CN116284189B - Method for synthesizing MANT-GTPγS - Google Patents
Method for synthesizing MANT-GTPγS Download PDFInfo
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- CN116284189B CN116284189B CN202310548359.1A CN202310548359A CN116284189B CN 116284189 B CN116284189 B CN 116284189B CN 202310548359 A CN202310548359 A CN 202310548359A CN 116284189 B CN116284189 B CN 116284189B
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 20
- 150000001875 compounds Chemical group 0.000 claims abstract description 68
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012312 sodium hydride Substances 0.000 claims abstract description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 7
- 229940125904 compound 1 Drugs 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 56
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 48
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 230000009471 action Effects 0.000 claims description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 24
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 claims description 16
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 14
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical class C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 14
- 229940126214 compound 3 Drugs 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 235000005074 zinc chloride Nutrition 0.000 claims description 12
- 239000011592 zinc chloride Substances 0.000 claims description 12
- 229940125898 compound 5 Drugs 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 229940125773 compound 10 Drugs 0.000 claims description 10
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000003729 cation exchange resin Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- PVZMXULSHARAJG-UHFFFAOYSA-N N,N-diethylethanamine molecular hydrogen Chemical compound [H][H].CCN(CC)CC PVZMXULSHARAJG-UHFFFAOYSA-N 0.000 claims description 6
- UNXNGGMLCSMSLH-UHFFFAOYSA-N dihydrogen phosphate;triethylazanium Chemical compound OP(O)(O)=O.CCN(CC)CC UNXNGGMLCSMSLH-UHFFFAOYSA-N 0.000 claims description 6
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 5
- 229940125797 compound 12 Drugs 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 claims description 4
- AALQBIFJJJPDHJ-UHFFFAOYSA-K trisodium;thiophosphate;dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=S AALQBIFJJJPDHJ-UHFFFAOYSA-K 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000013067 intermediate product Substances 0.000 abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000007791 liquid phase Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 239000007858 starting material Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- -1 isobutyryl Chemical group 0.000 description 5
- MFQCCKXOMGAYFM-UHFFFAOYSA-N n,n-diethylethanamine;trihydroxy(sulfanylidene)-$l^{5}-phosphane Chemical compound OP(O)(O)=S.CCN(CC)CC MFQCCKXOMGAYFM-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000030621 adenylate cyclase Human genes 0.000 description 2
- 108060000200 adenylate cyclase Proteins 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940127073 nucleoside analogue Drugs 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- BBRQBJGBTBRKDU-UHFFFAOYSA-M sodium;propan-2-one;perchlorate Chemical compound [Na+].CC(C)=O.[O-]Cl(=O)(=O)=O BBRQBJGBTBRKDU-UHFFFAOYSA-M 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- DSPRYHPLXXUNHS-XNIJJKJLSA-N 3'-MANT-GTP Chemical compound CNC1=CC=CC=C1C(=O)O[C@H]1[C@@H](O)[C@H](N2C3=C(C(N=C(N)N3)=O)N=C2)O[C@@H]1COP(O)(=O)OP(O)(=O)OP(O)(O)=O DSPRYHPLXXUNHS-XNIJJKJLSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- CNTIXUGILVWVHR-UHFFFAOYSA-N diphosphoryl chloride Chemical compound ClP(Cl)(=O)OP(Cl)(Cl)=O CNTIXUGILVWVHR-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000026415 nucleotide binding proteins Human genes 0.000 description 1
- 108091014756 nucleotide binding proteins Proteins 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing MANT-GTPγS, which has the following synthetic route. The invention designs and provides a complete brand-new synthesis method of MANT-GTPγS, which takes a compound 1 as a raw material, protects hydroxyl and amino except 2 positions of the compound, then uses sodium hydride as strong base, can prepare an intermediate product (compound 4) with MANT fluorescent groups in high yield, and further synthesizes a phosphoric acid side chain of the intermediate product on the basis, so that MANT-GTPγS is prepared in high yield.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a method for synthesizing MANT-GTPγS.
Background
MANT-GTPγS is a GTP mimetic and is a potent competitive Adenylate Cyclase (AC) inhibitor and YdeH inhibitor. The ribosyl group of the nucleoside analogue MANT-GTP is modified and the compactness of the MANT fluorophore and its attachment site is such that the nucleoside analogue hardly interferes with the nucleotide-protein interaction. Since MANT fluorescence is sensitive to the environment of the fluorophore, nucleotide-protein interactions can be detected directly. MANT nucleotides are important probes for detecting the structure and enzymatic activity of nucleotide binding proteins. MANT (N-methylated anhydride) was chosen because it is a very small fluorophore that attaches to the ribose moiety of a nucleotide during the coupling reaction. Proteins recognizing MANT nucleotide analogs have proven less sensitive than base and phosphate alterations in ribosyl groups. These analogs have very high quantum yields and resistance to photobleaching, and their absorption and emission spectra do not overlap with other biomolecules, particularly proteins and nucleic acids.
