CN106866748B - The preparation method of compound - Google Patents
The preparation method of compound Download PDFInfo
- Publication number
- CN106866748B CN106866748B CN201710197216.5A CN201710197216A CN106866748B CN 106866748 B CN106866748 B CN 106866748B CN 201710197216 A CN201710197216 A CN 201710197216A CN 106866748 B CN106866748 B CN 106866748B
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- Prior art keywords
- compound
- solution
- reaction
- acid
- dcm
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 112
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims abstract description 30
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000013067 intermediate product Substances 0.000 claims abstract description 22
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 12
- WFUGQJXVXHBTEM-UHFFFAOYSA-N 2-hydroperoxy-2-(2-hydroperoxybutan-2-ylperoxy)butane Chemical compound CCC(C)(OO)OOC(C)(CC)OO WFUGQJXVXHBTEM-UHFFFAOYSA-N 0.000 claims abstract description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000000694 effects Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 75
- 239000000243 solution Substances 0.000 claims description 72
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000012074 organic phase Substances 0.000 claims description 25
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 22
- 238000004440 column chromatography Methods 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 238000000926 separation method Methods 0.000 claims description 16
- OYLFUSSLXABVLB-UHFFFAOYSA-N 5-amino-6-[4,6-diamino-3-[3,5-dihydroxy-4-(methylamino)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol Chemical compound OC1C(NC)C(O)COC1OC1C(O)C(OC2C(C(O)C(O)C(C(C)O)O2)N)C(N)CC1N OYLFUSSLXABVLB-UHFFFAOYSA-N 0.000 claims description 14
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 14
- 150000002460 imidazoles Chemical group 0.000 claims description 14
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- JBWYRBLDOOOJEU-UHFFFAOYSA-N 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 JBWYRBLDOOOJEU-UHFFFAOYSA-N 0.000 claims description 8
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical class CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 8
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 claims description 8
- SEULWJSKCVACTH-UHFFFAOYSA-N 1-phenylimidazole Chemical class C1=NC=CN1C1=CC=CC=C1 SEULWJSKCVACTH-UHFFFAOYSA-N 0.000 claims description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 7
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 7
- 238000012805 post-processing Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical class N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000010790 dilution Methods 0.000 claims description 6
- 239000012895 dilution Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- AXNBHOOQHIIQFA-UHFFFAOYSA-N [S].C(F)(F)F Chemical compound [S].C(F)(F)F AXNBHOOQHIIQFA-UHFFFAOYSA-N 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- QSIFOTQDNVCTTM-UHFFFAOYSA-N 3-methyl-1h-imidazol-3-ium;trifluoromethanesulfonate Chemical class CN1C=CN=C1.OS(=O)(=O)C(F)(F)F QSIFOTQDNVCTTM-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- OBHWOLDGXCOBAK-UHFFFAOYSA-N [F].CS(O)(=O)=O Chemical compound [F].CS(O)(=O)=O OBHWOLDGXCOBAK-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 91
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 239000007832 Na2SO4 Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 7
- 238000004679 31P NMR spectroscopy Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000004519 grease Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 235000002597 Solanum melongena Nutrition 0.000 description 3
- 244000061458 Solanum melongena Species 0.000 description 3
- 229960001076 chlorpromazine Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 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 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)N(C(C)C)P(OC[C@](C)(C*)COP(CCCCCC1=CC=CC1*C1C=CC=C1)(OCCC1NC1)=O)[U]CCC#N Chemical compound CC(C)N(C(C)C)P(OC[C@](C)(C*)COP(CCCCCC1=CC=CC1*C1C=CC=C1)(OCCC1NC1)=O)[U]CCC#N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- -1 compound ferrocene derivatives Chemical class 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- GAIQQJIMVVUTQN-UHFFFAOYSA-N 1-(4-imidazol-1-ylphenyl)ethanone Chemical class C1=CC(C(=O)C)=CC=C1N1C=NC=C1 GAIQQJIMVVUTQN-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- DWYHDSLIWMUSOO-UHFFFAOYSA-N 2-phenyl-1h-benzimidazole Chemical compound C1=CC=CC=C1C1=NC2=CC=CC=C2N1 DWYHDSLIWMUSOO-UHFFFAOYSA-N 0.000 description 1
- 150000004941 2-phenylimidazoles Chemical class 0.000 description 1
- XHLKOHSAWQPOFO-UHFFFAOYSA-N 5-phenyl-1h-imidazole Chemical class N1C=NC=C1C1=CC=CC=C1 XHLKOHSAWQPOFO-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- JYOCKIVAXFOJOK-UHFFFAOYSA-N CCC(C)NC(C)C Chemical compound CCC(C)NC(C)C JYOCKIVAXFOJOK-UHFFFAOYSA-N 0.000 description 1
- KNLJUFRGTJZSKV-UHFFFAOYSA-N CCCCOPN(C(C)C)C(C)C Chemical compound CCCCOPN(C(C)C)C(C)C KNLJUFRGTJZSKV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- DZZVOTHALHKREO-UHFFFAOYSA-N c1cnc[N-]1-c1ccccc1 Chemical compound c1cnc[N-]1-c1ccccc1 DZZVOTHALHKREO-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000006202 diisopropylaminoethyl group Chemical group [H]C([H])([H])C([H])(N(C([H])([H])C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 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 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
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Abstract
The invention discloses a kind of preparation method of compound, the compound has structure shown in formula I, and the solution of intermediate product IV is prepared by compound II and compound III under the action of acid/azole complex for it；Compound V is added in intermediate product IV solution, intermediate product VI solution is prepared under the action of acid/azole complex；Methylethyl ketone peroxide solution is slowly added into the solution of intermediate product VI, intermediate product VII solution is made；Acetic acid hydrazine solution is slowly added into the solution of intermediate product VII, compound VIII is made；Compound VIII reacts under acid/azole complex effect with compound III is made compound I.
