.8Hz,3H),0.96(d,J＝6.7Hz,3H).13C NMR(100MHz,DMSO)δ169.2,157.0(q,J＝36.5Hz),137.5,135.9,131.8,127.7,125.7,124.1,116.4(q,J＝287.9Hz),60.1,30.1,20.5,19.5,19.3,14.4.HRMS(ESI)calcd for C15H19F3N2O2[M+H]+317.1472,found 317.1472.
N-(2-benzylphenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(1z).2.57g,68％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:10,v/v)；mp 227–228℃；1H NMR(400MHz,DMSO)δ9.85(s,1H),9.69(s,1H),7.34(d,J＝7.6Hz,1H),7.24–7.19(m,3H),7.17–7.14(m,5H),4.41(s,1H),4.14–3.80(m,2H),2.15(dd,J＝14.2,7.1Hz,1H),0.92(dd,J＝19.0,6.6Hz,6H)；13C NMR(100MHz,DMSO)δ169.4,157.0(q,J＝36.7Hz),140.7,136.1,135.7,130.6,129.2,128.7,126.9,126.6,126.4,126.4,116.4(d,J＝288.2Hz),59.9,36.8,30.3,19.4,19.1.HRMS(ESI)calcd for C20H21F3N2O2[M+H]+379.1628,found 379.1629.
实施例2底物3的合成
在空气下，将含有N-三氟乙酰基氨基酸衍生物1(0.25mmol)、芳基碘化物2(0.75mmol)、钯催化剂(0.05mmol，20mol％)、银盐(0.5mmol)、
分子筛和溶剂(2.5mL)的混合物置于带有聚四氟乙烯帽的35mL压力管中。将反应管在130℃下加热24小时。反应结束后，将反应混合物冷却至室温，用乙酸乙酯(3mL)稀释，并通过硅藻土过滤。然后，向滤液中加入15ml水，并用乙酸乙酯(15ml)萃取混合物3次。合并有机相，用无水硫酸钠干燥，过滤，有机相真空浓缩。浓缩物经硅胶柱层析分离，乙酸乙酯/石油醚(EA/PE＝1：7～1：20，V/V)洗脱，得到目标产物3
实施例3底物3的合成
在空气下，将含有N-三氟乙酰基氨基酸衍生物1(0.25mmol)、芳基碘化物2(0.75mmol)、醋酸钯(0.05mmol，20mol％)、碳酸银(0.5mmol)、
分子筛和DMAC(2.5mL)的混合物置于带有聚四氟乙烯帽的35mL压力管中。将反应管在130℃下加热24小时。反应结束后，将反应混合物冷却至室温，用乙酸乙酯(3mL)稀释，并通过硅藻土过滤。然后，向滤液中加入15ml水，并用乙酸乙酯(15ml)萃取混合物3次。合并有机相，用无水硫酸钠干燥，过滤，有机相真空浓缩。浓缩物经硅胶柱层析分离，乙酸乙酯/石油醚(EA/PE＝1：7～1：20，V/V)洗脱，得到目标产物3(3a～3I)。
化学式如下：
反应条件和反应结果如表2或表3所示：
表2
表3
部分化合物的表征数据如下：
N-(2-benzoylphenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(3a).85mg,87％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:20,v/v)；mp159-162℃；1H NMR(400MHz,CDCl3)δ11.29(s,1H),8.62(d,J＝8.2Hz,1H),7.71(d,J＝7.2Hz,2H),7.64–7.60(m,3H),7.51(t,J＝7.6Hz,2H),7.19–7.12(m,2H),4.60(dd,J＝8.3,5.2Hz,1H),2.37–2.29(m,1H),1.08(dd,J＝12.8,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ199.8,168.4,157.3(q,J＝37.1Hz),139.5,138.3,134.5,133.9,132.7,129.9,128.4,123.4,123.1,121.5,115.8(q,J＝287.6Hz),59.6,32.2,19.01,17.8.HRMS(ESI)calcd for C20H19F3N2O3[M+H]+393.1421,found 393.1425.