However, there is no report on the method of organic synthesis of MANT-GTPγS.
Disclosure of Invention
Based on the above, the invention aims to design a complete MANT-GTPγS synthesis route, and can obtain an intermediate product with MANT fluorescent groups with higher yield, thereby obtaining MANT-GTPγS to meet the market demand.
In order to achieve the above purpose, the invention comprises the following technical scheme.
A method for synthesizing man t-gtpγs, comprising the steps of:
(1) Under the action of alkali, reacting the compound 1 with 1,3 dichloro-1, 3-tetraisopropyl disiloxane to obtain a compound 2;
(2) Protecting the amino group in the compound 2 with tert-butoxycarbonyl to obtain a compound 3;
(3) Under the action of sodium hydride, the compound 3 reacts with 1-methylbenzoxazole to obtain a compound 4;
(4) Reacting the compound 4 with triethylamine hydrogen trifluoride to obtain a compound 5;
(5) Under the action of alkali, the compound 5 reacts with phosphorus oxychloride to obtain a compound 6;
(6) Removing tert-butoxycarbonyl in the compound 6 to obtain a compound 7;
(7) Under the action of 2,2' -dithiodipyridine and triphenylphosphine, the compound 7 reacts with imidazole to obtain a compound 8;
(8) Under the action of zinc chloride, the compound 8 reacts with triethylamine phosphate to obtain a compound 9;
(9) Under the action of 2,2' -dithiodipyridine and triphenylphosphine, the compound 9 reacts with imidazole to obtain a compound 10;
(10) Under the action of zinc chloride, the compound 10 reacts with the compound 11 (triethylamine thiophosphate) to obtain a compound 12, namely the MANT-GTPγS;
the reaction route is as follows:
。
wherein, the preparation method of the compound 11 comprises the following steps: dissolving sodium thiophosphate in water, adding into activated cation exchange resin, washing with water, collecting the eluate when the pH of the eluate is 2, and stopping collecting when the pH of the eluate is greater than 4; and adding triethylamine into the collected eluting liquid to neutralize to be neutral, and concentrating to obtain the compound 11.
The invention has the following beneficial effects:
in the prior art, no complete synthesis route of MANT-GTPγS exists, and the invention designs and provides a complete novel synthesis method of MANT-GTPγS.
Detailed Description
The technical scheme of the invention is further described by the following specific examples. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In the prior art, a complete synthesis route of MANT-GTPγS does not exist, and the demand of the market for the amount of MANT-GTPγS cannot be met. Therefore, the invention aims to design a complete synthetic route of MANT-GTPγS, and prepare MANT-GTPγS in batch with higher yield so as to meet market demands.
In accordance with the above objects, in one embodiment of the present invention, there is provided a method for synthesizing MANT-GTPγS, comprising the steps of:
(1) Under the action of alkali, reacting the compound 1 with 1,3 dichloro-1, 3-tetraisopropyl disiloxane to obtain a compound 2;
(2) Protecting the amino group in the compound 2 with tert-butoxycarbonyl to obtain a compound 3;
(3) Under the action of sodium hydride, the compound 3 reacts with 1-methylbenzoxazole to obtain a compound 4;
(4) Reacting the compound 4 with triethylamine hydrogen trifluoride to obtain a compound 5;
(5) Under the action of alkali, the compound 5 reacts with phosphorus oxychloride to obtain a compound 6;
(6) Removing tert-butoxycarbonyl in the compound 6 to obtain a compound 7;
(7) Under the action of 2,2' -dithiodipyridine and triphenylphosphine, the compound 7 reacts with imidazole to obtain a compound 8;
(8) Under the action of zinc chloride, the compound 8 reacts with triethylamine phosphate to obtain a compound 9;
(9) Under the action of 2,2' -dithiodipyridine and triphenylphosphine, the compound 9 reacts with imidazole to obtain a compound 10;
(10) Under the action of zinc chloride, the compound 10 reacts with the compound 11 (triethylamine thiophosphate) to obtain a compound 12, namely the MANT-GTPγS;
the reaction route is as follows:
。
the inventors found that: the protecting group on the amino group is important, and is generally protected by isobutyryl in the prior art, but since the hydroxyl group at the 2' -position is connected with a fluorescent ester group (MANT), if the protecting group is protected by isobutyryl, the MANT group is easily removed together after the protecting group is required to be deprotected under alkaline condition, so that the corresponding product cannot be prepared. The inventor discovers that the tert-Butyloxycarbonyl (BOC) is used for protecting amino, and the BOC is removed under the acidic condition, so that the hydrolysis of ester groups is not caused, and the target product can be prepared with high yield.
