CN115960014A - N-OH glutamine derivative and preparation method and application thereof - Google Patents
N-OH glutamine derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN115960014A CN115960014A CN202111177757.4A CN202111177757A CN115960014A CN 115960014 A CN115960014 A CN 115960014A CN 202111177757 A CN202111177757 A CN 202111177757A CN 115960014 A CN115960014 A CN 115960014A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- benzyl
- hydrogen
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002308 glutamine derivatives Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 50
- 239000001257 hydrogen Substances 0.000 claims abstract description 50
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 31
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 22
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims abstract description 9
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 8
- 239000010703 silicon Substances 0.000 claims abstract description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 8
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 117
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 87
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 58
- -1 tert-butyl peroxy alcohol Chemical compound 0.000 claims description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 56
- 238000006243 chemical reaction Methods 0.000 claims description 52
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 34
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 28
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 239000002585 base Substances 0.000 claims description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 18
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 108010016626 Dipeptides Proteins 0.000 claims description 17
- 238000010511 deprotection reaction Methods 0.000 claims description 17
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical group Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- 235000011181 potassium carbonates Nutrition 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 9
- 229930014626 natural product Natural products 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 235000017550 sodium carbonate Nutrition 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 8
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 8
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 claims description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 239000012026 peptide coupling reagents Substances 0.000 claims description 7
- 239000000758 substrate Substances 0.000 claims description 7
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 6
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910021555 Chromium Chloride Inorganic materials 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 3
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000006242 amine protecting group Chemical group 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 claims description 3
- 230000000840 anti-viral effect Effects 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 239000003443 antiviral agent Substances 0.000 claims description 3
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 3
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 claims description 3
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 3
- 239000012649 demethylating agent Substances 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003586 protic polar solvent Substances 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 3
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 claims description 3
- 229940102001 zinc bromide Drugs 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000003862 amino acid derivatives Chemical class 0.000 abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 150000001413 amino acids Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- HFWFBOCOXPEKBV-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(2-chloro-2-oxoethyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCC(=O)Cl)C3=CC=CC=C3C2=C1 HFWFBOCOXPEKBV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- 238000009833 condensation Methods 0.000 description 2
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- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 241000233866 Fungi Species 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000002715 bioenergetic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XSDLDLIXLLMXDY-UHFFFAOYSA-N n-methoxyhydroxylamine Chemical compound CONO XSDLDLIXLLMXDY-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- GYALMLCJYDIGKG-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]-n-(pyrazole-1-carboximidoyl)carbamate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(=N)N1C=CC=N1 GYALMLCJYDIGKG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to the field of N-OH amino acid derivatives, and discloses an N-OH glutamine derivative and a preparation method and application thereof. The N-OH glutamine has a structure represented by formula (I) wherein R is 1 Hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl and substituted benzyl; r 2 Hydrogen, C1-C20 alkyl, aryl and substituted aryl; r 3 Is hydrogen, alkyl substituted silicon base, benzyl, substituted benzyl, allyl, allyloxycarbonyl or tert-butyloxycarbonyl, wherein the substituent of the benzyl is selected from C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogenOne kind of (1); r is 1 、R 2 、R 3 Not hydrogen at the same time; the compound chiral carbon has a stereo configuration of R or S. According to the invention, the polar N-OH amino acid derivative, the efficient preparation method and the application of the N-OH amino acid derivative with high universality can be provided.
Description
Technical Field
The invention relates to the field of N-OH amino acid derivatives, in particular to an N-OH glutamine derivative and a preparation method and application thereof.
Background
N-OH amino acid fragments are widely present in natural product structures, and the introduction of N-OH groups into the molecular structure enhances the hydrogen bonding interaction of the target molecule with the target protein, increases the stability of certain proteases (Bianco, A. Et al, J.Pept. Sci.1998,4,471-478, marastoni, M. Et al, bioorg. Med. Chem.,2001,9, 939-945), and increases chelation with metals (Ye Y. Et al, biopolymers,2003,71,489-515, ye Y. Et al, biopolymers,2006,84, 472-489), in addition to which the peptide chain contains N-OH groups, can act as T Cell receptor antagonists (Hin, S. Et al, J.Immunol.1999,163, 2363-2367) and have a certain increase in biological activity (Maffioli, S.I. Et al, 2017,169, 1240.). Recently, molecules of natural products containing one N-OH amino acid fragment have been reported as (+) -Azinothricin, (+) -A83586C, (+) -ketaproptin, (+) -Citepptin, (+) -GE3, (+) -Kettaptin (Hale, K.J. et al, J.Chem.Commun.2010,46, 4021.), L-156373 (Elbatrachi, Y.M. Et al, org.Lett.2018,20, 2707.), aurantime fungus A and B (Grisiov, P.et al, bioelectricity and Bioenergetics, 1995,36, 57-59.), and Pseudoudinicin having a nucleotide peptide structure (Maffioli, S.I. et al, cell 2017, 1240, 169). Due to the characteristic of easy deterioration of the instability of the N-OH amino acid, the synthesis research of the N-OH amino acid and the N-OH peptide is hindered. The currently reported N-OH amino acid derivatives and synthetic methods are very limited and limited to the synthesis of non-polar N-OH amino acid derivatives.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide a polar N-OH amino acid derivative, a preparation method and application for preparing the N-OH amino acid derivative with high efficiency and universality.
Accordingly, in order to achieve the above object, the present invention provides, in a first aspect, an N-OH amino acid derivative which is a compound having a structure represented by formula (I);
in the formula (I), R 1 Hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl and substituted benzyl, wherein the substituent of the aryl and the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 2 hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, benzhydryl and trityl, wherein the substituent of the aryl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 3 is hydrogen, alkyl substituted silicon base, benzyl, substituted benzyl, allyl, allyloxycarbonyl or tert-butyloxycarbonyl, wherein the substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 1 、R 2 、R 3 not hydrogen at the same time;
the compound chiral carbon has a stereo configuration of R or S.