3-methyl-N-(2-(4-methylbenzoyl)phenyl)-2-(2,2,2-trifluoroacetamido)but anamide(3b).79mg,78％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:20,v/v)；mp 105–108℃；1H NMR(400MHz,CDCl3)δ11.20(s,1H),8.58(d,J＝8.0Hz,1H),7.70–7.52(m,4H),7.31(d,J＝7.9Hz,2H),7.16(td,J＝7.7,1.0Hz,2H),4.59(dd,J＝8.3,5.2Hz,1H),2.46(s,3H),2.38–2.27(m,1H),1.04(dd,J＝12.7,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ199.4,168.3,157.0(q,J＝37.2Hz),143.8,139.3,135.5,134.2,133.7,130.2,129.1,123.7,123.0,121.5,115.8(q,J＝290.4Hz),59.5,32.2,21.7,19.0,17.8.HRMS(ESI)calcd forC21H21F3N2O3[M+H]+407.1577,found 407.1584.
3-methyl-N-(2-(3-methylbenzoyl)phenyl)-2-(2,2,2-trifluoroacetamido)but anamide(3c).65mg,64％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:20,v/v)；mp 108-110℃；1H NMR(400MHz,CDCl3)δ11.29(s,1H),8.60(d,J＝8.3Hz,1H),7.65–7.58(m,2H),7.52(s,1H),7.47(d,J＝7.4Hz,1H),7.43(d,J＝7.6Hz,1H),7.38(t,J＝7.5Hz,1H),7.29–7.26(m,1H),7.20–7.13(m,1H),4.60(dd,J＝8.3,5.4Hz,1H),2.43(s,3H),2.39–2.20(m,1H),1.04(dd,J＝12.3,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ200.1,168.5,157.1(q,J＝37.6Hz),139.5,138.4,138.3,134.4,134.0,133.5,130.3,128.2,127.2,123.5,123.1,121.4,115.8(q,J＝287.8Hz),59.6,32.1,21.4,19.0,17.8.HRMS(ESI)calcd for C21H21F3N2O3[M+H]+407.1577,found 407.1581.
N-(2-(4-ethylbenzoyl)phenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butan amide(3e).76mg,72％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:20,v/v)；mp 113–116℃；1H NMR(400MHz,CDCl3)δ11.21(s,1H),8.58(d,J＝8.3Hz,1H),7.71–7.54(m,4H),7.32(d,J＝8.1Hz,2H),7.24(s,1H),7.16(t,J＝7.6Hz,1H),4.59(dd,J＝8.4,5.3Hz,1H),2.75(q,J＝7.6Hz,2H),2.37–2.28(m,1H),1.29(t,J＝7.6Hz,3H),1.04(dd,J＝12.7,6.8Hz,6H).13CNMR(100MHz,CDCl3)δ199.4,168.4,157.1(q,J＝37.5Hz),149.9,139.3,135.7,134.2,133.7,130.3,127.9,123.8,123.0,121.5,130.8(q,J＝287.8Hz),59.6,32.1,29.0,19.0,17.8,15.2.HRMS(ESI)calcd for C22H23F3N2O3[M+H]+421.1734,found 421.1739.
N-(2-(4-(tert-butyl)benzoyl)phenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(3f).65mg,58％yield；yellow liquid afterpurification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:20,v/v)；1H NMR(400MHz,CDCl3)δ11.24(s,1H),8.59(d,J＝8.2Hz,1H),7.71–7.64(m,3H),7.60(t,J＝7.9Hz,1H),7.52(s,1H),7.50(s,1H),7.27(d,J＝6.4Hz,1H),7.16(t,J＝7.6Hz,1H),4.59(dd,J＝8.3,5.3Hz,1H),2.37–2.28(m,1H),1.37(s,9H),1.04(dd,J＝13.0,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ199.4,168.4,157.1(d,J＝37.3Hz),156.7,139.3,135.4,134.2,133.8,130.1,125.4,123.8,123.0,121.5,115.8(q,J＝287.8Hz),59.6,35.2,32.1,31.1,19.0,17.8.HRMS(ESI)calcd for C24H27F3N2O3[M+H]+449.2047,found 449.2047.