In general biochemical reactions, sodium hydroxide is used as a base to react the hydroxyl groups of the compounds with 1-methylbenzoxazole to obtain fluorescent ester groups (MANT). However, the inventors found during the synthesis that: the compound of the invention cannot react with 1-methylbenzoxazole under the action of sodium hydroxide to obtain a corresponding product (compound 4). Based on this, the inventors found through repeated experimental study that the intermediate product (compound 4) with MANT fluorophor can be prepared in high yield by using sodium hydrogen as a base and reacting the 2' -hydroxyl in compound 3 with 1-methylbenzoxazole. On the basis, the side chain of phosphoric acid is further synthesized, and then MANT-GTPγS is prepared with higher yield.
In some embodiments of the invention, the base in step (1) is imidazole and/or pyridine.
In some embodiments of the invention, the molar ratio of compound 1,3 dichloro-1, 3-tetraisopropyl disiloxane to base in step (1) is 1:1-1.5:2-4, preferably 1:1-1.2:2.8-3.2; more preferably 1:1.1:3.
in some embodiments of the invention, the reaction of step (1) is performed in a solvent that is N, N-dimethylformamide and/or dimethylsulfoxide.
In some embodiments of the invention, the time of the reaction of step (1) is 8 hours to 16 hours, preferably 10 hours to 14 hours.
In some embodiments of the invention, step (2) comprises: under the action of alkali, the compound 2 reacts with di-tert-butyl dicarbonate to obtain a compound 3.
In some embodiments of the invention, the base in step (2) is triethylamine and/or N, N-diisopropylethylamine.
In some embodiments of the invention, the molar ratio of compound 2, di-tert-butyl dicarbonate to base in step (2) is 1:1-1.8:1.5-3, preferably 1:1.1-1.5:1.8-2.2; more preferably 1:1.3:2.
in some embodiments of the invention, the reaction of step (2) is performed in a solvent that is N, N-dimethylformamide and/or dimethylsulfoxide.
In some embodiments of the invention, the time of the reaction of step (2) is 8 hours to 16 hours, preferably 10 hours to 14 hours.
In some embodiments of the invention, the molar ratio of compound 3, 1-methylbenzoxazole to sodium hydride in step (3) is 1:2-4:1.5-3, preferably 1:2.5-3.5:1.5-2.5; more preferably 1:2.8-3.2:1.8-2.2; more preferably 1:3:2.
in some embodiments of the invention, the reaction of step (3) is performed in a solvent that is N, N-dimethylformamide and/or dimethylsulfoxide.
In some embodiments of the invention, the temperature of the reaction in step (3) is from 0 ℃ to 10 ℃ and the reaction time is from 2 hours to 5 hours.
In some embodiments of the invention, the temperature of the reaction in step (3) is from 0 ℃ to 5 ℃ and the reaction time is from 2 hours to 4 hours.
In some embodiments of the invention, the molar ratio of compound 4 to triethylamine hydrogen trifluoride of step (4) is 1:4-8, preferably 1:5-7, preferably 1:5.5-6.5, more preferably 1:5.8-6.2, more preferably 1:6.
in some embodiments of the invention, the reaction of step (4) is performed in a solvent, which is tetrahydrofuran and/or acetonitrile.
In some embodiments of the invention, the time of the reaction of step (4) is 8 hours to 16 hours, preferably 10 hours to 14 hours.
In some embodiments of the invention, the base in step (5) is a proton sponge and/or N, N-diisopropylethylamine, preferably a proton sponge.
In some embodiments of the invention, the molar ratio of compound 5, phosphorus oxychloride, and base of step (5) is 1:2-4:1-3, preferably 1:2.5-3.5:1.5-2.5; more preferably 1:2.8-3.2:1.8-2.8; most preferably 1:3:2.
in some embodiments of the invention, the reaction of step (5) is performed in a solvent that is at least one of trimethyl phosphate, triethyl phosphate, and acetonitrile.
In some embodiments of the invention, the time of the reaction of step (5) is from 0.5h to 3h.
In some embodiments of the invention, the time of the reaction of step (5) is 1h to 2h.
In some embodiments of the invention, step (6) comprises: in a solvent, the compound 6 reacts with acid to remove tert-butoxycarbonyl to obtain a compound 7.
In some embodiments of the invention, the acid of step (6) is trifluoroacetic acid and the solvent is dichloromethane and/or acetonitrile.
In some embodiments of the invention, the acid of step (6) is anhydrous hydrochloric acid and the solvent is ethyl acetate.
In some embodiments of the invention, the molar ratio of compound 6 to acid of step (6) is 1:8-12; preferably 1:9-11, more preferably 1:10.
in some embodiments of the invention, the reaction time of step (6) is 1h to 3h, preferably 1.5h to 2.5h, more preferably 2h.