Description
Technical field
The present invention relates to the preparation method of compound, and in particular to a kind of preparation method of compound, especially ferrocene
The preparation method of class compound.
Background technology
WO2009061941 discloses Compounds of structural formula I, which can mark on DNA fragmentation, as DNA electrifications
Probe is learned, (DNA such as prepared using radio isotope, fluorescence molecule, chemical illuminating reagent mark is visited with traditional method
Pin) to compare, electrochemical process has the features such as instrumentation is simple, cheap, and measure is accurate, quick, method high sensitivity.
WO2009061941 also describes the method that general formula N330 is prepared since raw material compound ferrocene derivatives, general formula
I inclusion compounds N330：
In this case, by the effect of 3- chlorpromazine chlorides and alchlor friedel-crafts acylation reaction occurs for ferrocene
Afterwards, substituted ferrocene is prepared by boronation hydrogen reduction；Alkalize after by esterification and N205 is made；N205 is in N, N-
Under the action of diisopropylethylamine, after being reacted with 2- cyanoethyls N, N- diisopropyl chloro phosphoramidite, in imidazoles trifluoromethyl
Under the action of sulfonate, QW50 is added, after the reaction was complete, the reaction of 2- methylethyl ketone peroxides is added, adds hydrazine acetate to reduce again afterwards
To compound N 329；N329 is prepared into compound N 330 with the reaction of 2- cyanoethyls N, N- diisopropyl chloro phosphoramidite.
The structural formula of QW50 is：
The syntheti c route of N330：
However, this method disclosed in WO2009061941 in reaction controlling there are many shortcomings, the key such as used
Material 2- cyanoethyls N, N- diisopropyl chloro phosphoramidite price is very expensive, easily anti-with the water in air during storage
Answer and degenerate；N205 and N329 and 2- cyanoethyls N, N- diisopropyl chloro phosphoramidite reaction yield are very low；This route is given birth to
When producing N330, the accessory substance of generation is more；These factors cause that the production cost of N330 is very high, and quality is difficult to control.
The content of the invention
In view of the deficiencies of the prior art, the present invention provide it is a kind of it is new can effective preparation structure compound of formula I synthesis side
Method, it is reacted, and critical component -- double (diisopropylaminoethyls) (2- cyanoethoxies) phosphine valency is cheap, easy to use and preservation, always
Yield is high, and preparation method is simple, easily operated.
In order to solve the above technical problems, the present invention provides following technical solution：
On the one hand, the present invention provides a kind of preparation method of compound shown in Formulas I, its specific preparation process is as follows：
Wherein, R1And R2It is each independently hydrogen or chlorine, bromine or iodine；
Step 1)：Compound II and compound III is prepared intermediate product IV's under the action of acid/azole complex
Solution；
Step 2)：Compound V is added in the solution prepared to step 1), is prepared under the action of acid/azole complex
To intermediate product VI solution；
Step 3)：Methylethyl ketone peroxide solution is slowly added into the solution of step 2), intermediate product VII solution is made；
Step 4)：Acetic acid hydrazine solution is slowly added into the solution of step 3), compound VIII is made；
Step 5)：Compound VIII reacts under acid/azole complex effect with compound III is made compound I.
Further, in the acid/azole complex, acid includes methanesulfonic acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, high chlorine
Acid, trifluoroacetic acid, tetrafluoro boric acid or hexafluorophosphoric acid；
The azole includes imidazoles, N- methylimidazoles, N- phenylimidazoles, N- (p- acetyl phenyl)-imidazoles, 2- methyl miaows
Azoles, 2- phenylimidazoles, 4-methylimidazole, 4- phenylimidazoles, benzimidazole, N- tolimidazoles, 2- tolimidazoles, 2-
Phenylbenzimidazol, 4,5- dicyano imidazoles or tetrazole.
Further, the acid/azole complex includes imidazoles fluoroform sulphonate, N- methylimidazole trifluoromethanesulfonic acids
Salt, N- phenylimidazoles fluoroform sulphonate, 4,5- dicyano imidazoles or tetrazole.
Further, in the step 1), the preparation process of compound II is as follows：
Step 11)：Compound II-2 is made with benzaldehyde reaction in compound II-1；
Step 12)：Compound II-3 is made with levulic acid reaction in compound II-2；
Step 13)：Compound II-4 is made by deprotection reaction in compound II-3；
Step 14)：Compound II is made in compound II-4 and DMTCl reactions.
Further, compound II and compound III is dissolved in solvent DCM at a temperature of 0~5 DEG C in the step 1),
The imidazoles trifluoromethyl sulfonic acid for being dissolved in acetonitrile is added, intermediate product IV solution is obtained after 0.5~1h of stirring reaction；Wherein compound
The molar ratio of II and compound III is 1:0.8~1.5；The molar ratio of compound II and imidazoles fluoroform sulphonate is 1:0.6~
3.0。
Further, the temperature is 0 DEG C；The stirring reaction 0.5h.