N-(2-(4-methoxybenzoyl)phenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)butanamide(3g).74mg,70％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:20,v/v)；mp 120–124℃；1H NMR(400MHz,CDCl3)δ11.00(s,1H),8.54(d,J＝8.2Hz,1H),7.75(d,J＝8.9Hz,2H),7.69–7.55(m,2H),7.20–7.11(m,2H),6.99(d,J＝8.9Hz,2H),4.57(dd,J＝8.3,5.2Hz,1H),3.91(s,3H),2.36–2.27(m,1H),1.06(dd,J＝12.0,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ197.9,168.2,163.6,157.0(q,J＝37.4Hz),138.9,133.8,133.1,132.7,115.8(q,J＝290.4Hz),130.5,124.3,123.1,121.6,113.7,59.5,55.6,32.2,19.0,17.8.HRMS(ESI)calcd forC21H21F3N2O4[M+H]+423.1526,found 423.1532.
N-(2-(4-chlorobenzoyl)phenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)buta namide(3h).73mg,68％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:20,v/v)；mp 132–135℃；1H NMR(400MHz,CDCl3)δ11.16(s,1H),8.60(d,J＝7.8Hz,1H),7.71–7.56(m,4H),7.53–7.45(m,2H),7.22–7.09(m,2H),4.58(dd,J＝8.3,5.3Hz,1H),2.39–2.26(m,1H),1.05(dd,J＝12.2,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ198.4,168.4,157.1(q,J＝29.7Hz),139.5,139.3,136.5,134.7,133.6,131.4,128.8,123.2,123.1,121.6,111.5(q,J＝278.5Hz),59.6,32.1,19.0,17.8.HRMS(ESI)calcd for C20H18ClF3N2O3[M+H]+427.1031,found427.1018.
4-(2-(3-methyl-2-(2,2,2-trifluoroacetamido)butanamido)benzoyl)benzoate(3i).81mg,72％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:15,v/v)；mp 121–122℃；1H NMR(400MHz,CDCl3)δ11.00(s,1H),8.54(d,J＝8.0Hz,1H),7.78–7.69(m,2H),7.66–7.52(m,2H),7.21–7.10(m,2H),7.06–6.92(m,2H),4.57(dd,J＝8.3,5.2Hz,1H),3.91(s,3H),2.36–2.26(m,1H),1.04(dd,J＝12.0,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ197.9,168.2,163.6,157.1(q,J＝37.2Hz),138.9,133.8,133.2,132.7,130.5,129.2,124.3,123.1,121.6,115.8(d,J＝287.2Hz),113.7,59.5,55.6,32.2,19.0,17.8.HRMS(ESI)calcd forC22H21F3N2O5[M+H]+451.1476,found 451.1480.
4-(2-(3-methyl-2-(2,2,2-trifluoroacetamido)butanamido)benzoyl)benzoate(3j).84mg,72％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:15,v/v)；mp 129–131℃；1H NMR(400MHz,CDCl3)δ11.33(s,1H),8.65(d,J＝8.4Hz,1H),8.17(d,J＝8.2Hz,2H),7.74(d,J＝8.2Hz,2H),7.64(t,J＝7.9Hz,1H),7.57(d,J＝7.8Hz,1H),7.32–7.22(m,1H),7.17(t,J＝7.6Hz,1H),4.61(dd,J＝8.2,5.6Hz,1H),4.44(q,J＝7.1Hz,2H),2.47–2.16(m,1H),1.43(t,J＝7.1Hz,3H),1.06(dd,J＝11.6,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ199.3,168.6,165.6,157.1(q,J＝37.7Hz),141.9,139.8,135.1,134.0,133.8,129.5,129.5,123.2,122.8 121.5,115.8(q,J＝287.8Hz),61.5,59.7,32.0,19.0,17.8,14.3.HRMS(ESI)calcd for C23H23F3N2O5[M+H]+465.1632,found 465.1638.
NN-(2-(4-cyanobenzoyl)phenyl)-3-methyl-2-(2,2,2-trifluoroacetamido)buta namide(3k).73mg,70％yield；yellow liquid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:15,v/v)；1H NMR(400MHz,CDCl3)δ11.24(s,1H),8.66(d,J＝8.0Hz,1H),7.80(q,J＝8.5Hz,4H),7.67(t,J＝7.9Hz,1H),7.53(dd,J＝7.9,1.4Hz,1H),7.23–7.11(m,2H),4.59(dd,J＝8.3,5.4Hz,1H),2.38–2.29(m,1H),1.06(dd,J＝12.1,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ198.2,168.6,157.1(q,J＝37.3Hz),141.9,140.0,135.5,133.7,132.2,130.1,123.3,122.2,121.7,115.8(q,J＝279.4Hz),117.8,115.9,59.7,32.0,19.0,17.8.HRMS(ESI)calcd for C21H18F3N3O3[M+H]+418.1373,found 418.1369.