In some embodiments of the invention, the molar ratio of compound 7, imidazole, 2' -dithiodipyridine, and triphenylphosphine of step (7) is 1:8-12:3-7:3-7, preferably 1:9-11:4-6:4-6; more preferably 1:10:5:5.
in some embodiments of the invention, the reaction of step (7) is performed in a solvent that is N, N-dimethylformamide and/or acetonitrile.
In some embodiments of the invention, the time of the reaction of step (7) is 8 hours to 16 hours, preferably 10 hours to 14 hours.
In some embodiments of the invention, the molar ratio of compound 8, triethylamine phosphate, and zinc chloride of step (8) is 1:2-4:1-3; preferably 1:2.5-3.5:1.5-2.5; more preferably 1:2.8-3.2:1.8-2.2, most preferably 1:3:2.
in some embodiments of the invention, the reaction of step (8) is performed in a solvent that is N, N-dimethylformamide and/or dimethylsulfoxide.
In some embodiments of the invention, the reaction of step (8) is performed under a blanket of nitrogen or an inert gas.
In some embodiments of the invention, the time of the reaction of step (8) is 8 hours to 16 hours, preferably 10 hours to 14 hours.
In some embodiments of the invention, the molar ratio of compound 9, imidazole, 2' -dithiodipyridine, and triphenylphosphine of step (9) is 1:8-12:3-7:3-7, preferably 1:9-11:4-6:4-6; more preferably 1:10:5:5.
in some embodiments of the invention, the reaction of step (9) is performed in a solvent that is N, N-dimethylformamide and/or acetonitrile.
In some embodiments of the invention, the time of the reaction of step (9) is 8 hours to 16 hours, preferably 10 hours to 14 hours.
In some embodiments of the invention, the molar ratio of compound 10, compound 11, and zinc chloride of step (10) is 1:2-4:1-3; preferably 1:2.5-3.5:1.5-2.5; more preferably 1:2.8-3.2:1.8-2.2, most preferably 1:3:2.
in some embodiments of the invention, the reaction of step (10) is performed in a solvent that is N, N-dimethylformamide and/or dimethylsulfoxide.
In some embodiments of the invention, the reaction of step (10) is performed under a blanket of nitrogen or an inert gas.
In some embodiments of the invention, the time of the reaction of step (10) is 8 hours to 16 hours, preferably 10 hours to 14 hours.
In some embodiments of the present invention, the method for preparing compound 11 in step (10) comprises the steps of: dissolving sodium thiophosphate in water, adding into activated cation exchange resin, washing with water, collecting the eluate when the pH of the eluate is 2, and stopping collecting when the pH of the eluate is greater than 4; and adding triethylamine into the collected eluting liquid to neutralize to be neutral, and concentrating to obtain the compound 11.
In some embodiments of the invention, the cation exchange resin is Amberchrom 50WX8 cation exchange resin.
In some embodiments of the present invention, the method of activating the activated cation exchange resin comprises the steps of: the cation exchange resin was activated with 1.5-2.5mol/L hydrochloric acid and then rinsed with water to neutrality.
The following are specific examples.
In the examples below, the reaction at which the reaction temperature is not noted is either at room temperature or at room temperature, for example, at room temperature of 15℃to 30 ℃.
Example 1
The synthetic route for MANT-GTPγS is as follows:
(1) Synthesis of Compound 2
10g of Compound 1 was weighed, dissolved in 50mLN, N-Dimethylformamide (DMF), 3 equivalents of imidazole and 1.1 equivalents of 1,3 dichloro-1, 3-tetraisopropyl disiloxane were added thereto, stirred for 12 hours, and analyzed for complete consumption of the starting material by liquid phase detection. Post-treatment: the reaction liquid was poured into 500ml of water, and a white solid was precipitated, followed by suction filtration to obtain the desired product, which was dried to 15g, and the yield was 81.0%.
The nuclear magnetic data of compound 2 are as follows:
1 H NMR(d6 DMSO)δ0.97(d,24H,CH 3 ),1.45(m,4H),3.77-4.03(m,3H),4.4(m,1H),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.63(s,2H,NH 2 ), 7.97(s,1H,CH), 12.09(s,1H,NH)。
(2) Synthesis of Compound 3
9.25g of Compound 2 was weighed, dissolved in 75ml of DMF, then 2 equivalents of triethylamine and 1.3 equivalents of di-tert-butyl dicarbonate were added, and the reaction was stirred for 12 hours, as detected by TLC, and the consumption of starting material was found to be complete. Post-treatment: the reaction liquid was poured into 300ml of water, a white solid was precipitated, and the desired product was obtained after suction filtration, 7g after drying, and the yield was 63.6%.
