CN107459526A - A kind of method by pentahomoserine synthesis of natural product (±) Pestaloxazine A - Google Patents
A kind of method by pentahomoserine synthesis of natural product (±) Pestaloxazine A Download PDFInfo
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- CN107459526A CN107459526A CN201710361754.3A CN201710361754A CN107459526A CN 107459526 A CN107459526 A CN 107459526A CN 201710361754 A CN201710361754 A CN 201710361754A CN 107459526 A CN107459526 A CN 107459526A
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- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 17
- 229930014626 natural product Natural products 0.000 title abstract description 9
- CZWARROQQFCFJB-UHFFFAOYSA-N L-2-Amino-5-hydroxypentanoic acid Chemical compound OC(=O)C(N)CCCO CZWARROQQFCFJB-UHFFFAOYSA-N 0.000 title abstract description 6
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 326
- 238000006243 chemical reaction Methods 0.000 claims abstract description 80
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 17
- 238000006482 condensation reaction Methods 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- 229910052717 sulfur Inorganic materials 0.000 claims description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 70
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 53
- -1 alkali metal hydrogencarbonate Chemical class 0.000 claims description 48
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000000460 chlorine Substances 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical group 0.000 claims description 34
- 238000002156 mixing Methods 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- 239000003960 organic solvent Substances 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 238000010189 synthetic method Methods 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 26
- 230000004048 modification Effects 0.000 claims description 26
- 238000012986 modification Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000003513 alkali Substances 0.000 claims description 25
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 229910052740 iodine Inorganic materials 0.000 claims description 24
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 22
- 229910052794 bromium Inorganic materials 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 239000011630 iodine Substances 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910000085 borane Inorganic materials 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000000543 intermediate Substances 0.000 claims description 9
- 239000011736 potassium bicarbonate Substances 0.000 claims description 9
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 9
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 9
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 8
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 8
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 229910000026 rubidium carbonate Inorganic materials 0.000 claims description 8
- WPFGFHJALYCVMO-UHFFFAOYSA-L rubidium carbonate Chemical compound [Rb+].[Rb+].[O-]C([O-])=O WPFGFHJALYCVMO-UHFFFAOYSA-L 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 229910020889 NaBH3 Inorganic materials 0.000 claims description 6
- 229910019020 PtO2 Inorganic materials 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 239000012448 Lithium borohydride Substances 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 3
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 3
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 claims description 3
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000012363 selectfluor Substances 0.000 claims description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 3
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052777 Praseodymium Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 10
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 235000007686 potassium Nutrition 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical class O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 abstract description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract description 2
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 239000000758 substrate Substances 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- 238000001914 filtration Methods 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 229910052710 silicon Inorganic materials 0.000 description 17
- 239000010703 silicon Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- 239000002994 raw material Substances 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- 238000001035 drying Methods 0.000 description 13
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 0 CC(CC*)=CC(N(CCC1)OC1(C(N[C@@]1(CCC2)ON2C(C=C(C)CCO*)=O)=O)NC1=O)=O Chemical compound CC(CC*)=CC(N(CCC1)OC1(C(N[C@@]1(CCC2)ON2C(C=C(C)CCO*)=O)=O)NC1=O)=O 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 239000007800 oxidant agent Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- 229910052681 coesite Inorganic materials 0.000 description 7
- 229910052906 cristobalite Inorganic materials 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- 229910052682 stishovite Inorganic materials 0.000 description 7
- 229910052905 tridymite Inorganic materials 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- FEBJSGQWYJIENF-UHFFFAOYSA-N nickel niobium Chemical compound [Ni].[Nb] FEBJSGQWYJIENF-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- MKIFAJANCQRLFV-UHFFFAOYSA-N butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](CCCC)C1=CC=CC=C1 MKIFAJANCQRLFV-UHFFFAOYSA-N 0.000 description 1
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005648 named reaction Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000002276 neurotropic effect Effects 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
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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Abstract
After obtaining Dui Cheng bisoxazines alkane spiral shell diketopiperazine compounds A with side chain compound B the step of condensation reaction prepares natural products (±) pestaloxazine A occurs for the serial reaction such as the method the present invention relates to one kind by pentahomoserine synthesis of natural product (±) pestaloxazine A, it is included by protected pentahomoserine through being condensed, aoxidize, cyclization.
Description
Technical field
The invention belongs to the fully synthetic field of natural products, and in particular to one kind is by pentahomoserine synthesis of natural product
(±)-pestaloxazine A method.Natural products (±)-pestaloxazine A structures are novel, activity is notable, possess
Develop the potentiality as anti-EV71 active medicines lead compound.
Background technology
Enterovirns type 71 (EV71) is the main pathogens for causing hand-foot-and-mouth disease, infect infant and preschool youngster more
It is virgin.Since hand-foot-and-mouth disease is classified as Class C infectious disease by health ministry in 2008, the cut-off end of the year 2014 country shares 11,890,000
Patient, cause 3220 people dead.Research in recent years shows that EV71 turns into a kind of important neurotropic virus, can cause acute relaxation
Slow property paralysis and encephalitis, cause cardiorespiratory failure and dead.At present, patient and death toll are also increasing year by year, but there is no
Effective EV71 vaccines or the anti-EV71 medicines of special efficacy.It can be seen that the anti-EV71 medicines that development structure is novel, mechanism of action is unique are
Resist the task of top priority of EV71 infection.
Natural products (±)-pestaloxazine A (hereinafter referred to as Formulas I) are Jia etc. from marine fungi
Isolated racemate compound, the compound have symmetric double in Pestalotiopsis sp. (ZJ-2009-7-6)
Oxazine alkane spiral shell diketopiperazine skeleton, antiviral activity test result show, racemic modification (±)-pestaloxazine A couple
EV71 shows preferable inhibitory activity IC50For 16.1 ± 0.8 μM, activity is better than positive control drug Ribavirin (IC50For
256.1 ± 15.1 μM) antiviral activity (Org.Lett., 2015,17:4216-4219).
In the prior art there has been no the report on natural products (±)-pestaloxazine A synthetic methods, lean on merely
Natural extraction is few to obtain the amount of the compound, and this greatly limits the research of its pharmacological activity and pharmacokinetics.Therefore,
A kind of chemical synthesis (±)-pestaloxazine A method is developed, seems particularly heavy for developing new anti-EV71 medicines
Will.
The content of the invention
The present invention provides a kind of synthetic method of compound of formula I, it is characterised in that comprises the following steps：
With formula B compounds condensation reaction occurs for formula A compounds, obtains compound of formula I；Wherein R1For H.
The present invention provides the synthetic method of another compound of formula I, it is characterised in that comprises the following steps：
(1) with formula B compounds condensation reaction occurs for formula A compounds, obtains Formula II compound；
(2) Formula II compound deprotection base R1, obtain compound of formula I；Wherein R1For hydroxyl protecting group.
The present invention provides the synthetic method of another compound of formula I, it is characterised in that comprises the following steps：
(1) with formula C compounds acylation reaction occurs for formula A compounds, obtains Formula II compound；
(2) Formula II compound deprotection base R1, obtain compound of formula I；
Wherein R1For hydroxyl protecting group；X is selected from halogen or optionally taken by one or more nitros, cyano group, azido, halogen
The C1-C6 alkoxies or C6-C10 aryloxy group in generation.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
The step of including by formula D compounds through reduction reaction formula A compounds：
Reaction obtains formula A compounds to formula D compounds under reducing agent effect in solvent；The reducing agent is selected from organic conjunction
Into middle conventional carbon-to-nitrogen double bon reducing agent, preferably H2With Pd/C, Pt/C, Ru/C, Rh/C, PtO2Or Raney's nickel (Raney
Nickel one or more of combinations in), or NaBH3CN、NaBH4、LiBH4, borine (BH3、B2H6) in one kind or several
Kind.In above-mentioned reduction reaction, the preferred methanol of solvent, ethanol, ethyl acetate, acetic acid, formic acid, dichloromethane, n-hexane, ether,
One or more in chloroform, acetonitrile, THF, water.Preferably -20 DEG C of reaction temperature is to reflux temperature, further preferably -15 DEG C, 0
DEG C, 20 DEG C, 30 DEG C, 40 DEG C or room temperature.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
The step of including by formula E compounds through ring-closure reaction formula D compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine).
Work as R2For H when, formula E compounds in the presence of initiator, alkali, in organic solvent occur ring-closure reaction obtain formula
D compounds；The initiator, which is selected from, contains Ag+Compound, benzoyl peroxide or TEMPO, wherein containing Ag+Compound is preferred
Ag2CO3、AgNO3、AgOAc、AgOTf、Ag2One or more in O；Alkali preferred alkali metal carbonate or alkali metal hydrogen carbonate
Salt, such as Li2CO3、Na2CO3、K2CO3、Rb2CO3、Cs2CO3、NaHCO3、KHCO3In one or more；Organic solvent is preferred
One or more of mixing in DMF, DMA, THF, acetonitrile, acetone, toluene, chloroform, carbon tetrachloride, dioxane, dichloromethane；
Reaction temperature is 0 DEG C to 60 DEG C, preferably 20 DEG C to 40 DEG C.
