CN100383121C - Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom - Google Patents
Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom Download PDFInfo
- Publication number
- CN100383121C CN100383121C CNB2006100132557A CN200610013255A CN100383121C CN 100383121 C CN100383121 C CN 100383121C CN B2006100132557 A CNB2006100132557 A CN B2006100132557A CN 200610013255 A CN200610013255 A CN 200610013255A CN 100383121 C CN100383121 C CN 100383121C
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- benzyl ester
- reaction
- synthesis
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- -1 benzyl ester Chemical class 0.000 title claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- UPNUIXSCZBYVBB-JVFUWBCBSA-N alvimopan Chemical compound C([C@@H](CN1C[C@@H]([C@](CC1)(C)C=1C=C(O)C=CC=1)C)C(=O)NCC(O)=O)C1=CC=CC=C1 UPNUIXSCZBYVBB-JVFUWBCBSA-N 0.000 claims description 12
- 229960004516 alvimopan Drugs 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 125000003277 amino group Chemical group 0.000 abstract 1
- 238000006257 total synthesis reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 238000003756 stirring Methods 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 11
- 235000011121 sodium hydroxide Nutrition 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 230000006837 decompression Effects 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- AERGPHKCLKRNGI-ZETCQYMHSA-N (2S)-2-[2-(hydroxymethyl)phenyl]propanoic acid Chemical compound OCC1=C(C=CC=C1)[C@@H](C(=O)O)C AERGPHKCLKRNGI-ZETCQYMHSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- DJCVZSHJJGZQBS-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(CNBr)=O Chemical compound C(C1=CC=CC=C1)OC(CNBr)=O DJCVZSHJJGZQBS-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 235000007715 potassium iodide Nutrition 0.000 description 3
- 229960004839 potassium iodide Drugs 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 229950004288 tosilate Drugs 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- AERGPHKCLKRNGI-UHFFFAOYSA-N 2-[2-(hydroxymethyl)phenyl]propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1CO AERGPHKCLKRNGI-UHFFFAOYSA-N 0.000 description 2
- CXYOBLKMEPOAPB-UHFFFAOYSA-N 4,4-dimethyl-2,3-dihydro-1h-pyridine Chemical compound CC1(C)CCNC=C1 CXYOBLKMEPOAPB-UHFFFAOYSA-N 0.000 description 2
- VEWPXSGLSLGDGZ-UHFFFAOYSA-N CN(C)C.C1CNC=CC1 Chemical compound CN(C)C.C1CNC=CC1 VEWPXSGLSLGDGZ-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 230000003113 alkalizing effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229930016911 cinnamic acid Natural products 0.000 description 2
- 235000013985 cinnamic acid Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229940059936 lithium bromide Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000014347 soups Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- 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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 1
- GGJSENCNLGMGEM-UHFFFAOYSA-N C1(=CC=CC=C1)CCN.C1(=CC=CC=C1)C(C(=O)O)C Chemical compound C1(=CC=CC=C1)CCN.C1(=CC=CC=C1)C(C(=O)O)C GGJSENCNLGMGEM-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010054048 Postoperative ileus Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 description 1
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 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
- 239000006227 byproduct Substances 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- FVLGPYFFONYLRZ-UHFFFAOYSA-N ethyl 2-benzylprop-2-enoate Chemical compound CCOC(=O)C(=C)CC1=CC=CC=C1 FVLGPYFFONYLRZ-UHFFFAOYSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a benzyl ester compound substituted by (+)-(3R, 4R)-[[2S-[[4-(3-hydroxyphenyl-3, 4-dimethyl-1-piperidinyl)-methyl]-1-oxo-3-phenylpropyl]amino group] acetic acid, a preparation method thereof, and a new technology for preparing mopipe by the compound. The present invention has the following new technology method that the synthesis of 'a chain type' of the original patent method is converted into the respective preparation of 'two chains'; the total synthesis step is obviously shortened; the synthesis cost is obviously reduced and is about one half of that of the original patent method, and the benzyl ester compound has market competitiveness in the price aspect. Simultaneously, the synthesis reaction condition of the new technology is mild; the synthesis operation steps are simple; each-step reaction does not need to be operated under the conditions, such as specific low temperature, absolutely no water, etc., and accordingly, the benzyl ester compound is suitable for industrialized production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry synthesis technical field, say so more specifically (+)-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl-3,4-dimethyl-piperidino)-methyl]-1-oxo-3-hydrocinnamyl] amino] acetic acid substituted benzyl ester cpds and preparation method thereof and with the novel process of this compound LY246736.
Background technology
LY246736 (alvimopan) is a kind of new selective opiate receptor antagonist, is mainly used in the treatment post operative ileus.The preparation method of this product report at present has two kinds of methods, patented method 1 is with (+)-3R, 4R-(3-hydroxy phenyl)-3,4-lupetidine, 2 benzyl acrylic acid ethyl ester are starting raw material, through addition, hydrolysis, carboxylic close, chiral column chromatography, hydrolysis totally five step prepared in reaction target compounds (seeing patent CN1065455A); The shortcoming of this method is respectively to go on foot reaction product to be soup compound, the separation of intermediate, purifying, and the chirality Separation of Enantiomers all needs the method preparation by column chromatography, therefore is not suitable for suitability for industrialized production.Patented method 2 is with (+)-3R, 4R-(3-hydroxy phenyl)-3,4-lupetidine, methyl acrylate are starting raw material, through addition, alkylation, fractionation, hydrolysis, carboxylic close, hydrolysis altogether six-step process prepare target compound (seeing patent CN1057294C).This method has solved the technological difficulties that can't realize suitability for industrialized production in the method 1; but shortcoming is must use in the alkylating prepared in reaction process diisopropylamine lithium as alkalizing agent; and need operate at low temperature (40 ℃), absolute anhydrous condition; diisopropylamine lithium is at home without any manufacturer production at present; and this material belongs to strongly alkaline compound; has severe corrosive; must be under the condition of nitrogen protection, low temperature, airtight preservation; preservation condition is relatively harsher, and therefore the operation of this step reaction is not easy to carry out future scale operation.