The nuclear magnetic data of compound 3 are as follows:
1 H NMR(d6 DMSO)δ0.97(d,24H,CH 3 ),1.42(s,9H),1.45(m,4H),2.0(s,1H,NH),3.77-4.03(m,3H),4.4(m,1H),4.75(m,1H),6.16(d,1H, J=7.0Hz),7.97(s,1H,CH), 12.09(s,1H,NH)。
(3) Synthesis of Compound 4
7g of Compound 3 was weighed, dissolved in 70ml of DMF, then 2 equivalents of sodium hydride was added under ice bath, after 10 minutes, 3 equivalents of 1-methylbenzoxazole were added under ice bath, and the reaction was carried out for 3 hours, and the consumption of the starting material was found to be complete by TLC. Post-treatment: the reaction liquid was poured into 200mL of ice water, extracted 3 times with ethyl acetate, 200mL each time, and the combined organic phases were concentrated to give 5.0g of crude product in 59% yield. Without purification, it was used directly in the next step.
The nuclear magnetic data of compound 4 are as follows:
1 H NMR(d6 DMSO)δ0.97(d,24H,CH 3 ),1.42(s,9H),1.45(m,4H),2.0(s,1H,NH),2.64(s,3H,CH 3 ), 3.77-4.03(m,3H),4.4(m,1H),4.75(m,1H),6.16(d,1H,J=7.0Hz),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.97(s,1H,CH), 12.09(s,1H,NH)。
(4) Synthesis of Compound 5
5.0g of Compound 4 was weighed, dissolved in 50ml of Tetrahydrofuran (THF), and then 6 equivalents of triethylamine hydrogen trifluoride were added thereto, followed by stirring for 12 hours, and the consumption of the starting material was found to be complete by TLC. Post-treatment: the reaction solution was concentrated to remove THF, then neutralized to neutrality with saturated sodium bicarbonate, and a yellow solid precipitated, filtered to give a yellow product, which was then dissolved with methanol and purified by reverse phase preparative column to give 1.25g of yellow product in 36.7% yield.
The nuclear magnetic data of compound 5 are as follows:
1 H NMR(d6 DMSO)δ1.42(s,9H),2.0(s,1H,NH),2.64(s,3H,CH 3 ),3.57-4.03(m,3H),3.94(s,1H,OH),4.4(m,1H),4.51(s,1H,OH),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.97(s,1H,CH), 12.09(s,1H,NH)。
(5) Synthesis of Compound 6
1.25g of Compound 5 was weighed, dissolved with 15ml of trimethyl phosphate, then 2 equivalents of proton sponge was added, 3 equivalents of phosphorus oxychloride was added under ice bath, after 1 hour of reaction, the liquid phase was analyzed for detection, the raw material consumption was complete, and the post-treatment: saturated sodium bicarbonate was added to neutralize to neutrality, and after filtration of the aqueous solution, the prepared liquid phase was separated and concentrated to give 1.167g of product with a yield of 80.8%.
The nuclear magnetic data of compound 6 are as follows:
1 H NMR(d6 DMSO)δ1.42(s,9H),2.0(s,1H,NH),2.64(s,3H,CH 3 ),3.57-4.03(m,3H),4.2(s,2H,OH),4.4(m,1H),4.51(s,1H,OH),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.97(s,1H,CH), 12.09(s,1H,NH)。
(6) Synthesis of Compound 7
1.167g of Compound 6 was weighed, dissolved in 10ml of methylene chloride, then 10 equivalents of trifluoroacetic acid were added thereto, and after stirring for 2 hours, the liquid phase was analyzed for detection, and the consumption of the raw material was complete. Post-treatment: the methylene dichloride and the trifluoroacetic acid are removed by rotary evaporation, the concentrated liquid is added into saturated sodium bicarbonate to be neutral, the aqueous solution is filtered, the prepared liquid phase is separated, and 650mg of the product is obtained after concentration, and the yield is 67.0%.
The nuclear magnetic data for compound 7 are as follows:
1 H NMR(d6 DMSO)δ2.64(s,3H,CH 3 ),3.57-4.03(m,3H),4.2(s,2H,OH),4.4(m,1H),4.51(s,1H,OH),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.63(s,2H,NH),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.97(s,1H,CH),12.09(s,1H,NH)。
(7) Synthesis of Compound 8
650mg of Compound 7 was weighed, dissolved in 10ml of DMF, 5 equivalents of 2,2' -dithiodipyridine, 10 equivalents of imidazole, 5 equivalents of triphenylphosphine were then added, the reaction was stirred for 12 hours, analytical liquid phase detection, complete consumption of starting material, work-up: slowly adding the solution into 0.2N sodium perchlorate acetone solution, precipitating, centrifuging to obtain 417mg of the required product, and obtaining 58.3% of yield.