Further, in the step 2), intermediate product IV solution obtained by step 1) is warmed to room temperature, adds compound V
After stirring evenly, the acetonitrile solution of N- methylimidazole trifluoromethyl sulfonic acids is added, is prepared after 1~4h is reacted at room temperature
Intermediate product VI solution；
In the step 3), the temperature of the intermediate product VI solution prepared by step 2) is down to 0~5 DEG C, is slowly added dropwise
The DCM solution of butanone is aoxidized, intermediate product VII solution is made,
In the step 4), the methanol solution of hydrazine acetate is slowly added in the intermediate product VII solution prepared by step 3)
Afterwards, 8~12h of room temperature reaction is slowly increased to, compound VIII is prepared by post processing；
The molar ratio of wherein compound II and compound V is 1:0.9~1.8；Compound II and N- methylimidazole fluoroforms
The molar ratio of sulfonate is 1:0.6~3.0；The molar ratio of compound II and methylethyl ketone peroxide is 1:0.7~2；Compound II with
The molar ratio of hydrazine acetate is 1:1~5.
Further, the step 2) reaction time is 2h；The reaction temperature of the step 3) is 0 DEG C；The step
4) reaction time is 10h.
Further, in step 4), the post-processing step is as follows：After reaction solution is washed, extracted with organic solvent
Take, concentrated after organic phase is dried, residue obtains compound VIII through column chromatography for separation after concentration.
Further, in the step 5), compound VIII, DCM, acetonitrile, N- phenylimidazoles trifluoromethyl sulfonic acid according to
Compound III is added in secondary addition reaction vessel, after dissolving in room temperature reaction 0.5~1h, post-treated obtained compound I；Its
The molar ratio of middle compound VIII and compound III is 1:0.8~1.5.
Further, in the step 5), compound VIII, DCM, acetonitrile, N- methylimidazoles fluoroform sulphonate are successively
Add in reaction vessel, compound III is added after dissolving in room temperature reaction 0.5~1h, post-treated obtained compound I；Wherein
The molar ratio of compound VIII and compound III is 1:0.8~1.5；Compound VIII and N- methylimidazole fluoroform sulphonates
Molar ratio be 1:0.6~3.0.
Further, in the step 5), compound VIII, DCM, acetonitrile, imidazoles fluoroform sulphonate sequentially add instead
Answer in container, compound III is added after dissolving in room temperature reaction 0.5~1h, post-treated obtained compound I；Wherein compound
The molar ratio of VIII and compound III is 1:0.8~1.5；The molar ratio of compound VIII and imidazoles fluoroform sulphonate is 1:
0.6~3.0.
Further, in the step 5), compound VIII, DCM, acetonitrile, 4,5- dicyano imidazoles sequentially add reaction
Compound III is added in container, after dissolving in room temperature reaction 0.5~1h, post-treated obtained compound I；Wherein compound
The molar ratio of VIII and compound III is 1:0.8~1.5；The molar ratio of compound VIII and 4,5- dicyano imidazoles is 1:0.6
~3.0.
Further, the reaction time of the step 5) is 0.5h.
Further, in the step 5), the post processing is directed to after DCM dilutions are added in reaction solution, is washed with water,
After water is mutually stripped with DCM, the organic phase of two steps merges, and compound I is made in column chromatography for separation after organic phase drying concentration.
Further, in the step 11), after compound II-1, TsOH is dissolved in THF, benzaldehyde is slowly added dropwise, in room temperature
After reacting 8~12h, compound II-2 is made；Wherein the molar ratio of compound II-1 and benzaldehyde is 1:0.9~1.5.
Further, in the step 12), compound II-2, DCC, DMAP are dissolved in DCM, are down to 0~5 DEG C, slowly drop
Add levulic acid, the reaction was continued 1~2h, is made compound II-3；Wherein the molar ratio of compound II-2 and levulic acid is 1:
1.0~1.5；The molar ratio of compound II-2 and DCC are 1:1.0~2.0.
Further, reaction temperature is 0 DEG C in the step 12), reaction time 2h.
Further, in the step 13), compound II-3 reacts at room temperature 1.5~3h deprotections in hydrochloric acid and methanol,
Compound II-4 is made.
Further, the reaction time is 2h in the step 13).
Further, in the step 14), compound II-4 is slowly added to DMTCl under the conditions of existing for TEA, DMAP
DCM solution, react 8~12h, post-process and compound II is made, wherein the molar ratio of compound II-4 and DMTCl is 1:0.8
~1.5.
Further, the reaction time is 10h in the step 14).
Further, in the step 14), post processing refers to that reaction solution is washed with water, 5% sodium bicarbonate solution respectively
Afterwards, water mutually merges, and water is mutually extracted with DCM；Organic phase concentration column chromatography for separation obtains compound II.
Beneficial effects of the present invention
The present invention relates to a kind of preparation method of compound shown in Formulas I, there is provided one kind reacts faster, yield higher, bar
Part is gentle, and production cost is low, possesses the extensive preparation method for preparing value.Method provided by the invention, goes out from compound II
Hair, can readily obtain compound I, and gross production rate is higher than 60%.The present invention is without the use of expensive reagent, and agents useful for same preserves convenient
Simply, product easy purification, quality are easy to control.
Method provided by the invention is simple, workable, and favorable reproducibility, cost is low, is adapted to commercial Application.