Summary of the invention
The objective of the invention is to disclose intermediate A Wei benzyl ester cpds of synthetic LY246736 and preparation method thereof, and explore by experiment, verify, finally set up the new synthetic method of this compound, solve the technological difficulties in the synthesis technique for preparing alvimopan, made it to be more suitable for large-scale industrial production.
LY246736 intermediate A Wei benzyl ester cpds of the present invention, chemical name is (+)-(3R, 4R)-and [[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] acetic acid substituted benzyl ester cpds has following structure:
Wherein: Y is electron-withdrawing groups such as hydrogen, chlorine, bromine or nitro; Y can be in ortho position, contraposition or a position of phenyl ring; Preferred Y is that hydrogen or Y are the contraposition at phenyl ring of bromine and bromine.
The preparation method of described compound: under the alkaline condition of organic solvent, compound III and Compound I I are carried out the N-alkylated reaction prepare Compound I
Wherein: X is chlorine, bromine, methylsulfonyl, benzenesulfonyl or p-bromobenzenesulfonyl; Y is electron-withdrawing groups such as hydrogen, chlorine, bromine or nitro; Preferred Y is that hydrogen or Y are the contraposition at phenyl ring of bromine and bromine.
Wherein the mole ratio of compound III and Compound I I is 1: 1～10, preferred 1: 1～3.
Wherein said organic solvent is methyl alcohol, ethanol, Virahol, DMF, propyl carbinol, ethylene glycol monomethyl ether or acetonitrile etc.
Wherein preparing the used alkali of Compound I is selected from: mineral alkali or organic bases, and wherein mineral alkali is selected from yellow soda ash, sodium bicarbonate, salt of wormwood, potassium hydroxide, sodium hydroxide etc.; Organic bases is selected from triethylamine, pyridine, methylamine or dimethylamine.
Another object of the present invention is with (+)-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] acetic acid substituted benzyl ester cpds is the novel process of the synthetic LY246736 of intermediate, this technology may further comprise the steps: compound (I) hydrogenation or hydrolysis are prepared target compound V.
Wherein the used catalyzer of Compound I hydrogenation is Pd/C; The weight ratio of Compound I and catalyzer is 1: 0.1～5, preferred 1: 0.1～1, be more preferably 1: 0.1～and 0.5.
The present invention with (+)-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] acetic acid substituted benzyl ester is that the synthetic route of the synthetic LY246736 of intermediate is:
Wherein, X is chlorine, bromine, methylsulfonyl, benzenesulfonyl or p-bromobenzenesulfonyl; Y is a hydrogen, chlorine, bromine or nitro.
The new synthesis process method is with optically pure individual isomer (+)-3R; 4R-(3-hydroxy phenyl)-3; 4-lupetidine, (S)-halogenated methyl phenylpropyl alcohol acyl glycine replace benzyl ester or (S)-alkylsulfonyl methylbenzene Propionylglycine, and to replace the benzyl ester be starting raw material; adopt the alkylating method of N-; the optical isomer of two chiralitys is synthesized the optically pure individual isomer product of preparation through alkylated reaction, and the method by hydrogenolysis or hydrolysis prepares target compound subsequently.
The advantage that the present invention adopts A Wei benzyl ester cpds to prepare the LY246736 novel process is:
1, new process under the condition of alkalescence, prepares single optical isomer through directed synthesizing of alkylated reaction with the optical isomer of two chiralitys.The reaction conditions of this synthetic method, post-treating method, configuration to the chiral centre of reaction raw materials, product does not change, and can obtain the material of ideal optical purity, saves the operation steps that adopts method that conventional chemical splits or the isolating method of chiral column to carry out stage enantiomer separation.The synthesis yield of new synthesis process method is about about 80%, compares with resolution yield in the patent documentation method about 34%, has significance and improves.
2, the synthesis step of new process is that synthetic changing into " two chain " with former patented method " chain type " prepares respectively, total synthetic step obviously shortens, synthetic cost obviously reduces, and is about 1/2nd of former patented method approximately, is having more the market competitiveness in price.
3, the synthetic reaction condition gentleness of novel process, the synthetic operation step is simple, and each step reaction does not need specific low temperature, absolute condition such as anhydrous to operate.This method has solved and has respectively gone on foot reaction product in the patented method 1 and be soup compound, the separation of intermediate, purifying etc. can't be realized the technological difficulties of suitability for industrialized production, also solved simultaneously and must use diisopropylamine lithium in the former patented method 2 in the alkylating prepared in reaction process as alkalizing agent, and the technological difficulties that need operate at low temperature (40 ℃), absolute anhydrous condition are more suitable for carrying out suitability for industrialized production.
