CN1984881A - 制备对映体形式2,3-二氨基丙酸衍生物的方法 - Google Patents
制备对映体形式2,3-二氨基丙酸衍生物的方法 Download PDFInfo
- Publication number
- CN1984881A CN1984881A CNA2005800233299A CN200580023329A CN1984881A CN 1984881 A CN1984881 A CN 1984881A CN A2005800233299 A CNA2005800233299 A CN A2005800233299A CN 200580023329 A CN200580023329 A CN 200580023329A CN 1984881 A CN1984881 A CN 1984881A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- alkyl
- hydrogen atom
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical class [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 144
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 57
- -1 nitro, amino Chemical group 0.000 claims description 46
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000010948 rhodium Substances 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 230000010933 acylation Effects 0.000 claims description 5
- 238000005917 acylation reaction Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical compound CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000012327 Ruthenium complex Substances 0.000 claims 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 abstract description 7
- 239000004305 biphenyl Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000010926 purge Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000006837 decompression Effects 0.000 description 9
- 229940017219 methyl propionate Drugs 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- 150000003851 azoles Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000012856 packing Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000009466 transformation Effects 0.000 description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- WGOBPPNNYVSJTE-HSZRJFAPSA-N [(2r)-1-diphenylphosphanylpropan-2-yl]-diphenylphosphane Chemical compound C([C@@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 WGOBPPNNYVSJTE-HSZRJFAPSA-N 0.000 description 4
- CTYPJIUQROQJBG-JWQCQUIFSA-N [(2r,4r)-4-diphenylphosphanylpentan-2-yl]-diphenylphosphane Chemical compound C=1C=CC=CC=1P([C@H](C)C[C@@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 CTYPJIUQROQJBG-JWQCQUIFSA-N 0.000 description 4
- VCHDBLPQYJAQSQ-KYJUHHDHSA-N [(4r,5r)-5-(diphenylphosphanylmethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-diphenylphosphane Chemical compound C([C@@H]1OC(O[C@H]1CP(C=1C=CC=CC=1)C=1C=CC=CC=1)(C)C)P(C=1C=CC=CC=1)C1=CC=CC=C1 VCHDBLPQYJAQSQ-KYJUHHDHSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- FWXAUDSWDBGCMN-ZEQRLZLVSA-N chiraphos Chemical compound C=1C=CC=CC=1P([C@@H](C)[C@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 FWXAUDSWDBGCMN-ZEQRLZLVSA-N 0.000 description 4
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 125000000160 oxazolidinyl group Chemical group 0.000 description 4
- ATAFDSCDEDHMOK-UHFFFAOYSA-N 3,3-diaminopropanoic acid Chemical class NC(N)CC(O)=O ATAFDSCDEDHMOK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229950004288 tosilate Drugs 0.000 description 3
- QOLRLVPABLMMKI-BRSBDYLESA-N (2r,5r)-1-[2-[(2r,5r)-2,5-diethylphospholan-1-yl]ethyl]-2,5-diethylphospholane Chemical compound CC[C@@H]1CC[C@@H](CC)P1CCP1[C@H](CC)CC[C@H]1CC QOLRLVPABLMMKI-BRSBDYLESA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 2
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 150000003283 rhodium Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- UDGKZGLPXCRRAM-UHFFFAOYSA-N 1,2,5-thiadiazole Chemical compound C=1C=NSN=1 UDGKZGLPXCRRAM-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000005955 1H-indazolyl group Chemical group 0.000 description 1