Embodiment
Brief description：
CTPPA：
DCM：Dichloromethane
Na2SO4：Sodium sulphate
MeCN：Acetonitrile
MeOH：Methanol
NaHCO3：Sodium acid carbonate
DMTCl：
DMAP：4-dimethylaminopyridine
TEA：Triethylamine
NaOH：Sodium hydroxide
DCC：Dicyclohexylcarbodiimide
THF：Tetrahydrofuran
TsOH：P-methyl benzenesulfonic acid
KI：Potassium iodide
DMF：Dimethylformamide
AcOK：Potassium acetate
NaBH4：Sodium borohydride
AlCl3：Alchlor
C2Cl6:Carbon trichloride
n-BuLi：N-BuLi
TMEDA：Tetramethylethylenediamine
DCI:4,5- dicyano imidazoles
To make those skilled in the art more fully understand technical scheme, with reference to embodiment to this
Invention is further described.
Embodiment
Embodiment 1
Take AlCl3(17.70g, 132.8mmol), DCM (200.0mL) are in the oblique two mouthfuls of flasks of 500mL, N2Under protection, drop
To 0 DEG C, 3- chlorpromazine chlorides (13.5mL, 141.6mmol) are slowly added dropwise, keeps the temperature 1h, obtains solution A；
Take DMF (80.0mL) that NaBH is added portionwise in 100mL eggplant type bottles4(6.10g, 161.2mmol), is warming up to 45
DEG C stirring 3h, obtain B solution；
Ferrocene (20.00g, 107.5mmol) is taken to be dissolved in DCM (52.0mL), N2Under protection, A is slowly added dropwise at room temperature
Solution, is added dropwise, and reacts 30 minutes at room temperature；0 DEG C is down to, B solution is slowly added dropwise, is added dropwise, it is small to be warmed to room temperature reaction 1
When.Water (200.0mL) is slowly added dropwise reaction is quenched, be layered, water is mutually extracted with DCM, is washed；Anhydrous Na2SO4Dry, concentration, obtains
Brown liquid compound 1.
Take compound 1, DMF (250.0mL), AcOK (29.20g, 279.6mmol), KI (29.60g, 178.5mmol) in
In 500mL eggplant-shape bottles, 95 DEG C of reaction 1h are warming up to；Room temperature is down to, is filtered；NaOH aqueous solutions (8mol/ is slowly added dropwise at room temperature
L), 1h is reacted at room temperature.It is extracted with ethyl acetate, merges organic phase, washing；Anhydrous Na2SO4It is dry, concentration, column chromatography for separation,
It is 59.1% to obtain 2,4 step overall yield of reaction of 15.51g brownish red oilies compound.
1H NMR(400MHz,CDCl3δppm):δ 1.30 (br, 1H, OH), 1.78 (dd, J=6.5,7.5Hz, 2H,
CH2CH2), OH 2.42 (t, J=7.7Hz, 2H, Fc-CH2), 3.68 (t, J=6.3Hz, 2H, CH2-OH),4.06-4.11(m,
9H,Fc-H).
Embodiment 2
THF (356.0mL), II-1 (24.00g, 200.0mmol), TsOH (1.20g, 6.3mmol) are taken in the oblique two mouthfuls of burnings of 1L
In bottle, benzaldehyde (21.4mL, 210.0mmol) is slowly added dropwise, is added dropwise, reacts 12h at room temperature.
PH is adjusted to 7.0 with ammonium hydroxide, decompression steams THF；Residue adds DCM (200.0mL) dissolvings, is washed with water 3 times (3
× 100mL), anhydrous Na2SO4Dry, concentration, obtains 37.12g compound as white solid II-2, yield 89.1%.
Embodiment 3
N2Under protection, take compound II-2 (5.00g, 24.0mol), DCC (6.43g, 31.2mmol), DMAP (0.293g,
2.4mmol), DCM (48.0mL) is down to 0 DEG C in the oblique two mouthfuls of flasks of 100mL；Be slowly added dropwise levulic acid (2.7mL,
26.4mmol), 1h is kept the temperature.Filtering, concentration, obtains blood red oily compounds II-3.
Gone to after MeOH (33.0mL) dissolvings are added into the flask for filling compound II-3 in the oblique two mouthfuls of flasks of 500mL,
Hydrochloric acid (33.2mL, 4mol/L) is added, reacts 2h at room temperature.
PH is adjusted to 7.0 with NaOH solution (33.2mL, 4mol/L), steams MeOH, is extracted with DCM (3 × 40mL), it is anhydrous
Na2SO4Dry, concentration, obtains brownish red oily compounds II-4.
N2Under protection, into the flask for filling compound II-4 add TEA (3.3mL, 23.9mmol), DMAP (0.265g,
2.2mmol)、DCM(27.7mL)；DMTCl (6.65g, the 23.9mmol) solution for being dissolved in DCM (27.7mL) is slowly added dropwise, reacts
Overnight.
With water (1 × 50mL), 5%NaHCO3(1 × 25mL) is washed；Merge water phase, water is mutually extracted with DCM (1 × 50mL)；
Merge organic phase, concentration, residue uses column chromatography, and obtains 6.41g pale yellow oil compounds II, 3 step total recoverys
51.3%.
1H NMR(400MHz,CDCl3δppm):δ0.90(s,3H,CH3-C),2.17(s,3H,CH3-CO),2.30(t,J
=6.5Hz, 1H, OH), 2.53 (t, J=6.5Hz, 2H, CH2-CH2), 2.72 (t, J=6.6Hz, 2H, CH2-CH2),3.01-
3.09(m,2H,CH2-O),3.45-3.46(m,2H,CH2-O),3.79(s,6H,OCH3),4.17(s,2H,CH2-O),6.82-
6.84(m,4H,Ph-H),7.21-7.41(m,9H,Ph-H).