Preferably, R 1 Is C1-C5 alkyl and/or benzyl.
Preferably, R 2 Hydrogen, benzyl, benzhydryl, trityl.
Preferably, R 3 The substituent of the benzyl group is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen.
Preferably, R 2 Is hydrogen, benzhydryl, trityl, R 3 Hydrogen and alkyl substituted silicon base.
Preferably, R 2 Is trityl, R 3 Is hydrogen.
Preferably, the stereoconfiguration of the chiral center of the compound is S.
Preferably, the structure of the N-OH glutamine is shown as a formula (II),
in a second aspect, the present invention provides a process for the preparation of an N-OH glutamine derivative, wherein the process comprises the steps of:
(1) Contacting the compound with the structure shown in the formula (III) with a deprotection reagent to remove the protecting group R 4 Then under the action of halogenated hydrocarbon and alkali, obtaining a compound with a structure shown in a formula (IV);
(2) Contacting the compound with the structure shown in the formula (IV) with an oxidant, and oxidizing secondary amine into nitrone to obtain the compound with the structure shown in the formula (V);
(3) Reacting the compound with the structure shown in the formula (V) with a hydroxylamine substrate to obtain the compound with the structure shown in the formula (I),
in the formula (I), the formula (III), the formula (IV) and the formula (V), R 1 、R 2 And R 3 Is defined in relation to R in the N-OH glutamine derivative of the first aspect of the invention 1 、R 2 And R 3 Are defined identically; r is 4 Is an amine protecting group.
Preferably, in step (1), the deprotection reagent is one or more of piperidine, diethylamine, morpholine and N-methylmorpholine, preferably piperidine and/or diethylamine.
Preferably, in step (1), the halogenated hydrocarbonIs chloroacetonitrile, bromoacetonitrile, CNCH 2 OMs and CNCH 2 More preferably one or more of OTs, chloroacetonitrile and bromoacetonitrile.
Preferably, in step (1), the base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, 2,6-lutidine and DIPEA, more preferably potassium carbonate and/or DIPEA.
Preferably, in step (1), the temperature of the reaction is in the range of 0 to 100 deg.C, more preferably 50 to 70 deg.C.
Preferably, in step (1), the reaction is carried out in the presence of a first solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, and ethyl acetate, more preferably DMF and/or acetonitrile, and further preferably acetonitrile.
Preferably, in step (2), the reaction temperature is from-50 to 50 ℃, more preferably from-10 to 0 ℃.
Preferably, in step (2), the oxidizing agent is one or more of Oxone, tert-butyl peroxy alcohol, hydrogen peroxide, peracetic acid, sodium hypochlorite and m-chloroperoxybenzoic acid, and preferably hydrogen peroxide and/or m-chloroperoxybenzoic acid.
Preferably, in step (2), the reaction is carried out in the presence of a second solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane and ethyl acetate, more preferably DMF and/or dichloromethane, further preferably dichloromethane.
Preferably, in the step (3), the hydroxylamine substrate is hydroxylamine hydrochloride, O-methylhydroxylamine, TBSONH 2 And BnONH 2 More preferably hydroxylamine hydrochloride.
Preferably, in step (3), the reaction temperature is from-50 to 50 ℃, more preferably from-10 to 0 ℃;
preferably, the reaction is carried out in the presence of a third solvent, which is a protic solvent selected from one or more of methanol, ethanol, propanol, isopropanol, trifluoroethanol and hexafluoroisopropanol, more preferably methanol and/or ethanol.
In a third aspect, the present invention provides the use of an N-OH glutamine derivative according to the first aspect of the present invention for the synthesis of dipeptides, natural products and drugs containing N-OH glutamine fragments.
Preferably, the natural product has a structure shown in a formula (VII),
preferably, the structure of the dipeptide is shown as the formula (VI),
in the formula (VI), R 1 、R 2 And R 3 Is as defined in claim 1 or 2;
R 5 is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH 2 CONH 2 、-CH 2 CH 2 CONH 2 、-CH 2 COOH、-CH 2 CH 2 COOH、-(CH 2 ) 1-5 NH 2 、-(CH 2 ) 1-5 NHC(NH)NH 2 ；
R 6 Hydrogen, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethoxycarbonyl.
Preferably, the drug is an antibacterial, antiviral or antitumor drug.
According to a fourth aspect of the present invention, there is provided a dipeptide, wherein the structure of the dipeptide is represented by formula (VI),
in the formula (VI), R 1 、R 2 And R 3 The definition of (1) and R in the N-OH glutamine derivative of the first aspect of the invention 1 、R 2 And R 3 The definitions of (A) are the same;
R 5 is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH 2 CONH 2 、-CH 2 CH 2 CONH 2 、-CH 2 COOH、-CH 2 CH 2 COOH、-(CH 2 ) 1-5 NH 2 、-(CH 2 ) 1-5 NHC(NH)NH 2 ；
R 6 Hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl.
In a fifth aspect, the present invention provides a process for producing the dipeptide of the fourth aspect, wherein the process comprises: condensing an acylating agent having a structure represented by formula (XI') with an N-OH glutamine derivative having a structure represented by formula (I) under an alkaline condition to obtain a compound having a formula (VI);
R 5 ' is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, -CH 2 OR 5” 、-CH 2 SR 5” 、-CH 2 CONHR 5” 、-CH 2 CH 2 CONHR 5” 、-CH 2 COOR 5” 、-CH 2 CH 2 COOR 5” 、-(CH 2 ) 1-5 NHR 5” 、-(CH 2 ) 1-5 NHC(NH)NHR 5” Wherein R is 5” Is tert-butyl, trityl, methyl or benzyl;
R 6 hydrogen, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethoxycarbonyl;
x is chlorine, bromine or iodine;
the compound chiral carbon has a stereo configuration of R or S.