3-methyl-N-(2-(4-nitrobenzoyl)phenyl)-2-(2,2,2-trifluoroacetamido)butan amide(3l).71mg,65％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:15,v/v)；mp 164–167℃；1H NMR(400MHz,CDCl3)δ11.28(s,1H),8.68(d,J＝7.8Hz,1H),8.42–8.30(m,2H),7.91–7.79(m,2H),7.74–7.63(m,1H),7.53(dd,J＝7.9,1.4Hz,1H),7.23–7.16(m,1H),7.12(d,J＝8.1Hz,1H),4.60(dd,J＝8.3,5.4Hz,1H),2.39–2.30(m,1H),1.06(dd,J＝12.1,6.8Hz,6H).13C NMR(100MHz,CDCl3)δ198.1,168.6,158.7(q,J＝25.2Hz),149.9,143.6,140.1,135.7,133.8,130.5,123.7,123.3,122.1,121.7,115.9(q,J＝267.5Hz),59.7,32.0,19.0,17.8.HRMS(ESI)calcd for C20H18F3N3O5[M+H]+438.1272,found 438.1272.
N-(2-((2-benzoylphenyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamide(3m).61mg,70％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:7,v/v)；mp 112–114℃；1H NMR(500MHz,CDCl3)δ11.22(s,1H),8.55(d,J＝8.6Hz,1H),7.69(d,J＝7.6Hz,2H),7.65–7.56(m,3H),7.49(t,J＝7.7Hz,2H),7.40(s,1H),7.16(t,J＝7.6Hz,1H),4.24(d,J＝4.9Hz,2H).13C NMR(100MHz,CDCl3)δ199.7,165.5,157.3(q,J＝37.8Hz),139.4,138.2,134.4,133.8,132.7,129.9,128.4,123.4,123.1,121.6,115.7(q,J＝287.5Hz),43.6.HRMS(ESI)calcd forC17H13F3N2O3[M+H]+351.0951,found 351.0959.
实施例4底物4的合成步骤：
在带有聚四氟乙烯盖的35mL压力管中，加入化合物3(0.11mmol)、碳酸铯(0.072g，0.22mmol)和2mL甲醇/水(1:1)。试管在65℃下加热12小时。将反应混合物冷却至室温，用乙酸乙酯(3mL)稀释，通过硅藻土过滤，滤液减压浓缩。浓缩物用乙酸乙酯/石油醚通过硅胶柱层析分离纯化，得到产物4(EA/PE＝1:2～1:5)。
反应式和反应产物如下：
3-isopropyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepiN-2-one(4a，CAS no.34124-69-1).25mg,82％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 200–202℃；1HNMR(400MHz,CDCl3)δ8.88(s,1H),7.62–7.50(m,3H),7.51–7.43(m,1H),7.43–7.35(m,3H),7.19(t,J＝7.5Hz,2H),3.16(d,J＝9.2Hz,1H),2.81–2.71(m,1H),1.24(d,J＝6.7Hz,3H),1.11(dd,J＝6.5,3.3Hz,3H).13C NMR(100MHz,CDCl3)δ170.9,168.7,139.5,138.4,131.5,131.1,130.2,129.8,128.2,127.6,123.2,121.1,69.3,29.0,20.4,19.1.HRMS(ESI)calcdfor C18H18N2O[M+H]+279.1492,found 279.1489.
3-isopropyl-5-(p-tolyl)-1,3-dihydro-2H-benzo[e][1,4]diazepiN-2-one(4b).30mg,93％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 214–215℃；1H NMR(400MHz,CDCl3)δ9.02(s,1H),7.57–7.48(m,1H),7.46(d,J＝7.7Hz,2H),7.38(d,J＝7.7Hz,1H),7.18–7.12(m,4H),3.12(d,J＝9.3Hz,1H),2.77(dd,J＝15.5,6.6Hz,1H),2.39(s,3H),1.23(d,J＝6.7Hz,3H),1.09(dd,J＝6.5,1.3Hz,3H).13C NMR(100MHz,CDCl3)δ171.1,168.5,140.4,138.4,136.8,131.4,131.1,129.8,128.8,127.8,123.1,121.1,69.2,29.0,21.4,20.4,19.1.HRMS(ESI)calcd for C19H20N2O[M+H]+293.1649,found 293.1646.