Work as R2For halogen (such as fluorine, chlorine, bromine, iodine) when, formula E compounds occur in the presence of alkali in organic solvent
Ring-closure reaction obtains formula D compounds；Alkali preferred as alkali alkoxide (such as CH3ONa, EtONa, t-BuOK), alkali metal
Hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH), alkali metal alkide (preferably n-
BuLi, t-BuLi), LiHMDS, NaHMDS, KHMDS, alkali carbonate (such as Li2CO3、Na2CO3、K2CO3、Rb2CO3、
Cs2CO3) or alkali metal hydrogencarbonate (such as NaHCO3、KHCO3Deng) in one or more；The preferred DMF, DMA of organic solvent,
One or more of mixing in THF, t-BuOH, acetonitrile, acetone, toluene, chloroform, carbon tetrachloride, dioxane, dichloromethane；
Reaction temperature be -80 DEG C to reflux temperature, preferably -40 DEG C to 40 DEG C, further preferred 0 DEG C, 20 DEG C, room temperature or 40 DEG C.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
The step of including by formula E compounds through ring-closure reaction formula A compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine).The ring-closure reaction is preferably formula E compounds in H2With Pd/
C、Pt/C、Ru/C、Rh/C、PtO2Or in the presence of one or more of combinations in Raney's nickel (Raney Nickel), or
In NaBH3CN, sodium borohydride, borine (BH3、B2H6) in one or more in the presence of occur ring-closure reaction obtain formula A chemical combination
Thing；The ring-closure reaction is preferably carried out in organic solvent, the preferred methanol of the organic solvent, ethanol, the tert-butyl alcohol, acetic acid second
One or more in ester, dichloromethane, n-hexane, ether, chloroform, acetonitrile, THF, DMF.Preferably 0 DEG C of reaction temperature extremely flows back
Temperature, further preferred room temperature, 40 DEG C or 50 DEG C；The ring-closure reaction is carried out optionally in the presence of alkali, the preferred alkali of alkali
Metal carbonate (such as Li2CO3、Na2CO3、K2CO3、 Rb2CO3、Cs2CO3) or alkali metal hydrogencarbonate (such as NaHCO3、KHCO3
Deng) in one or more.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
The step of including by formula F compounds and azanol (or its hydrochloride, sulfate) reaction formula E compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine).The reaction optionally organic solvent, water or organic solvent with
The in the mixed solvent of water is carried out, and is optionally added alkali, and the alkali is selected from pyridine, triethylamine, piperidines, ammonium hydroxide, sodium hydroxide, hydrogen
One or more in potassium oxide, ammoniacal liquor, sodium acetate, sodium carbonate, potassium carbonate or cesium carbonate etc..Reaction temperature is that room temperature extremely flows back
Temperature, preferably 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C or reflux temperature.The organic solvent preferred alcohol, isopropanol, the tert-butyl alcohol,
One or more in THF, dioxane, chloroform or acetonitrile.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
The step of including reaction formula F compounds oxidized by formula G compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine).The oxidation reaction is carried out in the presence of oxidant, institute
Oxidant is stated as the conventional reagent that hydroxyl is aoxidized to aldehyde radical in this area, preferably NCS/DMS (nitrogen chlorosuccinimides/dimethyl sulfide
Ether), PDC reagents, PCC reagents, Dess-Martin oxidants, Sarett reagents, Jone ' s reagents, in Collins reagents etc.
It is a kind of；The dosage of oxidant is preferably 2.0-4.0 times, more preferably 2.5-3.5 times of formula G compound moles；It is described
Oxidation reaction is carried out in a solvent, the one or more in the preferred dichloromethane of the solvent, chloroform, THF, DMF.Reaction temperature
It is preferred that -40 DEG C to 40 DEG C, further preferred 0 DEG C to room temperature.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
Include following steps：
Formula H compounds react to obtain formula G compounds, wherein R with halogenating agent2For halogen (such as fluorine, chlorine, bromine, iodine).Institute
State halogenating agent and be selected from F2、Cl2、Br2、I2, bromine water, chlorine water, HF, NFSI, Selectfluor (CAS RN: 140681-55-
6)、FClO3, NCS, NBS, NIS, one kind in N-bromoacetamide or C5H6Br2N2O2.Above-mentioned reaction is optionally entered in organic solvent
OK, it is a kind of or several in the preferred dichloromethane of the organic solvent, chloroform, carbon tetrachloride, carbon disulfide, acetonitrile, ether or THF etc.
Kind.Reaction temperature is -20 DEG C to reflux temperature, preferably -5 DEG C, 0 DEG C, room temperature.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
Include formula J compounds and optionally remove R in organic solvent4The step of ring-closure reaction forms formula H compounds, occurs for protection group：
Wherein R4For amino protecting group, R5It is described " optionally to be taken for optionally substituted alkyl, aryl, acyl group, sulfonyl
Generation " substituent is selected from one or more C1-C6 alkoxies, C6-C10 aryl, halogen or nitro.Remove R4The condition of protection group
Condition is removed for amino protecting group conventional in organic synthesis.
A kind of synthetic method of compound of formula I is provided in another embodiment of the present invention, it is characterised in that also optionally wrap
Include the step of with formula L compounds or its acid salt (preferably hydrochloride) condensation reaction formula J compounds occur for formula K compounds：
Wherein R4、R5Definition and above-mentioned formula J compounds in R4、R5Definition it is identical.
Serial midbody compound is provided in another embodiment of the present invention, it is characterised in that the intermediate has formula
Structure shown in II, B, C, E, F, G, J：
Wherein X is selected from halogen or optionally by one or more nitro, cyano group, folded
Nitrogen base, the C1-C6 alkoxies or C6-C10 aryloxy group of halogen substitution, R1For hydroxyl protecting group, R2For H or halogen, R4Protected for amino
Protect base, R5For optionally substituted alkyl, aryl, acyl group, sulfonyl, " optionally substituted " substituent be selected from one or
Multiple C1-C6 alkoxies, C6-C10 aryl, halogen or nitro.
The present invention also provides Formula II, the synthetic method of E, F, G, J midbody compound, it is characterised in that includes previously described formula I
The step of being related to Formula II, E, F, G, J midbody compound synthetic method in compound synthesis method.
A kind of midbody compound is provided in another embodiment of the present invention, it is characterised in that the midbody compound
With structure shown in Formula II：
Wherein R1Selected from AcCl, Bz, Piv, Et, Bn, Tr,
PMB, MOM, TBS, TES, TMS, TBDPS, Ts or Ms.
A kind of midbody compound is provided in another embodiment of the present invention, it is characterised in that the midbody compound
With structure shown in formula B：
Wherein R1Selected from Boc, AcCl, Bz, Piv, Me, Et, Tr, MMT, DMT, PMB, MOM,
TBS, TES, TMS, TBDPS, Ts or Ms.
A kind of midbody compound is provided in another embodiment of the present invention, it is characterised in that the midbody compound
With structure shown in formula C：
Wherein R1Selected from Ac, Boc, AcCl, Bz, Piv, Me, Et, Bn, Tr, MMT, DMT, PMB,
MOM, TBS, TES, TMS, TBDPS, Ts or Ms.
A kind of midbody compound is provided in another embodiment of the present invention, it is characterised in that the midbody compound
With structure shown in formula E：
Wherein R2Selected from H, F, Cl, Br or I.
A kind of midbody compound is provided in another embodiment of the present invention, it is characterised in that the midbody compound
With structure shown in formula F：
Wherein R2Selected from H, F, Cl, Br or I.
A kind of midbody compound is provided in another embodiment of the present invention, it is characterised in that the midbody compound
With structure shown in formula G：
Wherein R2Selected from H, F, Cl, Br or I.
The further preferably following compound of formula G intermediates of the present invention：
A kind of midbody compound is provided in another embodiment of the present invention, it is characterised in that the midbody compound
With structure shown in formula J：
Wherein R4Selected from Boc, Fmoc, Teoc, Troc, Cbz, Alloc, Ts, neighbour's (to)
Nitrobenzenesulfonyl, SES, Bn, PMB, Tr, MMT or DMT, R5Selected from Me, Et, n-Pr, i-Pr, t-Bu, Ph, p-nitrophenyl
Base, Ts or Ms.
The further preferably following compound of formula J intermediates of the present invention：
In addition formula J intermediates also include replacing with Me groups in above-mentioned midbody compound
Et, n-Pr, i-Pr, t-Bu, Ph, p-nitrophenyl, Ts or Ms intermediate.
Formula B, C, K, L compound used in the present invention can synthesize (Angew. by business customization purchase, by literature method
Chem.Int.Ed.2015,54,14070–14074；J.Org.Chem.1982,47,3358–3360；Tetrahedron
Letters,51,(2010),2119–2122；Protein&Peptide Letters,17(7),889-898,2010；
Synlett (2015),26(15),2131-2134；Tetrahedron Letters,44(20),3905-3909,2003；WO
2014084407 A1；CN 102443048A；) or can be obtained by following scheme.
The preparation scheme of formula B compounds：
By the compound that CAS registration numbers are 19710-84-0, in R1X (alkyl halide, halogenated silanes, carboxylic acid halides) or acid anhydrides
(R1OR1) in the presence of react, by this area routine post-processing operation, you can obtain corresponding formula B compounds；Wherein R1To have
Conventional hydroxyl protecting group, preferably optionally substituted acyl group, optionally substituted alkyl, optionally substituted silicon in machine synthesis
Base；Acyl group preferred C1-C6 acyl groups, the preferred C1-C6 alkyl of alkyl, the preferred C1-C6 alkyl silyls of silicon substrate or the C6-C10 aryl
Silicon substrate, " optionally substituted " substituent are selected from one or more C1-C6 alkoxies, C6-C10 aryl or halogen；Optionally
The further preferred acetyl group of substituted acyl group (Ac), chloracetyl (AcCl), benzoyl (Bz), pivaloyl group (Piv), appoint
The substituted preferred methyl of alkyl (Me) of choosing, ethyl (Et), benzyl (Bn), to methoxy-benzyl (PMB), trityl (Tr),
It is excellent to Methoxytrityl (MMT), dimethoxytrityl (DMT), methoxyl methyl (MOM), optionally substituted silicon substrate
Select t-Butyldimethylsilyl (TBS), triethyl group silicon substrate (TES), trimethyl silicon substrate (TMS) or tert-butyl diphenyl silicon substrate
(TBDPS)；X is halogen, preferably fluorine, chlorine, bromine or iodine.