- JCZAVVUIFWZMQI-UHFFFAOYSA-N 1h-thieno[2,3-d]imidazole Chemical compound N1C=NC2=C1C=CS2 JCZAVVUIFWZMQI-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- WIKVRBTVPSOQHJ-UHFFFAOYSA-N 2h-1,5,2-dithiazine Chemical compound C1SNC=CS1 WIKVRBTVPSOQHJ-UHFFFAOYSA-N 0.000 description 1
- WQQOBNITCUCURI-UHFFFAOYSA-N 3-cyclohexa-2,4-dien-1-ylpropanoic acid Chemical class OC(=O)CCC1CC=CC=C1 WQQOBNITCUCURI-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- BMZKZBWPMWEQAY-UHFFFAOYSA-N 6h-1,2,5-thiadiazine Chemical compound C1SN=CC=N1 BMZKZBWPMWEQAY-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ULBXWWGWDPVHAO-UHFFFAOYSA-N Chlorbufam Chemical compound C#CC(C)OC(=O)NC1=CC=CC(Cl)=C1 ULBXWWGWDPVHAO-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- QODJQAPYENPFSO-UHFFFAOYSA-N [Rh+].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 Chemical compound [Rh+].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QODJQAPYENPFSO-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 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 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 1
- 125000005509 dibenzothiophenyl group Chemical group 0.000 description 1
- JXSJBGJIGXNWCI-UHFFFAOYSA-N diethyl 2-[(dimethoxyphosphorothioyl)thio]succinate Chemical compound CCOC(=O)CC(SP(=S)(OC)OC)C(=O)OCC JXSJBGJIGXNWCI-UHFFFAOYSA-N 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 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
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- RFPMGSKVEAUNMZ-UHFFFAOYSA-N pentylidene Chemical group [CH2+]CCC[CH-] RFPMGSKVEAUNMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- BDDWSAASCFBVBK-UHFFFAOYSA-N rhodium;triphenylphosphane Chemical compound [Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BDDWSAASCFBVBK-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/85—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate 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
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种通过不对称氢化式(II)化合物来制备对映体形式的式(I)2,3-二氨基丙酸衍生物的方法。
Description
本发明涉及一种通过不对称氢化来制备对映体形式的式(I)2,3-二氨基丙酸衍生物的方法。式I化合物为适用于制备IkB激酶抑制剂(WO01/30774A1;WO2004/022553)的中间体。
众所周知,α,β-二氨基丙酸衍生物可以依据线路1(J Org Chem,Vol.66,11,2001,第4141-4147页)通过Rh-催化的不对称氢化来制备。但是,不对称氢化只由在两个氮原子均已被酰化时得以顺利进行。
线路1
尝试氢化N,N-二亚甲基胺或N,N-二亚甲基烯胺未获得成功。
目前已发现,不对称合成即使对于式II化合物也取代了成功。式I化合物的合成成功获得高产率和高对映体选择性(enantioselectivity)。
因此,本发明涉及一种获得式I化合物的方法,
其中,R1和R2相同或不同,且各自独立地为
1)氢原子,
2)-(C1-C4)-烷基,
3)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由R11单取代的、二取代的或三取代的,
其中R11为
a)F、Cl、I或Br,
b)-(C1-C4)-烷基,
c)-CN,
d)-CF3,
e)-OR5,其中R5为氢原子或-(C1-C4)-烷基,
f)-N(R5)-R6,其中R5和R6各自独立地为氢原子或-(C1-C4)-烷基,
g)-C(O)-R5,其中R5为氢原子或-(C1-C4)-烷基,或
h)-S(O)x-R5,其中x为整数0、1或2,且R5为氢原子或-(C1-C4)-烷基;
4)-CH(R7)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-CH3、F、Cl或溴单取代的、二取代的或三取代的,其中R7为氢原子或-(C1-C4)-烷基,或
5)4~15元Het环,其中Het环为未取代的或者独立地由-(C1-C5)-烷基、-(C1-C5)-烷氧基、卤素、硝基、氨基、三氟甲基、羟基、羟基-(C1-C4)-烷基、亚甲二氧基、亚乙二氧基、甲酰基、乙酰基、氰基、羟基羰基、氨基羰基或-(C1-C4)-烷氧基羰基单取代的、二取代的或三取代的;
R3为
1)氢原子,
2)-(C1-C4)-烷基,
3)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-(C1-C4)-烷基、F、Cl或溴单取代的、二取代的或三取代的,
4)-O-C(CH3)3,或
5)-O-CH(R7)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-CH3、F、Cl或溴单取代的、二取代的或三取代的,其中R7为氢原子或-(C1-C4)-烷基;
R4为
1)氢原子,
2)-(C1-C4)-烷基,或
3)-CH(R8)-芳基,其中R8为氢原子或-(C1-C4)-烷基,
该方法包括在氢和催化剂的存在下氢化式II化合物
其中,R1、R2、R3和R4各自如式I中所定义,且该化合物可以存在E或Z构型的双键。
本发明另外涉及一种获得式I化合物的方法,其中
R1为苯基或氢原子,
R2为苯基、吡啶基或噻唑基,其中苯基、吡啶基或噻唑基为未取代的或者由氟或氯取代,和
R3为苯基或-O-CH2-苯基,和
R4为甲基或乙基。
本发明另外涉及一种获得式III化合物或其盐的方法,
其中,R1、R2和R4各自如式I中所定义,
该方法包括
a)在氢和催化剂的存在下氢化式II化合物,
其中R1、R2、R3和R4各自如式I中所定义,
并使其转化为式I化合物,
和
b)将获得的式I化合物转化为式III化合物。
方法步骤b)例如依据T.Greene,P.Wuts在Protective Groups inOrganic Synthesis,Wiley-Interscience中针对分离酰胺或氨基甲酸酯描述的反应条件来进行。依据所选的反应条件,尤其是强碱性反应条件,式I化合物向式III化合物的直接转化导致不对称氢化形成的手性中心的外消旋或其它不期望的副反应。当式I化合物转化为化合物IV时,这点可以例如使用重碳酸叔丁酯或另一引入叔丁氧基羰基保护基团的试剂而受到阻止。将叔丁氧基羰基保护基团引入到适宜溶剂如乙腈、四氢呋喃或甲苯中,优选地借助于酰化催化剂如N,N-二甲基氨基吡啶(DMAP)。