Preferably, the base used is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.
Preferably, the solvent used is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
In a sixth aspect, the present invention provides a process for the preparation of a compound having the structure represented by formula (XII'), wherein the process comprises the steps of,
(1) Subjecting the dipeptide of the fourth aspect of the invention to a demethylation reagent to yield a compound of formula (VIII);
(2) Condensing a compound with a structure shown in a formula (VIII) with amine of a compound with a structure shown in a formula (IX) under the action of Lewis acid, a peptide coupling reagent and alkali to obtain a compound with a structure shown in a formula (X);
in the formulae (IX) and (X), R 7 And R 8 Each independently is C1-C5 alkyl, benzyl, substituted benzyl, C1-C5 acyl, propylidene, benzylidene, more preferably propylidene and/or benzylidene; r 9 And R 10 Each independently of the other is methyl, ethyl, propyl, butyl, tert-butyl, pentyl, neopentyl, more preferably methyl and/or tert-butyl;
(3) Reacting a compound with a structure shown in a formula (X) with a deprotection reagent, and then reacting with a pyrazole formamidine compound to obtain a compound with a structure shown in a formula (XI);
in the formula (XI), R 11 And R 12 Each independently hydrogen, methyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl;
(4) And (3) removing the protecting group of the compound with the structure shown in the formula (XI) under an acidic condition to obtain the compound with the structure shown in the formula (XI').
Preferably, in step (1), the demethylating reagent is one or more of lithium iodide, sodium iodide, potassium iodide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide.
Preferably, in step (1), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
Preferably, in step (2), the Lewis acid is one or more of TMSCl, TESCl, TBSCl, copper chloride, zinc chloride, ferric chloride, chromium chloride, nickel chloride, palladium chloride, cobalt chloride, bismuth chloride, copper bromide, ferric bromide, and zinc bromide.
Preferably, in the step (2), the peptide coupling reagent is 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', one or more of N' -tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxytis (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 7-aza-benzotriazol-1-yl-oxytis- (dimethylamino) phosphonium hexafluorophosphate, and (3H-1, 2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate.
Preferably, in the step (2), the base is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.
Preferably, in step (2), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
Preferably, in step (3), the deprotection reagent is one or more of piperidine, diethylamine, triethylamine and DBU.
Preferably, in step (3), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
Preferably, in step (4), the acid used for deprotection is one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid and hexafluorophosphoric acid.
Preferably, the acid is mixed with a solvent, the volume mixing ratio of the acid to the solvent is 1 (1-10), and the solvent is one or more of water, dichloromethane, acetone and acetonitrile.
The N-OH glutamine derivative provided by the invention has a very high application prospect in the aspect of drug synthesis, can be used as a key intermediate, and plays an important role in N-OH peptide preparation and N-OH amino acid-containing compound synthesis.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In the present invention, the term "on carbon" is understood by those skilled in the art to mean that the carbon is a chiral carbon and may be in an R-or S-shaped conformation.
In the present invention, specific examples of the "C1-C20 alkyl group" may be ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl and the like. Alkyl groups for a narrower range of carbon atoms may also be selected from this specific example based on the limitations in the number of carbon atoms.
In the present invention, specific examples of the "alkoxy group having 1 to 6 carbon atoms" may include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. Alkyl groups for a narrower range of carbon atoms may also be selected from this specific example based on the limitations of the number of carbon atoms.
In the present invention, specific examples of the "C1-C6 alkyl group" may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclohexyl and the like. Alkyl groups for a narrower range of carbon atoms may also be selected from this specific example based on the limitations in the number of carbon atoms.
The invention provides an N-OH glutamine derivative, which has a compound with a structure shown in a formula (I);
in the formula (I), R 1 Hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl and substituted benzyl, wherein the substituent of the aryl and the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 2 hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, benzhydryl and trityl, wherein the substituent of the aryl and the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 3 is hydrogen, alkyl substituted silicon base, benzyl, substituted benzyl, allyl, allyloxycarbonyl or tert-butyloxycarbonyl, wherein the substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 1 、R 2 、R 3 not hydrogen at the same time;
the compound chiral carbon has a stereo configuration of R or S.
Preferably, R 1 Is C1-C5 alkyl and/or benzyl.
Preferably, R 2 Hydrogen, benzyl, benzhydryl, trityl.
Preferably, R 3 The substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen.
Preferably, the stereoconfiguration of the chiral center of the compound is S.
According to some embodiments of the invention, R 2 Is hydrogen, benzhydryl, trityl, R 3 Hydrogen and alkyl substituted silicon base.
According to some embodiments of the invention, R 2 Is trityl, R 3 Is hydrogen.
According to some embodiments of the invention, R 1 Is a methyl group.
According to some embodiments of the invention, R 2 Is trityl.
According to some embodiments of the invention, R 3 Is hydrogen.
According to some embodiments of the invention, the compound has a stereoconfiguration of R or S.
According to some embodiments of the invention, the compound is of the structure of formula (II),
in a second aspect, the present invention provides a process for the preparation of an N-OH glutamine derivative, which process comprises the steps of:
(1) Contacting the compound with the structure shown in the formula (III) with a deprotection reagent to remove the protecting group R 4 Then under the action of halogenated hydrocarbon and alkali, obtaining a compound with a structure shown in a formula (IV);
(2) Contacting a compound with a structure shown in a formula (IV) with an oxidant, and oxidizing secondary amine into nitrone to obtain a compound shown in a formula (V);
(3) Reacting the compound with the structure shown in the formula (V) with a hydroxylamine substrate to obtain the compound with the structure shown in the formula (I);
in the formula (I), the formula (III), the formula (IV) and the formula (V), R 1 、R 2 And R 3 Are as defined above for the first aspect; r is 4 Is an amine protecting group.