4, the finished product of present method of novel process preparation can obtain by the method for hydrogenolysis, be white crystalline powder, have reduced in the product that carboxylic closes the issuable oxidized byproduct of reaction in the patent documentation.The content of the crude product of novel process preparation is about 96% in the experimentation, is about 88% according to the content of the crude product of former patented method preparation.The product appearance of novel process preparation is a white in addition, and the product appearance of former patented method preparation is an off-white color or light yellow, and according to the comprehensive comparison of quality product, the quality product of novel process more is better than the product of former patented method preparation.
Starting raw material (+)-3R of novel process, 4R-(3-hydroxy phenyl)-3, the synthesis route of 4-lupetidine:
Specific implementation method is seen patent CN1065455A.
The starting raw material of novel process (S)-2-halogenated methyl phenylpropyl alcohol acyl-N-benzyl-glycine replaces the synthetic route of benzyl ester thing:
Find in the experiment that Y is a polar group, as halo, nitro etc., the position of substitution is in contraposition, because electrophilic effect more helps to make A Wei benzyl ester thing to slough substituted benzyl by hydrogenolysis and prepares LY246736.(S)-and the synthetic method referenced patent EP0906900 of 2-halogenated methyl phenylpropyl alcohol acyl-N-benzyl-glycine benzyl ester substituent, EP0937710 is prepared.4-bromo-glycine benzyl ester tosilate is an industrial raw material.
Embodiment
The present invention will be further described below in conjunction with preparation example, embodiment.
One, preparation example 1:(S)-preparation of 2-halogenated methyl phenylpropyl alcohol acyl-glycine benzyl ester thing
1, the preparation of 3-hydroxyl-2-methene-3-methyl phenylpropionate
With the phenyl aldehyde of 67.3g, the methyl acrylate of 60ml, the triethylene diamine of 13.5g add in the reaction flask of 500ml, stirring at room 5 days, add 60ml water, 60ml concentrated hydrochloric acid, 120ml ethyl acetate, after mixing, layering, organic layer is washed 2 times with 20ml, the organic layer anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, get light yellow oil 110.5g, underpressure distillation, the cut of 85-90 ℃/7-9mmHg of collection, get colourless liquid 97.5g, content is greater than 98% (GC method), yield 80%.
2, the preparation of 2-methylol cinnamic acid
3-hydroxyl-2-methene-3-methyl phenylpropionate of 60g is dissolved in the diacetyl oxide of 65ml, stir the vitriol oil that drips 0.1ml down, be warming up to 95-100 ℃, stirred 4 hours, concentrating under reduced pressure gets yellow oil, yellow oil is dissolved in the methyl alcohol of 200ml, the sodium hydroxide of Dropwise 5 0g stirred concentrating under reduced pressure methyl alcohol 2 hours in the alkaline solution of the water configuration of 400ml, drip concentrated hydrochloric acid, regulate the pH value to 3-4, the ethyl acetate extraction of 100ml 3 times merges organic layer, concentrating under reduced pressure, get yellow oil 53g, content can directly drop into next step reaction greater than 90% (HPLC method).
3, the preparation of 2-methylol phenylpropionic acid
The 2-methylol cinnamic acid oily matter of 40g is added in the reaction flask of 500ml, 95% ethanol that adds 250ml, the Pd/C (10%) of adding 4g is warming up to 50-55 ℃, normal pressure hydrogenation, stirring reaction about 7 hours, filters until stopping to inhale hydrogen, concentrating under reduced pressure, get light yellow oil 35.8g, place gradually and solidify, content is greater than 95% (HPLC method).
4, the preparation of (S)-2-methylol phenylpropionic acid
The 2-methylol phenylpropionic acid of 35.8g is added in the water of 400ml, add (S)-phenylethylamine of 26.5f, be heated to 80-90 ℃ under stirring, all dissolving, be cooled to room temperature, separate out white, needle-shaped crystals gradually, filter drying, get 22.2g, fusing point 140-143 ℃, content is greater than 98% (HPLC method).(S)-2-methylol phenylpropionic acid phenylethylamine salt of 22.2g is added in the water of the ethyl acetate of 200ml and 100ml, add concentrated hydrochloric acid and regulate the pH value to 3-4, mix layering, the washing of organic layer usefulness 30ml 2 times, organic layer anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure gets shallow white oily matter 12.5g, places gradually and solidifies, content is greater than 95% (HPLC method), yield 34.9%.
5, (S)-2-methylol phenylpropyl alcohol acyl-4 '-preparation of bromo-glycine benzyl ester
(S)-2-methylol phenylpropionic acid with 10g, 24.2g 4-bromo-glycine benzyl ester tosilate, the tetrahydrofuran (THF) of 100ml adds in the reaction flask of 250ml, stirs the triethylamine that adds 7.5ml down, 7.3g 1-hydroxy benzo triazole (HoBt), the DCC that adds 11.2g after about 10 minutes, stirring at room 24 hours is filtered, filtrate decompression concentrate light yellow oil, add the ethyl acetate of 100ml, the hydrochloric acid 100ml of 1N stirred 0.5 hour, filter, layering, organic layer is washed 2 times with 20ml, and the saturated sodium bicarbonate of 20ml is washed 2 times, wash 1 time, the organic layer anhydrous magnesium sulfate drying filters concentrating under reduced pressure, get oily matter 30.5g, add toluene: sherwood oil (1: 1) heating for dissolving, white crystals 22.1g is separated out in the room temperature cooling gradually, content is greater than 98% (HPLC method), fusing point 71-75 ℃, yield 90%, optical purity is greater than 99%.