反应温度为0℃~120℃,优选为20℃~40℃。
反应时间通常为0.5~24小时,取决于混合物组成和所选温度范围。
随后在温和条件如甲醇镁下将获得的式IV化合物转化为式Ia化合物。
向式III化合物的转化通常在文献中公知的反应条件下进行,如T.Greene,P.Wuts in Protective Groups在Organic Synthesis,Wiley-Interscience中针对分离叔丁氧基羰基(BOC)保护基团描述的那样。
因此,本发明另外涉及一种获得式III化合物的方法,该方法包括:
a)在氢和催化剂的存在下氢化式II化合物,其中R1、R2、R3和R4各自如式I中所定义,并且使其转化为式I化合物,
b)使获得的式I化合物与重碳酸叔丁酯和酰化催化剂如N,N-二甲基氨基吡啶(DMAP)反应,由此获得式IV化合物,其中R1、R2、R3和R4各自如式I中所定义,和
c)随后将获得的式IV化合物转化为式Ia化合物,其中R1、R2、R3和R4各自如式I中所定义,
和
d)将获得的式Ia化合物转化为式III化合物或其盐,其中R1、R2、R3和R4各自如式I中所定义。
式IV化合物向式Ia化合物的转化例如通过用碱处理来实现,如氢氧化锂、肼或甲醇镁(文献:J.Org.Chem.1997,62,7054-7057)。在标准条件下分离叔丁氧基碳基,由此获得式III化合物,如在适宜溶剂中用三氟乙酸(TFA)、盐酸或对甲苯磺酸进行处理。
通过从适宜溶剂如甲醇、乙醇、1-丙醇、2-丙醇、正丁醇、2-丁醇和其酯中结晶式I或III化合物来排除不期望的对映体。在式III化合物情形中,优选以它们的(酸性)盐形式如盐酸盐、甲磺酸盐或对甲苯磺酸盐来进行结晶。这些条件下获得了大于99%的光学纯度。适宜地,可以在单罐工艺中进行全部反应序列,并不分离化合物IV和Ia。此时获得产率和光学纯度与上述值相一致。
术语“催化剂”表示例如E.N.Jacobson,A.Pfaltz,H.Yamamoto在Comprehensive Asymmetric Catalysis,Springer-Verlag,1999或X.Zhang,Chemical Reviews,2003,103,3029-3069和其引用文献中描述的化合物,例如光学活性铑、钌或铱络合物或其混合物。催化活性络合物通过金属络合物与光活性膦的反应来形成。在上述酰化的2,3-二氨基丙酸衍生物的情形中,Me-Duphos或Et-Duphos-铑络合物显示极佳的对映体选择性和转化率。另外众所周知的是,可以使用BICP、t-Bu-BisP、BDPMI、Et-FerroTANE、MalPHOS和MonoPHOS型铑络合物作为催化剂来制备手性β-氨基酸。
术语“-(C1-C4)-烷基”或“-(C1-C5)-烷基”被认为其含义为其碳链为直链或支化的且含有1~4或1~5个碳原子的烃基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基或戊基。
术语“-CH(R7)-”或“-CH(R8)-”被认为其含义为直链或支化的烃基,如亚甲基、亚乙基、亚异丙基、亚异丁基或亚戊基。例如,在R7为氢原子且芳基为苯基时,“-CH(R7)-”基团为苄基。
术语“-(C6-C14)-芳基”或“芳基”被认为其含义为环中具有6~14个碳原子的芳香碳基团。-(C6-C14)-芳基例如为苯基、萘基(例如1-萘基、2-萘基)、蒽基或芴基。优选的芳基为萘基、尤其是苯基。
术语“4~15元Het环”被认为其含义为具有4~15个碳原子的环体系,其存在于彼此键合的一个、两个或三个环体系中,且其含有一个、两个、三个或四个选自氧、氮或硫的相同或不同杂原子。这些环体系的实例为吖啶基、氮杂基、氮杂环丁基、氮丙啶基、benzimidazalinyl、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并苯硫基、苯并唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异唑基、苯并异噻唑基、咔唑基、4aH-咔唑基、咔啉基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、苯并二氢吡喃基、色烯基、噌啉基、十氢喹啉基、二苯并呋喃基、二苯并苯硫基、二氢呋喃[2,3-b]四氢呋喃基、二氢呋喃基、间二氧杂环戊基(dioxolyl)、二烷基、2H,6H-1,5,2-二噻嗪基、呋喃基、呋咱基(furazanyl)、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基(苯并咪唑基)、异四氢噻唑基、2-异四氢噻唑基、异噻唑基、异唑基、异唑烷基、2-异唑烷基、吗啉基、萘啶基、八氢异喹啉基、二唑基、1,2,3-二唑基、1,2,4-二唑基、1,2,5-二唑基、1,3,4-二唑基、唑烷基、唑基、唑烷基、oxothiolanyl、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、phenoxathiinyl、吩嗪基、二氮杂萘基、哌嗪基、哌啶基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶并苯硫基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四氢吡啶基、6H-1,2,5-噻二嗪基、1,2,3-噻重氮基、1,2,4-噻重氮基、1,2,5-噻重氮基、1,3,4-噻重氮基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并唑基、噻吩并咪唑基、硫代吗啉基、苯硫基、三嗪基、1,2,3-三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。
式I或II化合物中碳原子上的星号意味着,该特定碳原子为手性的且该混合物以R-或S-对映体存在。
式II化合物的不对称氢化有益地在温度为10℃~200℃和氢压力为1巴~200巴下进行。催化剂-反应物摩尔比有益地为1∶100~1∶10000。
适用于不对称氢化的溶剂例如为水,低级醇如甲醇、乙醇、丙醇或异丙醇,芳烃如甲苯,酮如丙酮,卤代烃如二氯甲烷,羧酸酯如乙酸乙酯,和醚如四氢呋喃。
此种形式的式I、III或IV的光活性2,3-二氢基丙酸衍生物(包括它们的对映体混合物和它们的盐形式)同样构成本发明的一部分主题。本文中对映体混合应当认为尤其是表示其中一种对映体相对于其它对映体富集的那些。
式II化合物是公知的,或者可以例如通过式IV化合物(其中R3和R4各自如上所定义)与式V胺(其中R1和R2各自如上所定义)反应来制备。
反应温度为0℃~120℃、优选为20℃~60℃。
反应时间通常为0.5~8小时,取决于混合物组成和所选温度范围。随后通过水性处理和用适宜溶剂(例如乙酸乙酯或二氯甲烷)萃取、或通过结晶,从反应混合物中除去获得的式II化合物。
本发明另一方面涉及新的式II化合物,其中R1和R2相同或不同,且各自独立地为
1)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由R11单取代的、二取代的或三取代的,
其中R11为
a)F、Cl、I或Br,
b)-(C1-C4)-烷基,
c)-CN,
d)-CF3,
e)-OR5,其中R5为氢原子或-(C1-C4)-烷基,
f)-N(R5)-R6,其中R5和R6各自独立地为氢原子或-(C1-C4)-烷基,
g)-C(O)-R5,其中R5为氢原子或-(C1-C4)-烷基,或
h)-S(O)x-R5,其中x为整数0、1或2,且R5为氢原子或-(C1-C4)-烷基;或
2)4~15元Het环,其中Het环为未取代的或者独立地由-(C1-C5)-烷基、-(C1-C5)-烷氧基、卤素、硝基、氨基、三氟甲基、羟基、羟基-(C1-C4)-烷基、亚甲二氧基、亚乙二氧基、甲酰基、乙酰基、氰基、羟基羰基、氨基羰基或-(C1-C4)-烷氧基羰基单取代的、二取代的或三取代的;
R3为
1)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-(C1-C4)-烷基、F、Cl或溴单取代的、二取代的或三取代的,
2)-O-C(CH3)3,