Embodiment 4
N2Under protection, compound II (8.60g, 16.5mmol), CTPPA (5.2mL, 16.5mmol), DCM (86.0mL) are taken
In the oblique two mouthfuls of flasks of 250mL, 0 DEG C is down to；Addition be dissolved in MeCN (8.6mL) N- methylimidazoles trifluoromethanesulfonic acid (3.83g,
16.5mmol) solution, keeps the temperature 30min；
Compound 2 (6.04g, 24.5mmol), then the imidazoles fluoroform sulphur that 8.6mLMeCN will be dissolved in are added into reaction solution
The solution of sour (5.40g, 24.7mmol) adds, and reaction solution is warmed to room temperature reaction 2h；
Reaction bulb is placed in ice bath and is down to 0 DEG C, be slowly added dropwise be dissolved in DCM (43.0mL) methylethyl ketone peroxide (5.2mL,
14.8mmol), the hydrazine acetate (7.60g, 82.5mmol) for being dissolved in MeOH (41.0mL) is slowly added dropwise, is warmed to room temperature after being added dropwise
Reaction is overnight.Reaction solution is washed with water (180mL)；Water is mutually extracted with DCM (1 × 180mL), merges organic phase, anhydrous Na2SO4It is dry
Dry, concentration, residue column chromatography for separation, obtains 6,4 step yield of brownish red grease 9.57g compounds as 74.2%.
1H NMR(400MHz,DMSO-d6δppm):δ0.95(s,s,3H,CH3- C, 2 isomers), 1.82-1.89 (m,
2H,CH2-CH2-Fc),2.37-2.39(m,2H,CH2-Fc),2.67-2.74(m,2H,CH2CN),3.03-3.08(m,2H,CH2-
O),3.44-3.50(m,2H,CH2-OH),3.79(s,6H,OCH3),4.02-4.22(m,16H,Fc-H,CH2-O,CH2OH),
6.82-6.84(m,4H,Ph-H),7.21-7.41(m,9H,Ph-H).
31P NMR(162MHz,DMSO-d6And 85%H3PO4Aqueous solution is as external standard) δ ppm:-0.62(s)；31P NMR masters
Scope of the peak (- 0.5ppm) in -10~20ppm integrates:100%.
Embodiment 5
N2Under protection, compound II (8.60g, 16.5mmol), CTPPA (5.8mL, 18.1mmol), DCM (86.0mL) are taken
In the oblique two mouthfuls of flasks of 250mL, 0 DEG C is down to；Add be dissolved in 8.6mL MeCN N- methylimidazoles trifluoromethanesulfonic acid (4.21g,
18.15mmol) solution, keeps the temperature 30min；
Compound 2 (3.62g, 14.8mmol), then the imidazoles fluoroform sulphur that 8.6mLMeCN will be dissolved in are added into reaction solution
The solution of sour (3.24g, 14.8mmol) adds, and reaction solution is warmed to room temperature reaction 2h；
Reaction bulb is placed in ice bath and is down to 0 DEG C, be slowly added dropwise be dissolved in DCM (43.0mL) methylethyl ketone peroxide (6.0mL,
14.8mmol), the hydrazine acetate (7.60g, 82.5mmol) for being dissolved in MeOH (41.0mL) is slowly added dropwise, is warmed to room temperature after being added dropwise
Reaction is overnight.Reaction solution is washed with water (180mL)；Water is mutually extracted with DCM (1 × 180mL), merges organic phase, anhydrous Na2SO4It is dry
Dry, concentration, residue column chromatography for separation, obtains 6,4 step total recoverys of brownish red grease 9.14g compounds as 70.9%.
Embodiment 6：
N2Under protection, compound II (8.60g, 16.5mmol), CTPPA (4.7mL, 14.8mmol), DCM (86.0mL) are taken
In the oblique two mouthfuls of flasks of 250mL, 0 DEG C is down to；Add be dissolved in 8.6mL MeCN N- methylimidazoles trifluoromethanesulfonic acid (3.45g,
14.85mmol) solution, keeps the temperature 30min；
Compound 2 (4.28g, 16.5mmol), then the imidazoles fluoroform sulphur that 8.6mLMeCN will be dissolved in are added into reaction solution
The solution of sour (3.60g, 16.5mmol) adds, and reaction solution is warmed to room temperature reaction 2h；
Reaction bulb is placed in ice bath and is down to 0 DEG C, be slowly added dropwise be dissolved in DCM (43.0mL) methylethyl ketone peroxide (6.0mL,
14.8mmol), the hydrazine acetate (7.60g, 82.5mmol) for being dissolved in MeOH (41.0mL) is slowly added dropwise, is warmed to room temperature after being added dropwise
Reaction is overnight.Reaction solution is washed with water (180mL)；Water is mutually extracted with DCM (1 × 180mL), merges organic phase, anhydrous Na2SO4It is dry
Dry, concentration, residue column chromatography for separation, obtains 6,4 step total recoverys of brownish red grease 9.35g compounds as 72.5%.