6, (S)-2-methylsulfonyl methylbenzene propionyl-4 '-preparation of bromo-glycine benzyl ester
With (S)-2-methylol phenylpropyl alcohol acyl-4 of 14g '-bromo-glycine benzyl ester adds in the toluene of 100ml, the pyridine that adds 15ml stirs the methylsulfonyl chloride that adds 9.5ml down, stirring at room 24 hours, the hydrochloric acid 100ml that adds 1N, stirred 0.5 hour, and filtered layering, organic layer is washed 2 times with the saturated sodium bicarbonate of 20ml, wash 1 time, the organic layer anhydrous magnesium sulfate drying filters, concentrating under reduced pressure, get oily matter 17.5g, add toluene: normal hexane (2: 1) heating for dissolving, room temperature cooling, separate out white crystals 14.2g gradually, content is greater than 98% (HPLC method), fusing point 91-93 ℃, yield 85%.
7, (S)-2-brooethyl phenylpropyl alcohol acyl-4 '-preparation of bromo-glycine benzyl ester
With (S)-2-methylsulfonyl methylbenzene propionyl-4 of 12g '-bromo-glycine benzyl ester is dissolved in the acetone of 100ml, adds the lithiumbromide of 7g, reflux 24 hours, room temperature cooling is filtered, and is evaporated to dried light yellow oil, place gradually and solidify, the ethanol that adds 10ml, heating for dissolving, cooling, filter the white crystals thing of 0.16g, content is greater than 98% (HPLC method), fusing point 94-95 ℃, yield 95%.
8, the preparation of (S)-2-methylol phenylpropyl alcohol acyl-glycine benzyl ester
With (S)-2-methylol phenylpropionic acid of 20g, the glycine benzyl ester tosilate of 40g, the tetrahydrofuran (THF) of 200ml add in the reaction flask of 500ml, stir the triethylamine that adds 14ml down, the 1-hydroxy benzo triazole (HoBt) of 04.6g, the DCC of adding 22.4g after about 10 minutes, stirring at room 24 hours is filtered, filtrate decompression concentrate light yellow oil, add the ethyl acetate of 200ml, the hydrochloric acid 200ml of 1N stirred 0.5 hour, filter, layering, organic layer is washed 2 times with 40ml, and the saturated sodium bicarbonate of 40ml is washed 2 times, wash 1 time, the organic layer anhydrous magnesium sulfate drying filters concentrating under reduced pressure, get oily matter 56g, add toluene: sherwood oil (1: 1) heating for dissolving, white crystals 33.9g is separated out in the room temperature cooling gradually, content is greater than 98% (HPLC method), 62 ℃ of fusing points, yield 93%, optical purity is greater than 99%.
9, the preparation of (S)-2-methylsulfonyl methylbenzene propionyl-glycine benzyl ester
(S)-2-methylol phenylpropyl alcohol acyl-glycine benzyl ester of 15.9g is added in the toluene of 100ml, the pyridine that adds 15ml stirs the methylsulfonyl chloride that adds 9.5ml down, stirring at room 24 hours, the hydrochloric acid 100ml that adds 1N, stirred 0.5 hour, and filtered layering, organic layer is washed 2 times with the saturated sodium bicarbonate of 20ml, wash 1 time, the organic layer anhydrous magnesium sulfate drying filters, concentrating under reduced pressure, get oily matter 19.3g, add toluene: normal hexane (2: 1) heating for dissolving, room temperature cooling, separate out white crystals 17.6g gradually, content is greater than 98% (HPLC method), fusing point 80-82 ℃, yield 89.3%.
10, the preparation of (S)-2-brooethyl phenylpropyl alcohol acyl-glycine benzyl ester
(S)-2-methylsulfonyl methylbenzene propionyl-glycine benzyl ester of 17g is dissolved in the acetone of 100ml, adds the lithiumbromide of 7.3g, reflux 24 hours, room temperature cooling is filtered, and is evaporated to dried light yellow oil, place gradually and solidify, the ethanol that adds 10ml, heating for dissolving, cooling, filter the white crystals thing of 15.8g, content is greater than 98% (HPLC method), fusing point 94-95 ℃, yield 96.4%.
Two, preparation example 2:(+)-and 3R, 4R-(3-hydroxy phenyl)-3, the preparation of 4-lupetidine
1,1, the preparation of 3-dimethyl-4-(3-isopropyl phenyl)-4-hydroxy piperidine
Under the condition of nitrogen protection, the different third oxygen benzene of the 3-bromo of 60g is joined among the THF of 150ml, be cooled to-72 ℃, slowly drip n-Butyl Lithium (2.5M) 150ml.Drip to finish, under-60--70 ℃ condition, stirred 1 hour.Drip 1 of 30g then, 3-dimethyl-4-piperidine ketone, temperature of reaction remains on-60--70 ℃ about, stirred 1 hour.Stirring joins 6N hydrochloric acid in the reaction solution down, and regulating PH is 1～2, divides water-yielding stratum, transfers pH to 12 with 20% sodium hydroxide, uses ethyl acetate extraction 3 times, and organic layer merges, and anhydrous sodium sulfate drying spends the night.Filter, filtrate decompression is concentrated into dried, the normal heptane recrystallization.Filter, behind the product drying white solid 35g, mp71.5-73.4 ℃, HPLC content is greater than 98.%, yield 57.1%.
