CN107176948A - The preparation of UD-CG115BS.acardi - Google Patents
The preparation of UD-CG115BS.acardi Download PDFInfo
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- CN107176948A CN107176948A CN201710595181.0A CN201710595181A CN107176948A CN 107176948 A CN107176948 A CN 107176948A CN 201710595181 A CN201710595181 A CN 201710595181A CN 107176948 A CN107176948 A CN 107176948A
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- cg115bs
- acardi
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- 229960002164 pimobendan Drugs 0.000 title claims abstract description 26
- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims description 33
- -1 4- methoxyphenylboronic acid pinacols ester Chemical class 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 229910019201 POBr3 Inorganic materials 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 claims description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 3
- SXLHAMYMTUEALX-UHFFFAOYSA-N (4-methoxyphenoxy)boronic acid Chemical compound COC1=CC=C(OB(O)O)C=C1 SXLHAMYMTUEALX-UHFFFAOYSA-N 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 2
- 231100000614 poison Toxicity 0.000 abstract description 2
- 230000007096 poisonous effect Effects 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 229940049706 benzodiazepine Drugs 0.000 description 20
- 150000002460 imidazoles Chemical class 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 5
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 0 CC(*)C(c1ccc(*)cc1)=O Chemical compound CC(*)C(c1ccc(*)cc1)=O 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 229910002666 PdCl2 Inorganic materials 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010583 slow cooling Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 230000003177 cardiotonic effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000001196 vasorelaxation Effects 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- VFIKPDSQDNROGM-UHFFFAOYSA-N 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical class C1=CC(OC)=CC=C1B1OC(C)(C)C(C)(C)O1 VFIKPDSQDNROGM-UHFFFAOYSA-N 0.000 description 1
- REBZXOIBOIJEAU-UHFFFAOYSA-N 3-chloro-2-methylpropanoyl chloride Chemical compound ClCC(C)C(Cl)=O REBZXOIBOIJEAU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- SSRUQAGKIDEVAI-UHFFFAOYSA-N CC(C1)C(c2ccc3nc(C(CC4)=CC=C4OC)[nH]c3c2)=NNC1=O Chemical compound CC(C1)C(c2ccc3nc(C(CC4)=CC=C4OC)[nH]c3c2)=NNC1=O SSRUQAGKIDEVAI-UHFFFAOYSA-N 0.000 description 1
- DJHQXARYBAZLHE-UHFFFAOYSA-N CC(CCl)C(c(cc1)ccc1NC(C)=O)=O Chemical compound CC(CCl)C(c(cc1)ccc1NC(C)=O)=O DJHQXARYBAZLHE-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940122434 Calcium sensitizer Drugs 0.000 description 1
- 102000002585 Contractile Proteins Human genes 0.000 description 1
- 108010068426 Contractile Proteins Proteins 0.000 description 1
- 241000721047 Danaus plexippus Species 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 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
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical class Br* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical group C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 229940106857 vetmedin Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the new preparation process of UD-CG115BS.acardi.The processing step is short, is not related to industrial a large amount of using by the Br limited to2, KCN, NaH etc. is dangerous and poisonous reagent, and simple to operate, reaction condition is gentle, and industrialized production has obvious advantage.
Description
Technical field
The present invention relates to the preparation of UD-CG115BS.acardi.
Background technology
UD-CG115BS.acardi (Pimobendan) (trade name Vetmedin) is public by German Boehringer Ingelheim
Department develops, and belongs to di-phosphate ester in a kind of cardiotonic drug with vasorelaxation action of Japan's listing first in 1994
Enzyme inhibitor, is clinically mainly used in the treatment of heart failure disease.The compound is with calcium sensibilization and type III phosphoric acid enzyme level
The cardiac stimulant expander of agent effect, the mechanism of action is different from traditional cardiotonic drug, and its positive inotropic effect is mainly due to strengthen the heart
Flesh contractile protein is to Ca2+Sensitiveness and the inhibitory action to phosphodiesterase iii (PDE III), be first listing calcium
Sensitizer class medicine.Research shows that the medical instrument has stronger vasorelaxation action and antiplatelet aggregative activity, almost without pair
Effect, can also treat chronic cardiac insufficiency and angina pectoris, can also prevent and treat arterial thrombosis.In addition, a large amount of clinical examinations
Test it is also show that heart failure patient Long-term Oral mode takes UD-CG115BS.acardi and can be effectively improved exercise tolerance and quality of the life.