Embodiment 7
N2Under protection, compound 6 (1.71g, 2.2mmol), DCM (31.1mL), acetonitrile (3.6mL), N- phenylimidazoles are taken
(1.05g, 2.2mmol) is in the oblique two mouthfuls of flasks of 100mL；CTPPA (0.76mL, 2.4mmol) is added, reacts 30min at room temperature.
100mLDCM dilute reaction solutions are added, dilution is washed with water (1 × 100mL), and organic phase retains；Water is mutually extracted with DCM
Take (1 × 50mL)；Merge organic phase, anhydrous Na2SO4Dry, concentration, residue column chromatography for separation, obtains 1.93g brownish red oilies
Compounds 7, yield 89.3%.
1H NMR(400MHz,DMSO-d6δppm):δ0.93-0.97(s,s,3H,CH3- C, 2 isomers), 1.05 (d, J
=6.7Hz, 12H, (CH3)2- CH-N), 1.10 (d, J=6.8Hz, 6H, (CH3)2-CH-N),1.77-1.79(m,2H,CH2-
CH2- Fc), 2.30 (t, J=7.6Hz, 2H, CH2- Fc), 2.69 (t, J=5.9Hz, 2H, CH2-CN),2.87-2.89(m,2H,
CH2- CN), 2.95 (dd, J=9.5,11.7Hz, 2H, CH2-O),3.44-3.54(m,4H,CH2-O),3.64-3.67(m,2H,
(CH3)2-CH-N),3.73(s,6H,OCH3),3.92-4.09(m,15H,Fc-H,CH2-O),6.86-6.88(m,4H,Ph-H),
7.22-7.38(m,9H,Ph-H).
31P NMR(162MHz,DMSO-d6And 85%H3PO4Aqueous solution is as external standard) δ ppm:146.7(s),-1.7(s)
；31Scope of the PNMR main peaks (- 0.5ppm) in -10~20ppm integrates:100%.
Embodiment 8：
N2Under protection, take compound 6 (1.71g, 2.2mmol), DCM (17.1mL), acetonitrile (3.4mL), DCI (0.24g,
2.2mmol) in the oblique two mouthfuls of flasks of 100mL；CTPPA (0.76mL, 2.4mmol) is added, reacts 30min at room temperature.
100mLDCM dilute reaction solutions are added, dilution is washed with water (1 × 100mL), and organic phase retains；Water is mutually extracted with DCM
Take (1 × 50mL)；Merge organic phase, anhydrous Na2SO4Dry, concentration, residue column chromatography for separation, obtains 1.86g brownish red oilies
Compounds 7, yield 86.1%.
Embodiment 9：
N2Under protection, take compound 6 (1.71g, 2.2mmol), DCM (17.1mL), acetonitrile (3.4mL), DCI (0.21g,
2.0mmol) in the oblique two mouthfuls of flasks of 100mL；CTPPA (0.76mL, 2.4mmol) is added, reacts 30min at room temperature.
100mLDCM dilute reaction solutions are added, dilution is washed with water (1 × 100mL), and organic phase retains；Water is mutually extracted with DCM
Take 1 × 50mL；Merge organic phase, anhydrous Na2SO4Dry, concentration, residue column chromatography for separation, obtains 1.80g brownish red grease
Compound 7, yield 83.3%.
Embodiment 10
Ferrocene (5.00g, 26.9mmol), n-hexane (32.5mL) are taken in 100mL three-necked flasks, nitrogen protection, puts
In ice bath；Add TMEDA (8.0mL, 53.0mmol)；N-BuLi (37.0mL, 59.2mmol), room temperature reaction is slowly added dropwise
5h；- 78 DEG C are down to, by C2Cl6(14.00g, 59.2mmol), which is dissolved in n-hexane (100mL), to be slowly added dropwise, and is transferred at room temperature
Reaction is overnight；
Reaction is quenched with water (20.0mL)；Diatomite filters, and isolates organic phase, water mutually extracts (3 with methyl tertiary butyl ether(MTBE)
×50mL)；Merge organic phase, anhydrous Na2SO4Dry, concentration, obtains 5.38g yellow-brown solids 8, yield 78.4%.
1H NMR(400MHz,CDCl3δppm):δ4.11-4.14(m,4H,Fc-H),4.40-4.42(m,4H,Fc-H).
Embodiment 11
Take AlCl3(2.90g, 21.6mmol), DCM (50.0mL) are placed in ice bath, slowly drip in 100mL eggplant type bottles
Add 3- chlorpromazine chlorides (2.2mL, 23.5mmol), stir 30min, obtain A liquid；
Take NaBH4(2.20g, 58.2mmol), diethylene glycol dimethyl ether (40.0mL) rise in 100mL round-bottomed flasks
45 DEG C of stirring 1h, obtain B liquid；
Compound 8 (5.00g, 19.6mmol), DCM (13.0mL) are taken in the oblique two mouthfuls of flasks of 250mL, N2Protection, slowly
A liquid is added dropwise, reacts at room temperature 30min；0 DEG C is down to, B liquid is slowly added dropwise, is warmed to room temperature reaction 30min.
Reaction is quenched with water (50.0mL)；Extracted (2 × 100mL) with DCM；Merge organic phase, wash (2 × 100mL)；Nothing
Water Na2SO4Dry, concentration, column chromatography for separation obtains brown liquid 9.
Compound 9, DMF (70.0mL), AcOK (5.20g, 52.8mmol), KI (5.20g, 31.6mmol) are taken in 250mL
In eggplant type bottle, 95 DEG C of reaction 1h are risen to；Room temperature is down to, diatomite filtering, filtrate is transferred in 500mL flasks, is slowly added dropwise
NaOH (8.40g, 8.0mol/L), reacts at room temperature 30min.
Water (200.0mL) quenching reaction is added, is extracted with ethyl acetate (2 × 200mL)；Merge organic phase, wash (2 ×
200mL)；Anhydrous Na2SO4Dry, concentration, column chromatography for separation obtains 3.37g brown liquids 10, four-step reaction total recovery 55.0%.
1H NMR(400MHz,CDCl3δppm):δ1.32(br,1H,OH),1.72-1.79(m,2H,CH2CH2OH),
2.31-2.43(m,2H,CH2-Fc),3.65-3.68(m,2H,CH2OH),4.01-4.10(m,3H,Fc-H),4.32-4.35(m,
4H,Fc-H).
Embodiment 12
N2Under protection, compound II (8.00g, 15.4mmol), CTPPA (4.9mL, 15.4mmol), DCM (80.0mL) are taken
In the oblique two mouthfuls of flasks of 250mL, 0 DEG C is down to；Add be dissolved in 8.0mL MeCN N- methylimidazoles trifluoromethanesulfonic acid (3.58g,
15.4mmol) solution, keeps the temperature 30min；
Compound 10 (7.17g, 22.9mmol) is added into reaction solution, then the imidazoles trifluoro of MeCN (8.0mL) will be dissolved in
The solution of methanesulfonic acid (5.07g, 23.1mmol) adds, and reaction solution is warmed to room temperature reaction 2h；
Reaction bulb is placed in ice bath and is down to 0 DEG C, be slowly added dropwise be dissolved in DCM (42.0mL) methylethyl ketone peroxide (5.0mL,
13.9mmol), the hydrazine acetate (7.11g, 77.1mmol) for being dissolved in MeOH (37.0mL) is slowly added dropwise, is warmed to room temperature after being added dropwise
Reaction is overnight.Reaction solution is washed with water (150mL)；Water is mutually extracted with DCM (1 × 150mL), merges organic phase, anhydrous Na2SO4It is dry
Dry, concentration, residue column chromatography for separation obtains 12.62g brownish reds oily compound 13, and four step yields are 78.0%.
1H NMR(400MHz,DMSO-d6δppm):δ0.88(s,3H,CH3-C),1.74-1.81(m,2H,CH2CH2Fc),
2.25-2.30(m,2H,CH2-Fc),2.86-2.90(m,4H,CH2-O,CH2CN),3.27-3.36(m,2H,CH2OH),3.73
(s,6H,CH3O),3.91-3.96(m,4H,CH2-O),4.04-4.11(m,3H,Fc-H),4.14-4.15(m,2H,CH2-O),
4.43-4.45(m,4H,Fc-H),4.60-4.63(m,1H,OH),6.87-6.89(m,4H,Ph-H),7.20-7.38(m,9H,
Ph-H).
31P NMR(162MHz,DMSO-d6And 85%H3PO4Aqueous solution is as external standard) δ ppm:-1.5(s)；31P NMR masters
Scope of the peak (- 0.5ppm) in -10~20ppm integrates:100%.
Embodiment 13
N2Under protection, compound 13 (5.00g, 5.9mmol), DCM (80mL), acetonitrile (10.0mL), N- phenylimidazoles are taken
(2.92g, 5.98mmol) is in the oblique two mouthfuls of flasks of 500mL；CTPPA (2.0mL, 6.4mmol) is added, reacts 30min at room temperature.
DCM (150mL) dilute reaction solution is added, dilution is washed with water (1 × 150mL), and organic phase retains；Water mutually uses DCM
Extract (1 × 150mL)；Merge organic phase, anhydrous Na2SO4Dry, concentration, residue column chromatography for separation, obtains 5.48g brownish reds oil
Shape compounds 14, yield 88.4%.
1H NMR(400MHz,DMSO-d6,ppm):δ0.93-0.96(s,s,3H,CH3- C, 2 isomers), 1.04-
1.12(m,12H,(CH3)2-CH-N),1.76-1.81(m,2H,CH2CH2Fc),2.24-2.32(m,2H,CH2-Fc),2.69(t,
J=5.8Hz, 2H, CH2CN),2.87-2.89(m,2H,CH2CN),2.93-2.98(m,2H,CH2-O),3.42-3.53(m,4H,
CH2O),3.64-3.66(m,2H,(CH3)2-CH-N),3.73(s,6H,CH3-O),3.93-3.98 (m,4H,CH2-O),4.06-
4.10(m,3H,Fc-H),4.14(br,2H,CH2-O),4.44(s,4H,Fc-H),6.86-6.88(m,4H,Ph-H),7.22-
7.38(m,9H,Ph-H).
31P NMR(162MHz,DMSO-d6And 85%H3PO4Aqueous solution is as external standard) δ ppm:-1.7(s),146.8；31Scope of the PNMR main peaks (- 0.5ppm) in -10~20ppm integrates:100%.
It is understood that the principle that embodiment of above is intended to be merely illustrative of the present and the exemplary implementation that uses
Mode, but the present invention is not limited thereto.For those skilled in the art, the essence of the present invention is not being departed from
In the case of refreshing and essence, various changes and modifications can be made therein, these variations and modifications are also considered as being comprised in the present invention's
In protection domain.
Claims (8)
1. the preparation method of compound shown in a kind of Formulas I, its specific preparation process is as follows：
Wherein, R1And R2It is each independently hydrogen, chlorine, bromine or iodine；
Step 1)：The molten of intermediate product IV is prepared under the action of acid/azole complex in compound II and compound III
Liquid；
Step 2)：Compound V is added in the solution prepared to step 1), in being prepared under the action of acid/azole complex
Between product VI solution；
Step 3)：Methylethyl ketone peroxide solution is slowly added into the solution of step 2), intermediate product VII solution is made；
Step 4)：Acetic acid hydrazine solution is slowly added into the solution of step 3), compound VIII is made；
Step 5)：Compound VIII is made under acid/azole complex or the effect of 4,5- dicyano imidazoles with compound III reactions
Compound I；
The acid/azole complex is imidazoles fluoroform sulphonate, N- methylimidazoles fluoroform sulphonate or N- phenylimidazoles three
Fluorine mesylate.
2. preparation method according to claim 1, wherein, compound II and compound III is dissolved in molten in the step 1)
In agent DCM at a temperature of 0~5 DEG C, the imidazoles fluoroform sulphonate for being dissolved in acetonitrile is added, is obtained after 0.5~1h of stirring reaction middle
Product IV solution；The molar ratio of wherein compound II and compound III is 1:0.8~1.5；Compound II and imidazoles fluoroform sulphur
The molar ratio of hydrochlorate is 1:0.6~3.0.
3. preparation method according to claim 1, wherein, it is in the step 2), intermediate product IV obtained by step 1) is molten
Liquid is warmed to room temperature, and after addition compound V is stirred evenly, the acetonitrile solution of N- methylimidazole fluoroform sulphonates is added, in room
Intermediate product VI solution is prepared after 1~4h of temperature reaction；
In the step 3), the temperature of the intermediate product VI solution prepared by step 2) is down to 0~5 DEG C, and peroxidating is slowly added dropwise
The DCM solution of butanone, is made intermediate product VII solution；
In the step 4), after being slowly added to the methanol solution of hydrazine acetate in the intermediate product VII solution prepared by step 3), delay
Slowly 8~12h of reaction is warmed to room temperature, compound VIII is prepared by post processing；
Wherein, the molar ratio of compound II and compound V is 1:0.9~1.8；Compound II and N- methylimidazole trifluoromethanesulfonic acids
The molar ratio of salt is 1:0.6~3.0；The molar ratio of compound II and methylethyl ketone peroxide is 1:0.7~2；Compound II and acetic acid
The molar ratio of hydrazine is 1:1~5.
4. preparation method according to claim 1, wherein, in the step 5), compound VIII, DCM, acetonitrile, acid/azoles
Class complex or 4,5- dicyano imidazole are sequentially added in reaction vessel, after dissolving add compound III room temperature reaction 0.5~
1h, post-treated obtained compound I；The molar ratio of wherein compound VIII and compound III is 1:0.8~1.5；Compound
The molar ratio of VIII and acid/azole complex is 1:0.6~3.0；
The acid/azole complex is N- phenylimidazoles fluoroform sulphonate or imidazoles fluoroform sulphonate.
5. preparation method according to claim 4, wherein, in the step 5), the post processing is directed in reaction solution
After adding DCM dilutions, it is washed with water, after water is mutually extracted with DCM, the organic phase of two steps merges, column chromatography after organic phase drying concentration
Compound I is made in separation.
6. preparation method according to claim 1, wherein, in the step 1), the preparation process of compound II is as follows：
Step 11)：Compound II-2 is made with benzaldehyde reaction in compound II-1；
Step 12)：Compound II-3 is made with levulic acid reaction in compound II-2；
Step 13)：Compound II-4 is made by deprotection reaction in compound II-3；
Step 14)：Compound II is made in compound II-4 and DMTCl reactions.
7. preparation method according to claim 6, wherein, in the step 11), compound II-1, TsOH is dissolved in THF
Afterwards, benzaldehyde is slowly added dropwise, after 8~12h is reacted at room temperature, compound II-2 is made；Wherein compound II-1 and benzaldehyde
Molar ratio is 1:0.9~1.5；
In the step 12), compound II-2, DCC, DMAP are dissolved in DCM, are down to 0~5 DEG C, levulic acid is slowly added dropwise, after
1~2h of continuous reaction, is made compound II-3；Wherein the molar ratio of compound II-2 and levulic acid is 1:1.0~1.5；Chemical combination
The molar ratio of thing II-2 and DCC are 1:1.0~2.0；
In the step 13), compound II-3 reacts at room temperature 1.5~3h deprotections in hydrochloric acid and methanol, and compound II- is made
4；
In the step 14), compound II-4 is slowly added to the DCM solution of DMTCl, instead under the conditions of existing for TEA, DMAP
8~12h is answered, post-processes and compound II is made, wherein the molar ratio of compound II-4 and DMTCl is 1:0.8~1.5.
8. preparation method according to claim 7, wherein, in step 14), the post-processing step is as follows：Reaction solution
After being washed respectively with water, 5% sodium bicarbonate solution, water mutually merges, and water is mutually extracted with DCM；Organic phase concentration column chromatography for separation obtains
To compound II.
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| CN103601761A (en) * | 2013-09-24 | 2014-02-26 | 中山大学达安基因股份有限公司 | Synthetic method of ferrocene derivatives |
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| CN103601761A (en) * | 2013-09-24 | 2014-02-26 | 中山大学达安基因股份有限公司 | Synthetic method of ferrocene derivatives |
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