2, (3S, 4R)-1,3-dimethyl-4-(3-isopropyl phenyl)-4-piperidyl methyl acetoacetic ester. the preparation of (+) two pairs of toluyl tartrates
With 36gl, 3-dimethyl-4-(3-isopropyl phenyl)-4-hydroxy piperidine, the 155ml ethyl acetate joins in the reaction flask, the cooling of external application frozen water, temperature maintenance drips the 16ml Vinyl chloroformate below 10 ℃.Drip and finish stirring at room 3 hours.React and finish adding 20% aqueous sodium hydroxide solution, regulating PH is 12, layering, and the organic layer anhydrous magnesium sulfate drying filters, and the filtrate decompression evaporate to dryness gets brown oil 48.2g.(+) two pairs of toluyl tartrate list hydrate is dissolved in 95% ethanol of 200ml, stir, be heated to 60 ℃, ethanol (150ml) solution of step reaction oily matter in the adding, reflux, slowly be cooled to room temperature, separate out a large amount of solids, filter, get (+) crude product-two pair toluyl tartrate 40.6 grams, 150～153 ℃ of fusing points, HPLC content be greater than 98.%, yield 41%.
3, the preparation of dimethyl tetrahydro pyridine
The piperidines ester tartrate of 32g is added in the 100ml ethyl acetate, add 260ml water, stir adding NaOH (20%) water liquid down, adjusting PH is 10-11.Organic phase anhydrous Na SO
4Dried overnight.Filter, the filtrate decompression evaporate to dryness gets 17.2g oily matter.
Gained oily matter with the dissolving of 100ml perhydronaphthalene, is transferred in the there-necked flask, is warming up to reflux state stirring reaction 18h under the nitrogen protection.Reaction finishes, and is cooled to room temperature, and adding 4N hydrochloric acid adjusting PH is 1～2, divides water-yielding stratum, and water layer is regulated pH value to 8 with 20%NaOH water liquid, with ethyl acetate 50ml extraction 3 times, merges organic phase, uses anhydrous Na SO
4Dried overnight.Filter, filtrate decompression is concentrated into dried red-brown oil 12g (theoretical amount 109g), and content is greater than 96% (HPLC).
4, the preparation of trimethylammonium tetrahydropyridine
Dimethyl tetrahydro pyridine and the 100ml tetrahydrofuran (THF) of 12g are added in the reaction flask, be cooled to-20 ℃.Temperature control-20 ℃ drips the n-Butyl Lithium of 45ml, dropwises the back insulation and stirs 0.5h for-20 ℃.Temperature is dropped to-45 ℃～-50 ℃, slowly drip (the CH of 6ml
3)
2SO
4Drip and finish, stir 0.5h.Naturally rise to room temperature then.Add the about 30ml of ammoniacal liquor, behind the stirring 20min, standing demix.Water layer extracts 2 times with ethyl acetate 20ml again, merges organic phase, and evaporated under reduced pressure gets red-brown oil 12g, and content is 88.9% (HPLC), and pure is 10.7g, yield 92.8%.
5, (+)-3R, 4R-(3-isopropyl phenyl)-1,3, the preparation of 4-trimethyl-piperidine
12g trimethylammonium tetrahydropyridine is added in the 90ml ethanol (95%), be cooled under 5 ℃ of conditions and add NaBH in batches
4, stir.Remove ice bath then, rise to room temperature (25 ℃～30 ℃) naturally, stir 3h.Reaction finishes, the filtering solid, and pressure reducing and steaming ethanol gets oily matter.Transferring pH with 20%NaOH water liquid is 8 (spending 150ml approximately), and ethyl acetate extraction merges organic phase.Evaporated under reduced pressure gets oily matter.Add 95% ethanol 120ml, (+)-two couple toluyl tartrate 20g, stir, reflux, treat molten clear after, naturally cooling places refrigerator and cooled to hide to spend the night to be crystallized then.Product filters the back and measures 95% ethanol (1200ml) recrystallizations with 5 times, and getting the product dry weight is 16.5g, and mp.153.6～154.2 ℃ (decomposition), HPLC content is 100%, yield 61.9%.
6, (+)-3R, 4R-(3-hydroxy phenyl)-3, the preparation of 4-lupetidine
The tartrate of 34g is joined in 150ml ethyl acetate and the 150ml water, and adding 20% buck adjusting pH under stirring is 8～9, stirs 0.5h.Layering, water extracts 2 times with ethyl acetate 70ml, merges organic phase, anhydrous MgSO
4Dry.The filtering siccative, the filtrate decompression evaporate to dryness gets oily matter 14.6g.
Oily matter is added in the reaction flask, add 120ml toluene, be heated to 85 ℃.Drip phenyl chloroformate, about 0.5h drips off, then temperature rising reflux 2h.Reaction finishes, and is cooled to room temperature, and 20%NaOH water drop is added, and transferring pH is 10～11.After stirring 15min, layering, transferring pH with concentrated hydrochloric acid is 2, washing, evaporated under reduced pressure gets red-brown oil 20g.
