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CN103483363B - Multifarious chiral aminoboronic acid and its preparation method and application - Google Patents

️Wed Dec 21 2016

CN103483363B - Multifarious chiral aminoboronic acid and its preparation method and application - Google Patents

Multifarious chiral aminoboronic acid and its preparation method and application Download PDF

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Publication number

CN103483363B

CN103483363B CN201210194758.4A CN201210194758A CN103483363B CN 103483363 B CN103483363 B CN 103483363B CN 201210194758 A CN201210194758 A CN 201210194758A CN 103483363 B CN103483363 B CN 103483363B Authority

China

Prior art keywords

carbon

substituted

group

compound

ester

Prior art date

2012-06-13

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

Application number

CN201210194758.4A

Other languages

Chinese (zh)

Other versions

CN103483363A (en

Inventor

孙智华

范尔康

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Shanghai Sai Jia Chemicals Co Ltd

Original Assignee

Shanghai Sai Jia Chemicals Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2012-06-13

Filing date

2012-06-13

Publication date

2016-12-21

2012-06-13 Application filed by Shanghai Sai Jia Chemicals Co Ltd filed Critical Shanghai Sai Jia Chemicals Co Ltd

2012-06-13 Priority to CN201210194758.4A priority Critical patent/CN103483363B/en

2014-01-01 Publication of CN103483363A publication Critical patent/CN103483363A/en

2016-12-21 Application granted granted Critical

2016-12-21 Publication of CN103483363B publication Critical patent/CN103483363B/en

Status Expired - Fee Related legal-status Critical Current

2032-06-13 Anticipated expiration legal-status Critical

Links

LDPIQRWHBLWKPR-UHFFFAOYSA-N aminoboronic acid Chemical compound NB(O)O LDPIQRWHBLWKPR-UHFFFAOYSA-N 0.000 title claims abstract description 26
238000002360 preparation method Methods 0.000 title claims abstract description 23
150000001875 compounds Chemical class 0.000 claims abstract description 45
-1 guanidine radicals Chemical class 0.000 claims description 70
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 46
238000000034 method Methods 0.000 claims description 45
229910052799 carbon Inorganic materials 0.000 claims description 43
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 40
238000006243 chemical reaction Methods 0.000 claims description 38
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 26
150000002466 imines Chemical class 0.000 claims description 23
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
239000002585 base Substances 0.000 claims description 20
XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 18
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
239000003153 chemical reaction reagent Substances 0.000 claims description 16
229910052794 bromium Inorganic materials 0.000 claims description 15
229910052736 halogen Inorganic materials 0.000 claims description 14
150000002367 halogens Chemical class 0.000 claims description 14
MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 14
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
125000001424 substituent group Chemical group 0.000 claims description 12
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
229910052801 chlorine Inorganic materials 0.000 claims description 10
239000000460 chlorine Substances 0.000 claims description 10
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 9
239000011737 fluorine Substances 0.000 claims description 9
229910052731 fluorine Inorganic materials 0.000 claims description 9
HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 9
229910052757 nitrogen Inorganic materials 0.000 claims description 9
239000012188 paraffin wax Substances 0.000 claims description 9
239000002243 precursor Substances 0.000 claims description 9
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
125000001624 naphthyl group Chemical group 0.000 claims description 8
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
238000006555 catalytic reaction Methods 0.000 claims description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
239000003960 organic solvent Substances 0.000 claims description 7
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical group COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 5
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
244000080767 Areca catechu Species 0.000 claims description 5
235000006226 Areca catechu Nutrition 0.000 claims description 5
JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 5
239000002253 acid Substances 0.000 claims description 5
239000003513 alkali Substances 0.000 claims description 5
229910001431 copper ion Inorganic materials 0.000 claims description 5
OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
125000004093 cyano group Chemical group *C#N 0.000 claims description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
229920006395 saturated elastomer Polymers 0.000 claims description 5
239000000126 substance Substances 0.000 claims description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
125000000217 alkyl group Chemical group 0.000 claims description 4
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
239000001257 hydrogen Substances 0.000 claims description 4
229910052739 hydrogen Inorganic materials 0.000 claims description 4
125000003373 pyrazinyl group Chemical group 0.000 claims description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
239000012312 sodium hydride Substances 0.000 claims description 4
229910000104 sodium hydride Inorganic materials 0.000 claims description 4
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 3
CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 3
125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
150000007984 tetrahydrofuranes Chemical group 0.000 claims description 3
NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
125000003545 alkoxy group Chemical group 0.000 claims description 2
125000005605 benzo group Chemical group 0.000 claims description 2
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 2
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
238000007363 ring formation reaction Methods 0.000 claims description 2
XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 2
239000011734 sodium Substances 0.000 claims description 2
229910052708 sodium Inorganic materials 0.000 claims description 2
125000001544 thienyl group Chemical group 0.000 claims description 2
125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 2
MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
150000002431 hydrogen Chemical class 0.000 claims 1
YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims 1
239000003814 drug Substances 0.000 abstract description 6
230000008901 benefit Effects 0.000 abstract description 4
239000002547 new drug Substances 0.000 abstract description 4
238000011160 research Methods 0.000 abstract description 3
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 102
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
239000002904 solvent Substances 0.000 description 23
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
238000004440 column chromatography Methods 0.000 description 20
239000000376 reactant Substances 0.000 description 20
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 19
238000005160 1H NMR spectroscopy Methods 0.000 description 19
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
239000000203 mixture Substances 0.000 description 18
239000000741 silica gel Substances 0.000 description 17
229910002027 silica gel Inorganic materials 0.000 description 17
239000003921 oil Substances 0.000 description 15
125000003118 aryl group Chemical group 0.000 description 14
238000000746 purification Methods 0.000 description 14
230000000694 effects Effects 0.000 description 9
238000003786 synthesis reaction Methods 0.000 description 9
0 CC1*(*)=C**(C)C1 Chemical compound CC1*(*)=C**(C)C1 0.000 description 8
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
230000015572 biosynthetic process Effects 0.000 description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
125000001072 heteroaryl group Chemical group 0.000 description 7
229910052763 palladium Inorganic materials 0.000 description 7
238000010189 synthetic method Methods 0.000 description 7
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
230000001629 suppression Effects 0.000 description 6
PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
150000001345 alkine derivatives Chemical class 0.000 description 5
239000003446 ligand Substances 0.000 description 5
239000012044 organic layer Substances 0.000 description 5
125000001151 peptidyl group Chemical group 0.000 description 5
QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 5
239000007787 solid Substances 0.000 description 5
239000000758 substrate Substances 0.000 description 5
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
239000004327 boric acid Substances 0.000 description 4
239000010949 copper Substances 0.000 description 4
WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 4
235000015177 dried meat Nutrition 0.000 description 4
239000003112 inhibitor Substances 0.000 description 4
229910052751 metal Inorganic materials 0.000 description 4
239000002184 metal Substances 0.000 description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
239000007832 Na2SO4 Substances 0.000 description 3
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
125000002947 alkylene group Chemical group 0.000 description 3
229910052796 boron Inorganic materials 0.000 description 3
235000019253 formic acid Nutrition 0.000 description 3
230000000415 inactivating effect Effects 0.000 description 3
239000010410 layer Substances 0.000 description 3
230000003287 optical effect Effects 0.000 description 3
230000004044 response Effects 0.000 description 3
238000000926 separation method Methods 0.000 description 3
229910052938 sodium sulfate Inorganic materials 0.000 description 3
208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 2
GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 description 2
YHIWBVHIGCRVLE-UHFFFAOYSA-N 3-bromo-1h-indole Chemical compound C1=CC=C2C(Br)=CNC2=C1 YHIWBVHIGCRVLE-UHFFFAOYSA-N 0.000 description 2
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 2
102000004157 Hydrolases Human genes 0.000 description 2
108090000604 Hydrolases Proteins 0.000 description 2
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
206010035226 Plasma cell myeloma Diseases 0.000 description 2
KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
241000700605 Viruses Species 0.000 description 2
LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
150000001299 aldehydes Chemical class 0.000 description 2
238000011914 asymmetric synthesis Methods 0.000 description 2
MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
239000004305 biphenyl Substances 0.000 description 2
235000010290 biphenyl Nutrition 0.000 description 2
125000006267 biphenyl group Chemical group 0.000 description 2
KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
229960001467 bortezomib Drugs 0.000 description 2
150000001728 carbonyl compounds Chemical class 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
229940125898 compound 5 Drugs 0.000 description 2
238000010276 construction Methods 0.000 description 2
150000004696 coordination complex Chemical class 0.000 description 2
150000004699 copper complex Chemical class 0.000 description 2
125000000753 cycloalkyl group Chemical group 0.000 description 2
238000011161 development Methods 0.000 description 2
206010012601 diabetes mellitus Diseases 0.000 description 2
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Abstract

The invention discloses a kind of multifarious chiral aminoboronic acid and its preparation method and application, described multifarious chiral aminoboronic acid, for having the compound shown in formula I or formula II, multifarious chiral aminoboronic acid of the present invention, abundant the type compound library is provided for new drug research, yield and stereo selectivity can be improved, the preparation cost of this 2 class medicine can be reduced and simplify synthetic route, the economic benefit having had.

Description

Multifarious chiral aminoboronic acid and its preparation method and application

Technical field

The present invention relates to belong to chiral aminoboronic acid and its preparation method and application.

Background technology

In nature, although there is not natural aminoboronic acid compounds, but boric acid base group therein has very The dis-guised of special native amino carboxylic acid, thus allow it have spectacular biological activity, described and native amino The aminoboronic acid compounds that acid feature is similar is the compound with following structure:

Wherein: R is the various substituent groups of natural amino acid feature.

Alpha-amino boronic acid is as the crucial pharmacophoric group of serinase Antagonism in recent years, is increasingly subject in drug design Pay close attention to.The physicochemical properties unique due to boron atom and space structure (there is the p track of sky and less atomic radius), Alpha-amino boronic acid can be designed to the various hydrolase inhibitor with important function.Such as document Shenvi, al., US4499082 (1985) announcement such as Shenvi peptidyl aminoboronic acid TM-1 compounds can be as the inhibitor of proteolytic enzyme, document Kentter, Shenvi, al., US5187157 (1993), US5242904(1993), US5250720(1993) and Kentter, Shenvi announcement Peptidyl aminoboronic acid TM-1 compounds can also serve as the reversible inhibitor of Insulin-Like serine hydrolase, can Act on thrombin, plasma kallikrein, plasmin, document Kleeman, al., US5169841 (1992) the aminoboronic acid TM-2 compounds of .Kleeman announcement N end connection peptidyl has the activity of suppression feritin, Kettner, al., WO200102424 (2001) Kettner etc. disclose the aminoboronic acid TM-3 compounds of peptidyl and have suppression c-type The effect of hepatitis virus, Kinder, al., US5106948 (1992) Kinder etc. reports N end and connects the aminoboronic acid of peptidyl TM-2 compounds has the effect of suppression growth of tumour cell, same Bachovchin, al., WO20070005991 (2007) Bachovchin etc. disclose peptidyl aminoboronic acid TM-4 compounds have suppression fibroblast activated protein (FPA) effect, this imply that this compounds has antineoplastic activity, and the correlational study in later stage shows have suppression The potential quality of cancer of pancreas, Fleming;Paul E.al., WO2011123502 (2011) Fleming and Paul E. etc. discloses containing ring third The aminoboronic acid TM-5 compounds of base has the effect that suppression tumor cell increases, and FDA have approved the first in the recent period and contains The myeloma inhibitor Bortezomib of alpha-amino boronic acid, this new drug has been used for clinic.It addition, document a) Snow, R.et.al., J.Am.Chem.Soc.,1994,116,10860-10869.b)Jack H.Lai,William W.Bachovchin,et.al.,J.Med.Chem.. 2007,50,2391-2398.c) George R.Lankas, et.al., Diabetes, 2005,54,2988-2994. reports, the dried meat amino of peptidyl Boric acid is the very effective inhibitor of two peptidyls dried meat aminase IV (DPP-4), can be as before the having very much of type ii diabetes The medicine of scape, the wherein PT-100 of U.S. Phenomix company, the III phase having completed FDA is clinical.

Document:

Snow, R.et.al., J.Am.Chem.Soc., 1994,116,10860-10869.:

Jack H.Lai,William W.Bachovchin,et.al.,J.Med.Chem.2007,50,2391-2398.

George R.Lankas,et.al.,Diabetes,2005,54,2988-2994.

K.Augustyns,P.Van der Veken,K.Senten and A.Haemers,Current Medicinal Chemistry,2005,12,971-998.

Pieter Van der Veken,Achiel Haemers and Koen Augustyns,Current Topics in Medicinal Chemistry, 2007,7,621-635.

Daniel J Drucker, Michael A Nauck, Lancet, 2006;368:1696–705.

Study in terms of chemosynthesis as aminoboronic acid or even corresponding optical voidness correspondence isomer, its practicality and various Property aspect still has the biggest challenge, the most effectively, succinct stereoselective syntheses aspect.With important serine The key intermediate of hydrolase inhibitor--as a example by the synthesis of dried meat aminoboronic acid, the general side using multistep to synthesize and split Method, how with Pinanediol diborane ester and pyrroles or nafoxidine as initiation material, such as document E.Scott Priestley, Carl P. Decicco, US20030008828, (2003,1). report, Article 1 route synthetic method step is long, and yield is low, Article 2 road DNA mitochondrial DNA selectivity is bad, and base reagent used is to humidity sensitive, and operability is poor, and reaction equation is as follows:

Method about the asymmetric synthesis of alpha-amino boronic acid is little at present, and the most only two kinds methods are in the news.A kind of It is the Mattheson being widely used in academic and industrial quarters¹¹Method, such as document: Donald S.Matteson and Kizhakethil M.Sadhu, J. Am.Chem.SOC.1981, the report of 103,5241-5242., is to utilize containing chirality The Pinanediol diborane ester of prothetic group prepares α-chloroboric acid ester, is then further converted into alpha-amino boronic acid, in the method, The side chain of alpha-amino boronic acid is all derived by alkylboronic acids, which greatly limits the possibility of their commercialization, reaction equation As follows:

The Kettner utilization of Dupont drugmaker is made electrophilic reagent side chain and is expanded the method for Matteson, Such as document Sharada Jagannathan, Timothy P.Forsyth, and Charles A.Kettner, J.Org.Chem.2001, The report of 66,6375-6380., although enriching the multiformity of aminoboronic acid to a certain extent, but with regard to its reagent used With applicable scope, still there is significant limitation.Reaction equation is as follows:

The above-mentioned method preparing aminoboronic acid all needs the synthesis through multistep, if directly by a step direct construction targeted The method of compound is ideal, and little for the addition report of carba double bond about boron, document Grace Mann, Kevin D. John, and R.Tom Baker, Org.Lett., 2000, it is sub-that 2 (14), 2105-2108.Baker etc. report an example N-aryl aromatic aldehyde Amine reacts the alpha-amino boronic acid ester obtaining racemization under platinum complex is catalyzed with Bis (catecholato) diboron (B2cat2), instead Answer formula as follows:

On this basis, directly with the method for asymmetric synthesis of chirality t-butyl sulfonamide induction, Ellman develop Success, is shown in document Melissa A.Beenen, Chihui An, and Jonathan A.Ellman, J.Am.Chem.Soc..2008,130, The report of 6910 6911, the method utilizes pinacol diborane ester under the catalysis of (ICy) CuOtBu/ sodium tert-butoxide and chirality The reaction of tert-butyl group sulfenimide obtains chiral alpha-aminoboronic acid derivatives, although it has highly-solid selectively and to fat The advantage that alkyl group substituted imine substrate yield is higher, but current the method is yet suffered to the problem of two aspects, 1) It uses the Cabbeen copper complex of tertiary fourth oxygen copper of NHC as catalyst, this catalyst can only specific place (as Glove box) in preparation and deposit, which has limited it industrialization use prospect；2) method of Ellman is at substrate type On there is limitation, generally for the yield good (yield: 74-88%) of alkyl amino boric acid, and test discovery, aryl ammonia The yield of ylboronic acid is bad (yield: 52-61%), even can not get target product；

The core of the method for Ellman is to use the t-butyl sulfonamide substrate containing chiral sulfoxide prothetic group to Cu (I)-azepine card The boron ester additive reaction of guest's catalysis carries out spatial chemistry induction.Since Wanzlick and Ofele is in nineteen sixty-eight reported first Since azepine Cabbeen (NHC) and metal complex¹⁵, existing many stable, this compounds separable successively¹⁶It is in the news, And this compounds usually obtains good effect when catalytic organometallic reacts¹⁷, see document a) Herrmann, W.A. Angew.Chem.Int.Ed.2002,41,1290-1309.b)Zinn,F.K.;Viciu,M.S.;Nolan,S.P.Annu. Rep.Prog.Chem.,Sect.B.2004,100,231-249.c)Scott,N.M.;Nolan,S.P.Eur.J.Inorg. The report of Chem.2005,1815-1828；

From the perspective of to electronics intensity, the azepine Cabbeen phosphine compound electrical with richness compares similar, is that a class is neutral 2-electronq donor.Can form complex with multiple transition metal, Coordinate property is similar to the organophosphorus ligand of electron rich, But the two stereochemical nature has again significantly difference, see document: a) Scholl, M.;Trnka,T.M.;Morgan,J.P.; Grubbs,R.H.Tetrahedron Lett.1999,40,2247-2250.b)Scholl,M.;Ding,S.;Lee,C.W.; Grubbs,R.H.Org.Lett.1999,1,953-956.c)Trnka,T.M.;Grubbs,R.H.Acc.Chem.Res. 2001,34,18-29.d)Huang,J.K.;Stevens,E.D.;Nolan,S.P.;Petersen,J.L.J.Am.Chem. Soc.1999,121,2674-2678.e)Ackermann,L.;Furstner,A.;Weskamp,T.;Kohl,F.J.; The report of Herrmann, W.A.Tetrahedron Lett.1999,40,4787-4790.；

Interaction with metal is based on σ-key, and metal d track is relatively weak to the π feedback effect of Cabbeen, is a special dictionary Neutral σ-the part of type, is shown in document: a) Bielawski, C.W.;Grubbs,R.H.Angew.Chem.Int.Ed.2000,39, 2903-2906.b)Bielawski,C.W.;Benitez,D.;Grubbs, R.H.Science, 2002,297,2041-2044.'s Report；

The reaction utilizing azepine Cabbeen (NHC) metal complex to be catalyzed all successfully is applied to Heck, In Suzuki-Miyaura, Kumada, Sonogashira, Still, Negishi, Buchwald-Harting reaction, see document:

Herrmann,W.A.,Reisinger,C.P.,Siegler,M.,J.Organomet.Chem.1998,557,93-96.

Zhang,C.,Huang,J.,Trudell,M.L.,Nolan,S.P.,J.Org.Chem.,1999,64,3804-3805.

Grasa,G.A.,Nolan,S.P.,Org.Lett.,2001,3,119-122.

Huang,J.,Nolan,S.P.J.Am.Chem.Soc.,1999,121,9889-9890.b)Bohm,V.P.W., Gstottmayr,C.W.K.,Weskamp,T.,Herrmann,W.A.,Angew.Chem.Iht.Ed.2001,40, 3387-3389.

Eckhardt, M., Fu, G.C., J Am.Chem.Soc., 2003,125,13642-13643.b) Aitenhoff, G., Wuertz,S.,Glorius,F.Tetrahedron Lett.2006,47,2925-2928.

Grasa,G.A.,Nolan,S.P.,Org.Lett.,2001,3,119-122.

Hadei, N., Kantchev, E.A.B., Obrien, C.J., Organ, M.G., J.Org.Chem., 2005,70, 8503-8507.

J.Huang,G.Grasa,S.P.Nolan,Org.Lett.,1999,1,1307-1309.b)Stauffer,S.R.,Lee,S., Stambuli,J.P.,Hauck,S.I.,Hartwig,J.F.,Org.Lett.,2000,2,1423-1426.c)Marion,N., Navarro,O.,Mei,J.,Stevens,E.D.,Scott,N.M.,Nolan,S.P.,J.Am.Chem.Soc.,2006,128, 4101-4111

1993, report first case Cu (I)-azepine Cabbeen (NHC) complex { [(NHC)₂Cu][O₃SCF₃]}²⁸, see document: Arduengo,A.J.III.,Dias,H.V.R.,Calabrese,J.C.,Davidson,F.,Organometallics,1993,12, 3405-3409. report；

Document: Jurkauskas, V., Sadighi, J.P., Buchwald, S.L., Org.Lett., 2003,5,2417-2420. report Leading, Buchwald group is prepared for single NHC support copper (I) complex with copper (I) with now producing azepine Cabbeen, it was demonstrated that and Cu (I)- Azepine Cabbeen (NHC) complex is typical two synergic agent, and it is along with substituent group and the increase of metal combination ability on nitrogen, Its collaborative power the most substantially increases.And it is used in α, the reduction of the carbon-carbon double bond of beta-unsaturated carbonyl compounds, literary composition Offer: Kang-Sang Lee, Adil, R.Zhugralin and Amir H.Hoveyda, J.Am.Chem.Soc., 2009,131, 7253-7255. reports, and Hoveyda group utilizes azepine Cabbeen to exist at metal salt-free and is catalyzed α, beta-unsaturated carbonyl Compounds and diborate reaction, build β-borate carbonyl compound.

Make a general survey of the construction method of aminoboronic acid, azepine Cabbeen and copper complex thereof at catalysis diborane reagent, carba double bond to be added Becoming the utilization in reaction, other research groups are up to the present in the progress in aminoboronic acid synthesis field, from reaction Certain vacancy that mechanism all exists to methodology and do not explore clearly local, and the entering of the synthetic methodology in this field One step development, will push directly on such compound library multifarious, thus the research and development to new drug will have extremely important effect.

Summary of the invention

It is an object of the invention to disclose a kind of multifarious chiral aminoboronic acid and its preparation method and application, existing to overcome The drawbacks described above that technology exists, meets the needs of association area development.

Multifarious chiral aminoboronic acid of the present invention, for having the compound shown in formula I or formula II:

Wherein:

R represents containing the linear paraffin base of 1-12 carbon, the branched alkane alkyl containing 1-12 carbon, the alkene containing 2-6 carbon Base, alkynes containing 2-6 carbon, aromatic ring yl, aromatic heterocyclic, substituted linear paraffin base containing 1-12 carbon, substituted Branched alkane alkyl containing 1-12 carbon, substituted alkylene containing 2-6 carbon, substituted alkynes containing 2-6 carbon, take The aromatic ring yl in generation or substituted aromatic heterocyclic；

Preferably, described aromatic ring yl is phenyl, naphthyl or anthryl；

Preferably, described aromatic heterocyclic is pyridine radicals, pyrimidine radicals, pyrazinyl, pyrrole radicals, purine radicals or indyl；

Described substituted linear paraffin base containing 1-12 carbon, substituted branched alkane alkyl containing 1-12 carbon, replacement The alkylene containing 1-12 carbon, substituted alkynes, substituted aromatic ring yl or substituted aromatic heterocyclic containing 2-6 carbon, Substituent group is hydroxyl, ether, carbonyl, amino, amide groups, guanidine radicals, nitro, cyano group or halogen, and described halogen is preferred Chlorine；

R₁=R₂Represent catechu phenolic ester, pinacol ester, dimethylamino ester or (1S, 2S, 3R, 5S)-(+)-2,3-pinane diol (Pinanediol) ester；

R₄Represent the tert-butyl group, methyl, trifluoromethyl, p-methylphenyl, p-methoxyphenyl or 2,4,6-trimethylphenyl；

R₅For hydrogen, the saturated or unsaturated cycloalkyl group of 1-8 carbon, the nitrogenous or cyclic hydrocarbon group of oxygen, containing 1-12 carbon Straight or branched alkyl, the alkylene containing 2-6 carbon, the alkynes base containing 2-6 carbon, aromatic ring yl, aromatic heterocyclic or Halogen；Described for chlorine, bromine, iodine or fluorine；Preferably chlorine；

Described aromatic ring yl is for replacing or unsubstituted phenyl, naphthyl or anthryl, and substituent group is the saturated or unsaturated of 1-4 carbon Alkyl, hydroxyl, methoxyl group, trifluoromethyl, amino or halogen, described halogen is fluorine, chlorine or bromine etc.；

Described aromatic heterocyclic is substituted or unsubstituted pyridine radicals, pyrimidine radicals, pyrazinyl, pyrrole radicals, purine radicals, indole Base, substituent group is the saturated of 1-4 carbon or unsaturated alkyl, hydroxyl, methoxyl group, trifluoromethyl, amino or halogen, as Fluorine, chlorine or bromine etc.；

Preferably, R=R₅, for the substituted or unsubstituted ring-type saturated or unsaturated aliphatic hydrocarbon of 1-8 carbon；

N is the integer of 1～6；

Preferably, R is that methyl, propyl group, isopropyl, isobutyl group, 3-chloropropyl, adamantyl, 3-are to methoxybenzyl Epoxide propyl group, 4-phthalyl amido butyl, phenyl, p-methoxyphenyl, p-methylphenyl, rubigan, benzyl Base, to benzyloxy-benzyl or naphthyl；

Preferably, R=R5, and be cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenycyclopropyl or suberyl；

Preferably, described multifarious chiral aminoboronic acid is:

The preparation method of formula I compound of the present invention, comprises the steps:

(1) in organic solvent, under univalent copper ion and azepine carbene precursor are catalyzed, or before alkali and azepine Cabbeen Under body catalysis, imine compound I ' and diborane reagent are reacted, from product, then collect formula I Compound, reaction temperature is 15～30 DEG C, and the response time is 1-48 hour, and preferably 24～48 hours, yield existed 78-93.5%, optical purity is 98%.Reaction expression such as formula III:

R、R₁、R₂、R₄And R₅It is defined as above, R₃=R_3’=R₁；

Described univalent copper ion derives from Cu-lyt., cuprous bromide or Hydro-Giene (Water Science).；

Described alkali selected from sodium tert-butoxide, sodium carbonate, potassium carbonate, 1,5-diaza-bicyclo [5,4,0] hendecene-5, cesium carbonate or Sodium hydride；

Described organic solvent is selected from oxolane, benzene, DMF, ether, dichloromethane, chloroform or acetonitrile etc.；

Described azepine carbene precursor is the compound with following chemical constitution:

Wherein: R₆Represent the alkyl of unsubstituted and substituted 1-6 carbon, the alkoxyl of substituted 1-6 carbon, halogen, Nitro, amino, replacement or and the benzene of ring, aromatic ring or heteroaromatic etc.；

Preferably hydrogen, 3-fluorine, 3-nitro, 3-methyl, 3-methoxyl group or benzo；

M, Q are nitrogen or carbon；

R₇Represent 1-8 carbon alkyl, carbene alkyl, the alkynes base of 1-8 carbon or the aryl of 1-8；

X^-Represent fluorine, chlorine, bromine or iodine ion；

Ar₁Representing phenyl, substituted-phenyl or aromatic heterocyclic, the substituent group of substituted-phenyl is methyl, fluorine, methoxyl group, cyanogen Base or nitro；Aromatic heterocyclic is pyridine radicals, 6-picolyl, naphthyl, pyrazinyl, pyrrole radicals, thienyl or pyrimidine Base；

Wherein, preferred azepine carbene precursor is:

The preparation method of described azepine carbene precursor,

Under the catalysis of hydrochloric acid and formic acid, compound L-n and trimethyl orthoformate are reacted, then from product Middle collection type (L-n ') compound, reaction temperature is 60～100 DEG C, and the response time is 1-6 hour, and yield is at 89-95%. Reaction expression is as follows:

Compound L-n and the weight ratio with trimethyl orthoformate are 1:1-20；

The weight of hydrochloric acid is the 0.1～150% of compound L-n consumption；

The weight of formic acid is the 0.1～150% of compound L-n consumption；

The preparation method of compound L-n comprises the steps:

By the adjacent aryl diamine (1eq) shown in formula (L-m), bromide (1eq), three (dibenzalacetone) two palladium (Pd2 (dba)₃) (5%eq) (wherein, the weight content of palladium (Pd) is 21.5%), 2,2'-double diphenyl phosphine-1,1'-dinaphthalene (BINAP) (7.5%eq), sodium tert-butoxide (3eq) and toluene (1ml/mmol, for bromide) in nitrogen is protected, 60-110 DEG C Reaction overnight, then collects product from product.Productivity 70% ~ 90%.Under reaction expression such as formula:

R₆, M, Q, Ar₁It is defined as above；

Described three (dibenzalacetone) two palladium (Pd2 (dba)₃) (5%eq) (palladium (Pd) weight content of reagent is 21.5%) Refer to the palladium (Pd) part by weight (please explain it is what meaning, Luo great Chen) at three (dibenzalacetone) two palladium

Described three (dibenzalacetone) two palladium (Pd2 (dba)₃) rule of origin of adoptable commercialization.

Described bromide is the substituted aromatic ring of bromine or the substituted heteroaromatic of bromine, and with substituent group on aromatic ring or in heteroaromatic The substituted aromatic ring of bromine or heteroaromatic；

Preferred:

The substituted aromatic ring of described bromine is bromobenzene, complete deuterated bromobenzene；

The substituted heteroaromatic of described bromine is 2-bromopyridine, 3-bromopyridine, 4-bromopyridine, 3-bromo indole or 3-Bromopyrimidine；

On aromatic ring, the substituted aromatic ring of bromine with substituent group is that fluorobromobenzene, to nitre to methyl bromobenzene, to methoxybromobenzene Bromide benzene or to cyano group bromobenzene

In heteroaromatic the substituted heteroaromatic of bromine with substituent group be 5-trifluoromethyl-2-bromopyridine, 6-methyl-2-bromopyridine, 4-nitrogen, nitrogen dimethyl-2-bromopyridine, 5-trifluoromethyl-3-bromo indole, 5-methyl-3-Bromopyrimidine or 3-methyl-2-bromo-pyrazine；

Described bromide all can use the product of commercialization；

Referring specifically to embodiment.

The preparation of described group with imine moiety I ', can refer to document (MaryAnn T.Robak, Melissa A.Herbage, and Jonathan A.Ellman；Chemical Reviews,2010,110(6),3609.) logical method synthesis, the most all kinds of commercializations Aldehydes or ketones compound react gained with (R)-t-butyl sulfonamide.Its reaction expression is:

The most identical definition of wherein R, R5, for all kinds of commercialization aldehydes or ketones.(R)-t-butyl sulfonamide and tetraethoxy Titanium is commercial prod.

Wherein, the chemical constitution of representational group with imine moiety I ' is:

Described diborane reagent is to have the compound as shown in formula B:

Wherein: R₁、R₂It is defined as above described, R₃=R_3’=R₁；

Described diborane reagent can commercialization buying.

Preferably, described diborane reagent selected from catechu phenolic ester, pinacol ester, dimethylamino ester, (1S, 2S, 3R, 5S)-(+)-2,3-pinane diol (Pinanediol) ester or Sp²-Sp³The diborane reagent of hydridization；Concrete knot Structure is as follows:

Pinacol ester diborane catechu phenolic ester diborane Pinanediol ester diborane dimethylamino ester diborane

Miscellaneous pinacol 2-2-aminopropane. alcohol diborane (Sp²-Sp³The diborane reagent of hydridization)

The weight ratio of each component is as follows:

Compound I ': diborane reagent=1: 1～3；

Compound I ': univalent copper ion or alkali=1: 0.05～0.2；

Compound I ': azepine carbenes=1: 0.05～0.2；

The preparation method of formula II compound of the present invention, comprises the steps:

In organic solvent, in the presence of alkaline matter, compound (I ") is carried out cyclization, then from product Middle collection obtains formula II compound；Reaction temperature is 15～30 DEG C, and the response time is 1-48 hour, preferably 24～ 48 hours, yield was at 78-93.5%, and optical purity is 98%, and reaction expression is as follows:

Wherein:

R₁、R₂、R₄, n is defined as above；

X represents Cl, Br, OSO₂CF₃、OSO₂CH₃；

The preparation method of compound (I "), is shown in embodiment 5.

Described alkaline matter is selected from sodium tert-butoxide, sodium carbonate, potassium carbonate, 1,5-diaza-bicyclo [5,4,0] hendecene-5, carbon Acid caesium or sodium hydride；

Described organic solvent is oxolane, benzene, DMF, ether, dichloromethane, chloroform or acetonitrile etc.；

The weight ratio of each component is as follows:

Compound (I "): alkaline matter=1: 1～3, preferably 1～2；

The multifarious chiral aminoboronic acid of the present invention, may be used for preparing the various medicine with critical treatment effect and (swells Tumor, type-II diabetes, hepatitis C, virus etc.), it is specifically related to the compound 4 as prepared by the present invention and can be used to make Standby myeloma inhibitor Bortezomib, preparation method is shown in document Melissa A.Beenen, Chihui An, and as follows Jonathan A.Ellman；The report of J.Am.Chem.Soc.2008,130,6910 6911；As prepared by the present invention Compound C-3, by with conventional deprotection method (in the methanol solution of 4N hydrogen chloride react), sloughing the tert-butyl group Sulfinyl, forms the hydrochlorate of dried meat aminoboronic acid ester, can be used to prepare the U.S. Phenomix of introduction part The PT-100 of company, it is very effective DPP-4 inhibitor, can control as the most promising of type ii diabetes Treating medicine, the III phase having completed FDA is clinical, preparation method reference literature a) Snow, R.et.al., J.Am.Chem. Soc.,1994,116,10860-10869.b)Jack H.Lai,William W.Bachovchin,et.al.,J.Med.Chem. 2007,50,2391-2398.c) George R.Lankas, et.al., Diabetes, 2005,54,2988-2994. report.

The medicine have the advantages that described multifarious chiral aminoboronic acid, wherein prepared by the present invention involved Chemical compound lot is that other synthetic methods cannot be prepared at present, provides abundant the type compound for new drug research Storehouse；The compound 4 prepared by this law and compound C3, can improve yield and stereo selectivity, can reduce this 2 The preparation cost of class medicine and simplification synthetic route.The economic benefit having had.

Detailed description of the invention

The borate addition representativeness synthetic method to tert-butyl group sulfenimide:

Logical method 1(has Cu-lyt. to participate in):

Reaction is among nitrogen protection, is initially charged 0.2mmol ligand L-01 ' (0.1eq.), 0.2mmol Cu-lyt. (0.1eq.), 0.2mmol sodium tert-butoxide (0.1eq.) and solvent benzol (10ml), it is stirred at room temperature 4hr；

Reactant liquor is become green to light/dark balance from colourless.Afterwards, by molten for 2mmol tert-butyl group sulfenimide (1eq.) 2mmol borate (1eq.), in benzene (5ml), is dissolved in benzene (5ml), is added in reaction tube by solution.It After, room temperature reaction 48hr.Reaction process is monitored with TLC.Reaction adds EA(30ml after terminating) dilution, and use K₂CO₃Washing organic layer.Afterwards with EA(2 × 30ml) aqueous layer extracted.Merge organic layer Na₂SO₄It is dried, mistake Filter, concentrating under reduced pressure.Product deactivated silica gel (inactivating with water) uses chloroform/methanol body through row column chromatography for separation, developing solvent System.

Logical method 2(participates in without Cu-lyt .):

Reaction is among nitrogen protection, is initially charged 0.2mmol azepine carbene precursor L-01 ' (0.1eq.), 0.2mmol Cesium carbonate (0.1eq.) and solvent benzol (10ml), be stirred at room temperature 4hr.Reactant liquor is become green to somber from colourless Color.Afterwards, 2mmol tert-butyl group sulfenimide (1eq.) is dissolved in benzene (5ml), by 2mmol boric acid Ester (1eq.) is dissolved in benzene (5ml), is added in reaction tube.Afterwards, room temperature reaction 48hr.Anti-with TLC monitoring Answer process.Reaction adds EA(30ml after terminating) dilution, and use K₂CO₃Washing organic layer.Afterwards with EA(2 × 30ml) aqueous layer extracted.Merge organic layer Na₂SO₄It is dried, filters, concentrating under reduced pressure.Product deactivated silica gel (is used Water inactivates) through row column chromatography for separation, developing solvent uses chloroform/methanol system.

The synthesis of azepine carbene precursor L-01 ':

1st step: the synthesis of compound L-01:

O-phenylenediamine (2.162g, 20mmol), bromobenzene (6.281g, 40mmol), Pd₂(dba)₃(0.916g, 1mmol) (the Pd content of reagent is 21.5%), 2,2'-double diphenyl phosphine-1,1'-dinaphthalene (BINAP), (0.934g, 7.5%eq), uncle Sodium butoxide (5.766g, 3eq) and dry toluene (20ml) add in the reaction tube of nitrogen protection, temperature 110 DEG C.Instead Should be overnight.After reaction, solid gone out by liquid filter paper, and washs solid by ethyl acetate, and gained liquid merges, rotation Dry, crossing post and taking product is pale solid 4.478g, productivity 86%.

¹H-NMR(CDCl₃,δ,ppm):7.33-7.29(m,6H),7.01-6.91(m,8H),5.65(s,2H, NH).¹³C-NMR(CDCl₃,δ,ppm):145.0,135.0,129.4,122.5,120.4,119.5,116.7.

2nd step: compound L-01 ' synthesis:

Upper step product 2.11g(8mmol) add in 16ml trimethyl orthoformate, instilling 0.8ml weight concentration is 36% Concentrated hydrochloric acid, and 2 formic acid.It is heated to 80 degree, reacts 2 hours.TLC follows the tracks of raw material and disappears.Reactant liquor revolves Dry.With chloroform/normal hexane recrystallization.Productivity 90%.White solid 2.21g.

¹H-NMR(DMSO,δ,ppm):10.64(s,1H),7.98-7.95(m,6H),7.83-7.74(m,8H).¹³C-NMR(DMSO,δ,ppm):143.3,133.5,131.7,131.2,130.9,128.3,125.9,114.3.

Embodiment 1

The preparation of aminoboronic acid ester and sign:

Compound (1). use logical method 1 to react.

Add 295mg(2mmol) tert-butyl group sulfenimide Compound1 ', react 48 hours.

Reactant mixture is purified through row column chromatography by the silica gel inactivated with water, and developing solvent is chloroform/methanol system.Gained Product is that character is at ambient temperature for light yellow oil (253mg, yield:85%).

¹H-NMR(DMSO,δ,ppm):4.78(d,j=6.4,0.43H,NH),4.34(dd,j₁=1.6Hz,j₂=8.8Hz,1H), 2.93(m,1H,CHN),2.30(m,1H),2.17(m,1H),1.97(m,1H),1.87(m,1H),1.73(m,1H),1.32(s, 3H),1.26(s,3H),1.20(d,j=7.2Hz,3H),1.12(m,1H),1.09(s,9H),0.82(s, 3H).¹³C-NMR(DMSO,δ,ppm):85.9,77.5,55.5,51.3,38.3,35.4,28.8,27.3,26.3,24.1,23.1, 19.2,19.1.

Embodiment 2

Logical method 2 is used to react.

Add 351mg(2mmol) tert-butyl group sulfenimide Compound2 ', react 48 hours.

¹H-NMR(DMSO,δ,ppm):4.76(d,j=6.8Hz,1H,NH),4.34(dd,j₁=2Hz,j₂=8.8Hz,1H), 2.82(m,1H,CHN),2.30(m,1H),2.16(m,1H),1.97(m,1H),1.87(m,1H),1.71(m,1H), 1.56(m,2H),1.34(m,2H),1.32(s,3H),1.25(s,3H),1.13(m,1H),1.08(s,9H),0.87(t,j=7.2Hz, 3H),0.82(s,3H).¹³C-NMR(DMSO,δ,ppm):85.9,77.4,55.7,51.2,38.3,35.5,35.5,28.8, 27.3,26.4,24.1,23.1,20.1,14.5.

Embodiment 3

Logical method 1 is used to react.

Add 351mg(2mmol) imines Compound3 ', react 48 hours.Reactant mixture is by losing with water The silica gel lived through is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature Pale yellow oil (308mg, yield:88%).

¹H-NMR(DMSO,δ,ppm):4.73(d,j=6.8Hz,1H,NH),4.34(m,1H),2.66(t,j=6.4Hz,1H, CHN),2.32(m,1H),2.16(m,1H),1.98(m,1H),1.87(m,2H),1.70(m,1H),1.32(s,3H),1.25(s, 3H),1.18(m,1H),1.09(s,9H),0.92(d,j=7.2Hz,6H),0.82(s,3H).¹³C-NMR(DMSO,δ,ppm): 77.4,55.9,51.2,38.3,35.5,31.2,28.9,27.3,26.5,24.2,23.0,20.8,20.0.

Embodiment 4

Logical method 1 is used to react.

Add 379mg(2mmol) imines Compound4 ', react 48 hours.Reactant mixture is by losing with water The silica gel lived through is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature Colorless oil (341mg, yield:90%).

¹H-NMR(CDCl₃,δ,ppm):4.33(dd,j₁=2Hz,j₂=8.8Hz,1H),3.52(s,br,1H,NH),3.15(m, 1H,CHN),3.10(m,1H),2.35(m,1H),2.23(m,1H),2.07(m,1H),1.93(m,1H),1.87(m,1H), 1.76(m,1H),1.60(m,1H),1.41(s,3H),1.31(s,3H),1.21(s,9H),1.17(m,1H),0.95(dd, j₁=1.2Hz,j₂=6.4Hz,6H),0.86(s,3H).¹³C-NMR(CDCl₃,δ,ppm):86.2,78.2,56.0,51.2,42.8, 39.5,38.2,35.4,28.5,27.0,26.4,25.6,24.0,22.7,22.6,22.5.

Embodiment 5

Logical method 1 is used to react.

Add 420mg(2mmol) imines Compound5 ', react 48 hours.Reactant mixture is by losing with water The silica gel lived through is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature Pale yellow oil (373mg, yield:89%).

¹H-NMR(DMSO,δ,ppm):4.90(d,j=6.4Hz,0.4H,NH),4.36(dd,j₁=2Hz,j₂=6.8Hz,1H), 3.63(t,j=6.4Hz,2H),2.85(t,j=7.2Hz,1H,CHN),2.32(m,1H),2.17(m,1H),1.98(t,j=5.6Hz, 1H),1.88(m,1H),1.81(m,2H),1.72(m,2H),1.70(m,1H),1.33(s,3H),1.26(s,3H),1.13(m, 1H),1.09(s,9H),0.82(s,3H).¹³C-NMR(DMSO,δ,ppm):86.0,77.5,55.8,51.2,45.9,38.3, 35.4,30.6,30.5,30.1,28.8,27.3,26.4,24.1,23.1.

Embodiment 6

Logical method 1 is used to react.

Add 535mg(2mmol) imines Compound6 ', react 48 hours.Reactant mixture is by losing with water The silica gel lived through is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature Pale yellow oil (455mg, yield:85%).

¹H-NMR(DMSO,δ,ppm):4.38(m,1H,NH),4.36(m,1H),2.46(d,j=8.4Hz,1H,CHN), 2.33(m,1H),2.18(m,1H),1.99(t,j=5.6Hz,1H),1.94(m,3H),1.88(m,1H),1.69(m,7H), 1.57(m,3H),1.49(m,3H),1.33(s,3H),1.26(s,3H),1.18(m,1H),1.09(s,9H),0.82(s, 3H).¹³C-NMR(DMSO,δ,ppm):86.0,77.3,56.2,51.2,38.3,37.1,35.7,35.6,28.9,28.4,27.3, 26.6,24.2,23.0.

Embodiment 7

Universal method 1 is used to react.

Add 623mg(2mmol) imines Compound7 ', react 48 hours.Reactant mixture is by losing with water The silica gel lived through is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature Pale yellow oil (542mg, yield:87%).

¹H-NMR (DMSO, δ, ppm): 7.23 (d, j=8.4Hz, 2H), 6.90 (m, 2H), 4.78 (m, 0.5H, NH), 4.36(s,2H),4.33(dd,j₁=1.6Hz,j₂=7.2Hz,1H),3.74(s,3H),3.38(m,2H),2.83(m,1H,CHN), 2.30(m,1H),2.15(m,1H),1.98(m,1H),1.86(m,1H),1.72(m,1H),1.64(m,4H),1.31(s,3H), 1.25(s,3H),1.15(m,1H),1.08(s,9H),0.81(s,3H).¹³C-NMR(DMSO,δ,ppm):159.1,131.0, 129.5,114.0,85.9,77.5,71.9,69.7,55.7,55.5,51.2,38.4,38.3,36.0,35.5,30.0,30.0,28.9, 28.8,27.4,27.3,27.1,26.4,24.1,23.1.

Embodiment 8

Universal method 1 is used to react.

Add 669mg(2mmol) imines Compound8 ', react 48 hours.Reactant mixture was by inactivating with water Silica gel through row column chromatography purification, developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature for yellowish Color grease (609mg, yield:91%).¹H-NMR(DMSO,δ,ppm):7.86(m,4H),4.74(d,j=6.4Hz,1H, NH),4.21(m,1H),3.57(t,j=6.8Hz,2H),2.78(m,1H,CHN),2.22(m,1H),2.00(,1H),1.86(m, 1H),1.69(m,1H),1.58(m,5H),1.30(m,2H),1.22(s,3H),1.19(s,3H),1.06(s,9H),1.03(m, 1H),0.78(s,3H).¹³C-NMR(DMSO,δ,ppm):168.4,134.8,132.1,123.4,85.9,77.4,55.6, 51.1,38.2,37.9,35.4,32.7,28.7,28.3,27.3,26.4,24.1,23.0.

Embodiment 9

Logical method 1 is used to react.

Add 418mg(2mmol) imines Compound9 ', react 48 hours.Reactant mixture is by losing with water The silica gel lived through is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature Pale yellow oil (368mg, yield:88%).

¹H-NMR(DMSO,δ,ppm):7.28(m,4H),7.18(m,1H),5.47(d,j=5.6Hz,0.44H,NH), 4.34 (m, 1H), 4.13 (d, j=5.6Hz, 1H, CHN), 2.29 (m, 1H), 2.02 (m, 1H), 1.93 (m, 1H), 1.78 (m, 1H),1.59(m,1H),1.26(s,3H),1.21(s,3H),1.13(s,9H),0.86(m,1H),0.78(s,3H).¹³C-NMR(DMSO,δ,ppm):141.7,128.6,127.7,126.8,86.2,77.7,56.2,51.2,38.3,35.3,28.6, 27.2,26.0,24.1,23.1.

Embodiment 10

Universal method 1 is used to react.

Add 479mg(2mmol) imines Compound10 ', react 48 hours.Reactant mixture is by with water The silica gel inactivated is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom be character at ambient temperature For pale yellow oil (436mg, yield:91%).

¹H-NMR(DMSO,δ,ppm):7.26(d,j=8.8Hz,2H),6.86(d,j=8.8Hz,2H),5.30(d,j=4.2Hz, 0.53H, NH), 4.33 (m, 1H), 4.05 (d, j=5.6Hz, 1H, CHN), 3.73 (s, 3H), 2.28 (m, 1H), 2.04 (m, 1H), 1.94(m,1H),1.81(m,1H),1.63(m,1H),1.25(s,3H),1.20(s,3H),1.12(s,9H),0.89(m,1H), 0.79(s,3H).¹³C-NMR(DMSO,δ,ppm):158.4,133.3,129.1,114.0,86.2,77.6,56.1,55.5, 51.2,38.3,35.4,28.7,27.2,26.1,24.1,23.1.

Embodiment 11

Universal method 1 is used to react.

Add 447mg(2mmol) imines Compound11 ', react 48 hours.Reactant mixture is by losing with water The silica gel lived through is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom is that character is at ambient temperature Pale yellow oil (402mg, yield:90%).

¹H-NMR(DMSO,δ,ppm):7.23(d,j=8Hz,2H),7.10(d,j=7.6Hz,2H),5.34(d,j=5.6Hz,1H, NH),4.33(dd,j₁=1.6Hz,j₂=8.8Hz,1H),4.07(d,j=6Hz,1H,CHN),2.27(m,1H),2.27(s,3H), 2.03(m,1H),1.93(m,1H),1.79(m,1H),1.64(m,1H),1.25(s,3H),1.21(s,3H),1.12(s,9H), 0.89(m,1H),0.79(s,3H).¹³C-NMR(DMSO,δ,ppm):138.6,135.8,129.2,127.8,86.2,77.7, 56.1,51.3,38.3,35.4,28.7,27.2,26.1,24.1,23.1,21.1.

Embodiment 12

Universal method 1 is used to react.

Add 488mg(2mmol) imines Compound12 ', react 48 hours.Reactant mixture is by with water The silica gel inactivated is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom be character at ambient temperature For pale yellow oil (405mg, yield:83%).

¹H-NMR(DMSO,δ,ppm):7.38(m,4H),4.23(m,1H),4.17(m,1H,NH),4.17(m,1H, CHN),2.28(m,1H),2.18(m,1H),1.93(m,1H),1.86(m,1H),1.70(m,1H),1.30(s,3H),1.25(s, 3H),1.14(s,9H),1.13(m,1H),0.81(s,3H).¹³C-NMR(DMSO,δ,ppm):139.5,131.9,130.0, 128.6,83.4,76.1,55.7,51.8,47.7,38.4,36.0,29.0,27.4,26.4,24.1,23.1.

Embodiment 13

Universal method 1 is used to react.

Add 447mg(2mmol) imines Compound13 ', react 48 hours.Reactant mixture is by with water The silica gel inactivated is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom be character at ambient temperature For pale yellow oil (398mg, yield:89%).

¹H-NMR(DMSO,δ,ppm):7.24(m,5H),4.88(d,j=6Hz,1H,NH),4.23(m,1H),3.12(m, 1H,CHN),2.96(m,1H),2.85(m,1H),2.25(m,1H),1.93(m,1H),1.88(m,1H),1.78(m,1H), 1.64(m,1H),1.24(s,3H),1.21(s,3H),1.08(s,9H),0.80(m,1H),0.77(s, 3H).¹³C-NMR(DMSO,δ,ppm):139.2,129.6,128.6,126.7,86.0,77.5,55.7,51.1,38.2,35.2, 28.6,27.3,26.1,24.1,23.0.

Embodiment 14

Universal method 1 is used to react.

Add 519mg(2mmol) imines Compound15 ', react 48 hours.Reactant mixture is by with water The silica gel inactivated is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom be character at ambient temperature For pale yellow oil (441mg, yield:85%).

¹H-NMR(DMSO,δ,ppm):7.88(m,4H),7.51(m,3H),4.32(d,j=8.4Hz,1H,NH), 4.32(m,1H),4.22(d,j=8.4Hz,1H,CHN),2.28(m,1H),2.18(m,1H),1.93(m,1H),1.87(m,1H), 1.67(m,1H),1.30(s,3H),1.25(s,3H),1.17(s,9H),1.13(m,1H),0.81(s, 3H).¹³C-NMR(DMSO,δ,ppm):138.0,133.3,132.7,128.2,128.0,128.0,126.8,126.6, 126.5,126.2,83.3,76.1,55.7,51.8,48.7,48.5,38.4,36.0,29.0,27.4,26.4,24.1,23.2.

Embodiment 15

Universal method 1 is used to react.

Add 447mg(2mmol) imines Compound18 ', react 48 hours.Reactant mixture is by with water The silica gel inactivated is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom be character at ambient temperature For pale yellow oil (250mg, yield:56%).

¹H-NMR(DMSO,δ,ppm):7.42(m,2H),7.30(m,2H),7.17(m,1H),5.17(s,0.5H,NH), 4.33(m,1H),2.28(m,1H),2.05(m,1H),1.92(m,1H),1.78(m,1H),1.67(s,3H),1.53(m,1H), 1.21(s,3H),1.19(s,9H),1.13(s,3H),0.89(m,1H),0.77(s,3H).¹³C-NMR(DMSO,δ,ppm): 146.2,128.3,128.2,127.2,126.5,126.4,86.4,77.8,56.6,51.3,38.4,35.4,31.2,28.6,27.2, 26.6,26.2,24.1,23.3,23.1.

Embodiment 16

Universal method 1 is used to react.

Add 402mg(2mmol) imines Compound18 ', react 48 hours.Reactant mixture is by with water The silica gel inactivated is through row column chromatography purification, and developing solvent is chloroform/methanol system.Products therefrom be character at ambient temperature For pale yellow oil (488mg, yield:64%).

¹H-NMR(DMSO,δ,ppm):4.48(s,1H,NH),4.35(m,1H),2.87(m,1H,CHN),2.20(m, 1H),2.05(m,2H),1.91(m,2H),1.68(m,4H),1.50(m,1H),1.36(s,3H),1.28(m,7H),1.12(s, 3H),1.09(s,9H),0.82(s,3H).¹³C-NMR(DMSO,δ,ppm):86.0,77.5,55.8,51.2,45.9,38.3, 35.4,30.6,30.5,30.1,28.8,27.3,26.4,24.1,23.1.

Embodiment 17

The lower borate addition representativeness synthetic method to tert-butyl group sulfenimide of different ligands catalysis.

1) having selected ligand L-01 respectively, tert-butyl group sulfenimide is added by L-02, L-03, L-06 according to borate Becoming and react under representative synthetic method (method 1) reaction condition, with hutanal imines as substrate, result is not sent out Existing target product.

2) selected ligand L-020 respectively ', L-021 ', L-022 ' according to the borate addition to tert-butyl group sulfenimide React under representative synthetic method (method 1) reaction condition, with hutanal imines as substrate, found that: target The yield of product is respectively 91%, and 35%, 42%.

The preparation method of compound (I "): use the general method synthesis of above method 1.

Embodiment 18

The cyclisation representativeness synthetic method of terminal halogen substituted aminoboronic acid ester.

Reaction is among nitrogen protection.Add 2mmol terminal halogen substituted aminoboronic acid ester, the 2.1mmol tert-butyl alcohol Sodium (1.05eq.) and solvent DMF (10ml), be stirred at room temperature 6hr.Reaction process is monitored with TLC.Reaction EA(30ml is added after end) and water (30ml).With EA(2 × 30ml) aqueous layer extracted.Merge organic layer Na₂SO₄ It is dried, filters, concentrating under reduced pressure.Product deactivated silica gel (inactivating with water) uses chlorine through row column chromatography for separation, developing solvent Imitative/methanol system.

The structure of terminal halogen substituted aminoboronic acid ester is as follows:

Embodiment 19

Use the universal method of aminoboronic acid ester substituted to terminal halogen through row reaction.Add 780mg(2mmol) Imines Compound5, reacts 6 hours.Reactant mixture is purified through row column chromatography by the silica gel inactivated with water, Developing solvent is chloroform/methanol system.Products therefrom be character at ambient temperature for pale yellow oil (586mg, yield: 83%).

¹H-NMR(DMSO,δ,ppm):4.36(dd,j₁=2Hz,j₂=6.8Hz,1H),3.63(t,j=6.4Hz,2H),2.85(t, j=7.2Hz,1H),2.32(m,1H),2.17(m,1H),1.98(t,j=5.6Hz,1H),1.88(m,1H),1.81(m,2H), 1.72(m,2H),1.70(m,1H),1.33(s,3H),1.26(s,3H),1.13(m,1H),1.09(s,9H),0.82(s, 3H).¹³C-NMR(DMSO,δ,ppm):86.0,77.5,55.8,51.2,45.9,38.3,35.4,30.6,30.5,30.1, 28.8,27.3,26.4,24.1,23.1。

Claims (10)

The preparation method of the most multifarious chiral aminoboronic acid, it is characterised in that comprise the steps:

(1) in organic solvent, under univalent copper ion and azepine carbene precursor are catalyzed, or before alkali and azepine Cabbeen Under body catalysis, imine compound (I) ' and diborane reagent are reacted, then collection type from product (I) compound, reaction expression such as formula III:

Wherein:

R represent the linear paraffin base containing 1-12 carbon, branched alkane alkyl containing 1-12 carbon, phenyl, naphthyl, anthryl, Substituted linear paraffin base containing 1-12 carbon, the substituted branched alkane alkyl containing 1-12 carbon；

Described substituted linear paraffin base containing 1-12 carbon, the substituent group of the substituted branched alkane alkyl containing 1-12 carbon For hydroxyl, ether, carbonyl, amino, amide groups, guanidine radicals, nitro, cyano group or halogen；

R₁=R₂, represent catechol ester group, pinacol ester group or (1S, 2S, 3R, 5S)-(+)-2,3-pinane diol (Pinanediol) Ester group；

R₃=R_3’=R₁；

R₄Represent the tert-butyl group, methyl, trifluoromethyl, p-methylphenyl, p-methoxyphenyl or 2,4,6-trimethylphenyl；

R₅For hydrogen.
The preparation method of multifarious chiral aminoboronic acid the most according to claim 1, it is characterised in that R=R₅, Substituted or unsubstituted ring-type saturated or unsaturated aliphatic hydrocarbon for 1-8 carbon.
The preparation method of multifarious chiral aminoboronic acid the most according to claim 2, it is characterised in that R=R₅, And be cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenycyclopropyl or suberyl.
4., according to the preparation method of the multifarious chiral aminoboronic acid described in any one of claims 1 to 3, its feature exists In, R be methyl, propyl group, isopropyl, isobutyl group, 3-chloropropyl, adamantyl, 3-to methoxybenzyl epoxide propyl group, 4-phthalyl amido butyl, phenyl, p-methoxyphenyl, p-methylphenyl, rubigan, benzyl, to benzyloxy Base benzyl or naphthyl.
Method the most according to claim 1, it is characterised in that described univalent copper ion derives from Cu-lyt., bromine Change cuprous or Hydro-Giene (Water Science).；

Described alkali selected from sodium tert-butoxide, sodium carbonate, potassium carbonate, 1,5-diaza-bicyclo [5,4,0] hendecene-5, cesium carbonate or Sodium hydride；

Described organic solvent is selected from oxolane, benzene, DMF, ether, dichloromethane, chloroform or acetonitrile etc.；

Described azepine carbene precursor is the compound with following chemical constitution:

Wherein: R₆Represent the alkyl of unsubstituted and substituted 1-6 carbon, the alkoxyl of substituted 1-6 carbon, halogen, Nitro, amino, replacement or and the phenyl of ring；

M, Q are nitrogen or carbon；

R₇Represent 1-8 carbon alkyl or phenyl；

X^-Represent fluorine, chlorine, bromine or iodine ion；

Ar₁Representing phenyl, substituted-phenyl, the substituent group of substituted-phenyl is methyl, fluorine, methoxyl group, cyano group or nitro； Aromatic heterocyclic is pyridine radicals, 6-picolyl, naphthyl, pyrazinyl, pyrrole radicals, thienyl or pyrimidine radicals.
Method the most according to claim 5, it is characterised in that R₆For hydrogen, 3-fluorine, 3-nitro, 3-methyl, 3- Methoxyl group or benzo.
Method the most according to claim 5, it is characterised in that azepine carbene precursor is:

The chemical constitution of described group with imine moiety I ' is:

Described diborane reagent is to have the compound as shown in formula B:

Wherein: R₃=R_3’=R₁。
Method the most according to claim 7, it is characterised in that described diborane reagent is selected from catechu phenolic ester, frequently Any alcohol ester, (1S, 2S, 3R, 5S)-(+)-2,3-pinane diol (Pinanediol) ester.
The preparation method of the most multifarious chiral aminoboronic acid, it is characterised in that comprise the steps:

In organic solvent, in the presence of alkaline matter, compound (I ") is carried out cyclization, then from product Middle collection obtains formula II compound；Reaction expression is as follows:

Wherein:

R₅Represent the linear paraffin base containing 1-12 carbon, branched alkane alkyl containing 1-12 carbon, phenyl, naphthyl, anthracene Base, substituted linear paraffin base containing 1-12 carbon, the substituted branched alkane alkyl containing 1-12 carbon；

Described substituted linear paraffin base containing 1-12 carbon, the substituent group of the substituted branched alkane alkyl containing 1-12 carbon For hydroxyl, ether, carbonyl, amino, amide groups, guanidine radicals, nitro, cyano group or halogen；

R₁=R₂, represent catechu phenolic ester, pinacol ester or (1S, 2S, 3R, 5S)-(+)-2,3-pinane diol (Pinanediol) ester；

R₄Represent the tert-butyl group, methyl, trifluoromethyl, p-methylphenyl, p-methoxyphenyl or 2,4,6-trimethylphenyl；

N is the integer of 1～6；

X represents Cl, Br, OSO₂CF₃、OSO₂CH₃。
Method the most according to claim 9, it is characterised in that described alkaline matter is selected from sodium tert-butoxide, carbon Acid sodium, potassium carbonate, 1,5-diaza-bicyclo [5,4,0] hendecene-5, cesium carbonate or sodium hydride.

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