In the present invention, the compound represented by the formula (III) can be obtained commercially or can be prepared. The compound represented by the formula (III) is not particularly limited, and can be produced by a method conventionally used in the art (Sieber, P.; riniker, B. Tetrahedron Letters 1991,32, 739.).
According to the present invention, preferably, the deprotection reagent used in the reaction in step (1) is one or more of piperidine, diethylamine, morpholine and N-methylmorpholine, more preferably piperidine and/or diethylamine.
According to the present invention, it is preferred that the reaction in step (1) is carried out usingThe halogenated hydrocarbon is chloroacetonitrile, bromoacetonitrile, CNCH 2 OMs and CNCH 2 More preferably one or more of OTs, chloroacetonitrile and bromoacetonitrile.
According to the present invention, the base used in the reaction in step (1) is preferably one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, 2,6-lutidine and DIPEA, more preferably potassium carbonate and/or DIPEA;
according to the present invention, preferably, in step (1), the temperature of the reaction is 0 to 100 ℃, more preferably 50 to 70 ℃.
According to the present invention, preferably, in step (1), the reaction is carried out in the presence of a first solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, and ethyl acetate, more preferably DMF and/or acetonitrile, and further preferably acetonitrile.
In the present invention, in the step (1), the molar ratio of the compound having a structure represented by formula (III) to the deprotection reagent may be 1: (1-100), preferably 1: (1-50), more preferably 1: (5-20).
In the present invention, in the step (1), the molar ratio of the compound having the structure represented by the formula (III) to the halogenated hydrocarbon may be 1: (1-100), preferably 1: (1-50), more preferably 1: (1-3).
In the present invention, in the step (1), the molar ratio of the compound having the structure represented by formula (III) to the base may be 1: (1-100), preferably 1: (1-60), more preferably 1: (1-5).
According to the present invention, preferably, in step (2), the temperature of the reaction is from-50 to 50 ℃, preferably from-10 to 0 ℃;
according to the present invention, preferably, the oxidizing agent is one or more of Oxone, t-butanol peroxide, hydrogen peroxide, peracetic acid, sodium hypochlorite and m-chloroperoxybenzoic acid, preferably hydrogen peroxide and/or m-chloroperoxybenzoic acid;
according to the present invention, preferably, the reaction is carried out in the presence of a second solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane and ethyl acetate, more preferably DMF and/or dichloromethane, further preferably dichloromethane.
According to the invention, the molar ratio of the compound of formula (IV) to the oxidizing agent may be 1: (1-20), preferably 1: (1-10), more preferably 1: (1-3).
According to the present invention, preferably, in the step (3), the hydroxylamine substrate is hydroxylamine hydrochloride, methoxyhydroxylamine, TBSONH 2 And BnONH 2 More preferably hydroxylamine hydrochloride.
According to the present invention, preferably, in step (3), the temperature of the reaction is from-50 to 50 ℃, more preferably from-10 to 0 ℃.
According to the present invention, preferably, in step (3), the reaction is carried out in the presence of a third solvent, which is a protic solvent selected from one or more of methanol, ethanol, propanol, isopropanol, trifluoroethanol, and hexafluoroisopropanol, more preferably methanol and/or ethanol.
In the present invention, the molar ratio of the compound having the structure represented by formula (V) to the hydroxylamine substrate may be 1: (1-20), preferably 1: (1-10), more preferably 1: (3-6).
In the present invention, the post-treatment of the steps (1), (2) and (3) is not particularly limited, and various purification methods generally used in the art may be employed as long as the requirements of the present invention can be satisfied.
In a third aspect, the present invention provides the use of an N-OH glutamine derivative according to the first aspect of the present invention for the synthesis of dipeptides, natural products and drugs containing N-OH glutamine fragments.
Preferably, the natural product has a structure shown in a formula (VII),
preferably, the drug is an antibacterial, antiviral or antitumor drug.
The fourth aspect of the present invention provides a dipeptide, wherein the structure of the dipeptide is shown in formula (VI),
in the formula (VI), R 1 、R 2 And R 3 Is defined in relation to R in the first aspect of the invention 1 、R 2 And R 3 The definitions of (A) are the same;
R 5 is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH 2 CONH 2 、-CH 2 CH 2 CONH 2 、-CH 2 COOH、-CH 2 CH 2 COOH、-(CH 2 ) 1-5 NH 2 、-(CH 2 ) 1-5 NHC(NH)NH 2 ；
R 6 Hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl.
In a fifth aspect, the present invention provides a method for producing the dipeptide according to the fourth aspect, wherein the method comprises: condensing an acylating agent having a structure represented by formula (XI') with an N-OH glutamine derivative having a structure represented by formula (I) according to the first aspect of the present invention under an alkaline condition to obtain a compound having a formula (VI),
R 5 ' is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, -CH 2 OR 5” 、-CH 2 SR 5” 、-CH 2 CONHR 5” 、-CH 2 CH 2 CONHR 5” 、-CH 2 COOR 5” 、-CH 2 CH 2 COOR 5” 、-(CH 2 ) 1-5 NHR 5” 、-(CH 2 ) 1-5 NHC(NH)NHR 5” Wherein R is 5” Is tert-butyl, trityl, methyl or benzyl;
R 6 hydrogen, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethoxycarbonyl;
x is chlorine, bromine or iodine;
the compound chiral carbon has a stereo configuration of R or S.
Preferably, the base used for the above condensation is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate. In addition, the molar ratio of the used amount of the base to the compound shown in the formula (I) is (1-10): 1.
preferably, the solvent used for the above condensation is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
Preferably, the molar ratio of the compound of formula (I) used to the acylating agent of formula (XI ") is 1: (1-10).