Gained oil, 20ml glacial acetic acid, 20ml Hydrogen bromide are added in the reaction flask stirring heating back flow reaction 18h.Be cooled to room temperature, reaction solution adds entry 100ml, uses normal heptane extraction, and transferring pH with 20%NaOH water liquid is 9～10.Separate out pink solid 8.1g, mp180.8～183 ℃, content is greater than 98% (HPLC), yield 76%.
Three, embodiment 1:
1, (+)-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] acetate-4 '-preparation of bromo benzyl ester
The A method:
With 10g (+)-3R, 4R-(3-hydroxy phenyl)-3, the 4-lupetidine, 25.9g (S)-2-methylsulfonyl methylbenzene propionyl-4 '-bromo-glycine benzyl ester, the Virahol of 300ml, the salt of wormwood of 9.6g, the potassiumiodide of 0.1g add in three mouthfuls of reaction flasks of 500ml, reflux 8 hours, TCL method detection reaction raw material primitive reaction is (R fully
fValue is about 0.4, ethyl acetate/petroleum ether=1/1.5), be cooled to room temperature, filter, concentrating under reduced pressure gets the about 28.2g of yellow oil.The product content of preparation is about 80.4% (HPLC method), yield 78.6%.Can directly drop into next step reacts.
Get oily matter 1 gram by column separating purification, get the about 0.5g of pure product, content is greater than 95%.
1H?NMR(400MHz，DMSO)δ：0.64(d，3H)，1.16(s，3H)，1.41(d，1H)，1.86(d，1H)，2.0-2.9(m，10H)，3.84(dd，2H)，5.13(d，2H)，6.52-6.67(m，3H)，7.04-7.35(m，10H)，8.44(t，1H)，9.12(s，1H)
The B method:
With 5g (+)-3R, 4R-(3-hydroxy phenyl)-3,4-dimethyl-1-piperidines, 11.9g (S)-bromomethyl phenylpropyl alcohol acyl glycine-4 '-bromo benzyl ester, 100 milliliters Virahol, the salt of wormwood of 4.8 grams, a spot of potassiumiodide add in three mouthfuls of reaction flasks of 250ml, reflux 8 hours, TCL method detection reaction raw material primitive reaction is (R fully
fValue is about 0.4, ethyl acetate/petroleum ether=1/1.5), be cooled to room temperature, filter, be evaporated to the greatest extent, get the about 14.8g of oily matter, content is about 81.2%, and yield 83.1% can directly drop into next step and react.
Embodiment 2
(+)-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] preparation of acetate
Get the about 25g of reaction oily matter of step A method preparation, add in the reaction flask of 500ml, add acetate 300ml, the Pd/C of 5g (10%), normal temperature and pressure hydrogenation is stirred and was stopped to inhale hydrogen in 5 hours, filter, filtrate decompression is concentrated into to the greatest extent, adds sodium hydroxide (10%) and regulates pH value to 10, the concentrated hydrochloric acid acidifying is regulated the pH value to 5-6, stirring at room 1 hour, filter, filter cake washes twice with distillation, dry white crystalline powder 12.9g, fusing point 204-206 ℃ of getting.Content is greater than 96%.
The crude product of 12.9g is added the distilled water of 80ml, in the ethanol of 40ml, under the stirring condition, drip 20% sodium hydroxide, regulate pH value to 10, solids all dissolves.The concentrated hydrochloric acid acidifying is regulated the pH value to 5-6, and stirring at room 1 hour is filtered, and filter cake vacuumizes dry white crystalline powder 11.5g with twice, 120 ℃ of distillation washing, and fusing point 205-206 ℃, content is greater than 99%, yield 79.9%.
1H?NMR(400MHz，DMSO-d6)：δ9.18(1H)，8.34(t，1H)，7.04-7.26(m，6H)，6.53-6.69(m，3H)，3.67(m，2H)，2.14-2.91(m，11H)，1.91(d，1H)，1.45(d，1H)，1.19(s，3H)，0.65(d，3H)；
13C?NMR(100MHz，DMSO-d6)：δ173.64，171.25，157.07，151.45，139.95，128.86(2C)，128.77((2C)，128.08，125.84，116.02，112.45，112.15，59.71，54.73，49.98，43.89，41.03，37.93，37.82，35.51，29.82，27.12，15.67；
IR(KBr)：3450.34，3242.29，3010.06，2978.24，2927.59，1687.23，1588.65，917.84，872.79，865.72，781.78，752.11，704.86
The B method:
The oily matter of the about 10g of reaction product of last step B method, add in the reaction flask of 100ml, add the sodium hydroxide (1N) of 20ml, the ethanol of 10ml, stirred 2 hours, the concentrated hydrochloric acid acidifying is regulated the pH value to 5-6, stirring at room 1 hour, filter, filter cake washes twice with distillation, dry off-white color crystalline powder 5.4g, fusing point 204-206 ℃ of getting.
The crude product of 5.4g is added the distilled water of 40ml, in the ethanol of 20ml, under the stirring condition, drip 20% sodium hydroxide, regulate pH value to 10, solids all dissolves.The concentrated hydrochloric acid acidifying is regulated the pH value to 5-6, and stirring at room 1 hour is filtered, and filter cake vacuumizes dry white crystalline powder 4.9g with twice, 120 ℃ of distillation washing, and fusing point 205-206 ℃, content is greater than 99%, yield 84.0%.