3-isopropyl-5-(4-methoxyphenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepiN-2-one(4c，CAS no.152236-83-4).32mg,94％yield；white solid after purificationby column chromatography(eluent,ethyl acetate/petroleum ether ＝1:5,v/v)；mp227–228℃；1H NMR(400MHz,CDCl3)δ9.48(s,1H),7.53–7.49(m,3H),7.36(d,J＝7.2Hz,1H),7.19(d,J＝8.1Hz,1H),7.14(t,J＝7.6Hz,1H),6.86(d,J＝8.8Hz,2H),3.82(s,3H),3.08(d,J＝9.2Hz,1H),2.83–2.57(m,1H),1.20(d,J＝6.7Hz,3H),1.09(d,J＝6.5Hz,3H).13CNMR(100MHz,CDCl3)δ171.5 168.0,161.3,138.5,132.1,131.4,131.4,131.1,127.8,123.1,121.3,111.5,69.2,55.4,29.0,20.4,19.1.HRMS(ESI)calcd for C19H20N2O2[M+H]+309.1598,found 309.1621.
4-(3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepiN-5-yl)benzoate(4d).32mg,86％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:3,v/v)；mp 230–232℃；1HNMR(400MHz,CDCl3)δ9.65(d,J＝40.0Hz,1H),8.07–7.97(m,2H),7.67–7.46(m,2H),7.52(t,J＝7.7Hz,1H),7.32–7.19(m,2H),7.15(t,J＝7.1Hz,1H),3.92(s,3H),3.15(d,J＝9.1Hz,1H),2.87–2.7(m,1H),1.22(d,J＝6.6Hz,3H),1.09(dd,J＝17.5,6.5Hz,3H).13C NMR(100MHz,CDCl3)δ171.0,168.0,167.0,143.4,138.6,131.8,131.4,130.7,129.8,129.4,127.1,123.3,121.4,69.6,52.3,29.0,20.4,19.1.HRMS(ESI)calcd for C20H20N2O3[M+H]+337.1547,found 337.1544.
3-isopropyl-7-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepiN-2-one(4e).29 mg,89％yield；white solid after purification by columnchromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 212–214℃；1HNMR(400MHz,CDCl3)δ8.37(s,1H),7.65–7.51(m,2H),7.46–7.41(m,1H),7.41–7.34(m,2H),7.32(dd,J＝8.2,1.5Hz,1H),7.13(s,1H),7.04(d,J＝8.2Hz,1H),3.11(d,J＝9.2Hz,1H),2.93–2.67(m,1H),2.32(s,3H),1.20(d,J＝6.7Hz,3H),1.07(dd,J＝6.4,4.2Hz,3H).13CNMR(100MHz,CDCl3)δ170.7,168.6,139.6,136.0,133.1,132.5,131.0,130.1,129.8,128.2,127.6,120.9,69.3,29.0,20.8,20.3,19.1.HRMS(ESI)calcd for C19H20N2O[M+H]+293.1649,found 293.1646.
3-isopropyl-7-methoxy-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepiN-2-one(4f，CAS no.2226130-96-5).31mg,91％yield；white solid after purificationby column chromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp191–192℃；1H NMR(400MHz,CDCl3)δ9.50(d,J＝25.4Hz,1H),7.65–7.52(m,2H),7.46–7.29(m,3H),7.15(t,J＝7.3Hz,1H),7.07(dd,J＝8.9,2.8Hz,1H),6.81–6.78(m,1H),3.71(d,J＝2.3Hz,3H),3.12(d,J＝9.3Hz,1H),2.81–2.71(m,1H),1.21(d,J＝6.7Hz,3H),1.08(dd,J＝18.7,6.5Hz,3H).13C NMR(100 MHz,CDCl3)δ171.0,168.2,154.9,139.3,132.3,130.2,129.8,128.5,128.2,122.7,118.7,114.2,69.4,55.7,29.0,20.4,19.2.HRMS(ESI)calcdfor C19H20N2O2[M+H]+309.1598,found 309.1585.
7-chloro-3-isopropyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepiN-2-one(4g，CAS no.14404-96-7).33mg,97％yield；white solid after purification bycolumn chromatography(eluent,ethyl acetate/petroleum ether＝1:5,v/v)；mp 225–226℃；1H NMR(400MHz,CDCl3)δ10.01(d,J＝3.9Hz,1H),7.57–7.49(m,2H),7.44(m,2H),7.41–7.34(m,2H),7.31(d,J＝1.6Hz,1H),7.17(d,J＝8.7Hz,1H),3.10(d,J＝9.2Hz,1H),2.88–2.60(m,1H),1.21(d,J＝6.7Hz,3H),1.08(dd,J＝6.5,3.6Hz,3H).13C NMR(100MHz,CDCl3)δ171.3,167.6,138.8,137.3,131.7,130.5,130.3,129.8,128.8,128.5,128.4,122.9,69.5,29.0,20.4,19.1.HRMS(ESI)calcd for C18H17ClN2O[M+H]+313.1102,found313.1111.
5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepiN-2-one(4h，CAS no.2898-08-0).24mg,94％yield；white solid after purification by column chromatography(eluent,ethyl acetate/petroleum ether＝1:2,v/v)；mp 175–177℃；1H NMR(400MHz,CDCl3)δ9.47(s,1H),7.51(m,3H),7.44(t,J＝7.3Hz,1H),7.38(t,J＝7.5Hz,2H),7.32(dd,J＝7.8,1.0Hz,1H),7.20(d,J＝7.9Hz,1H),7.18–7.11(m,1H),4.33(s,2H).13C NMR(100MHz,CDCl3)δ172.2,171.1,139.4,138.8,131.7,131.4,130.3,129.7,128.2,127.3,123.4,121.1,56.7.HRMS(ESI)calcd for C15H12N2O[M+H]+237.1023,found 237.1028。
Claims (9)
1.一种N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，包括以下步骤：
在钯催化剂和银添加剂的存在下，含有N-三氟乙酰基氨基酸衍生物与碘苯化合物进行芳基化氧化反应，得到苯酰基苯取代的N-三氟乙酰基氨基酸衍生物；
其中，R2选自H、C1～C6烷基、C1～C6烷氧基或卤素；
R1选自H、C1～C6烷基、C1～C6烷氧基、C1～C6烷氧羰基、氰基、硝基或卤素；
R为H、C1～C6烷基或者甲硫基取代的C1～C6烷基。
2.根据权利要求1所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，R2选自H、甲基、甲氧基、F、Cl或Br。
3.根据权利要求1所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，R1选自H、甲基、甲氧基、甲氧羰基、乙氧羰基、氰基、硝基、F、Cl或Br。
4.根据权利要求1所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，R为H、甲基、1,1环乙基或者甲硫基取代的乙基。
5.根据权利要求1所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，所述的钯催化剂为醋酸钯。
6.根据权利要求1所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，所述的添加剂为碳酸银。
7.根据权利要求1所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，所述的芳基化氧化反应的溶剂为DMAC，反应时还添加
分子筛。
8.根据权利要求1所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的制备方法，其特征在于，所述的芳基化氧化反应的温度为110～140℃，反应时间为20～30小时。
9.一种如权利要求1～8任一项所述的N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物的应用，其特征在于，包括：
在碳酸铯的作用下，N-(2-苯甲酰基苯基)-2-三氟乙酰氨基烷酰胺衍生物在甲醇和水的混合溶剂中进行环合反应，得到所述的5-芳基-1,4-苯二氮杂-2-酮类化合物；
反应温度为60～70℃，反应时间为10～15小时。
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| Title |
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| H.H. KAEGI ET AL.: "THE PREPARATION OF 7-CHLORO-5-(2-CHLOROPHENYL)-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE-5-14C", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》, no. 8, pages 975 - 979 * |
| PRABHAKAR SINGH ET AL.: "Palladium(II)-Catalyzed Sp3/Sp2 γ- and δ-C-H Functionalization of Aryl Amines using 5-Methylisoxazole-3-Carboxamide as Directing Group", 《ASIAN J. ORG. CHEM.》, vol. 8, pages 877 - 886 * |
| YONGJU XIE ET AL.: "Pd-Catalyzed Arylation/Oxidation of Benzylic C H Bond", 《ORGANIC LETTERS》, vol. 14, no. 5, pages 1238 - 1241 * |
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