The sixth aspect of the present invention provides a process for producing a compound having a structure represented by the formula (XII), wherein the process comprises the steps of,
(1) Under the action of a demethylating reagent, the N-OH glutamine derivative provided by the fourth aspect of the invention obtains a compound with a structure shown in a formula (VIII);
(2) Condensing a compound with a structure shown in a formula (VIII) with amine of a compound with a structure shown in a formula (IX) under the action of Lewis acid, a peptide coupling reagent and alkali to obtain a compound with a structure shown in a formula (X);
in the formulae (IX) and (X), R 7 And R 8 Each independently is C1-C5 alkyl, benzyl, substituted benzyl, C1-C5 acyl, propylidene, benzylidene, more preferably propylidene and/or benzylidene; r 9 And R 10 Each independently of the others, methyl, ethyl, propyl, butyl, tert-butyl, pentyl, neopentyl, more preferably methyl and/or tert-butyl;
(3) Reacting a compound with a structure shown in a formula (X) with a deprotection reagent, and then reacting with a pyrazole formamidine compound to obtain a compound with a structure shown in a formula (XI);
in the formula (XI), R 11 And R 12 Each independently hydrogen, methyl, t-butyloxycarbonyl, fluorenylmethyloxycarbonyl, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf).
(4) And (5) removing the protecting group of the compound with the structure shown in the formula (XI) under an acidic condition to obtain the compound with the structure shown in the formula (XI').
Preferably, in the step (1), the methyl-removing reagent is one or more of lithium iodide, sodium iodide, potassium iodide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide.
Preferably, in step (1), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
Preferably, in step (1), the molar ratio of the amount of the structural compound represented by formula (VI) to the amount of the demethylating agent is 1: (1-20), more preferably 1: (5-12).
Preferably, in step (1), the temperature required for the reaction is from 0 to 100 ℃, more preferably from 50 to 100 ℃.
Preferably, in step (2), the Lewis acid is one or more of TMSCl, TESCl, TBSCl, copper chloride, zinc chloride, ferric chloride, chromium chloride, nickel chloride, palladium chloride, cobalt chloride, bismuth chloride, copper bromide, ferric bromide, and zinc bromide.
Preferably, in the step (2), the peptide coupling reagent is 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', one or more of N' -tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxytis (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 7-aza-benzotriazol-1-yl-oxytis- (dimethylamino) phosphonium hexafluorophosphate, and (3H-1, 2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate.
Preferably, in the step (2), the base is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.
Preferably, in step (2), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
Preferably, in the step (2), the molar ratio of the structural compound shown in the formula (VIII) to the Lewis acid is 1: (1-10), more preferably 1: (1-5), more preferably 1: (1-2).
Preferably, in step (2), the molar ratio of the amount of the structural compound represented by formula (VIII) to the amount of the peptide coupling reagent is 1: (1-10), more preferably 1: (1-4), more preferably 1: (1-2).
Preferably, in the step (2), the molar ratio of the used amount of the structural compound shown in the formula (VIII) to the used amount of the base is 1: (1-10) more preferably 1: (1-4).
Preferably, in step (2), the molar ratio of the amount of the compound represented by the structure of formula (VIII) to the amount of the compound represented by the structure of formula (IX) is 1: (1-10), more preferably 1: (1-3).
Preferably, in step (3), the deprotection reagent is one or more of piperidine, diethylamine, triethylamine and DBU.
Preferably, in step (3), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
Preferably, in step (3), the volume ratio of the solvent to the deprotection reagent is 1: (1-10), more preferably 1: (3-8).
Preferably, in the step (3), the molar ratio of the usage amount of the compound with the structure shown in the formula (X) to the usage amount of the pyrazole formamidine compound is 1: (1-10), more preferably 1: (1-3).
Preferably, in step (4), the acid used for deprotection is one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid and hexafluorophosphoric acid.
Preferably, the acid is mixed with the solvent, and the volume mixing ratio of the acid to the solvent is 1 (1-10), more preferably 1: (6-10), wherein the solvent is one or more of water, dichloromethane, acetone and acetonitrile.
Preferably, in step (4), the volume of the mixed acid and solvent required for 1mmol of the structural compound represented by formula (XI) is 1-10 ml.
The present invention will be described in detail below by way of examples.
In the following preparations and examples, the raw materials used were all obtained commercially without specific description.
Example 1
Synthesis of N-OH glutamine derivatives
(1) VIII (1.0 g,1.6 mmol) was dissolved in dichloromethane (10 mL) and placed in an ice-water bath. Then diethylamine (5 mL) was added, the reaction was slowly warmed to room temperature and continued, and the end of the reaction was checked by TLC. After disappearance of the starting material, the solvent and diethylamine are removed by concentration to give a crude product containing XII which is fed directly to the next step without further purification.
(2) 10mL of acetonitrile was then added, and bromoacetonitrile (240mg, 2mmol) and DIPEA (430mg, 3.34mmol) were added to the acetonitrile solution. The temperature is increased to 60 ℃ and the reaction is continued for 5h until the raw materials disappear. And detecting the reaction end point by TLC. After completion of the reaction, water (10 mL) was added and extracted three times with ethyl acetate (10 mL). The organic phases were combined, mgSO 4 Drying and silica gel column chromatography (petroleum ether: ethyl acetate = 2).
(3) To a solution of XIII (100mg, 0.23mmol) in dichloromethane (5 mL) was added m-CPBA (85%) (94mg, 0.46mmol) under ice-water bath conditions. Then gradually heating to room temperature, and detecting the reaction end point by TLC reaction. The reaction was then quenched with Na2S2O3 solution and saturated NaHCO was added 3 The solution (5 mL) was stirred for an additional 20min, extracted three times with dichloromethane (10 mL), and the organic phases combined, anhydrous MgSO 4 Dried and concentrated to give crude product containing XIV, which was taken to the next step without further purification.
(4) Hydroxylamine hydrochloride (76.5 mg, 1.1mmol) was added to the methanolic nitrone XIV solution (3.5 mL), the reaction was carried out at 60 ℃ until the starting material disappeared, and the end of the reaction was checked by TLC. After the reaction was completed, the solvent was concentrated under vacuum, and then dissolved with dichloromethane, the solid was filtered off, and the filtrate was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate = 1) to obtain a product II (80.0 mg, 87%). 1 H NMR(500MHz,CDCl 3 )δ7.31–7.22(m,15H),6.71(s,1H),5.50(br,1H),3.74(s,3H),3.50(dd,J＝8.5,5.3Hz,1H),2.43(m,1H),2.34(m,1H),2.07(m,2H)
Application of N-OH glutamine derivative
Example 1
Synthesis of N-OH-containing glutamine dipeptide.
To a suspension of II (500mg, 1.2mmol) in dichloromethane (10 mL) was added pyridine (189mg, 2.4 mmol). A solution of Fmoc-Gly-Cl (379mg, 1.2mmol) in dichloromethane (1 mL) was then added dropwise. The reaction was 10 min and TLC showed the starting material was completely reacted. Concentrating under vacuum, adding water (10)mL), extracted three times with ethyl acetate (10 mL). The organic phases were combined, anhydrous MgSO 4 Drying, filtration and column chromatography gave XV (808mg, 97%) as a white solid. 1 H NMR(500MHz,CDCl 3 )δ8.74(s,1H),7.69(d,J＝7.6Hz,2H),7.58(d,J＝7.5Hz,2H),7.32(t,J＝7.5Hz,2H),7.24(t,J＝7.5Hz,2H),7.22–7.14(m,15H),6.76(s,1H),5.48(s,1H),4.89(dd,J＝11.2,4.0Hz,1H),4.37–4.31(m,2H),4.20(t,J＝7.2Hz,1H),4.11–4.04(m,1H),3.72(dd,J＝18.6,4.7Hz,1H),3.61(s,3H),2.64(m,1H),2.28(m,2H),2.11(m,1H)。
Example 2
DIPEA (309mg, 2.4mmol) was added to a solution of II (500mg, 1.2mmol) in DMF (10 mL). A solution of Fmoc-Gly-Cl (379mg, 1.2mmol) in dichloromethane (1 mL) was then added dropwise. The reaction was 10 min and TLC showed the starting material was completely reacted. Concentrate under vacuum, add water (10 mL) and extract three times with ethyl acetate (10 mL). The organic phases were combined and anhydrous MgSO 4 Drying, filtration and column chromatography gave XV (749mg, 90%) as a white solid.
Example 3
Synthesizing natural products containing N-OH glutamine.
200mg of the compound represented by the formula (XV) was dissolved in 5mL of ethyl acetate, and 388mg of anhydrous lithium iodide was added, followed by heating to 80 ℃ and refluxing for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the pH was adjusted to 4 with 0.1N dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium thiosulfate, dried, concentrated, and subjected to silica gel column chromatography to obtain 137mg of a white solid (the compound having the structure represented by formula (XVI)), with a yield of 73%.
684mg of the compound having the structure represented by the formula (XVI) was suspended in 10mL of dichloromethane, and 387mg of DIPEA and 130mg of TMSCl were added under ice-water bath conditions, followed by reaction for 10 minutes. 456mg of HATU and 395mg of amine (IX) were added. The reaction was then allowed to slowly warm to room temperature for half an hour. Extracted twice with water and 10mL of ethyl acetate. The organic phases were combined, dried, concentrated, and subjected to silica gel column chromatography to obtain 743mg of a foamy solid (the compound having the structure represented by formula (XVII)), which was found to be 70% in yield.
200mg of the compound having the structure represented by the formula (XVII) was dissolved in 5mL of dichloromethane at room temperature, 5mL of diethylamine was added, the reaction was carried out for 10 minutes, the reaction mixture was completely reacted, concentrated under vacuum, toluene was taken as a dry solvent, the solvent was dissolved in 5mL of DMF, 49mg of DIPEA and N, N-di-tert-butoxycarbonyl-1H-pyrazole-1-carboxamidine were added, and the end point of the reaction was monitored by TLC. After the reaction, 15mL of water was added, extraction was performed twice with 20mL of ethyl acetate, and the organic phases were combined, dried, concentrated, and subjected to silica gel column chromatography to obtain 153mg of a foamy solid (the compound having the structure represented by formula (XVIII)), with a yield of 75%
The compound having the structure shown in formula (XVIII) was dissolved in 10mL of 70% acetic acid, slowly heated to 50 ℃ for reaction, after the reaction was completed, the solvent was concentrated, toluene was taken up with the solvent, then 10mL of trifluoroacetic acid/dichloromethane (9) was added, and the reaction was completed after 5 minutes. Concentration and C18 column chromatography gave the product, i.e., 205mg of the compound having the structure represented by formula (XVII), in 94% yield. 1 H NMR(500MHz,DMSO)δ11.11(s,1H),10.89(m,1H),9.86(s,1H),7.89(t,J＝5.2Hz,1H),7.40(m,1H),7.32(s,1H),6.87(s,1H),4.78(m,1H),4.41(s,1H),4.32–4.17(m,1H),4.14–4.10(m,1H),3.99(m,1H),3.72(s,2H),3.29–3.25(m,1H),3.18–3.16(m,1H),2.13–2.08(s,3H),2.01–1.96(m,2H)。
Example 4
200mg of the compound represented by the formula (XV) was dissolved in 5mL of methanol, and 20mg of sodium methoxide was added, followed by heating to 80 ℃ and refluxing for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the pH was adjusted to 4 with 0.1N dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium thiosulfate, dried, concentrated, and subjected to silica gel column chromatography to obtain 159mg of a white solid (the compound having the structure represented by formula (XVI)) in 85% yield.
684mg of the compound having the structure represented by the formula (XVI) was suspended in 10mL of dichloromethane, 387mg of triethylamine and 130mg of copper chloride were added under ice-water bath conditions, and the reaction was carried out for 10 minutes. 456mg of HBTU and 395mg of amine (IX) were added. The reaction was then allowed to slowly warm to room temperature for half an hour. Extracted twice with water and 10mL of ethyl acetate. The organic phases were combined, dried, concentrated, and subjected to silica gel column chromatography to obtain 743mg of a foamy solid (the compound having the structure represented by formula (XVII)), which was found to be 70% in yield.
Taking 200mg of the compound with the structure shown in the formula (XVII) to dissolve in 5mL of DMF at room temperature, then adding 5mL of triethylamine, reacting for 10 minutes, completely reacting the raw materials, concentrating under vacuum, taking toluene with dry solvent, then dissolving in 5mL of DMF, adding 49mg of DIPEA and N, N-di-tert-butoxycarbonyl-1 hydro-pyrazole-1-formamidine, and monitoring the reaction endpoint by TLC. After the reaction, 15mL of water was added, extraction was performed twice with 20mL of ethyl acetate, and the organic phases were combined, dried, concentrated, and subjected to silica gel column chromatography to obtain 163mg of a foamy solid (the compound having the structure represented by formula (XVIII)), with a yield of 80%
The compound having the structure shown in formula (XVIII) was dissolved in 10mL of 50% acetic acid, slowly raised to 100 ℃ for reaction, and after the reaction was completed, the solvent was concentrated, toluene was taken up with the solvent, and then 10mL of trifluoroacetic acid/dichloromethane (5) was added, and the reaction was completed after 5 minutes. Concentration and C18 column chromatography gave 185mg of the product, i.e., the compound of the structure represented by formula (XVII), in 85% yield.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (11)
1. An N-OH glutamine derivative characterized in that the N-OH glutamine has a structure represented by the formula (I),
in the formula (I), R 1 Hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl and substituted benzyl, wherein the substituent of the aryl and the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 2 is hydrogen, C1-C20 alkyl, aryl, substituted aryl, benzyl, benzhydryl and trityl, wherein the substituent of the aryl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 3 is hydrogen, alkyl substituted silicon base, benzyl, substituted benzyl, allyl, allyloxycarbonyl or tert-butyloxycarbonyl, wherein the substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
R 1 、R 2 、R 3 not hydrogen at the same time;
the compound chiral carbon has a stereo configuration of R or S.
2. A derivative according to claim 1, wherein R 1 Is C1-C5 alkyl and/or benzyl;
preferably, R 2 Hydrogen, benzyl, benzhydryl, trityl;
preferably, R 3 Is hydrogen, alkyl substituted silicon base, benzyl, substituted benzyl, allyl, allyloxycarbonyl or tert-butyloxycarbonyl, wherein the substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro and halogen;
preferably, R 2 Is hydrogen, benzhydryl, trityl, R 3 Hydrogen, alkyl substituted silicon base;
preferably, R 2 Is trityl, R 3 Is hydrogen;
preferably, the stereoconfiguration of the chiral center of the compound is S.
3. The derivative according to claim 1 or 2, wherein the N-OH glutamine has a structure represented by formula (II),
4. a process for preparing an N-OH glutamine derivative, comprising the steps of:
(1) Contacting the compound with the structure shown in the formula (III) with a deprotection reagent to remove the protecting group R 4 Then under the action of halogenated hydrocarbon and alkali, obtaining a compound with a structure shown in a formula (IV);
(2) Contacting the compound with the structure shown in the formula (IV) with an oxidant, and oxidizing secondary amine into nitrone to obtain a compound with the structure shown in the formula (V);
(3) Reacting the compound with the structure shown in the formula (V) with a hydroxylamine substrate to obtain the compound with the structure shown in the formula (I),
in the formula (I), the formula (III), the formula (IV) and the formula (V), R 1 、R 2 And R 3 Is as defined in claim 1 or 2; r 4 Is an amine protecting group.
5. The process according to claim 4, wherein in step (1), the deprotection reagent is one or more of piperidine, diethylamine, morpholine and N-methylmorpholine, preferably piperidine and/or diethylamine;
preferably, in step (1), the halogenated hydrocarbon is chloroacetonitrile, bromoacetonitrile, CNCH 2 OMs and CNCH 2 One or more of OTs, more preferably chloroacetonitrile and bromoacetonitrile;
preferably, in step (1), the base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, 2,6-lutidine and DIPEA, more preferably potassium carbonate and/or DIPEA;
preferably, in step (1), the temperature of the reaction is 0 to 100 ℃, more preferably 50 to 70 ℃;
preferably, in step (1), the reaction is carried out in the presence of a first solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane and ethyl acetate, more preferably DMF and/or acetonitrile, further preferably acetonitrile;
preferably, in step (2), the reaction temperature is from-50 to 50 ℃, more preferably from-10 to 0 ℃;
preferably, in the step (2), the oxidant is one or more of Oxone, tert-butyl peroxy alcohol, hydrogen peroxide, peracetic acid, sodium hypochlorite and m-chloroperoxybenzoic acid, preferably hydrogen peroxide and/or m-chloroperoxybenzoic acid;
preferably, in step (2), the reaction is carried out in the presence of a second solvent, which is an aprotic solvent selected from one or more of DMF, acetone, acetonitrile, DMSO, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, and ethyl acetate, more preferably DMF and/or dichloromethane, and further preferably dichloromethane;
preferably, in the step (3), the hydroxylamine substrate is hydroxylamine hydrochloride, O-methylhydroxylamine, TBSONH 2 And BnONH 2 More preferably hydroxylamine hydrochloride;
preferably, in step (3), the reaction temperature is from-50 to 50 ℃, more preferably from-10 to 0 ℃;
preferably, the reaction is carried out in the presence of a third solvent, which is a protic solvent selected from one or more of methanol, ethanol, propanol, isopropanol, trifluoroethanol and hexafluoroisopropanol, more preferably methanol and/or ethanol.
6. Use of the N-OH glutamine derivative of any one of claims 1-3 for the synthesis of dipeptides, natural products and drugs containing N-OH glutamine fragments.
7. The use of claim 6, wherein the natural product has the structure of formula (VII),
preferably, the structure of the dipeptide is shown as the formula (VI),
in the formula (VI), R 1 、R 2 And R 3 Is as defined in claim 1 or 2;
R 5 is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH 2 CONH 2 、-CH 2 CH 2 CONH 2 、-CH 2 COOH、-CH 2 CH 2 COOH、-(CH 2 ) 1-5 NH 2 、-(CH 2 ) 1-5 NHC(NH)NH 2 ；
R 6 Hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl;
preferably, the drug is an antibacterial, antiviral or antitumor drug.
8. A dipeptide is characterized in that the structure of the dipeptide is shown as a formula (VI),
in the formula (VI), R 1 、R 2 And R 3 Is as defined in claim 1 or 2;
R 5 is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, hydroxymethyl, mercaptomethyl, -CH 2 CONH 2 、-CH 2 CH 2 CONH 2 、-CH 2 COOH、-CH 2 CH 2 COOH、-(CH 2 ) 1-5 NH 2 、-(CH 2 ) 1-5 NHC(NH)NH 2 ；
R 6 Hydrogen, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethoxycarbonyl.
9. A process for producing the dipeptide of claim 8, the process comprising: condensing an acylating agent of formula (XI ") with an N-OH glutamine derivative of formula (I) according to any one of claims 1-3 under basic conditions to give a compound of formula (VI);
R 5 ' is hydrogen, C 1 -C 5 Alkyl, benzyl, substituted benzyl, indolyl, -CH 2 OR 5” 、-CH 2 SR 5” 、-CH 2 CONHR 5” 、-CH 2 CH 2 CONHR 5” 、-CH 2 COOR 5” 、-CH 2 CH 2 COOR 5” 、-(CH 2 ) 1-5 NHR 5” 、-(CH 2 ) 1-5 NHC(NH)NHR 5” Wherein R is 5” Is tert-butyl, trityl, methyl or benzyl;
R 6 hydrogen, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 2-trichloroethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, preferably tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl;
x is chlorine, bromine or iodine;
the stereo configuration of the chiral carbon of the compound is R or S;
preferably, the base used is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate;
preferably, the solvent used is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate.
10. A process for the preparation of a compound having the structure of formula (XI'), which comprises the steps of,
(1) Subjecting the dipeptide of claim 8 to a demethylating agent to yield a compound having the structure of formula (VIII);
(2) Condensing a compound with a structure shown in a formula (VIII) with amine of a compound with a structure shown in a formula (IX) under the action of Lewis acid, a peptide coupling reagent and alkali to obtain a compound with a structure shown in a formula (X);
in the formulae (IX) and (X), R 7 And R 8 Each independently is C1-C5 alkyl, benzyl, substituted benzyl, C1-C5 acyl, propylidene, benzylidene, more preferably propylidene and/or benzylidene; r 9 And R 10 Each independently of the other is methyl, ethyl, propyl, butyl, tert-butyl, pentyl, neopentyl, more preferably methyl and/or tert-butyl;
(3) Reacting the compound with the structure shown in the formula (X) with a deprotection reagent, and then reacting with a pyrazole formamidine compound to obtain a compound with the structure shown in the formula (XI);
in the formula (XI), R 11 And R 12 Each independently hydrogen, methyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, 2,4,6, 7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf);
(4) Removing a protecting group of the compound with the structure shown in the formula (XI) under an acidic condition to obtain a compound with the structure shown in the formula (XI'),
11. the method according to claim 10, wherein in step (1), the demethylating agent is one or more of lithium iodide, sodium iodide, potassium iodide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide;
preferably, in step (1), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate;
preferably, in step (2), the Lewis acid is one or more of TMSCl, TESCl, TBSCl, copper chloride, zinc chloride, ferric chloride, chromium chloride, nickel chloride, palladium chloride, cobalt chloride, bismuth chloride, copper bromide, ferric bromide and zinc bromide;
preferably, in the step (2), the peptide coupling reagent is 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', one or more of N' -tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxytis (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 7-aza-benzotriazol-1-yl-oxytis- (dimethylamino) phosphonium hexafluorophosphate, and (3H-1, 2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate;
preferably, in the step (2), the base is one or more of pyridine, triethylamine, DIPEA, imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium bicarbonate.
Preferably, in step (2), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate;
preferably, in step (3), the deprotection reagent is one or more of piperidine, diethylamine, triethylamine and DBU;
preferably, in step (3), the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, DMF, acetonitrile and ethyl acetate;
preferably, in the step (4), the acid used for deprotection is one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid and hexafluorophosphoric acid;
preferably, the acid is mixed with a solvent, the volume mixing ratio of the acid to the solvent is 1 to 10, and the solvent is one or more of water, dichloromethane, acetone and acetonitrile.
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| US20150210740A1 (en) * | 2012-08-09 | 2015-07-30 | New-Anti-Infectives Consortium S.C.A.R.L. | Pseudouridimycin (pum) and its derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150210740A1 (en) * | 2012-08-09 | 2015-07-30 | New-Anti-Infectives Consortium S.C.A.R.L. | Pseudouridimycin (pum) and its derivatives |
Non-Patent Citations (2)
| Title |
|---|
| SONIA I. MAFFIOLI等: "Discovery, properties, and biosynthesis of pseudouridimycin, an antibacterial nucleoside‑analog inhibitor of bacterial RNA polymerase", JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY, vol. 46, 31 December 2019 (2019-12-31), pages 335 - 343, XP036720167, DOI: 10.1007/s10295-018-2109-2 * |
| 张哲;阮乐;: "甘氨酰-L-谷氨酰胺的合成", 化学试剂, no. 02, 15 February 2011 (2011-02-15), pages 77 - 178 * |
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