Embodiment 3
1, (+)-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] preparation of acetate-benzyl ester
With 15g (+)-3R, 4R-(3-hydroxy phenyl)-3, the 4-lupetidine, 30g (S)-2-methylsulfonyl methylbenzene propionyl-glycine benzyl ester, the Virahol of 450ml, the salt of wormwood of 15 grams, the potassiumiodide of 0.15g add in three mouthfuls of reaction flasks of 1000ml, reflux 8 hours, TCL method detection reaction raw material primitive reaction is (R fully
fValue is about 0.35, ethyl acetate/petroleum ether=1/1.5), be cooled to room temperature, filter, concentrating under reduced pressure gets the about 36.7g of yellow oil.The product content of preparation is about 0.77% (HPLC method), yield 75.1%.Can directly drop into next step reacts.
Get oily matter 2 grams by column separating purification, get the about 0.35g of pure product, content is greater than 95%.
1H?NMR(400MHz，DMSO)δ：0.66(d，3H)，1.13(s，3H)，1.47(d，1H)，1.91(d，1H)，2.1-3.0(m，10H)，3.94(dd，2H)，5.23(d，2H)，6.52-6.70(m，3H)，7.04-7.45(m，11H)，8.49(t，1H)，9.02(s，1H)。
Embodiment 4
(+)-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] preparation of acetate
Get the about 30g of reaction oily matter of embodiment 3 methods preparation, add in the reaction flask of 500ml, add acetate 300ml, the Pd/C of 9g (10%), normal temperature and pressure hydrogenation is stirred and was stopped to inhale hydrogen in 5 hours, filter, filtrate decompression is concentrated into to the greatest extent, adds sodium hydroxide (10%) and regulates pH value to 10, the concentrated hydrochloric acid acidifying is regulated the pH value to 5-6, stirring at room 1 hour, filter, filter cake washes twice with distillation, dry white crystalline powder 15.8g, fusing point 204-206 ℃ of getting.Content is greater than 95%.
The crude product of 15.8g is added the distilled water of 80ml, in the ethanol of 40ml, under the stirring condition, drip 20% sodium hydroxide, regulate pH value to 10, solids all dissolves.The concentrated hydrochloric acid acidifying is regulated the pH value to 5-6, and stirring at room 1 hour is filtered, and filter cake vacuumizes dry white crystalline powder 12.4g with twice, 120 ℃ of distillation washing, and fusing point 205-206 ℃, content is greater than 99%, yield 65.1%.
Claims (7)
1. have (+) of following structure-(3R, 4R)-[[2S-[[4-(3-hydroxy phenyl)-3,4-dimethyl-piperidino] methyl]-1-oxo-3-hydrocinnamyl] amino] acetic acid substituted benzyl ester cpds:
Wherein, Y is chlorine, bromine or nitro.
2. the preparation method of compound that claim 1 defines is characterized in that under the alkaline condition of organic solvent, Compound I I and compound III is carried out the N-alkylated reaction prepare Compound I;
Wherein: X is chlorine, bromine, methylsulfonyl, benzenesulfonyl or p-bromobenzenesulfonyl; Y is chlorine, bromine or nitro.
3. preparation method as claimed in claim 2, wherein the mole ratio of compound III and Compound I I is 1: 1～10.
4. preparation method as claimed in claim 2, wherein said organic solvent is ethanol, methyl alcohol, Virahol, propyl carbinol or ethylene glycol monomethyl ether.
5. preparation method as claimed in claim 2, wherein used alkali is selected from: yellow soda ash, sodium bicarbonate or salt of wormwood; Triethylamine, pyridine, methylamine alcohol solution or dimethylamine.