The nuclear magnetic data for compound 8 are as follows:
1 H NMR(d6 DMSO)δ2.64(s,3H,CH 3 ),3.57-4.03(m,3H),4.4(m,1H),4.51(s,1H,OH),4.8(s,1H,OH),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.63(s,2H,NH),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.02(d,1H,J=7.5Hz,0.4Hz),7.26(d,1H,J=7.5Hz,10.4Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.88(d,1H,J=0.4Hz,0.4Hz),7.97(s,1H,CH),12.09(s,1H,NH)。
(8) Synthesis of Compound 9
416mg of Compound 8 was weighed, dissolved in 4ml of DMF, 2 equivalents of zinc chloride was added, then 3 equivalents of triethylamine phosphate was added, the reaction was stirred for 12 hours under the protection of nitrogen, the liquid phase was analyzed for detection, the consumption of raw materials was complete, and the work-up was carried out: the solution was added with 10ml of water, and after filtration, the liquid phase was separated to give the product, which was concentrated and lyophilized to give 183mg, yield 41.7%.
The nuclear magnetic data of compound 9 are as follows:
1 H NMR(d6 DMSO)δ2.64(s,3H,CH 3 ),3.57-4.03(m,3H),4.2(s,3H,OH),4.4(m,1H),4.51(s,1H,OH),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.63(s,2H,NH),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.97(s,1H,CH),12.09(s,1H,NH)。
(9) Synthesis of Compound 10
183mg of Compound 9 was weighed, dissolved in 3ml of DMF, 5 equivalents of 2,2' -dithiodipyridine, 10 equivalents of imidazole, 5 equivalents of triphenylphosphine were then added, the reaction was stirred for 12 hours, analytical liquid phase detection, complete consumption of starting material, work-up: slowly adding the solution into 0.2N sodium perchlorate acetone solution, precipitating, centrifuging to obtain the desired product 100mg, and the yield is 50.3%.
The nuclear magnetic data of compound 10 are as follows:
1 H NMR(d6 DMSO)δ2.64(s,3H,CH 3 ),3.57-4.03(m,3H),4.2(s,1H,OH),4.4(m,1H),4.51(s,1H,OH),4.8(s,1H,OH),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.63(s,2H,NH),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.02(d,1H,J=7.5Hz,0.4Hz),7.26(d,1H,J=7.5Hz,10.4Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.88(d,1H,J=0.4Hz,0.4Hz),7.97(s,1H,CH),12.09(s,1H,NH)。
(10) Synthesis of Compound 11 (triethylamine thiophosphate)
The 50g Amberchrom 50WX8 cation exchange resin was loaded onto a glass silica gel column, then 100ml of 2N HCl was used to activate the Amberchrom 50WX8 cation exchange resin, and when the effluent liquid pH was <2, this indicated that activation was complete, and then distilled water was used to wash it to neutrality. Dissolving 3g of sodium thiophosphate with 30ml of distilled water, loading the solution into activated cation exchange resin, washing the resin with distilled water all the time, starting to collect when the pH of effluent liquid is=2, stopping collecting when the pH of effluent liquid is >4, neutralizing the collected solution to be neutral by using triethylamine, and concentrating the aqueous solution to obtain the triethylamine thiophosphate. After lyophilization, a brown solid was obtained, weighing 1.5g.
The nuclear magnetic data of compound 11 are as follows:
1 H NMR(d6 DMSO)δ1.03(t,9H,CH 3 ,J=8.0Hz),1.5(s,1H,SH),2.52(q,6H,CH 2 ,J=8.0Hz),4.8(s,2H,OH)。
(11) Synthesis of Compound 12
100mg of compound 10 was weighed, dissolved in 2ml of DMF, 2 equivalents of zinc chloride was added, then 3 equivalents of self-made triethylamine thiophosphate (compound 11) was added, the reaction was stirred for 12 hours under the protection of nitrogen, and the liquid phase was analyzed for detection that the consumption of the raw material was complete. Post-treatment: the solution was added with 5ml of water, filtered, and the liquid phase was separated to give the product, which was concentrated and lyophilized to give 30mg in 28% yield. The mass spectrum confirmed correct.
The nuclear magnetic data of compound 12 are as follows:
1 H NMR(d6 DMSO)δ1.5(s,1H,SH),2.64(s,3H,CH 3 ),3.57-4.03(m,3H),4.2(s,2H,OH),4.4(m,1H),4.51(s,1H,OH),4.75(m,1H),4.8(s,1H,OH),6.16(d,1H,J=7.0Hz),6.63(s,2H,NH),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.97(s,1H,CH),12.09(s,1H,NH)。
comparative example 1 Synthesis of Compound 4
1.4g of Compound 3 was weighed, dissolved in 20ml of DMF, then 2 equivalents of sodium hydroxide (2.2 ml of aqueous sodium hydroxide solution, concentration: 2N) was added under ice bath, after 10 minutes, 3 equivalents of 1-methylbenzoxazole were added under ice bath, and the reaction was carried out for 3 hours, and the consumption of the starting material was found to be complete but no product point of Compound 4 was found.
Comparative example 2
The synthetic route for MANT-GTPγS was designed as follows:
(1) - (4) Synthesis of Compounds 1 to 5 same as in example 1.
(5) Synthesis of Compound 13
1g of Compound 5 was weighed, dissolved in 15ml of methylene chloride, 10 equivalents of trifluoroacetic acid were then added thereto, and after stirring for 2 hours, the liquid phase was analyzed for detection, and the consumption of the raw material was complete. Post-treatment: the methylene dichloride and the trifluoroacetic acid are removed by rotary evaporation, the concentrated liquid is added into saturated sodium bicarbonate to be neutral, the aqueous solution is filtered, the prepared liquid phase is separated, and the concentrated product is obtained in 500mg, and the yield is 62%.
The nuclear magnetic data of compound 13 are as follows:
1 H NMR(d6 DMSO)δ2.64(s,3H,CH 3 ),3.57-4.03(m,3H),3.94(s,1H,OH),4.4(m,1H),4.51(s,1H,OH),4.75(m,1H),6.16(d,1H, J=7.0Hz),6.63(s,2H,NH 2 ),6.72(s,1H,NH),6.82(m,1H),6.93(d,1H,J=7.5Hz,1.5Hz),7.39(m,1H),7.75(d,1H,J=7.5Hz,1.5Hz),7.97(s,1H,CH),12.09(s,1H,NH)。
(6) Synthesis of Compound 14
500mg of Compound 13 was weighed, dissolved with 8ml of trimethyl phosphate, 1.5 equivalents of pyrophosphoryl chloride was added under ice bath and nitrogen protection, and after reacting for 1 hour, the sample was quenched with 1N TEAB (carbon dioxide of triethylamine) aqueous solution, and the molecular weight of the diphosphate intermediate Compound 14 was not detected by analytical liquid phase detection, but the raw material consumption was complete, and the resultant by-product was not analyzed.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (14)
1. A method for synthesizing man t-gtpγs, comprising the steps of:
(1) Under the action of alkali, reacting the compound 1 with 1,3 dichloro-1, 3-tetraisopropyl disiloxane to obtain a compound 2;
(2) Protecting the amino group in the compound 2 with tert-butoxycarbonyl to obtain a compound 3;
(3) Under the action of sodium hydride, the compound 3 reacts with 1-methylbenzoxazole to obtain a compound 4;
(4) Reacting the compound 4 with triethylamine hydrogen trifluoride to obtain a compound 5;
(5) Under the action of alkali, the compound 5 reacts with phosphorus oxychloride to obtain a compound 6;
(6) In a solvent, reacting the compound 6 with acid to remove tert-butoxycarbonyl in the compound 6 to obtain a compound 7;
(7) Under the action of 2,2' -dithiodipyridine and triphenylphosphine, the compound 7 reacts with imidazole to obtain a compound 8;
(8) Under the action of zinc chloride, the compound 8 reacts with triethylamine phosphate to obtain a compound 9;
(9) Under the action of 2,2' -dithiodipyridine and triphenylphosphine, the compound 9 reacts with imidazole to obtain a compound 10;
(10) Under the action of zinc chloride, the compound 10 reacts with the compound 11 to obtain a compound 12, namely the MANT-GTPγS;
the reaction route is as follows:
。
2. the method of synthesizing man t-gtpγs of claim 1, wherein the base in step (1) is imidazole and/or pyridine; and/or the number of the groups of groups,
the molar ratio of the compound 1,3 dichloro-1, 3-tetraisopropyl disiloxane to the base in the step (1) is 1:1-1.5:2-4; and/or the number of the groups of groups,
the reaction of step (1) is carried out in a solvent, wherein the solvent is N, N-dimethylformamide and/or dimethyl sulfoxide; and/or the number of the groups of groups,
the reaction time in the step (1) is 8-16 hours.
3. The method of synthesizing man t-gtpγs of claim 1, wherein step (2) comprises: under the action of alkali, the compound 2 reacts with di-tert-butyl dicarbonate to obtain a compound 3.
4. The method for synthesizing MANT-GTPγS according to claim 3, wherein the base in step (2) is triethylamine and/or N, N-diisopropylethylamine; and/or the number of the groups of groups,
the molar ratio of the compound 2, the di-tert-butyl dicarbonate and the base in the step (2) is 1:1-1.8:1.5-3; and/or the number of the groups of groups,
the reaction of the step (2) is carried out in a solvent, wherein the solvent is N, N-dimethylformamide and/or dimethyl sulfoxide; and/or the number of the groups of groups,
the reaction time in the step (2) is 8-16 hours.
5. The method of synthesizing man t-gtpγs of claim 1, wherein the molar ratio of the compound 3, 1-methylbenzzole to sodium hydride in step (3) is 1:2-4:1.5-3; and/or the number of the groups of groups,
the reaction of the step (3) is carried out in a solvent, wherein the solvent is N, N-dimethylformamide and/or dimethyl sulfoxide; and/or the number of the groups of groups,
the temperature of the reaction in the step (3) is 0-10 ℃, and the reaction time is 2-5 h.
6. The method of synthesizing man t-gtpγs of claim 1, wherein the molar ratio of compound 4 to triethylamine hydrogen trifluoride of step (4) is 1:4-8; and/or the number of the groups of groups,
the reaction of step (4) is carried out in a solvent, wherein the solvent is tetrahydrofuran and/or acetonitrile; and/or the number of the groups of groups,
the reaction time in the step (4) is 8-16 hours.
7. The method of synthesizing man t-gtpγs of claim 1, wherein the base in step (5) is a proton sponge and/or N, N-diisopropylethylamine; and/or the number of the groups of groups,
the molar ratio of the compound 5, phosphorus oxychloride and the alkali in the step (5) is 1:2-4:1-3; and/or the number of the groups of groups,
the reaction in the step (5) is carried out in a solvent, wherein the solvent is at least one of trimethyl phosphate, triethyl phosphate and acetonitrile; and/or the number of the groups of groups,
the reaction time in the step (5) is 0.5h-3h.
8. The method of synthesizing man t-gtpγs of claim 1, wherein the acid of step (6) is trifluoroacetic acid and the solvent is dichloromethane and/or acetonitrile; and/or the number of the groups of groups,
the molar ratio of the compound 6 to the acid in the step (6) is 1:8-12; and/or the number of the groups of groups,
the reaction time in the step (6) is 1h-3h.
9. The method of synthesizing man t-gtpγs of claim 1, wherein the molar ratio of compound 7, imidazole, 2' -dithiodipyridine and triphenylphosphine of step (7) is 1:8-12:3-7:3-7; and/or the number of the groups of groups,
the reaction of step (7) is carried out in a solvent which is N, N-dimethylformamide and/or acetonitrile; and/or the number of the groups of groups,
the reaction time in the step (7) is 8-16 hours.
10. The method of synthesizing man t-gtpγs of claim 1, wherein the molar ratio of compound 8, triethylamine phosphate and zinc chloride in step (8) is 1:2-4:1-3; and/or the number of the groups of groups,
the reaction of step (8) is carried out in a solvent, wherein the solvent is N, N-dimethylformamide and/or dimethyl sulfoxide; and/or the number of the groups of groups,
the reaction in the step (8) is carried out under the protection of inert gas; and/or the number of the groups of groups,
the reaction time in the step (8) is 8-16 hours.
11. The method of synthesizing man t-gtpγs of claim 1, wherein the molar ratio of compound 9, imidazole, 2' -dithiodipyridine and triphenylphosphine of step (9) is 1:8-12:3-7:3-7; and/or the number of the groups of groups,
the reaction of step (9) is carried out in a solvent which is N, N-dimethylformamide and/or acetonitrile; and/or the number of the groups of groups,
the reaction time in the step (9) is 8-16 hours.
12. The method of synthesizing man t-gtpγs of claim 1, wherein the molar ratio of compound 10, compound 11 and zinc chloride in step (10) is 1:2-4:1-3; and/or the number of the groups of groups,
the reaction of step (10) is carried out in a solvent which is N, N-dimethylformamide and/or dimethyl sulfoxide; and/or the number of the groups of groups,
the reaction in the step (10) is carried out under the protection of inert gas; and/or the number of the groups of groups,
the reaction time in the step (10) is 8-16 hours.
13. The method of synthesizing man-gtpγs according to any one of claims 1-12, wherein the preparation method of compound 11 in step (10) comprises the steps of: dissolving sodium thiophosphate in water, adding into activated cation exchange resin, washing with water, collecting the eluate when the pH of the eluate is 2, and stopping collecting when the pH of the eluate is greater than 4; and adding triethylamine into the collected eluting liquid to neutralize to be neutral, and concentrating to obtain the compound 11.
14. The method of synthesizing man t-gtpγs of claim 13, wherein the cation exchange resin is Amberchrom 50WX8 cation exchange resin; and/or the number of the groups of groups,
the activation method of the activated cation exchange resin comprises the following steps: the cation exchange resin was activated with 1.5mol/L to 2.5mol/L hydrochloric acid and then rinsed with water to neutrality.
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