The preparation scheme of formula C compounds：
(1) when X is halogen,
By formula B compounds, in SOX2(sulfenyl halogen), (COX)2(oxalyl halogen) or PX3In the presence of (phosphorus trihalide)
Reaction, by this area routine post-processing operation, you can obtain corresponding formula C compounds；R1B compounds as described above for formula
Definition in preparation scheme；
(2) X is the C1-C6 alkoxy or C6-C10 optionally substituted by one or more nitros, cyano group, azido, halogen
During aryloxy group,
Acyl chlorides and XH (such as dichloromethane) in organic solvent, react in the presence of alkali (such as pyridine, triethylamine), press
This area routine post-processing operation, you can obtain corresponding formula C compounds；R1The compounds of B as described above for formula prepare scheme
In definition.
Formula K, L compound it is commercially available or business customization obtain, can also pentahomoserine be raw material pass through ability
Simply protect-be deprotected operation can be prepared by domain；Note：Formula L compounds can also be prepared by formula K compounds by following scheme：
Formula K compounds and R5OH, after condensation reaction occurs, then remove R4Protection group, you can obtain formula L compounds；Wherein
R4For amino protecting group, R5For optionally substituted alkyl, aryl, acyl group, sulfonyl, " optionally substituted " substituent
Selected from one or more C1-C6 alkoxies, C6-C10 aryl, halogen or nitro.
" condensation reaction " of the present invention uses peptide condensation reagent conventional in organic synthesis.It is conventional in the organic synthesis
Peptide condensing agent preferred reagent a and reagent b combination, reagent a is selected from dicyclohexylcarbodiimide (DCC), diisopropyl carbon two
Imines (DIC), 1- ethyls-(3- dimethylaminopropyls) carbodiimide (EDC), double (2- oxo -3- oxazolidinyls) secondary phosphinylidynes
One or more in chlorine (BOPCl), or its hydrochloride；Reagent b is selected from dimethylamino naphthyridine (DMAP), 1- hydroxy benzos
Triazole (HOBT), N, the one or more in N- diisopropylethylamine (DIPEA).The peptide condensing agent is further preferred
BOPCl/DIPEA, DCC (or DCCHCl)/HOBT, DCC (or DCCHCl)/DMAP or EDC (or EDCHCl)/HOBT.
The condensation reaction is optionally added Et3N。
" condensation reaction " of the present invention, is preferably carried out in organic solvent, the preferred dichloromethane of the organic solvent, chlorine
Imitative, carbon tetrachloride, acetonitrile, benzene,toluene,xylene, chlorobenzene, THF, ether, acetone, ethyl acetate, glycol dimethyl ether, DMF,
One or more of mixing in dioxane.
" acylation reaction " of the present invention is preferably carried out in organic solvent, and is optionally added organic base or inorganic base, its
Described in organic base be selected from pyridine, morpholine, triethylamine, sodium acetate, quinoline, imidazoles, dimethylaniline, 2,6- lutidines,
One or more in DMAP, inorganic base are selected from alkali carbonate (such as Na2CO3、K2CO3、Li2CO3、 Cs2CO3) or alkali metal
Bicarbonate (such as NaHCO3、KHCO3) in one or more；The preferred dichloromethane of the organic solvent, chloroform, carbon tetrachloride,
In acetonitrile, benzene,toluene,xylene, chlorobenzene, THF, ether, acetone, ethyl acetate, glycol dimethyl ether, DMF, dioxane
One or more mixing.
" hydroxyl protecting group " of the present invention is conventional hydroxyl protecting group in organic synthesis, preferably optionally substituted acyl
Base, optionally substituted alkyl, optionally substituted silicon substrate；The preferred C1-C6 acyl groups of the acyl group, the preferred C1-C6 alkyl of alkyl,
The preferred C1-C6 alkyl silyls of silicon substrate or C6-C10 aryl silicon substrates, " optionally substituted " substituent are selected from one or more
C1-C6 alkoxies, C6-C10 aryl or halogen；The optionally substituted further preferred acetyl group of acyl group (Ac), chloracetyl
(AcCl), benzoyl (Bz), pivaloyl group (Piv), the optionally substituted preferred methyl of alkyl (Me), ethyl (Et), benzyl
(Bn), to methoxy-benzyl (PMB), trityl (Tr), to Methoxytrityl (MMT), dimethoxytrityl
(DMT), methoxyl methyl (MOM), the optionally substituted preferred t-Butyldimethylsilyl of silicon substrate (TBS), triethyl group silicon substrate
(TES), trimethyl silicon substrate (TMS) or tert-butyl diphenyl silicon substrate (TBDPS).
The present invention relates to deprotection base R1The step of, optionally carry out in organic solvent, the remove-insurance guard strip of use
Part is that hydroxyl protecting group conventional in organic synthesis removes condition, specifically, works as R1For optionally substituted acyl group when, removing
The preferred alkalescence condition of condition, further preferred alkali metal alcoholates (such as MeONa, EtONa), alkali metal hydroxide (such as NaOH,
KOH), alkali carbonate (such as K2CO3、Cs2CO3)；Work as R1For optionally substituted alkyl when, remove condition preferred acidic condition
Or Pd-C/H2, described acid condition further preferred TFA, HCOOH, HOAc, HCl, H2SO4、H2SO4-SiO2、TfOH-SiO2、
HClO4-SiO2、NaHSO4-SiO2、BCl3、BBr3In one or more；Work as R1For optionally substituted silicon substrate when, remove bar
The preferred fluoro quaternary ammonium salt (preferably TBAF) of part or acid condition, the further preferred TFA, CSA of the acid condition, TsOH, HOAc,
HCl、HF、H2SO4-SiO2、TfOH-SiO2、 HClO4-SiO2。
" amino protecting group " of the present invention is amino protecting group conventional in organic synthesis, and preferably carbamates is protected
Protect base, sulfonamides protection group, alkyls protection group, phthalyl class protection group；The carbamates protection group is excellent
Select tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), trimethylsilyl ethoxycarbonyl (Teoc), trichloro-ethoxycarbonyl
(Troc), benzyloxycarbonyl group (Cbz), allyloxycarbonyl (Alloc) etc.；The preferred p-toluenesulfonyl of sulfonamides protection group
(Ts), adjacent (to) nitrobenzenesulfonyl, 2- (trimethyl silicane) ethylsulfonyl (SES) etc.；The alkyls protection group is preferably optional
Substituted benzyl, further preferred benzyl (Bn), to methoxy-benzyl (PMB), trityl (Tr), to Methoxytrityl
(MMT), dimethoxytrityl (DMT)；The phthalyl class protection group is the phthalyl that optionally substitutes, institute
State " optionally substituting " substituent and be selected from one or more C1-C6 alkoxies, nitro, cyano group or halogens, the phthalyl
The further preferred phthalyl of class protection group, monoethyl diformyl etc..
The present invention relates to deprotection base R4The step of, optionally carry out in organic solvent, the remove-insurance guard strip of use
Part is that amino protecting group conventional in organic synthesis removes condition, for example, working as R4For Boc, Tr, MMT, DMT when, removing condition it is excellent
Select acid condition, further preferred HCl, CF3COOH、CCl3COOH etc.；Work as R4For Fmoc, Teoc, Troc when, removing condition it is excellent
Select alkalescence condition, further preferred piperidines, diethylamine, dicyclohexyl amine, to dimethylamino pyrrole quinoline, diisopropylethylamine etc., its
In work as R4Can also to use Pd/C and H during Fmoc2Removed；Work as R3Or R4For Cbz when, removing condition preferred catalytic hydrogenolysis, gold
Category reduction or acidolysis, further preferred Pd and H2, Pd/C and H2, the combination of sodium, acetamide and liquefied ammonia, or HCl, HBr,
CH3COOH、CF3One or more in COOH etc.；Work as R4For Alloc when, the preferred dimetone of removing condition or N, N'- dimethyl
The combination of barbiturates and Pd (0), wherein Pd (0) preferably Pd (PPh3)4, double (dibenzalacetone) palladiums；Work as R4For Bn, PMB
When, remove condition preferred catalytic hydrogenolysis, further preferred Pd/C or Pd (OH)2With H2Combination；Work as R4For the adjacent benzene optionally substituted
During diformyl, the preferred hydrazinolysis of removing condition or NaBH4Reduction.