3)-O-CH(R7)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-CH3、F、Cl或溴单取代的、二取代的或三取代的,其中R7为氢原子或-(C1-C4)-烷基;
R4为
1)氢原子,
2)-(C1-C4)-烷基,或
3)-CH(R8)-芳基,其中R8为氢原子或-(C1-C4)-烷基。
本发明另一方面涉及新的式IV化合物,
其中,R1和R2相同或不同,且各自独立地为
1)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由R11单取代的、二取代的或三取代的,
其中R11为
a)F、Cl、I或Br,
b)-(C1-C4)-烷基,
c)-CN,
d)-CF3,
e)-OR5,其中R5为氢原子或-(C1-C4)-烷基,
f)-N(R5)-R6,其中R5和R6各自独立地为氢原子或-(C1-C4)-烷基,
g)-C(O)-R5,其中R5为氢原子或-(C1-C4)-烷基,或
h)-S(O)x-R5,其中x为整数0、1或2,且R5为氢原子或-(C1-C4)-烷基;或
2)4~15元Het环,其中Het环为未取代的或者独立地由-(C1-C5)-烷基、-(C1-C5)-烷氧基、卤素、硝基、氨基、三氟甲基、羟基、羟基-(C1-C4)-烷基、亚甲二氧基、亚乙二氧基、甲酰基、乙酰基、氰基、羟基羰基、氨基羰基或-(C1-C4)-烷氧基羰基单取代的、二取代的或三取代的;
R3为
1)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-(C1-C4)-烷基、F、Cl或溴单取代的、二取代的或三取代的,
2)-O-C(CH3)3,或
3)-O-CH(R7)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-CH3、F、Cl或溴单取代的、二取代的或三取代的,其中R7为氢原子或-(C1-C4)-烷基;
R4为
1)氢原子,
2)-(C1-C4)-烷基,或
3)-CH(R8)-芳基,其中R8为氢原子或-(C1-C4)-烷基。
因此,本发明涉及一种获得新的式IV化合物的方法,该方法包括:
a)在氢和催化剂的存在下氢化式II化合物,其中R1、R2、R3和R4各自如新的式II化合物中所定义,并且使其转化为式I化合物,和
b)使获得的式I化合物与重碳酸叔丁酯和酰化催化剂如二甲基氨基吡啶(DMAP)反应,由此获得式IV化合物,
其中R1、R2、R3和R4各自如新的式II化合物中所定义。
式I、II、III和IV化合物适合作为制备IkB激酶抑制剂的中间体(WO01/30774A1)。
下文中参照实施例详细地描述本发明。通过1H NMR(400MHz,于DMSO-D6中)确定最终产物;每种情形中,给出了主峰或两个主峰。温度以摄氏度给出;RT含义为室温(22℃~26℃)。所用缩写解释为或者对应于常规惯例。
实施例1
2-苯甲酰基氨基-3-二苯基氨基丙烯酸甲酯的制备
将66g(266mmol)2-苯甲酰基氨基-3-二甲基氨基丙烯酸甲酯和50g(295mmol)二苯基胺在40℃下溶解于1300ml异丙醇中。将该溶液与60ml(725mmol)浓盐酸在5分钟(min)内混合,并且再搅拌10min。减压下蒸发掉550ml溶剂,将悬浮液冷却到10℃并过滤出结晶产物。
产物:83.5g(理论值的84%)
1H NMR:3.62(s,3H),6.95-7.10(m,6H),7.20-7.30(m,8H),7.32-7.40(m,1H),7.61(s,1H),8.70(s,1H)。
实施例2
2-苄氧基羰基氨基-3-二苯基氨基丙烯酸甲酯的制备
将36g(129mmol)2-苄氧基羰基氨基-3-二甲基氨基丙烯酸甲酯和24.12g(142mmol)二苯基胺在40℃下溶解于630ml异丙醇中。随后,将该溶液与17.4ml浓盐酸在5min内混合,并且在40℃下再搅拌30min。将反应溶液浓缩到300ml,并缓慢与300ml水混合。吸滤出结晶产物,并在减压下在40℃下干燥。
产物:30.5g(理论值的59%)
1H NMR:3.62(s,3H),4.68(s,2H),6.95-7.10(m,6H),7.20-7.50(m,9H),7.61(s,1H)。
实施例3
外消旋的2-苯甲酰基氨基-3-二苯基氨基丙酸甲酯的制备
排除氧气之后,在高压釜中装入1g(2.68mmol)2-苯甲酰基氨基-3-二苯基氨基丙烯酸甲酯和40mg(0.042mmol)氯化三(三苯基膦)铑(I)。用氩气吹扫之后,加入40ml无氧甲醇。将高压釜气密封闭,在RT下氢化该溶液20小时(h)。使高压釜减压并用氮气吹扫。减压下蒸发掉溶剂,将残余物通过用硅胶60填充的柱子层析(洗脱液:1∶1乙酸乙酯/庚烷)。在减压下已蒸馏掉溶剂之后,剩余白色固体,其用于方法的配方,并且用作通过手性相上HPLC测量对映体纯度的测试体系。
HPLC柱子:Chiralpak OD 4×250
洗脱液:45∶2∶1己烷/EtOH/MeOH+0.1%二乙胺
温度:30℃
反应物停留时间:13.2分钟
S-对映体停留时间:11.8分钟
R-对映体停留时间:14.2分钟
产物:0.5g(理论值的50%)
1H NMR:3.62(s,3H),4.15-4.35(m,2H),4.75-4.90(m,1H),6.90-7.05(m,6H),7.20-7.30(m,4H),7.40-7.48(m,2H),7.50-7.60(m,1H),7.70-7.78(d,2H),8.85(d,1H)。
实施例4
(S)-2-苯甲酰基氨基-3-二苯基氨基丙酸甲酯的制备
排除氧气和水份之后,在安瓿中装入100mg 2-苯甲酰基氨基-3-二苯基氨基丙烯酸甲酯(0.255mmol)和1.9mg(0.0026mmol,0.01当量)[(S,S)-Et-FerroTANE-Rh]BF4。用氩气吹扫之后,加入5ml无氧甲醇。将安瓿气密封闭,并且在20巴氢压力下在高压釜中氢化24h。使高压釜减压并用氮气吹扫。通过HPLC测量氢化转化率。通过实施例4中所述方法,通过手性相上HPLC测量对映体选择性。[(R,R)-Et-FerroTANE-Rh]BF4催化剂生产出相同产率和对映体纯度的相应R衍生物。
ee:87%
实施例5
(S)-和(R)-2-苯甲酰基氨基-3-二苯基氨基丙酸甲酯的制备
类似于实施例4,用各种催化剂和溶剂来氢化2-苯甲酰基氨基-3-二苯基氨基丙烯酸甲酯。在未预先制备的催化剂情形中,由光活性膦配体和等摩尔量作为铑(I)盐的[Rh(cod)Cl]2原位制得活性催化剂。结果汇编于下面表1中。
表1:
RCS | 催化剂/配体 | 铑盐 | 压力[巴] | 溶剂 | 转化率[%] | ee[%] |
1∶100 | [(R,R)-Et-FerroTANE-Rh]BF4[268220-96-8] | 无 | 20 | 甲苯 | 97 | 90 |
1∶100 | [(R,R)-Et-FerroTANE-Rh]BF4[268220-96-8] | 无 | 20 | 甲醇 | 95 | R87 |
1∶100 | [(R,R)-Et-FerroTANE-Rh]BF4[268220-96-8] | 无 | 20 | 二氯甲烷 | 97 | 85 |
1∶100 | [(S,S)-Et-FerroTANE-Rh]BF4[268220-96-8] | 无 | 20 | 甲醇 | 94 | S86 |
1∶100 | [(R,R)-Me-DUPHOS-Rh]CF3SO3[136705-77-6] | 无 | 20 | 甲苯 | NC | nd |
1∶100 | [(R,R)-Me-DUPHOS-Rh]CF3SO3[136705-77-6] | 无 | 20 | 甲醇 | 71 | 90 |
1∶100 | [(R,R)-Me-DUPHOS-Rh]CF3SO3[136705-77-6] | 无 | 20 | 二氯甲烷 | 65 | 86 |
1∶100 | (R)-(S)-JOSIPHOS[155806-35-2] | 有 | 20 | 甲苯 | 68 | 36 |
1∶100 | (R)-(S)-JOISPHOS[155806-35-2] | 有 | 20 | 甲醇 | 91 | 31 |
1∶100 | (R)-(S)-JOSIPHOS[155806-35-2] | 有 | 20 | 二氯甲烷 | 82 | 11 |
1∶100 | L-BPPM-E[61478-28-2] | 有 | 20 | 甲苯 | 21 | 68 |
1∶100 | L-BPPM-E[61478-28-2] | 有 | 20 | 甲醇 | 80 | 35 |
1∶100 | L-BPPM-E[61478-28-2] | 有 | 20 | 二氯甲烷 | 5 | 45 |
1∶100 | (S)-BINAPHANE[544461-38-3] | 有 | 20 | 甲苯 | 37 | 6 |
1∶100 | (S)-BINAPHANE[544461-38-3] | 有 | 20 | 甲醇 | 31 | 48 |
1∶100 | (S)-BINAPHANE[544461-38-3] | 有 | 20 | 二氯甲烷 | 19 | 46 |
1∶100 | (R)-(-)-tert-Ferro[155830-69-6] | 有 | 20 | 甲醇 | 59 | 99 |
1∶100 | (R)-(-)-Cyclohexyl-Ferro[167416-28-6] | 有 | 20 | 甲醇 | 11 | 99 |
1∶100 | (R,R)-BDPP[96183-46-9] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (S,S)-CHIRAPHOS[64896-28-2] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (R,R)-DIOP[32305-98-9] | 有 | 20 | 甲醇 | 5 | 95 |
1∶100 | (R)-PROPHOS[67884-32-6] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (S,S)-NORPHOS[71042-55-2] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (R,R)-iPr-DUPHOS[136705-65-2] | 有 | 20 | 甲醇 | 30 | 99 |
1∶100 | [(R,R)-Et-BPE[136705-62-9] | 有 | 20 | 甲醇 | 62 | 99 |
1∶100 | [(R,R)-Me-BPE-Rh]CF3SO3[213343-69-2] | 无 | 20 | 甲醇 | 55 | 96 |
1∶100 | (R)-Me-BOPHOZ[406680-93-1] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | MonoPhos[157488-65-8] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | MonoPhos[157488-65-8] | 有 | 20 | 二氯甲烷 | NC | nd |
1∶100 | MonoPhos[490023-37-5] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | MonoPhos[490023-37-5] | 有 | 20 | 二氯甲烷 | NC | nd |
1∶100 | MonoPhos[380230-02-4] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | Mo无Phos[380230-02-4] | 有 | 20 | 二氯甲烷 | NC | nd |
RCS=催化剂与基质的摩尔比例
NC=无转化
nd=未检测
“ee[%]”栏中R或S含义为特定的R或S对映体
实施例6
排除氧气之后,在高压釜中装入表1中规定用量的2-苯甲酰基氨基-3-二苯基氨基丙烯酸甲酯和[(R,R)-Me-DUPHOS-Rh]CF3SO3。用氩气吹扫之后,加入下面规定用量的无氧甲醇。将高压釜气密封闭,在RT和30巴氢压力下氢化该溶液20h。使高压釜减压并用氮气吹扫。通过HPLC测量氢化转化率。通过实施例4中所述方法,通过手性相上HPLC测量对映体选择性。结果示于下面表2中。
表2:
催化剂/基质比例 | 催化剂 | 反应物[g] | 转化率[%] | ee[%] |
1∶1000 | [(R,R)-Me-DUPHOS-Rh]CF3SO3 | 26 | 25 | 87 |
实施例7
排除氧气之后,在高压釜中装入表2中规定用量的2-苯甲酰基氨基-3-二苯基氨基丙烯酸甲酯和[(S,S)-Et-FerroTANE-Rh]BF4。用氩气吹扫之后,加入下面规定用量的无氧甲醇。将高压釜气密封闭,在RT和30巴氢压力下氢化该溶液20h。使高压釜减压并用氮气吹扫。将该溶液过滤,与相同量水在40℃下混合并在RT下搅拌2h。吸滤出结晶产物,并在减压下在45℃下干燥到恒重。通过HPLC测量氢化转化率。通过实施例4中所述方法,通过手性相上HPLC测量对映体选择性。结果示于下面表3中。
表3:
催化剂/基质比例 | 催化剂 | 反应物[g] | 转化率[%] | ee[%] | 产率[%] |
1∶1000 | [(S,S)-Et-FerroTANE-Rh]BF4[268220-96-8] | 26 | 98 | 85 | 89 |
1∶2500 | [(S,S)-Et-FerroTANE-Rh]BF4[268220-96-8] | 26 | 99 | 84 | 88 |
1∶5000 | [(S,S)-Et-FerroTANE-Rh]BF4[268220-96-8] | 26 | 98 | 86 | 90 |
1∶10000 | [(S,S)-Et-FerroTANE-Rh]BF4[268220-96-8] | 26 | 73 | 85 | n.i. |
1∶5000 | [(S,S)-Et-FerroTANE-Rh]BF4[268220-96-8] | 260 | 98 | 85 | 89 |
n.i.=未分离
实施例8
排除氧气之后,在高压釜中装入1g(2.68mmol)2-苄氧基羰基氨基-3-二苯基氨基丙烯酸甲酯和40mg(0.042mmol)氯化三(三苯基膦)铑(I)。用氩气吹扫之后,加入40ml无氧甲醇。将高压釜气密封闭,在RT下氢化该溶液20h。使高压釜减压并用氮气吹扫。减压下蒸发掉溶剂,将残余物通过用硅胶60填充的柱子来纯化(洗脱液:1∶1乙酸乙酯/庚烷)。在减压下已蒸馏掉溶剂之后,剩余白色固体,其用于方法的配方,并且用作通过手性相上HPLC测量对映体纯度的测试体系。
HPLC柱子:Chiralpak OD 4×250
洗脱液:50∶2∶1己烷/EtOH/MeOH+0.1%二乙胺
温度:30℃
反应物停留时间:19.2分钟
S-对映体停留时间:14.6分钟
R-对映体停留时间:16.0分钟
产物:0.2g(理论值的20%)
1H NMR:3.60(s,3H),3.95-4.15(m,2H),4.35-4.45(m,1H),4.92-5.05(m,2H),6.90-7.00(m,6H),7.15-7.40(m,9H),7.85-7.90(d,1H)。
实施例9
类似于实施例5,用各种催化剂和溶剂来氢化2-苄氧基羰基氨基-3-二苯基氨基丙烯酸甲酯。在未预先制备的催化剂情形中,由光活性膦配体和等摩尔量作为铑(I)盐的[Rh(cod)Cl]2原位制得活性催化剂。结果汇编于下面表4中。
表4:
RCS | 催化剂/配体 | 铑盐 | 压力[巴] | 溶剂 | 转化率[%] | ee[%] |
1∶100 | [(R,R)-Et-FerroTANE-Rh]BF4[268220-96-8] | 无 | 20 | 甲苯 | 15 | 43 |
1∶100 | [(R,R)-Et-FerroTANE-Rh]BF4[268220-96-8] | 无 | 20 | 甲醇 | 2 | nd |
1∶100 | [(R,R)-Et-FerroTANE-Rh]BF4[268220-96-8] | 无 | 20 | 二氯甲烷 | 4 | nd |
1∶100 | [(R,R)-Me-DUPHOS-Rh]CF3SO3[136705-77-6] | 无 | 20 | 甲苯 | 15 | nd |
1∶100 | [(R,R)-Me-DUPHOS-Rh]CF3SO3[136705-77-6] | 无 | 20 | 甲醇 | 25 | 61 |
1∶100 | [(R,R)-Me-DUPHOS-Rh]CF3SO3[136705-77-6] | 无 | 20 | 二氯甲烷 | 29 | 46 |
1∶100 | (R)-(S)-JOSIPHOS[155806-35-2] | 有 | 20 | 甲苯 | 13 | nd |
1∶100 | (R)-(S)-JOSIPHOS[155806-35-2] | 有 | 20 | 甲醇 | 35 | 28 |
1∶100 | (R)-(S)-JOSIPHOS[155806-35-2] | 有 | 20 | 二氯甲烷 | 17 | 43 |
1∶100 | L-BPPM-E[61478-28-2] | 有 | 20 | 甲苯 | 5 | nd |
1∶100 | L-BPPM-E[61478-28-2] | 有 | 20 | 甲醇 | 7 | nd |
1∶100 | L-BPPM-E[61478-28-2] | 有 | 20 | 二氯甲烷 | 6 | nd |
1∶100 | (S)-BINAPHANE[544461-38-3] | 有 | 20 | 甲苯 | <5 | nd |
1∶100 | (S)-BINAPHANE[544461-38-3] | 有 | 20 | 甲醇 | <5 | nd |
1∶100 | (S)-BINAPHANE[544461-38-3] | 有 | 20 | 二氯甲烷 | <5 | nd |
1∶100 | [(R,R)-Me-BPE-Rh]CF3SO3 | 无 | 20 | 甲醇 | 36 | 73 |
1∶100 | (R)-(-)-tert-Ferro[155830-69-6] | 有 | 20 | 甲醇 | 85 | 21 |
1∶100 | (R)-(S)-JOSIPHOS | 有 | 20 | 甲醇 | 99 | 24 |
1∶100 | [(R,R)-Et-FerroTANE-Rh]BF4 | 有 | 20 | 甲醇 | 52 | 60 |
1∶100 | (R,R)-BDPP[96183-46-9] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (S,S)-CHIRAPHOS[64896-28-2] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (R,R)-DIOP[32305-98-9] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (R)-PROPHOS[67884-32-6] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | (S,S)-NORPHOS[71042-55-2] | 有 | 20 | 甲醇 | NC | nd |
1∶100 | [(R,R)-Et-BPE-Rh]BF4 | 有 | 20 | 甲醇 | 6 | 23 |
1∶100 | (R)-Me-BOPHOZ(Eastman) | 无 | 20 | 甲醇 | 25 | 16 |
RCS=催化剂与基质的比例
NC=无转化
nd=未测量
<=小于
实施例10
(S)-2-(苯甲酰基-叔丁氧基羰基氨基)-3-二苯基氨基丙酸甲酯的制备
将18.7g(S)-2-(苯甲酰基-叔丁氧基羰基氨基)-3-二苯基氨基丙酸甲酯(ee=85%)、20.6g重碳酸二叔丁酯和1.2g N,N-二甲基氨基吡啶溶解于90ml乙腈中,并在40℃下搅拌3小时。减压下蒸馏掉乙腈,将剩余残留物在300ml二异丙基醚中收取(take up)并热过滤。过夜之后结晶出无色固体产物。
产物:23.7g(理论值的88%)
1H NMR:1.38(s,9H),3.70(s,3H),4.35-4.58(m,2H),5.45-5.52(m,1H),6.93-7.05(m,6H),7.13-7.18(m,2H),7.22-7.30(m,4H),7.32-7.30(m,2H),7.45-7.52(m,1H)。
实施例11
(S)-2-(叔丁氧基羰基氨基)-3-二苯基氨基丙酸甲酯的制备
将1.3g(S)-2-(苯甲酰基-叔丁氧基羰基氨基)-3-二苯基氨基丙酸甲酯溶解于13ml甲醇中,并与2.74ml甲醇镁在甲醇中的1M溶液混合。将溶液在RT下搅拌过夜和在减压下浓缩。将残余物在乙酸乙酯中收取并用水洗涤。将乙酸乙酯相在硫酸镁上干燥,过滤和在减压下浓缩。从少量二异丙基醚/庚烷中结晶残余物。
产物:0.95g(理论值的90%)
1H NMR:1.38(s,9H),3.55(s,3H),4.10-4.25(m,2H),4.50-4.62(m,1H),5.10-5.25(m,1H),6.90-7.05(m,6H),7.20-7.30(m,4H)。
实施例12
(S)-2-氨基-3-二苯基氨基丙酸甲酯对甲苯磺酸盐的制备
将18.5g(S)-2-(叔丁氧基羰基氨基)-3-二苯基氨基丙酸甲酯(ee=85%)溶解于100ml二氯甲烷中,并与50ml三氟乙酸(TFA)混合。将溶液在回流下加热30分钟,并随后在减压下浓缩至体积100ml。将溶液用水洗涤并与9g对甲苯磺酸混合。加入125ml正丁醇,并蒸发掉剩余的二氯甲烷。为了结晶对甲苯磺酸盐,将该溶液冷却到RT并搅拌过夜。吸滤出固体,并在减压下干燥到恒重。
产物:16.6g(理论值的81%,基于期望的异构体),
1H NMR:2.38(s,3H),3.30(s,3H),4.10-4.35(m,3H),5.45-5.52(m,1H),6.73-6.95(m,6H),7.01-7.05(m,2H),7.10-7.18(m,4H),7.58-7.62(m,2H),8.30-8.55(s,宽,3H,NH)。
ee:99%。
实施例13
2-苯甲酰基氨基-3-苯基氨基丙烯酸甲酯的制备
将10g(39.5mmol)2-苯甲酰基氨基-3-二甲基氨基丙烯酸甲酯和11.1g(118mmol)苯胺在40℃下溶解于200ml异丙醇中。将该溶液与3.6ml(43.5mmol)浓盐酸在5分钟(min)内混合,并再搅拌10min。加入200ml去离子水,将悬浮液冷却到10℃并过滤出结晶产物。
产物:11.5g(理论值的92%)
1H NMR:3.62(s,3H);6.90-7.00(m,1H);7.19(d,2H);7.25-7.30(m,2H);7.48-7.61(m,3H);7.93(d,1H);8.02(d,2H);8.90(d,1H);9.15(s,1H)。
实施例14
2-苯甲酰基氨基-3-(4-氟代苯基氨基)丙烯酸甲酯的制备
将10g(39.5mmol)2-苯甲酰基氨基-3-二甲基氨基丙烯酸甲酯和11.4g(118mmol)4-氟苯胺在40℃下溶解于200ml异丙醇中。将该溶液与3.6ml(43.5mmol)浓盐酸在5分钟(min)内混合,并再搅拌30min。将悬浮液冷却到10℃并过滤出结晶产物。
产物:12.4g(理论值的94%)
1H NMR:3.62(s,3H);7.05-7.24(m,4H);7.48-7.52(m,3H);7.88(d,1H);8.00-8.04(m,2H);8.90(d,1H);9.15(s,1H)。
实施例15
2-苯甲酰基氨基-3-(吡啶-2-基氨基)丙烯酸甲酯的制备
将10g(39.5mmol)2-苯甲酰基氨基-3-二甲基氨基丙烯酸甲酯和11.3g(118mmol)2-氨基吡啶在40℃下溶解于200ml异丙醇中。将该溶液与3.96ml(48mmol)浓盐酸在5分钟(min)内混合,并再搅拌30min。将悬浮液冷却到10℃并过滤出结晶产物。
产物:7.3g(理论值的60%)
1H NMR:3.62(s,3H);6.92-6.97(m,1H);7.02(d,1H);7.45-7.70(m,4H);8.02(d,2H);8.22-8.24(m,1H);8.60(d,1H);9.22(s,1H);9.45(d,1H)。
实施例16
2-苯甲酰基氨基-3-(噻唑-2-基氨基)丙烯酸甲酯的制备
将10g(39.5mmol)2-苯甲酰基氨基-3-二甲基氨基丙烯酸甲酯和11.3g(118mmol)2-氨基噻唑在40℃下溶解于200ml异丙醇中。将该溶液与3.96ml(48mmol)浓盐酸在5分钟(min)内混合,并再搅拌60min。加入75ml去离子水,将悬浮液冷却过夜并过滤出结晶产物。
产物:8.6g(理论值的70%)
1H NMR:3.62(s,3H);7.08(d,1H);7.32(d,1H);7.45-7.60(m,3H);8.02(d,2H);8.22(d,1H);9.28(s,1H);10.45(d,1H)。
Claims (12)
1、式II化合物
其中,R1和R2相同或不同,且各自独立地为
1)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由R11单取代的、二取代的或三取代的,
其中R11为
a)F、CI、I或Br,
b)-(C1-C4)-烷基,
c)-CN,
d)-CF3,
e)-OR5,其中R5为氢原子或-(C1-C4)-烷基,
f)-N(R5)-R6,其中R5和R6各自独立地为氢原子或-(C1-C4)-烷基,
g)-C(O)-R5,其中R5为氢原子或-(C1-C4)-烷基,或
h)-S(O)x-R5,其中x为整数0、1或2,且R5为氢原子或-(C1-C4)-烷基;或者
2)4~15元Het环,其中Het环为未取代的或者独立地由-(C1-C5)-烷基、
-(C1-C5)-烷氧基、卤素、硝基、氨基、三氟甲基、羟基、羟基-(C1-C4)-烷基、亚甲二氧基、亚乙二氧基、甲酰基、乙酰基、氰基、羟基羰基、氨基羰基或-(C1-C4)-烷氧基羰基单取代的、二取代的或三取代的;
R3为
1)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-(C1-C4)-烷基、F、Cl或溴单取代的、二取代的或三取代的,
2)-O-C(CH3)3,或
3)-O-CH(R7)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-CH3、F、Cl或溴单取代的、二取代的或三取代的,
其中R7为氢原子或-(C1-C4)-烷基;
R4为
1)氢原子,
2)-(C1-C4)-烷基,或
3)-CH(R8)-芳基,
其中R8为氢原子或-(C1-C4)-烷基。
3、一种获得式I化合物的方法,
其中,R1和R2相同或不同,且各自独立地为
1)氢原子,
2)-(C1-C4)-烷基,
3)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由R11单取代的、二取代的或三取代的,
其中R11为
a) F、Cl、I或Br,
b)-(C1-C4)-烷基,
c)-CN,
d)-CF3,
e)-OR5,其中R5为氢原子或-(C1-C4)-烷基,
f)-N(R5)-R6,其中R5和R6各自独立地为氢原子或-(C1-C4)-烷基,
g)-C(O)-R5,其中R5为氢原子或-(C1-C4)-烷基,或
h)-S(O)x-R5,其中x为整数0、1或2,且R5为氢原子或-(C1-C4)-烷基;
4)-CH(R7)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-CH3、F、Cl或溴单取代的、二取代的或三取代的,其中R7为氢原子或-(C1-C4)-烷基,或
5)4~15元Het环,其中Het环为未取代的或者独立地由-(C1-C5)-烷基、-(C1-C5)-烷氧基、卤素、硝基、氨基、三氟甲基、羟基、羟基-(C1-C4)-烷基、亚甲二氧基、亚乙二氧基、甲酰基、乙酰基、氰基、羟基羰基、氨基羰基或-(C1-C4)-烷氧基羰基单取代的、二取代的或三取代的;
R3为
1)氢原子,
2)-(C1-C4)-烷基,
3)-(C6-C14)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-(C1-C4)-烷基、F、Cl或溴单取代的、二取代的或三取代的,
4)-O-C(CH3)3,或
5)-O-CH(R7)-芳基,其中芳基为未取代的或者独立地由-NO2、-O-CH3、F、Cl或溴单取代的、二取代的或三取代的,
其中R7为氢原子或-(C1-C4)-烷基;
R4为
1)氢原子,
2)-(C1-C4)-烷基,或
3)-CH(R8)-芳基,
其中R8为氢原子或-(C1-C4)-烷基,
该方法包括在氢和催化剂的存在下氢化式II化合物
其中,R1、R2、R3和R4各自如式I中所定义,且式II化合物可以存在E或Z构型的双键。
4、权利要求3的方法,其中获得式I化合物,其中:
R1为苯基或氢原子,
R2为苯基、吡啶基或噻唑基,其中苯基、吡啶基或噻唑基为未取代的或者由氟或氯取代,和
R3为苯基或-O-CH2-苯基,和
R4为甲基或乙基。
5、权利要求3或4的方法,其中所用催化剂包含铑络合物、钌络合物或铱络合物或其混合物。
6、权利要求3~5中一项或多项的方法,其中催化剂与式II化合物的摩尔比例为1∶100~1∶10000。
7、权利要求3~6中一项或多项的方法,其中在温度为10℃~200℃和氢压力为1巴~200巴下进行氢化。
8、权利要求3~7中一项或多项的方法,其中所用溶剂包括水,醇如甲醇、乙醇、丙醇或异丙醇,芳烃如甲苯,酮如丙酮,卤代烃如二氯甲烷,羧酸酯如乙酸乙酯,和醚如四氢呋喃,或其混合物。
12、一种获得权利要求2的式IV化合物的方法,其包括:
a)在氢和催化剂的存在下氢化权利要求1的式II化合物,
其中R1、R2、R3和R4各自如权利要求2中所定义,
并且使其转化为式I化合物,和
b)使获得的式I化合物与重碳酸叔丁酯和酰化催化剂如二甲基氨基吡啶反应,由此获得式IV化合物,
其中R1、R2、R3和R4各自如权利要求2中所定义。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004033406.4 | 2004-07-10 | ||
DE102004033406A DE102004033406A1 (de) | 2004-07-10 | 2004-07-10 | Verfahren zur Herstellung der enantiomeren Formen von 2,3-Diaminopropionsäurederivaten |
PCT/EP2005/006920 WO2006005436A1 (de) | 2004-07-10 | 2005-06-28 | Verfahren zur herstellung der enantiomeren formen von 2,3-diaminopropionsäurederivaten |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1984881A true CN1984881A (zh) | 2007-06-20 |
CN1984881B CN1984881B (zh) | 2012-02-29 |
Family
ID=35207448
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2005800233299A Expired - Fee Related CN1984881B (zh) | 2004-07-10 | 2005-06-28 | 制备对映体形式2,3-二氨基丙酸衍生物的方法 |
Country Status (12)
Country | Link |
---|---|
US (2) | US7514578B2 (zh) |
EP (1) | EP1778627B1 (zh) |
JP (1) | JP4861317B2 (zh) |
KR (1) | KR20070039037A (zh) |
CN (1) | CN1984881B (zh) |
AT (1) | ATE387423T1 (zh) |
AU (1) | AU2005261977B2 (zh) |
CA (1) | CA2573243A1 (zh) |
DE (2) | DE102004033406A1 (zh) |
IL (1) | IL180571A0 (zh) |
MX (1) | MX2007000042A (zh) |
WO (1) | WO2006005436A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103209961A (zh) * | 2010-08-12 | 2013-07-17 | 赛诺菲 | 用于制备2,3-二氨基丙酸衍生物的对映异构体形式的方法 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE112005000772B4 (de) * | 2004-04-07 | 2017-12-28 | Waters Technologies Corp. (N.D.Ges.D. Staates Delaware) | Flüssigchromatographiereagenz und Verfahren zum Auftrennen von Enantiomeren |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4136656A1 (de) * | 1991-11-07 | 1993-05-13 | Basf Ag | Verwendung von 3-amino-2-(benzoylamino)acrylsaeureestern als stabilisatoren fuer organische materialien |
DE10237722A1 (de) | 2002-08-17 | 2004-08-19 | Aventis Pharma Deutschland Gmbh | Indol- oder Benzimidazolderivate zur Modulation der IKappaB-Kinase |
AR049274A1 (es) * | 2004-05-12 | 2006-07-12 | Aventis Pharma Inc | Acido2-{[2-(2-metilaminopirimidin-4-il)-1h-indol-5-carbonil]amino}-3-(fenilpiridin-2-ilamino)propionico sustancialmente puro como inhibidor selectivo de la quinasa ikk-2 |
-
2004
- 2004-07-10 DE DE102004033406A patent/DE102004033406A1/de not_active Withdrawn
-
2005
- 2005-06-28 KR KR1020077000573A patent/KR20070039037A/ko active IP Right Grant
- 2005-06-28 CA CA002573243A patent/CA2573243A1/en not_active Abandoned
- 2005-06-28 MX MX2007000042A patent/MX2007000042A/es active IP Right Grant
- 2005-06-28 CN CN2005800233299A patent/CN1984881B/zh not_active Expired - Fee Related
- 2005-06-28 AU AU2005261977A patent/AU2005261977B2/en not_active Ceased
- 2005-06-28 DE DE502005003019T patent/DE502005003019D1/de active Active
- 2005-06-28 AT AT05758872T patent/ATE387423T1/de not_active IP Right Cessation
- 2005-06-28 JP JP2007519672A patent/JP4861317B2/ja not_active Expired - Fee Related
- 2005-06-28 WO PCT/EP2005/006920 patent/WO2006005436A1/de active IP Right Grant
- 2005-06-28 EP EP05758872A patent/EP1778627B1/de not_active Not-in-force
-
2007
- 2007-01-04 IL IL180571A patent/IL180571A0/en not_active IP Right Cessation
- 2007-01-10 US US11/621,654 patent/US7514578B2/en not_active Expired - Fee Related
-
2009
- 2009-04-06 US US12/418,737 patent/US8053590B2/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103209961A (zh) * | 2010-08-12 | 2013-07-17 | 赛诺菲 | 用于制备2,3-二氨基丙酸衍生物的对映异构体形式的方法 |
Also Published As
Publication number | Publication date |
---|---|
EP1778627A1 (de) | 2007-05-02 |
DE502005003019D1 (de) | 2008-04-10 |
CA2573243A1 (en) | 2006-01-19 |
IL180571A0 (en) | 2007-06-03 |
JP2008505860A (ja) | 2008-02-28 |
EP1778627B1 (de) | 2008-02-27 |
AU2005261977B2 (en) | 2010-11-04 |
AU2005261977A1 (en) | 2006-01-19 |
US8053590B2 (en) | 2011-11-08 |
CN1984881B (zh) | 2012-02-29 |
MX2007000042A (es) | 2007-03-27 |
US7514578B2 (en) | 2009-04-07 |
KR20070039037A (ko) | 2007-04-11 |
US20070238778A1 (en) | 2007-10-11 |
JP4861317B2 (ja) | 2012-01-25 |
DE102004033406A1 (de) | 2006-02-16 |
ATE387423T1 (de) | 2008-03-15 |
WO2006005436A1 (de) | 2006-01-19 |
US20090203918A1 (en) | 2009-08-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2518435C (en) | Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation | |
EP1856028A1 (en) | Process to chiral beta amino acid derivatives by asymmetric hydrogenation | |
CN110615744A (zh) | 一种布瓦西坦中间体及其制备方法 | |
EP2172443A1 (en) | Method for producing optically active amine | |
KR20070002101A (ko) | (+)-시스-세르트랄린의 신규한 제조 방법 | |
CN1984881B (zh) | 制备对映体形式2,3-二氨基丙酸衍生物的方法 | |
EP2566843A2 (en) | Process for the preparation of chiral beta amino carboxamide derivatives | |
CN115322100A (zh) | 一种δ,ε-烯基酮类化合物及其制备方法与应用 | |
CN109651160A (zh) | 一种催化苯乙炔氢胺化反应制备烯胺类化合物的方法 | |
CA2716694A1 (en) | Process | |
CN105111134A (zh) | 一种制备(r)-或(s)-3-氨基哌啶双盐酸盐的方法 | |
CN113121413B (zh) | 一种jak3酶抑制剂关键中间体的制备方法 | |
CN117700373A (zh) | 一种吗啉环类化合物及衍生物与制备方法和应用 | |
WO2003024981A2 (de) | Verfahren zur herstellung optisch aktiver, hydroxygruppen enthaltender verbindungen | |
JPH0365243A (ja) | 反応促進剤 | |
CN115999636A (zh) | 一种用于制备n-取代苯胺类化合物的催化剂及其应用 | |
JPH0390050A (ja) | 光学活性な1―アルキルアミノ―3―アリールオキシ―2―プロパノール類の製造方法 | |
CN104030997A (zh) | 一种用于埃索美拉唑不对称合成的催化剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1101820 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1101820 Country of ref document: HK |
|
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120229 Termination date: 20130628 |