UD-CG115BS.acardi it is chemical entitled:4,5- dihydros -6- [2- (4- methoxyphenyls) -1H- benzimidazole -5- bases] -5- methyl -3
(2H)-pyridazinone, with following chemical structural formula：
The patent document for preparing UD-CG115BS.acardi of open report is more at present.Early in nineteen eighty-two Austel et al.
(US4361563) report the synthetic route using chlorobenzene as initiation material for the first time, through pay-gram acylation reaction, nitration reaction,
The α positions bromination of carbonyl, malonate nucleophilic displacement of fluorine, KOH hydrolysis, heating decarboxylation, ammonification, esterification, anisoyl chloride acyl
The steps such as change, hydrazine hydrate cyclization, hydrogenation, cyclization complete the fully synthetic of UD-CG115BS.acardi.The route steps length (totally 12 steps are reacted),
And the route is present when aminating reaction needs autoclave, bromination the shortcomings of need to be with corrosivity very strong bromine, therefore industrialized production
Limited to.Related synthetic route is as follows：
Piao Yang and Duan Yongxi et al. (Chinese pharmaceutical chemistry magazine, 1994,4,41) are developed using antifebrin as raw material
Synthetic route.The route by pay-gram acylation reaction, Mannich reactions, quaternary amine salinization, cyaniding replace, nitrify etc. 10 steps
Reaction completes the synthesis of UD-CG115BS.acardi.It is due to react although the route has shortened compared to the routes of US 4361563
It is related to the KCN using severe toxicity in journey, thus is not suitable for amplification production.The specific synthetic route of technique of the reports such as Piao Yang is such as
Shown in lower：
Wang Si think ofs et al. (Chinese pharmaceutical chemistry magazine, 1997,7,185) combines patent US 4361563 and Piao Yang etc.
The technique of people, it was recently reported that using antifebrin as raw material, by pay-gram acylation reaction, bromo-reaction, diethyl malonate nucleophilic
The step reaction of substitution reaction etc. 9 prepares the synthetic route of UD-CG115BS.acardi.It is due to react although the route step has shortened
Not only related equally to using strong reagents of corrosivity such as bromines in journey, and use the NaH of high-risk, thus industrialized production
It is similarly subjected to limitation.The specific synthetic route of the technique is as follows：
Permitted to help the route that monarch et al. (synthesis chemistry, 1999,7,194) reports a synthesis UD-CG115BS.acardi.The route is same
Sample uses antifebrin as initiation material, first by carrying out paying-gram acylation reaction, one with 3- chloro-2-methyls propionyl chloride
Step obtains 4- (3- chloro-2-methyls propiono) antifebrin, and the latter passes through cyano group substitution reaction, nitration reaction, Zn/NH4Cl again
Reduction reaction etc. realizes the synthesis of UD-CG115BS.acardi.It is due to 3- chloro-2-methyl propionyl chloride business although the route synthesis step is short
Industry is difficult to relate equally to the KCN using severe toxicity in a large amount of buyings and course of reaction, thus industrialized production is restricted.
The specific synthetic route of the technique is as follows：
The method of the synthesis UD-CG115BS.acardi of the disclosed report of summary, the conjunction of the report such as US4361563 patents, Piao Yang
Synthetic route and being permitted into reports such as route, Wang Sisi helps the synthetic routes of the reports such as monarch and has used industrially largely make respectively
With by the Br2 limited to, KCN, NaH/Br2 etc., and the implementation of nitration reaction is directed to, these routes are not appropriate for industry
Change amplification production.Therefore, the UD-CG115BS.acardi synthetic route of one suitable industrial amplification production of exploitation is for UD-CG115BS.acardi medicine
Industrialization be even more important.
The content of the invention
The key of the present invention is the method for one newly developed suitable industrialized production UD-CG115BS.acardi, the following institute of synthetic route
Show：
The first step is related to 5- (2- halos propiono) -1,3- dihydro -2H- benzos [d] imidazoles -2- ketone (Formulas I) and malonic acid
Nucleophilic substitution occurs for dimethyl ester or diethyl malonate, generates 2- (1- oxos -1- (2- oxo -2,3- dihydro -1H- benzos
[d] imidazoles -5- bases) -1- propionyl -2- bases) diester malonate (formula III)；
The X of Formulas I1For Cl, Br.
The R of Formula II1For Me, Et.
The R of formula III1For Me, Et.
Alkali used in first step reaction includes K2CO3,Na2CO3,Cs2CO3, t-BuOK, LiHMDS, NaHMDS, LDA etc.；
Solvent used in first step reaction includes THF, DMF, Dioxane, CH3CN, DMSO etc..
Second step is 2- (1- oxos -1- (2- oxo -2,3- dihydro -1H- benzos [d] imidazoles -5- bases) -1- propionyl -2-
Base) diester malonate (formula III) is in POCl3Or POBr3Effect is lower to occur halogenating reaction generation 2- (1- (2- halo -1H- benzos
[d] imidazoles -6- bases) -1- propionyl -2- bases) diester malonate (formula IV).
The reaction dissolvent of second step includes toluene, benzene, ethyl acetate, THF or directly uses POCl3、POBr3Make simultaneously
It is that solvent and reaction reagent are carried out.
3rd step is 2- (1- (2- halo -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases) diester malonate (formula
IV) occur Suzuki couplings instead with p-methoxyphenyl boric acid or 4- methoxyphenylboronic acid pinacols ester under Pd catalysts conditions
Should, realize 2- (1- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases) diester malonate (formula
V preparation).
The R of Formula V1For Me, Et.
Pd catalyst used in three-step reaction includes Pd (OAc)2、Pd(PPh3)4、PdCl2、PdCl2(PPh3)2、
PdCl2(dppf)·CH2Cl2、Pd2(dba)3、Pd2(dba)3·CHCl3(t-Bu3P)2One or more in Pd；Wherein,
Dppf represents double (diphenyl see base) ferrocene；Dba represents dibenzalacetone；OAc represents acetate；
Solvent used in three-step reaction includes i-PrOH, benzene, THF, glycol dimethyl ether, CH3CN、NMP、
One or more in Dioxane, toluene, EtOH and DMF；
Alkali used in three-step reaction includes NaHCO3、KF、KHCO3、K2CO3、Na2CO3、Et3N、CsF、Cs2CO3、
NaOH、KOH、LiOH、(iPr)2NEt、Et3N and K3PO4In one or more；
Four-step reaction is 2- (1- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases)
Ester hydrolysis reaction occurs in the presence of inorganic base for diester malonate (Formula V), obtains 2- (1- (2- (4- methoxyphenyls) -1H-
Benzo [d] imidazoles -6- bases) -1- propionyl -2- bases) malonic acid (Formula IV).
Alkali is including NaOH, LiOH, KOH, CsOH etc. used in four-step reaction.
Solvent used in four-step reaction includes EtOH, MeOH, THF, DMF, CH3One kind in CN, i-PrOH or this
The mixed solvent of a little solvent and water compositions.
The reaction of 5th step is 2- (1- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases)
Malonic acid (Formula IV) carries out decarboxylic reaction in a heated condition, obtain 4- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -
6- yls) -3- methyl -4- ketobutyric acids (Formula VII)；
Solvent used in the reaction of 5th step includes DMF, DMSO, CH3CN, NMP, PhOPh etc.；
The temperature of 5th step reaction is 80-150 DEG C；
Six-step process is 4- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -3- methyl -4- oxo fourths
Sour (Formula VII) and hydration hydrazine reaction, obtains UD-CG115BS.acardi compound.
The solvent of six-step process includes MeOH, EtOH, THF, CH3CN etc..
The preparation technology for the UD-CG115BS.acardi that the present invention is described, step is short, and industrial a large amount of use is not related to and is limited to
Br2, KCN, NaH etc. is dangerous and poisonous reagent, and simple to operate, reaction condition is gentle, and industrialized production has obvious advantage.
Embodiment
It can more specifically understand the present invention by the following examples, but it illustrates rather than the limitation present invention
Scope.
Embodiment
1. prepare 2- (1- oxos -1- (2- oxo -2,3- dihydro -1H- benzos [d] imidazoles -5- bases) -1- propionyl -2- bases)
Dimethyl malenate (formula III) (R1=Me)
Under nitrogen protection, potassium tert-butoxide (150g, 1338mmol) is added into reaction bulb, then anhydrous DMSO (600mL)
Add, 10min is stirred at room temperature in system.Dimethyl malenate (120g, 908mmol), which divides 10 times, to be carefully added into reaction system,
Note keeping temperature of reaction system to be no more than 40 DEG C during addition.Addition finishes rear system stirring 20min.Then, Formula I
(X1=Cl) (202g, 899mmol) add by several times, keeps temperature of reaction system to be no more than 40 DEG C in adition process, addition is finished
System stirring reaction shows reaction raw materials compound of formula I (X to TLC afterwards1=Cl) disappear.System is slowly added to H2O (2000mL) quenches
Go out reaction, then add the careful regulation system pH of glacial acetic acid between 6-7.System adds CH2Cl2(3 × 1500mL) is extracted, and is closed
And organic phase use saturated common salt water washing 2 times (2 × 1000mL), anhydrous sodium sulfate drying, removal of solvent under reduced pressure after filtering
Obtain compound formula III (R1=Me) (262g, crude product), the crude product is not further purified, and is directly used in next step reaction).
2. prepare 2- (1- (chloro- 1H- benzos [d] imidazoles -6- bases of 2-) -1- propionyl -2- bases) dimethyl malenate (formula IV)
(R1=Me, X2=Cl)
Formula III compound (the R of the gained of embodiment 11=Me) crude product (262g) is dissolved in dry toluene (2000mL), system
Ice salt bath is cooled to 0-5 DEG C, and then nitrogen protection is lower is slowly added dropwise POCl by dropping funel3(450mL), addition finishes rear body
System is slowly heated to back flow reaction 2 hours to TLC point plate tracking mode III compounds and disappeared.System slow cooling to 50 DEG C or so,
Then the complete POCl of careful removed under reduced pressure solvent and unreacted3.CH is added into residue2Cl2(1000mL) and H2O
System is carefully added into saturation NaHCO after (500mL), stirring 10min3Regulation system pH to 6.5 or so.Separate organic phase, aqueous phase
Add CH2Cl2(2 × 500mL) is extracted.Merge organic phase, organic phase uses saturated common salt water washing 2 times (2 × 500mL), anhydrous
Sodium sulphate is dried, and obtains yellowish-brown crude product after filtering after removal of solvent under reduced pressure.The crude product is recrystallized using EtOAc/ heptane systems
To compound formula IV (R1=Me, X2=Cl) (227g, two step yields 75%).
3. prepare 2- (1- oxos -1- (2- oxo -2,3- dihydro -1H- benzos [d] imidazoles -5- bases) -1- propionyl -2- bases)
Diethyl malonate (formula III) (R1=Et)
Under nitrogen protection, Cs2CO3(120g, 368mmol) is added into reaction bulb, and then DMF (150mL) is added, system
10min is stirred at room temperature.Diethyl malonate (20g, 125mmol) is added in reaction system.Addition finishes rear system stirring
30min.Then, Formula I (X1=Br) (33.5g, 124.5mmol) is added, and addition finishes rear system and is warming up to 80 DEG C instead
It should stay overnight.System slow cooling, then removed under reduced pressure organic solvent.Residue adds H2O (800mL) and CH2Cl2(500mL)。
System separates organic phase, aqueous phase CH after being sufficiently stirred for2Cl2(2 × 300mL) is extracted twice, and merges organic phase, and organic phase uses full
With brine It 2 times (2 × 300mL), anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains compound formula III (R1=after filtering
Et) (38.3g, crude product), the crude product is not further purified, and is directly used in next step reaction).
4. prepare 2- (1- (bromo- 1H- benzos [d] imidazoles -6- bases of 2-) -1- propionyl -2- bases) diethyl malonate (formula IV)
(R1=Et, X2=Br)
Under nitrogen protection, formula III compound (R1=Et) crude product (38.3g) of the gained of embodiment 3 is dissolved in THF (100mL)
In, system ice salt bath is cooled to 0-5 DEG C, and then nitrogen protection is lower is slowly added dropwise POBr3 (26mL) by dropping funel, has added
System is slowly heated to back flow reaction 2 hours to TLC point plate tracking mode III compounds and disappeared after finishing.System slow cooling, then
Careful heating removed under reduced pressure solvent and the complete POBr of unreacted3.CH is added into residue2Cl2(200mL) and H2O
System is carefully added into saturation NaHCO after (200mL), stirring 10min3Regulation system pH to 6.5 or so.Separate organic phase, aqueous phase
Add CH2Cl2(2 × 150mL) is extracted.Merge organic phase, organic phase uses saturated common salt water washing 2 times (2 × 150mL), nothing
Aqueous sodium persulfate is dried, and obtains brown crude product after filtering after removal of solvent under reduced pressure.The crude product uses EtOAc/ heptane systems recrystallization two
It is secondary to obtain compound formula IV (R1=Et, X2=Br) (30.6g, two step yields 59.8%).
5. prepare 2- (1- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases) malonic acid
Dimethyl ester (Formula V) (R1=Me)
Compound formula IV (product of embodiment 2) (R is added in reaction bulb1=Me, X2=Cl) (125g, 370mmol) and
K2CO3(153.5g, 1110.6mmol, 3.0eq), nitrogen protection is lower to add Dioxane (5.0L) and DMF (1.5L).Addition is finished
The lower room temperature of system stirring vacuumizes 1 hour (removal oxygen) of degassing afterwards, is then added under nitrogen protection into reaction system to first
Phenyl boric acid (84.5g, 556mmol, 1.5eq) and Pd (PPh3)4(43g,37.2mmol,0.1eq).Addition finishes rear body
System uses nitrogen displacement 3 times.System is heated to 80 DEG C and reacted 6 hours, is then naturally cooling to room temperature.System removed under reduced pressure is molten
Agent, residue adds CH2Cl2(1500mL) is stirred vigorously 2 hours, filtering, and solid uses CH after collecting2Cl2(500mL) is violent
Agitator treating 2 hours, is then filtered again.Merge the filtrate filtered twice, be separately added into H2O (500mL) washings, saturated common salt
Water (500mL) is washed, and organic phase uses anhydrous sodium sulfate drying, is filtered, removed under reduced pressure solvent, and residue uses methanol/heptane
Polishing purification, obtains Formula V (R1=Me) (112g, 73.8%).
6. prepare 2- (1- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases) malonic acid
Diethylester (Formula V) (R1=Et)
Compound formula IV (product of embodiment 4) (R is added in reaction bulb1=Et) (28g, 68mmol) and (iPr)2NEt
(22.0g, 170mmol, 2.5eq), nitrogen protection is lower to add DMF (1.0L).Addition finishes the lower room temperature of rear system stirring and vacuumized
Deaerated 1 hour (removal oxygen), and 4- methoxyphenylboronic acid pinacol esters are then added into reaction system under nitrogen protection
(19.1g, 81.6mmol, 1.2eq) and PdCl2(dppf).CH2Cl2(2.8g,3.43mmol,0.05eq).Addition finishes rear body
System uses nitrogen displacement 3 times.System is heated to 100 DEG C and reacted 12 hours, is then naturally cooling to room temperature.System removed under reduced pressure is molten
Agent, residue adds CH2Cl2(500mL) and H2O (200mL), separates organic phase after stirring, aqueous phase adds CH2Cl2(2×
100mL) extract.Merge organic phase, organic phase uses saturated common salt water washing 2 times (2 × 150mL), anhydrous sodium sulfate drying, mistake
Ethanol/heptane polishing purification is used after filter after removal of solvent under reduced pressure, Formula V (R are obtained1=Et) (20.3g, 68.2%).
7. prepare 2- (1- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases) malonic acid
(Formula IV)
Formula V (R1=Me) (95g, 231mmol) prepared by embodiment 5 is dissolved in EtOH (150mL), Ran Houxiang
The NaOH aqueous solution is added in system (37g NaOH are dissolved in 520mL H2O, 4.0eq).After addition is finished, system is stirred at room temperature
Overnight.50 DEG C of system is careful to be removed under reduced pressure alcohol solvent, and the remaining aqueous solution uses 3M HCl regulation systems pH value to 1.0-
1.5.System adds EtOAc extractions (3 × 500mL), and organic phase uses saturated common salt water washing 2 times (2 × 300mL), anhydrous sulphur
Sour sodium is dried, and obtains compound Formula IV (83.8g) after filtering after removal of solvent under reduced pressure, is not required to purifying, is directly used in next step.
8. 4- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- the bases) -3- methyl -4- ketobutyric acid (formulas of preparation
VII)
Compound Formula IV (83.8g) prepared by embodiment 7 is dissolved in DMF (150mL), and system is to slowly warm up to 130-
140 DEG C, insulation reaction 3 hours.System Temperature fall, then Rotary Evaporators high vacuum removed under reduced pressure organic solvent.Gained is residual
Excess is not required to purifying for the compound (72.1g) of Formula VII, is directly used in next step reaction.
9. prepare UD-CG115BS.acardi
Ethanol EtOH (250mL) and hydrazine hydrate are directly added into the compound Formula VII (72.1g) prepared by embodiment 8
(120mL), addition finishes the slow temperature rising reflux of rear system 12 hours.System Temperature fall, then high vacuum removed under reduced pressure is organic
Solvent and the complete hydrazine hydrate of unreacted.DMF (250mL) is added into residue, slow heating stirring is to dissolved clarification, then to molten
H is slowly added dropwise in clear system2Stirred 1 hour after O (250mL), completion of dropping, system is cooled to 60 DEG C, filtered on buchner funnel, institute
Obtain after solid is dried is that (51.6g, 67%) three step total recoverys is to UD-CG115BS.acardi.
10. prepare 2- (1- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- bases) -1- propionyl -2- bases) malonic acid
(Formula IV)
Formula V (R1=Et) (15g, 34.2mmol) prepared by embodiment 6 is dissolved in THF (50mL), Ran Houxiang
(11.3g CsOH are dissolved in 200mL H to the addition CsOH aqueous solution in system2In O, 2.2eq).After addition is finished, system room temperature is stirred
Mix overnight.After completion of the reaction, then system adds EtOAc extractions using the careful regulation system pH value of 6M HCl between 1-1.5
(3 × 100mL), organic phase uses saturated common salt water washing 2 times (2 × 60mL), and anhydrous sodium sulfate drying is removed under reduced pressure after filtering
Compound Formula IV (14.3g) is obtained after solvent, purifying is not required to, is directly used in next step.
11. 4- (2- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- the bases) -3- methyl -4- ketobutyric acid (formulas of preparation
VII)
Compound Formula IV (14.3g) prepared by embodiment 10 is dissolved in NMP (40mL), and system is to slowly warm up to 130-
140 DEG C, insulation reaction 3 hours.System Temperature fall, then Rotary Evaporators high vacuum removed under reduced pressure organic solvent.Gained is residual
Excess is not required to purifying for the compound (13.5g) of Formula VII, is directly used in next step reaction.
12. prepare UD-CG115BS.acardi
CH is directly added into the compound Formula VII (13.5g) prepared by embodiment 113CN (50mL) and hydrazine hydrate
(25mL), addition finishes the slow temperature rising reflux of rear system 12 hours.System Temperature fall, then high vacuum removed under reduced pressure is organic molten
Agent and the complete hydrazine hydrate of unreacted.DMF (50mL) is added into residue, slow heating stirring is to dissolved clarification, then to dissolved clarification
H is slowly added dropwise in system2Stirred 1 hour after O (50mL), completion of dropping, system is cooled to 60 DEG C, and filtered on buchner funnel, gained is solid
Body is that (7.10g, 62.1%) three step total recoverys is to UD-CG115BS.acardi after drying.
Claims (11)
1. a preparation technology for preparing UD-CG115BS.acardi, with following synthetic route：
2. the compound with formula III chemical constitution shown in claim 1.
3. the formula III compound shown in claim 2 is prepared by Formula I and the reaction of compound Formula II
, the X wherein in Formulas I1For Br, Cl, the R in Formula II1For Me, Et, the R in formula III1For Me, Et.
4. the compound with formula IV chemical constitution shown in claim 1.
5. the formula IV compound shown in claim 4 is in POCl by formula III compound3Or POBr3The lower reaction of effect is prepared into
Arrive.X wherein in formula IV2For Br, Cl, R1For Me, Et.
6. the R in the compound with Formula V chemical constitution shown in claim 1, Formula V1For Me, Et.
7. the Formula V compound shown in claim 6 be by formula IV compound under Pd catalysts conditions and p-methoxyphenyl
Boric acid or 4- methoxyphenylboronic acid pinacols ester occur what coupling reaction was prepared.
8. the compound with Formula IV chemical constitution shown in claim 1.
Prepared 9. the Formula IV compound shown in claim 8 is hydrolyzed in the basic conditions by Formula V compound.
10. the compound with Formula VII chemical constitution shown in claim 1.
11. the UD-CG115BS.acardi in claim 1 is prepared by Formula VII compound and hydration hydrazine reaction.
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| CN107176948B (en) | 2019-07-16 |
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Address after: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Patentee after: Southeast University Address before: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee before: WISDOM PHARMACEUTICAL Co.,Ltd. Patentee before: Southeast University Address after: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Patentee after: Southeast University Address before: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee before: Jiangsu Huiju Pharmaceutical Co.,Ltd. Patentee before: Southeast University |
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