Conventional peptide condensation reagent in organic synthesis of the present invention, including all peptides condensation described in documents below
Reagent：" 1. the general situation of development (one) of peptide condensation reagent in organic synthesis ", Xu Yueyi, etc.,《Ningbo chemical industry》, the 2nd phase in 2009,
The 43-47 pages；" 2. the general situation of development (two) of peptide condensation reagent in organic synthesis ", Xu Yueyi, etc.,《Ningbo chemical industry》, 2009
3rd phase, the 38-49 pages；" 3. the general situation of development (three) of peptide condensation reagent in organic synthesis ", Xu Yueyi, etc.,《Ningbo chemical industry》,
4th phase in 2009, the 37-45 pages.
" conventional hydroxyl protecting group in organic synthesis " of the present invention and " conventional hydroxyl protecting group in organic synthesis
Removing condition ", including "《The guarantor of protection group (original work the 5th edition)-hydroxyl (glycol containing 1,2-, 1,3- glycol) in organic synthesis
Shield》, Xu Sheng, translate, publishing house of East China University of Science, the 1st edition, in January, 2016 " and all hydroxyl protecting groups and hydroxyl described in a book
Base protection group removes condition.
" conventional amino protecting group in organic synthesis " of the present invention and " conventional amino protecting group in organic synthesis
Removing condition ", including "《The protection of protection group (original work the 5th edition)-amino, alkynes hydrogen, phosphate in organic synthesis》, Xu Sheng,
Translate, publishing house of East China University of Science, the 1st edition, in January, 2016 " all amino protecting groups and amino protecting group described in a book
Removing condition.
During without specified otherwise, " halogen " of the present invention preferably fluorine, chlorine, bromine, iodine；Described " acyl group " preferred C1-C6
Alkanoyl (alkanoyl containing 1-6 carbon atom), C6-C10 aroyls (the monocyclic or bicyclic fragrant acyl containing 6-10 carbon atom
Base), further preferred formoxyl, acetyl group, propiono, pivaloyl group, benzoyl；Described " alkyl " is straight or branched
Alkyl, preferably C1-C6 alkyl (straight or branched alkyl containing 1-6 carbon atom), further preferred methyl, ethyl, propyl group,
Normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, n-hexyl；Described " aryl " is aryl, preferably monocyclic, bicyclic,
Fused ring aryl, further preferred C6-C10 aryl (the monocyclic or bicyclic aryl containing 6-10 carbon atom), still more preferably
Phenyl, naphthyl；Described " sulfonyl " preferably mesyl, benzenesulfonyl, p-toluenesulfonyl；Described " C1-C6 alcoxyls
Base " is the straight or branched alkoxyl containing 1-6 carbon atom, preferably methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, just
Butoxy, positive hexyloxy；Described " C6-C10 aryloxy group " is the monocyclic or bicyclic aryloxy group containing 6-10 carbon atom, excellent
Select phenoxy group, (o-, m- or p-) toloxyl, (1-, 2- or 3-) naphthoxy；Described " C1-C6 alkyl silyls " is to contain 1-6
The straight or branched alkyl silicon substrate of individual carbon atom, preferably t-Butyldimethylsilyl (TBS), triethyl group silicon substrate (TES), trimethyl
Silicon substrate (TMS)；Described " C6-C10 aryl silicon substrate " is the monocyclic or bicyclic aryl silicon substrate containing 6-10 carbon atom, preferably uncle
Butyl diphenyl silicon substrate (TBDPS)；Described " organic solvent " preferably methanol, ethanol, the tert-butyl alcohol, dichloromethane, chloroform, tetrachloro
Change carbon, acetonitrile, benzene,toluene,xylene, chlorobenzene, THF, ether, n-hexane, acetone, ethyl acetate, glycol dimethyl ether, DMF,
One or more of mixing in DMA, dioxane, pyridine, triethylamine, formic acid, acetic acid, trifluoroacetic acid.
The structural formula of bisoxazines alkane spiral shell diketopiperazine framework compound involved in the present invention(such as
Compound in the range of Formulas I, II, A, D) and diketopiperazine framework compound structural formula(such as wrap
The compound being contained in the range of formula E, F, G, H), in the case of without specified otherwise, hand in diketopiperazine ring in structure above
Property carbon atom spatial configuration be (S, S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:1 is mixed
It is racemic modification during conjunction, is one kind in single enantiomter (S, S) or (R, R) when one of which is configured as 0.
The synthetic method of compound of formula I of the present invention, also optionally using chiral resolution technology by compound of formula I
The step of being split as single enantiomter (S, S) or (R, R) configuration.The preferred chiral column of chiral resolution technology is split or hand
Property reaction reagent split.
In formula E structural formula of compound in oximido groupKey represents that carbon-to-nitrogen double bon can be " E " type,
It can be " Z " type.
The formula H compounds being related in the present invention are actually R2For H when formula G compounds.
Amino acids starting compound (i.e. formula K, L compound) used in the present invention can by it is commercially available, customize or press
Literature method is made by oneself to obtain, and wherein the configuration of amino acid can be D types, L-type or DL mixed types.
Chinese and English abbreviation used in the present invention is abbreviated form conventional in organic synthesis field.
It should be understood that the synthetic method of compound of formula I of the present invention can be mutually combined to form the various excellent of the present invention
The synthetic method of Formulas I compound or the synthetic method of its any intermediate are selected, as space is limited, does not tire out one by one state herein.
It should also be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
Each technical characteristic of body description can be combined with each other, so as to form new or preferable technical scheme.As space is limited, herein no longer
Tire out one by one and state.
Embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments only are not used for limiting the scope of the present invention or implementation principle, reality of the invention for being better understood from inventing
The mode of applying is not limited to herein below.
Embodiment 1
Weigh formula B compounds (R1For H, 130mg, 1.0mmol) it is dissolved in toluene/acetonitrile (volume ratio 3/2) of 25mL dryings
In mixed liquor, DCC (1.0mmol), DMAP (0.2mmol) are added, after stirring 15 minutes at room temperature, adds formula A compounds
(25.6mg, 0.1mmol), after being heated to 60 to 65 DEG C of reactions 24 hours, after filtering, being concentrated under reduced pressure, through silica gel column chromatography (silica gel
The mesh of mesh number 200~300, eluant, eluent：Ethanol/methylene=1/10), compound of formula I (44.2mg) is obtained with 92% yield,
ESI-MS(m/z)：481.2[M+H]+。
Note：The formula A compounds used in the reaction are racemic modification, and obtained compound of formula I is also racemic modification.
Embodiment 2
(1) R is used1For R in TBS formula B compounds (1.0mmol) alternative embodiment 11For H formula B compounds, according to reality
The operation (silica gel column chromatography eluant, eluent is changed to petrol ether/ethyl acetate) in example 1 is applied, Formula II chemical combination can be obtained with 93% yield
Thing (65.9mg, R1For TBS), ESI-MS (m/z)：709.4[M+H]+；
(2) Formula II compound (50mg, 0.07mmol, R are weighed1For TBS) it is dissolved in 5.0mL THF, add 1.0mL
Bu4NF THF solution (Bu4NF concentration is 1.0mol/L), after reacting at room temperature 0.5~2h, add water (1.0 mL) terminating reaction,
Remove THF under reduced pressure, extracted with EtOAc (20mL), organic layer anhydrous Na2SO4Dry, filtering, concentration, through recrystallization or silica gel
Column chromatography obtains white solid 30.5mg, as compound of formula I (yield is about 90%).
Note：R is used in the embodiment1Formula B compounds for the similar silicon-based protecting group such as TES, TMS, TBDPS participate in instead
Should, can also similar yield compound of formula I is prepared；The solid of chiral carbon in the formula A compounds used in the embodiment
It is configured as (S, S), obtains the compound of formula I of corresponding (S, S) configuration.
Embodiment 3
(1) formula A compounds (25.6mg, 0.1mmol) are weighed to be dissolved in 5mL THF, add 200 μ L triethylamines, formula Cization
Compound (0.25mmol, X Cl, R1For MOM) and catalytic amount DMAP, at room temperature react 2h after, TLC detection reaction raw materials
Almost it is wholly absent, (25mL) is extracted with ethyl acetate twice, anhydrous sodium sulfate drying organic layer, after concentration, through silica gel column layer
(eluant, eluent is EtOAc/ petroleum ether=10 for analysis：1~6：1) Formula II compound (48.4 mg, X Cl, R, are obtained1For MOM), production
Rate 85.2%, ESI-MS (m/z)：569.3[M+H]+；
(2) Formula II compound (30mg, 0.05mmol, R are weighed1For MOM) it is dissolved in 5.0mL CH2Cl2In, add 60 μ L tri-
Fluoroacetic acid (TFA), after reacting at room temperature 4h, add saturation NaHCO3Solution terminating reaction, uses CH2Cl2(20mL) is extracted, organic layer
Use anhydrous Na2SO4Dry, filtering, concentration, white solid 21mg, as compound of formula I are obtained through recrystallization or silica gel column chromatography
(yield is about 83%).
Note：R is used in the embodiment1For Bn, PMB, Tr, MMT, DMT, X Cl, Br,Deng formula C compounds
Reaction is participated in, the compound of formula I of corresponding spatial configuration can be prepared with 62%~85% yield；Used in the embodiment
The spatial configuration of chiral carbon is (R, R) in formula A compounds, obtains the compound of formula I of corresponding (R, R) configuration.
The formula A compounds for reacting used in embodiment 1-3 can be replaced the spatial configuration of asymmetric carbon atom for (S, S) or
The formula A compounds of (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when
It is one kind in single enantiomter (S, S) or (R, R) when one of which is configured as 0, can obtains that there is corresponding three-dimensional structure
The compound of formula I of type, reaction yield is more than 60%.
Embodiment 4
Formula D compounds (25mg, 0.1mmol) are weighed to be dissolved in EtOH (10ml), addition thunder niobium nickel (Raney-Nickel,
1.0g), in 1atm H2Under effect, at 25~30 DEG C after stirring reaction 12h, thunder niobium nickel is filtered to remove, after being concentrated under reduced pressure, is obtained
To formula A compounds (20mg), yield is 80% or so, ESI-MS (m/z)：257.1[M+H]+。
Note：Use Pd/C, Pt/C, Ru/C, Rh/C or PtO2Substitute the thunder niobium nickel in the embodiment, can with 75% to
90% yield not waited obtains formula A compounds；In the formula D compounds used in the embodiment the spatial configuration of chiral carbon for (S,
S), the formula A compounds of corresponding (S, S) configuration are obtained, can also use the racemic modification of formula D compounds or the isomery of (R, R) configuration
Body is raw material, and the formula A compounds with respective configuration can be obtained with more than 75% yield.
Embodiment 5
Weigh 2.56g formula E compounds (R2For H, 10mmol) it is dissolved in 150mL DMA (DMA), add
Enter 1.0equiv.Ag2CO3(10mmol)、0.5equiv.K2CO3(5mmol), after reacting 24 hours at room temperature, after routine
Processing, silica gel column chromatography, obtain 2.02g formula D compounds, yield is about that 80%, HPLC purity is 98.4%, ESI-MS (m/
z)：253.1[M+H]+。
Note：Ag in above-mentioned reaction2CO3It can be replaced AgNO3、AgOAc、AgOTf、Ag2O or TEMPO, its mole dosage are
1.0-2.0 times of formula E compounds, K2CO3It can be replaced Na2CO3、Rb2CO3、Cs2CO3、NaHCO3Or KHCO3；Solvent DMA can be replaced
The one or more of mixing being changed in DMF, THF, acetonitrile, acetone, toluene, chloroform, carbon tetrachloride, dioxane, dichloromethane,
Reaction temperature can be 0 to 60 DEG C between, preferably 20 to 40 DEG C, formula D compounds, HPLC can be obtained with 65% to 85% yield
Purity is more than 96%；The formula E compounds used in the embodiment are racemic modification, also can use single enantiomer (S, S) or
The formula E compounds of (R, R) configuration are raw material, and the formula D compounds with respective configuration can be obtained with more than 62% yield.
Embodiment 6
Weigh 325mg formula E compounds (R2For Cl, 1.0mmol) it is dissolved in 25mL DMF, 2.0 are added at room temperature
equiv.K2CO3(2.0mmol), it is heated to 50~60 DEG C and reacts 1.5 hours or so, add saturated nacl aqueous solution terminating reaction,
Extracted (50mL × 3) with ether, merge organic phase, after anhydrous sodium sulfate drying, filtering, concentration, through silica gel column chromatography, obtain
219mg formula D compounds, yield are about that 87%, HPLC purity is 97.5%.
Note：R can be used2For the formula E compounds in F, Cl, Br, I above-mentioned reaction of formula E compounds replacement；Using
NaOMe、NaOEt、t-BuOK、NaOH、KOH、LiOH、n-BuLi、t-BuLi、LiHMDS、NaHMDS、 KHMDS、NaH、LiH、
KH、Li2CO3、Na2CO3、Cs2CO3、Rb2CO3、NaHCO3、KHCO3Any of replace K in above-mentioned reaction2CO3, its mole
Dosage is 0.1-3.0 times of formula E compounds；Using DMF, DMA, THF, t-BuOH, acetonitrile, acetone, toluene, chloroform, four chlorinations
The DMF in above-mentioned reaction is replaced in one or more of mixing in carbon, dioxane, dichloromethane；Reaction temperature can be -80 DEG C
To reflux temperature, preferably -40 DEG C to 40 DEG C, further preferred 0 DEG C, 20 DEG C, room temperature or 40 DEG C；The side recorded according to the present embodiment
Method, can be with about using any combination of above-mentioned reaction condition (including formula E compounds, alkali and its dosage, solvent, temperature)
45% to 89% yield not waited obtains corresponding formula D compounds, and HPLC purity is more than 90%.The formula used in the embodiment
The spatial configuration of chiral carbon is (S, S) in E compounds, obtains the formula D compounds of corresponding (S, S) configuration, can also use formula E chemical combination
The isomers of the racemic modification of thing or (R, R) configuration is raw material, and the formula D with respective configuration can be obtained with similar yield
Compound.
Embodiment 7
Weigh formula D compounds (50mg, 0.2mmol) to be dissolved in AcOH (10mL), add NaBH3CN (1.6mmol), in room
The lower stirring reaction of temperature is stayed overnight, and adds saturation Na2CO3Solution (about 70mL) terminating reaction, is extracted with ethyl acetate (120mL × 3),
Merge organic phase, successively with saturated sodium bicarbonate, NaCl, anhydrous sodium sulfate drying, after filtering, being concentrated under reduced pressure, through silicon
Plastic column chromatography, obtains formula A compounds (38mg), and yield is 75% or so, ESI-MS (m/z)： 257.1[M+H]+。
Or weigh formula D compounds (50mg, 0.2mmol) and be dissolved in EtOH (10ml), add NaBH4(2.0 mmol),
Stirring reaction is stayed overnight at room temperature, adds saturation NH4Cl solution (about 5mL) terminating reaction, be extracted with ethyl acetate (40mL ×
3) organic phase, is merged, successively with saturated sodium bicarbonate, NaCl, anhydrous sodium sulfate drying, after filtering, being concentrated under reduced pressure, warp
Silica gel column chromatography, obtains formula A compounds (40mg), and yield is 78% or so.Note：Use LiBH4Substitute in the embodiment
NaBH4, formula A compounds can be obtained similar to yield；And the etoh solvent in the embodiment can also use methanol, ethanol, acetic acid
One or more of mixing in ethyl ester, dichloromethane, chloroform, acetonitrile, THF substitute, and yield is between 70%~83%.
Or weigh formula D compounds (50mg, 0.2mmol) and be dissolved in THF (10mL), add BH3·THF(1 M in
THF, 2.0mL), at room temperature after 24~48h of stirring reaction, after adding 2N NaOH solutions (about 2mL) continuation stirring reaction 2h,
It is extracted with ethyl acetate (40mL × 3), merges organic phase, after with anhydrous sodium sulfate drying, filtering, being concentrated under reduced pressure, through silicagel column
Chromatography, obtains formula A compounds (38mg), and yield is 75% or so.Note：Use B2H6Substitute the BH in the embodiment3, can be with class
Formula A compounds are obtained like yield.
Note：The spatial configuration of chiral carbon is (S, S) in the formula D compounds used in the embodiment, obtains corresponding (S, S) structure
The formula A compounds of type, it is raw material that can also use the racemic modification of formula D compounds or the isomers of (R, R) configuration, can be with similar
Yield obtain the formula A compounds with respective configuration.
Embodiment 8
Weigh formula E compounds (R2For H, 51mg, 0.2mmol) it is dissolved in EtOH (12ml), add thunder niobium nickel (Raney-
Nickel, 1.0g), in 1atm H2Under effect, at 25~30 DEG C after 12~16h of stirring reaction, thunder niobium nickel is filtered to remove, is subtracted
After pressure concentration, formula A compounds (43mg) are obtained, yield is 84% or so, ESI-MS (m/z)：257.1[M+H]+。
Note：Use Pd/C, Pt/C, Ru/C, Rh/C or PtO2Substitute the thunder niobium nickel in the embodiment, can with 56% to
86% yield not waited obtains formula A compounds.
Or weigh formula E compounds (R2For H, 51mg, 0.2mmol) it is dissolved in THF (10mL), add BH under ice bath3·
THF (1M in THF, 2.5mL), slowly recover after being heated to 40 DEG C of h of stirring reaction 18~24 to room temperature, add appropriate
Saturation Na2CO3After solution, it is extracted with ethyl acetate (50mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filtering, decompression
After concentration, through silica gel column chromatography, formula A compounds (37mg) are obtained, yield is 73% or so.Note：Use B2H6、NaBH4、
LiBH4Or NaBH3CN/AcOH substitutes the BH in the embodiment3, formula A compounds can be obtained with 55%~76% yield.
The reaction temperature of above two formula E preparation of compounds of formula A compounds can be at 0 DEG C to arbitrarily being selected between reflux temperature
Select, the solvent of reaction selection methanol, ethanol, the tert-butyl alcohol, ethyl acetate, dichloromethane, n-hexane, ether, chloroform, acetonitrile,
One or more in THF, DMF, it differs only in the yield in reaction time and production A compounds.
Note：The formula E compounds used in the embodiment are racemic modification, can also use single enantiomer (S, S) or (R, R)
The formula E compounds of configuration are raw material, and the formula A compounds with respective configuration can be obtained with more than 45% yield.
Embodiment 9
Weigh 226mg formula F compounds (R2For H, 1.0mmol) it is dissolved in 40mL ethanol, 2.5equiv. is added at room temperature
NH2OHHCl (2.5mmol) and NaAc (2.5mmol), after being heated to 1~2h of reflux temperature reaction, TLC checks raw material almost
It is wholly absent, after being concentrated under reduced pressure, adds ethyl acetate (100mL) dilution, washed successively with water, saturation NaCl, organic phase nothing
Aqueous sodium persulfate is dried, and after filtering, being concentrated under reduced pressure, through silica gel column chromatography, obtains 195mg formula E compounds (R2For H), yield is about
76%, ESI-MS (m/z)：257.1[M+H]+, HPLC purity is 95.7%.
Note：Alkali NaAc in above-mentioned reaction replaces with pyridine, triethylamine, piperidines, ammonium hydroxide, sodium hydroxide, hydroxide
One or more in potassium, ammoniacal liquor, sodium carbonate, potassium carbonate or cesium carbonate；Etoh solvent replace with isopropanol, the tert-butyl alcohol, THF,
One or more in dioxane, chloroform or acetonitrile, formula E compounds, HPLC can be prepared with more than 70% yield
Purity is more than 92%.
Or weigh (NH2OH)2·H2SO4(1.0mmol) is dissolved in 10mL water, and 1.8mL 1M NaOH are added dropwise at room temperature
Solution, 265mg formula F compounds (R is added under ice bath2For Cl, 0.9mmol) after stirring reaction 0.5h, it is heated to 80 DEG C of continuation
2h is reacted, ethyl acetate (100mL) dilution is added, is washed successively with water, saturation NaCl, organic phase anhydrous sodium sulfate drying,
After filtering, being concentrated under reduced pressure, through silica gel column chromatography, 202mg formula E compounds (R is obtained2For Cl), yield is about 69%, ESI-MS
(m/z)：325.0[M+H]+, 327.0 [M+2+H]+, HPLC purity is 96.5%.
Or weigh 384mg formula F compounds (R2For Br, 1.0mmol) it is dissolved in 50mL ethanol, 4.0 are added at room temperature
equiv.NH2OHHCl (4.0mmol) and pyridine (4.0mmol), after being heated to reflux temperature reaction about 1.5h, TLC checks former
Material is almost wholly absent, and after being concentrated under reduced pressure, is added ethyl acetate (100mL) dilution, is washed successively with water, saturation NaCl, organic
Phase anhydrous sodium sulfate drying, after filtering, being concentrated under reduced pressure, through silica gel column chromatography, obtain 364mg formula E compounds (R2For Br),
Yield is about 88%, ESI-MS (m/z)：414.9[M+2+H]+, 412.9 [M+H]+。
According to the method described in the embodiment, using R2Can also be similar for F or I formula F compounds participation reaction
Yield obtains corresponding formula E compounds (R2For F or I).
Note：The formula F compounds used in the embodiment are racemic modification, can also use single enantiomer (S, S) or (R, R)
The formula F compounds of configuration are raw material, and the formula E compounds with respective configuration can be obtained with similar yield.
Embodiment 10
Weigh 230mg formula G compounds (R2For H, 1.0mmol) it is dissolved in 25mL CH2Cl2In, Dess- is added at room temperature
Martin oxidants (2.5mmol), after reaction being stirred at room temperature 3~4 hours, TLC detection raw materials are almost wholly absent, and add 5%
Na2S2O3Solution (2mL) terminating reaction, add CH2Cl2Dilute (50mL), washed successively with water, saturated sodium-chloride, anhydrous slufuric acid
Sodium is dried, filtering, after filtrate decompression concentration, through silica gel column chromatography, obtains 208mg formula F compounds (R2For H), yield is about
92%, HPLC purity are 97.3%.
Note：Dess-Martin oxidants in above-mentioned reaction could alternatively be NCS/DMS (nitrogen chlorosuccinimide/bis-
Methyl sulfide), PDC reagents, PCC reagents, Sarett reagents, Jone ' s reagents, one kind in Collins reagents etc., oxidant
Dosage is preferably 2.0-4.0 times, more preferably 2.5-3.5 times of formula G compound moles；Solvent C H2Cl2It can be replaced
One or more in chloroform, THF, DMF, preferably -40 DEG C to 40 DEG C, further preferred 0 DEG C to room temperature of reaction temperature；According to
The method that the present embodiment is recorded, using any group of above-mentioned reaction condition (including formula oxidant and its dosage, solvent, temperature)
Close, corresponding formula F compounds can be obtained with about 63% to 94% yield not waited, HPLC purity is more than 90%.
Or take pyridine (4.0mmol) to add in 20mL dichloromethane, add CrO at -15 DEG C3(2.0mmol), stirring
After 3~4 hours, formula G compounds (R is added2For Cl, 1.0mmol, 299mg formula G compounds are dissolved in 6mL dichloromethane), slowly
0 DEG C is warming up to, reaction overnight, filtering, filtrate concentration, through silica gel column chromatography, obtains 230mg formula F compounds (R2For Cl), receive
Rate is about 78%, ESI-MS (m/z)：295.0[M+H]+, 297.0 [M+2+H]+, HPLC purity is 96.7%.
Or weigh NCS (4mmol) and be dissolved in the dichloromethane of 15mL dryings, add DMS at -5 DEG C to -15 DEG C
(8mmol), keep the temperature to continue after stirring 0.5h, be cooled to -78 DEG C, add formula G compounds (R2For Br, 1mmol, 388mg
Formula G compounds are dissolved in 5mL dichloromethane), kept for -78 DEG C continue to react 2h or so, 2mL triethylamines are added dropwise, continue to react 1h
Afterwards, clear-cutting forestland is to room temperature, after stirring reaction 3h, adds dchloromethane (50 mL), is washed successively with water, saturation NaCl,
Organic phase anhydrous sodium sulfate drying, after filtering, being concentrated under reduced pressure, through silica gel column chromatography, obtain 246mg formula F compounds (R2For
Br), yield is about 64%, ESI-MS (m/z)：384.9[M +2+H]+, 382.9 [M+H]+.Note：R during this is reacted2For Br's
Formula G compounds replace with R2For H, Cl, F or I formula G compounds, corresponding formula F compounds can be obtained with similar yield.
The spatial configuration of chiral carbon is (S, S) in the formula G compounds used in the embodiment, obtains corresponding (S, S) configuration
Formula F compounds, it is raw material that can also use the racemic modification of formula G compounds or the isomers of (R, R) configuration, can be with similar
Yield obtain the formula F compounds with respective configuration.
Embodiment 11
Weigh 230mg formula H compounds (1.0mmol) and be dissolved in 30mL CCl4In, add 2.2equiv.Br under ice bath2
(2.2mmol), clear-cutting forestland is to after reacting at room temperature 2~3h, and TLC detection raw materials are almost wholly absent, after being concentrated under reduced pressure, through silica gel
Column chromatography obtains 291mg formula G compounds (R2For Br), yield is that 75% or so, HPLC purity is 95.3%.
Note：Using F2、Cl2、I2, bromine water, chlorine water, HF, NFSI, Selectfluor (CAS RN:140681-55-6)、
FClO3, NCS, NBS, NIS, any of N-bromoacetamide or C5H6Br2N2O2 substitute Br in the present embodiment2, its mole dosage
For 2.0~3.5 times of formula H compounds, reaction temperature is -20 DEG C to reflux temperature, preferably -5 DEG C, 0 DEG C, room temperature, using dichloro
One or more of mixing in methane, chloroform, carbon tetrachloride, carbon disulfide, ether, THF or acetonitrile are substituted in the present embodiment
Carbon tetrachloride；The method recorded according to the present embodiment, it is (including halogenating agent and its dosage, temperature, molten using above-mentioned reaction condition
Agent) any combination, can with about 52% to 78% not wait yield obtain corresponding formula G compounds, HPLC purity is 90%
More than.
The spatial configuration of chiral carbon is (S, S) in the formula H compounds used in the embodiment, obtains corresponding (S, S) configuration
Formula G compounds, it is raw material that can also use the racemic modification of formula H compounds or the isomers of (R, R) configuration, can be with similar
Yield obtains the formula G compounds with respective configuration.
Embodiment 12
Weigh 362mg formula J compounds (R5For Me, R4For Boc, 1.0mmol) it is dissolved in 50mL EtOAc, add 3M HCl
(5mL), reaction is stirred at room temperature 1~2 hour, dilutes (50mL) with EtOAc, successively with saturation NaHCO3, water, saturation NaCl wash
Wash, anhydrous sodium sulfate drying, filter, after being concentrated under reduced pressure, through silica gel column chromatography, obtain 203mg formula H compounds, yield is about
88%, HPLC purity are 96.5%.
Or weigh 499mg formula J compounds (R5For Et, R4For Fmoc, 1.0mmol) it is dissolved in 40mL THF, add at room temperature
Enter morpholine (6.5mL), after reaction being stirred at room temperature 4~5 hours, be heated to reflux temperature, continue reaction 1~2 hour, decompression is dense
After contracting, through silica gel column chromatography, 164mg formula H compounds are obtained, yield is about that 71%, HPLC purity is 98.0%.
The spatial configuration of chiral carbon is (S, S) in the formula J compounds used in the embodiment, obtains corresponding (S, S) configuration
Formula H compounds, it is raw material that can also use the racemic modification of formula J compounds or the isomers of (R, R) configuration, can be with similar
Yield obtain the formula H compounds with respective configuration.
Embodiment 13
Weigh 303mg formula K compounds (R4For Boc, 1.3mmol) and 184mg formula L compounds hydrochloride (R5For Me,
1.0mmol) it is dissolved in 60mL CH2Cl2In, add Et3After N (1.2mmol) stirrings 15min, 203mg HOBT are added under ice bath
It is (1.5mmol) and appropriateAfter (molecular sieve) is stirred for 15min, add 288 mg EDCHCl (1.5mmol) and
Et3N (4.5mmol), clear-cutting forestland add 96mg EDCHCl (0.5mmol) to reaction 5 hours or so is stirred at room temperature, after
Overnight, TLC detections formula L compounds are almost wholly absent for continuous reaction, are filtered to remove solid, filtrate is successively with 1N HCl, saturation
NaHCO3, saturation NaCl washing, anhydrous sodium sulfate drying, filtering, after being concentrated under reduced pressure, through silica gel column chromatography, obtain 337mg formulas J
Compound (R5For Me, R4For Boc), yield is about 93%, ESI-MS (m/z)：363.2[M+H]+, HPLC purity is 97.0%.
Note：Using R4For Fmoc, Teoc, Troc, Cbz, Alloc, Ts, SES, Bn, PMB, Tr, MMT or DMT formula Kization
Compound substitutes the formula K compounds in the present embodiment, R5For optionally substitute alkyl, aryl, acyl group, sulfonyl (such as Me, Et,
N-Pr, i-Pr, t-Bu, Ph, p-nitrophenyl, Ts or Ms) formula L compound or its salt hydrochlorates substitute formula L in the present embodiment
The hydrochloride of compound, the EDC in the present embodiment is substituted using any of BOPCl, DCC, DIC, EDC or its hydrochloride
HCl, its mole dosage are 1.0~2.5 times of formula K compounds, and this implementation is substituted using any of DMAP, HOBT, DIPEA
HOBT in example, its mole dosage are 1.0~2.5 times of formula K compounds, and reaction temperature is for -15 DEG C to room temperature, and preferably 0 DEG C extremely
30 DEG C, using one kind in dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, chlorobenzene, THF, ether, dioxane or acetonitrile
Or several mixing substitute the dichloromethane in the present embodiment；The method recorded according to the present embodiment is (when using non-hydrochloride form
Condensing agent when, triethylamine can be not added with, in addition, being not added withAlso condensation reaction can occur), using above-mentioned reaction condition (bag
Include formula K, L compound, peptide condensing agent and its dosage, temperature, solvent) any combination, can with about 76% to 95% not wait
Yield obtains corresponding formula J compounds, and HPLC purity is more than 90%.
The spatial configuration of chiral carbon is S (i.e. the Kosé acid starting materials of L- penta) in formula K, the L compound used in the embodiment, is obtained
To the formula J compounds of corresponding (S, S) configuration, can also use formula K, L compound racemic modification (i.e. the Kosé acid starting materials of DL- penta) or
The isomers (i.e. the Kosé acid starting materials of D- penta) of R configurations is raw material, and the formula Jization with respective configuration can be obtained with similar yield
Compound.
Embodiment 14
Because the compound in the range of formula B, C, K, L can be commercially available by business customization, R is only enumerated in the present embodiment1
For TBS, X Cl,R4For Boc, R5For the preparation method of Me formula B, C-1, C-2, L compound.In addition, this area
Technical staff can suitably be adjusted according to the method described in the present embodiment or to it, can also be according in the prior art
Other similar approach recorded carry out that the compound in the range of other formula B, C, K, L is prepared, as space is limited, herein not one by one
It is tired to state.
Weigh Compound (CAS RN：Compound 1.0mmol 19710-84-0) is dissolved in 10mL THF, is added under ice bath
Enter TBSCl (2.0mmol) and imidazoles (2.5mmol), after keeping condition of ice bath stirring reaction 30min, slowly recovery to room temperature, instead
It should stay overnight, filter, after 1M LiOH (4.0mL) stirrings being dissolved in after filtrate concentration 1.5 hours, add water (4.0mL) to dilute, use ether
Extract (15mL × 3), merge organic phase, anhydrous magnesium sulfate is dried, and filtering, produces that formula B compounds are standby, and yield is about after concentration
95%, purity more than 90%.
Weigh formula B compounds (1.0mmol) to be dissolved in 10mL DMF, SOCl is added under ice bath2(3.0mmol), slowly
Recover to room temperature, after 4~6h of stirring reaction, concentrate produce formula C-1 compounds it is standby (general now-making-now-using, yield 80% with
On).
Weigh p-nitrophenol (1.0mmol) to be dissolved in 10 dichloromethane, add formula C-1 compounds (1.0 at room temperature
Mmol), triethylamine (0.5mL), after reaction 1-2h is stirred at room temperature, concentration, formula C-2 compounds are produced through silica gel column chromatography
280mg, yield are about 76.6%.
The preparation scheme of formula L compounds：
Formula K compounds (1.0mmol) are weighed, are dissolved in 10mL methanol, DCC (20mmol) and DMAP is added under ice bath
(15mmol), recover to after reaction being stirred at room temperature about 12 hours, filtering, after filtrate concentration, be dissolved in 10mL dichloromethane, room temperature
Lower addition 2mL morpholines, are heated to 35 DEG C, after about reacting 1 hour, concentration, through silica gel column chromatography, obtain formula L compound 125mg, receive
Rate is about 85%, HPLC purity 94.3%.
The step of not illustrated in all embodiments of the invention, for example, reaction temperature, the time, post-processing approach (including
Purification process), column chromatography silica gel mesh number, dosage, eluant, eluent species and ratio etc. belong to the ordinary skill of organic synthesis field
Knowledge, those skilled in the art can select suitable method and step according to being actually needed.
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Bibliography is all incorporated as in this application in all documents that the present invention refers to, just as each document quilt
It is individually recited as with reference to such.In addition, it is to be understood that after the above of the present invention has been read, those skilled in the art
The present invention can be made various changes or modifications, these equivalent form of values equally fall within what the application appended claims were limited
Scope.
Claims (10)
1. a kind of synthetic method of compound of formula I, it is characterised in that comprise the following steps：
Method one：
With formula B compounds condensation reaction occurs for formula A compounds, obtains compound of formula I；Wherein R1For H.
Or method two：
(1) with formula B compounds condensation reaction occurs for formula A compounds, obtains Formula II compound；
(2) Formula II compound deprotection base R1, obtain compound of formula I；Wherein R1For hydroxyl protecting group.
Or method three：
(1) with formula C compounds acylation reaction occurs for formula A compounds, obtains Formula II compound；
(2) Formula II compound deprotection base R1, obtain compound of formula I；Wherein R1For hydroxyl protecting group；X is selected from halogen or optional
The C1-C6 alkoxies or C6-C10 aryloxy group substituted by one or more nitros, cyano group, azido, halogen.
The spatial configuration of asymmetric carbon atom is in diketopiperazine cyclic group in Formulas I, II, A structural formula of compound in the claim
(S, S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when it
It is one kind in single enantiomter (S, S) or (R, R) when middle one kind is configured as 0.
2. the synthetic method of the compound of formula I described in claim 1, it is characterised in that also optionally include by formula D compounds through also
The step of original reaction formula A compounds：
Reaction obtains formula A compounds to formula D compounds under reducing agent effect in solvent；The reducing agent is in organic synthesis
Conventional carbon-to-nitrogen double bon reducing agent, preferably H2With Pd/C, Pt/C, Ru/C, Rh/C, PtO2Or in Raney's nickel (Raney Nickel)
One or more of combinations, or NaBH3CN、NaBH4、LiBH4, borine (BH3、B2H6) in one or more.It is above-mentioned to go back
Original reaction in, the preferred methanol of solvent, ethanol, ethyl acetate, acetic acid, formic acid, dichloromethane, n-hexane, ether, chloroform, acetonitrile,
One or more in THF, water.Preferably -20 DEG C of reaction temperature to reflux temperature, further preferably -15 DEG C, 0 DEG C, 20 DEG C, 30
DEG C, 40 DEG C or room temperature.
In claim Chinese style D, the A structural formula of compound in diketopiperazine cyclic group asymmetric carbon atom spatial configuration for (S,
S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when wherein one
It is one kind in single enantiomter (S, S) or (R, R) when kind is configured as 0.
3. the synthetic method of the compound of formula I described in claim 2, it is characterised in that also optionally include by formula E compounds through ring
The step of closing reaction formula D compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine).
Work as R2For H when, formula E compounds in the presence of initiator, alkali, in organic solvent occur ring-closure reaction obtain formula D chemical combination
Thing；The initiator, which is selected from, contains Ag+Compound, benzoyl peroxide or TEMPO, wherein containing Ag+The preferred Ag of compound2CO3、
AgNO3、AgOAc、AgOTf、Ag2One or more in O；Alkali preferred alkali metal carbonate or alkali metal hydrogencarbonate, such as
Li2CO3、Na2CO3、K2CO3、Rb2CO3、Cs2CO3、NaHCO3、KHCO3In one or more；The preferred DMF, DMA of organic solvent,
One or more of mixing in THF, acetonitrile, acetone, toluene, chloroform, carbon tetrachloride, dioxane, dichloromethane；Reaction temperature
For 0 DEG C to 60 DEG C, preferably 20 DEG C to 40 DEG C.
Work as R2For halogen (such as fluorine, chlorine, bromine, iodine) when, formula E compounds in the presence of alkali, in organic solvent occur cyclization it is anti-
Formula D compounds should be obtained；Alkali preferred as alkali alkoxide (such as CH3ONa, EtONa, t-BuOK), alkali metal hydroxide
Thing (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH), alkali metal alkide (preferably n-BuLi,
T-BuLi), LiHMDS, NaHMDS, KHMDS, alkali carbonate (such as Li2CO3、Na2CO3、K2CO3、Rb2CO3、Cs2CO3) or
Alkali metal hydrogencarbonate (such as NaHCO3、KHCO3Deng) in one or more；The preferred DMF, DMA of organic solvent, THF, t-BuOH,
One or more of mixing in acetonitrile, acetone, toluene, chloroform, carbon tetrachloride, dioxane, dichloromethane；Reaction temperature for-
80 DEG C to reflux temperature, preferably -40 to 40 DEG C, further preferred 0 DEG C, 20 DEG C, room temperature or 40 DEG C.
In claim Chinese style D, the E structural formula of compound in diketopiperazine cyclic group asymmetric carbon atom spatial configuration for (S,
S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when wherein one
It is one kind in single enantiomter (S, S) or (R, R) when kind is configured as 0.
4. the synthetic method of the compound of formula I described in claim 1, it is characterised in that also optionally include by formula E compounds through ring
The step of closing reaction formula A compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine)；The ring-closure reaction is preferably formula E compounds in H2With Pd/C, Pt/
C、Ru/C、Rh/C、PtO2Or in the presence of one or more of combinations in Raney's nickel (Raney Nickel), Huo Zhe
NaBH3CN, sodium borohydride, borine (BH3、B2H6) in one or more in the presence of occur ring-closure reaction obtain formula A chemical combination
Thing；The ring-closure reaction is preferably carried out in organic solvent, the preferred methanol of the organic solvent, ethanol, the tert-butyl alcohol, acetic acid second
One or more in ester, dichloromethane, n-hexane, ether, chloroform, acetonitrile, THF, DMF.Preferably 0 DEG C of reaction temperature extremely flows back
Temperature, further preferred room temperature, 40 DEG C or 50 DEG C；The ring-closure reaction is carried out optionally in the presence of alkali, the preferred alkali of alkali
Metal carbonate (such as Li2CO3、Na2CO3、K2CO3、Rb2CO3、Cs2CO3) or alkali metal hydrogencarbonate (such as NaHCO3、KHCO3Deng)
In one or more.
In claim Chinese style E, the A structural formula of compound in diketopiperazine cyclic group asymmetric carbon atom spatial configuration for (S,
S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when wherein one
It is one kind in single enantiomter (S, S) or (R, R) when kind is configured as 0.
5. the synthetic method of the compound of formula I described in claim 3 or 4, it is characterised in that also optionally include by formula F compounds with
Azanol (or its hydrochloride, sulfate) reacts the step of formula E compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine)；The reaction is optionally in the mixed of organic solvent, water or organic solvent and water
Carried out in bonding solvent, be optionally added alkali, the alkali is selected from pyridine, triethylamine, piperidines, ammonium hydroxide, sodium hydroxide, hydroxide
One or more in potassium, ammoniacal liquor, sodium acetate, sodium carbonate, potassium carbonate or cesium carbonate etc..Reaction temperature is room temperature to the temperature that flows back
Degree, preferably 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C or reflux temperature.The organic solvent preferred alcohol, isopropanol, the tert-butyl alcohol, THF,
One or more in dioxane, chloroform or acetonitrile.
In claim Chinese style E, the F structural formula of compound in diketopiperazine cyclic group asymmetric carbon atom spatial configuration for (S,
S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when wherein one
It is one kind in single enantiomter (S, S) or (R, R) when kind is configured as 0.
6. the synthetic method of the compound of formula I described in claim 5, it is characterised in that also optionally include by formula G compounds through oxygen
The step of changing reaction formula F compounds：
Wherein R2For H or halogen (such as fluorine, chlorine, bromine, iodine).
In claim Chinese style G, the F structural formula of compound in diketopiperazine cyclic group asymmetric carbon atom spatial configuration for (S,
S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when wherein one
It is one kind in single enantiomter (S, S) or (R, R) when kind is configured as 0.
7. the synthetic method of the compound of formula I described in claim 6, it is characterised in that also optionally comprise the following steps：
Formula H compounds react to obtain formula G compounds, wherein R with halogenating agent2For halogen (such as fluorine, chlorine, bromine, iodine).The halogen
F is selected from for reagent2、Cl2、Br2、I2, bromine water, chlorine water, HF, NFSI, Selectfluor (CAS RN:140681-55-6)、
FClO3, NCS, NBS, NIS, one kind in N-bromoacetamide or C5H6Br2N2O2.Above-mentioned reaction is optionally carried out in organic solvent,
It is one or more of in described organic solvent preferred dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, acetonitrile, ether or THF etc..
In claim Chinese style H, the G structural formula of compound in diketopiperazine cyclic group asymmetric carbon atom spatial configuration for (S,
S) or (R, R) mixing, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when wherein one
It is one kind in single enantiomter (S, S) or (R, R) when kind is configured as 0.
8. the synthetic method of the compound of formula I described in claim 7, it is characterised in that also optionally optionally exist including formula J compounds
R is removed in organic solvent4The step of ring-closure reaction forms formula H compounds, occurs for protection group：
Wherein R4For amino protecting group, R5It is described " optionally substituted for optionally substituted alkyl, aryl, acyl group, sulfonyl
" substituent is selected from one or more C1-C6 alkoxies, C6-C10 aryl, halogen or nitro.
The spatial configuration of asymmetric carbon atom is (S, S) in diketopiperazine cyclic group in the claim Chinese style H structural formula of compound
Or the mixing of (R, R), the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, works as one of which
It is one kind in single enantiomter (S, S) or (R, R) when being configured as 0.
9. the synthetic method of the compound of formula I described in claim 8, it is characterised in that also optionally include formula K compounds and formula Lization
The step of condensation reaction formula J compounds occur for compound or its acid salt (preferably hydrochloride)：
Wherein R4、R5Definition and claim 8 in R4、R5Definition it is identical.
The spatial configuration of asymmetric carbon atom is each independently the mixed of S or R in claim Chinese style K, the L structural formula of compound
Close, the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing, when one of which is configured as 0,
For one kind in single enantiomter S or R.
10. a kind of midbody compound, it is characterised in that the intermediate has Formula II, structure shown in B, C, E, F, G, J：
Wherein X is selected from halogen or optionally substituted by one or more nitros, cyano group, azido, halogen
C1-C6 alkoxies or C6-C10 aryloxy group, R1For hydroxyl protecting group, R2For H or halogen, R4、R5Definition and claim 8
Middle R4、R5Definition it is identical.
The synthetic method of Formula II, E, F, G, J midbody compound, it is characterised in that comprising be related in claim 1,5-9 Formula II,
E, the step of F, G, J midbody compound synthetic method.
A kind of midbody compound, it is characterised in that the midbody compound has structure shown in Formula II：
Wherein R1Selected from AcCl, Bz, Piv, Et, Bn, Tr, PMB, MOM,
TBS, TES, TMS, TBDPS, Ts or Ms.
A kind of midbody compound, it is characterised in that the midbody compound has structure shown in formula B：
Wherein R1Selected from Boc, AcCl, Bz, Piv, Me, Et, Tr, MMT, DMT, PMB, MOM, TBS, TES,
TMS, TBDPS, Ts or Ms.
A kind of midbody compound, it is characterised in that the midbody compound has structure shown in formula C：
Wherein R1Selected from Ac, Boc, AcCl, Bz, Piv, Me, Et, Bn, Tr, MMT, DMT, PMB, MOM, TBS,
TES, TMS, TBDPS, Ts or Ms.
A kind of midbody compound, it is characterised in that the midbody compound has structure shown in formula E：
Wherein R2Selected from H, F, Cl, Br or I.
A kind of midbody compound, it is characterised in that the midbody compound has structure shown in formula F：
Wherein R2Selected from H, F, Cl, Br or I.
A kind of midbody compound, it is characterised in that the midbody compound has structure shown in formula G：
Wherein R2Selected from H, F, Cl, Br or I.
The midbody compound of above-mentioned formula G structures, it is characterised in that selected from following compound：
A kind of midbody compound, it is characterised in that the midbody compound has structure shown in formula J：
Wherein R4Selected from Boc, Fmoc, Teoc, Troc, Cbz, Alloc, Ts, neighbour (to) nitre
Base benzenesulfonyl, SES, Bn, PMB, Tr, MMT or DMT, R5Selected from Me, Et, n-Pr, i-Pr, t-Bu, Ph, p-nitrophenyl, Ts
Or Ms.
The midbody compound of above-mentioned formula J structures, it is characterised in that selected from following compound：
In addition formula J intermediates also include by Me groups in above-mentioned midbody compound replace with Et,
N-Pr, i-Pr, t-Bu, Ph, p-nitrophenyl, Ts or Ms intermediate.
In the claim in Formula II, E, F, G, J compound and its particular compound included asymmetric carbon atom three-dimensional structure
Type is the mixing of (S, S) or (R, R), and the mixed proportion of the two is arbitrary proportion, when the two is with 1:It is racemic modification during 1 mixing,
It is one kind in single enantiomter (S, S) or (R, R) when one of which is configured as 0.
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