6. one kind is the technology of the synthetic LY246736 of intermediate with the defined compound of claim 1, it is characterized in that: Compound I hydrogenation or hydrolysis are prepared target compound V;
7. technology as claimed in claim 6, wherein the used catalyzer of Compound I hydrogenation is Pd/C; The weight ratio of Compound I and catalyzer is 1: 0.1～0.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100132557A CN100383121C (en) | 2006-03-07 | 2006-03-07 | Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100132557A CN100383121C (en) | 2006-03-07 | 2006-03-07 | Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1827598A CN1827598A (en) | 2006-09-06 |
| CN100383121C true CN100383121C (en) | 2008-04-23 |
Family
ID=36946179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100132557A Active CN100383121C (en) | 2006-03-07 | 2006-03-07 | Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100383121C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011161646A2 (en) | 2010-06-25 | 2011-12-29 | Ranbaxy Laboratories Limited | Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101429154B (en) * | 2008-11-14 | 2011-01-05 | 天津泰普药品科技发展有限公司 | Anhydrous alvimopan and medicament composition thereof |
| CN101838233A (en) * | 2010-05-27 | 2010-09-22 | 北京万全阳光医学技术有限公司 | Preparation method of alvimopan key intermediate |
| CN101967118B (en) * | 2010-10-14 | 2013-01-30 | 成都苑东药业有限公司 | Preparation method of alvimopan |
| CN102127005B (en) * | 2011-01-05 | 2012-11-21 | 博瑞生物医药技术(苏州)有限公司 | Intermediate of alvimopan and synthesis method thereof |
| CN102417463B (en) * | 2011-11-03 | 2016-12-21 | 北京华禧联合科技发展有限公司 | The preparation method of alvimopan |
| CN102757379B (en) * | 2012-07-17 | 2014-01-22 | 上海皓元生物医药科技有限公司 | Preparation method of alvimopan |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0506478A1 (en) * | 1991-03-29 | 1992-09-30 | Eli Lilly And Company | Piperidine derivatives |
| EP0657428A1 (en) * | 1993-12-08 | 1995-06-14 | Eli Lilly And Company | Preparation of 3,4,4-trisubstitutedpiperidinyl-n-alkylcarboxylates and intermediates, useful as opioid antagonists |
-
2006
- 2006-03-07 CN CNB2006100132557A patent/CN100383121C/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0506478A1 (en) * | 1991-03-29 | 1992-09-30 | Eli Lilly And Company | Piperidine derivatives |
| EP0657428A1 (en) * | 1993-12-08 | 1995-06-14 | Eli Lilly And Company | Preparation of 3,4,4-trisubstitutedpiperidinyl-n-alkylcarboxylates and intermediates, useful as opioid antagonists |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011161646A2 (en) | 2010-06-25 | 2011-12-29 | Ranbaxy Laboratories Limited | Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof |
| WO2011161646A3 (en) * | 2010-06-25 | 2012-03-15 | Ranbaxy Laboratories Limited | Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1827598A (en) | 2006-09-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100383121C (en) | Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom | |
| CN108689968B (en) | Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam | |
| CN103282361B (en) | Asymmetric synthesis method, related raw material and preparation method of (S,S)-2,8-diazabicyclo[4,3,0]nonane | |
| KR20140035484A (en) | Method of producing beraprost | |
| WO2021056811A1 (en) | Imine salt derivative and preparation method therefor, and preparation method for nicotine | |
| CN110204486B (en) | Synthesis method of quinoline derivative | |
| CN105566319A (en) | Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane | |
| CN102399166B (en) | The Stopholidine of optical siomerism and the preparation method of derivative thereof | |
| JP2020172529A (en) | Method for producing (4s)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile | |
| CN101967118A (en) | Preparation method of alvimopan | |
| JP6904519B2 (en) | Manufacturing methods and intermediates for synthesizing intermediates for the antitumor drug niraparib | |
| CN103113351B (en) | Method for preparing optically pure chiral sulfoxide compound | |
| CN102964307B (en) | Dabigatran etexilate related substance and preparation method thereof | |
| CN103980120A (en) | Synthesis method of D,L-danshensu isopropyl ester | |
| CN102993257A (en) | New fulvestrant preparation method | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN110016029B (en) | Preparation method of 3-fluoro-1H-pyrrolo [2,3-b ] pyridine-2-carboxylic acid | |
| KR101001646B1 (en) | Method of preparing r-+-lansoprazole and intermediate used therein | |
| CN101514201A (en) | Preparation method for (4,7-cis)-octahydro-pyrrolo[3,4-b]pyridine and moxifolxacin | |
| CN106810485A (en) | A kind of Preparation Method And Their Intermediate of chiral boxidine alkanone | |
| CN109988098A (en) | The synthetic method of one kind (R)-N- tertbutyloxycarbonyl -3- hydroxymethyl piperidine | |
| CN104030923B (en) | A kind of synthetic method of DL tanshinol borneol ester | |
| CN102898397B (en) | Synthesis method of (4aR,10bR)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-ol substance and hydrochloride thereof | |
| CN115716859B (en) | Preparation method of brain sterol intermediate cholest-5, 24-diene-3-acetate | |
| CN107629039A (en) | The preparation method and intermediate of deuterated acrylamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SHANGHAI GUOCHUANG MEDICAL CO., LTD. Effective date: 20120309 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20120309 Address after: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Co-patentee after: SHANGHAI GUOCHUANG MEDICINE Co.,Ltd. Patentee after: TIANJIN TAIPU PHARMACEUTICAL SCIENCE & TECHNOLOGY DEVELOPMENT Co.,Ltd. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: TIANJIN TAIPU PHARMACEUTICAL SCIENCE & TECHNOLOGY DEVELOPMENT Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200429 Address after: 300462 No.101, Xinye 8th Street, Tianjin Economic and Technological Development Zone Co-patentee after: SHANGHAI GUOCHUANG MEDICINE Co.,Ltd. Patentee after: TIANJIN TAIPU PHARMACEUTICAL Co.,Ltd. Address before: No. 308, Anshan West Road, Nankai District, Tianjin Co-patentee before: SHANGHAI GUOCHUANG MEDICINE Co.,Ltd. Patentee before: TIANJIN TAIPU PHARMACEUTICAL SCIENCE & TECHNOLOGY DEVELOPMENT Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: No. 101, Xinye 8th Street, Tianjin Economic and Technological Development Zone, 300462 Patentee after: TIANJIN TAIPU PHARMACEUTICAL Co.,Ltd. Patentee after: Shanghai Guochuang Pharmaceutical Co.,Ltd. Address before: No. 101, Xinye 8th Street, Tianjin Economic and Technological Development Zone, 300462 Patentee before: TIANJIN TAIPU PHARMACEUTICAL Co.,Ltd. Patentee before: SHANGHAI GUOCHUANG MEDICINE Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |