CN113754597B - Benzhydryl piperazine compound containing linear olefin and preparation method thereof - Google Patents
Benzhydryl piperazine compound containing linear olefin and preparation method thereof Download PDFInfo
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- -1 Benzhydryl piperazine compound Chemical class 0.000 title claims abstract description 34
- 150000001336 alkenes Chemical class 0.000 title claims abstract description 29
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006772 olefination reaction Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- RSJBEKXKEUQLER-UHFFFAOYSA-N dicyclohexyl(3-dicyclohexylphosphanylpropyl)phosphane Chemical compound C1CCCCC1P(C1CCCCC1)CCCP(C1CCCCC1)C1CCCCC1 RSJBEKXKEUQLER-UHFFFAOYSA-N 0.000 claims abstract description 10
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims description 56
- 239000003513 alkali Substances 0.000 claims description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 32
- 238000001035 drying Methods 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 239000003446 ligand Substances 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 230000035484 reaction time Effects 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 230000001590 oxidative effect Effects 0.000 claims description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 claims description 11
- 239000012044 organic layer Substances 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 239000005457 ice water Substances 0.000 claims description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 239000010410 layer Substances 0.000 claims description 8
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- YOCBOYPGZVFUCQ-UHFFFAOYSA-L nickel(2+);tricyclohexylphosphane;dichloride Chemical compound Cl[Ni]Cl.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 YOCBOYPGZVFUCQ-UHFFFAOYSA-L 0.000 claims description 5
- 235000011056 potassium acetate Nutrition 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 238000004321 preservation Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 abstract description 9
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract description 9
- 238000005859 coupling reaction Methods 0.000 abstract description 9
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- 230000008878 coupling Effects 0.000 abstract description 6
- 238000010168 coupling process Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 abstract description 5
- TYSIABGIEWSXEI-UHFFFAOYSA-N 1-bromo-2-[bromo(phenyl)methyl]benzene Chemical compound C=1C=CC=C(Br)C=1C(Br)C1=CC=CC=C1 TYSIABGIEWSXEI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 4
- 238000012827 research and development Methods 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 239000002547 new drug Substances 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 229940079593 drug Drugs 0.000 description 11
- 229940126062 Compound A Drugs 0.000 description 7
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 7
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 description 7
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 150000008640 diphenylmethylpiperazines Chemical class 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000011161 development Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 3
- 125000006643 (C2-C6) haloalkenyl group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 229940124623 antihistamine drug Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000014 opioid analgesic Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 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 1
- HUHJIJQHHFHKQG-UHFFFAOYSA-N 2-tert-butylpiperazine-1-carboxylic acid Chemical compound CC(C)(C)C1CNCCN1C(O)=O HUHJIJQHHFHKQG-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- GWFKSQSXNUNYAC-AATRIKPKSA-N [(e)-hex-1-enyl]boronic acid Chemical compound CCCC\C=C\B(O)O GWFKSQSXNUNYAC-AATRIKPKSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Abstract
The embodiment of the invention discloses a benzhydryl piperazine compound containing linear olefin and a preparation method thereof, which are expected to directly act on focus or be used as molecular building blocks to participate in the research and development of new drugs. The preparation method of the novel benzhydryl piperazine compound containing the linear olefin takes 1-bromo-2- (bromo (phenyl) methyl) benzene as a raw material, and the target compound is obtained through nucleophilic substitution and carbon-carbon coupling two-step reaction. The carbon-carbon coupling reaction is preferably a catalytic reaction of a catalytic system consisting of Pd 2(dba)3 and 1, 3-bis (dicyclohexylphosphino) propane, so that the reaction activity is obviously improved, the reaction is realized in high yield, and particularly, a NiCl 2(PCy3)2 and tricyclohexylphosphine catalytic system is adopted for the reaction, so that the reaction result is ideal, and a reference is provided for the nickel catalyst to catalyze the carbon-carbon coupling of the compound. The whole preparation route has stable reaction, mild conditions, simple and convenient operation and high reaction yield.
Description
Technical Field
The embodiment of the invention relates to the technical field of medicines, in particular to a benzhydryl piperazine compound containing linear olefins and a preparation method thereof.
Background
The benzhydryl piperazine compound can be used as antihistamine drugs and opioid analgesic drugs for treating or relieving dermatitis, dizziness, apoplexy, diabetes, moderate pain and other diseases (US 20090176792A 1); the compounds can also be used as key intermediates for synthesizing drugs for regulating calcium channel activities and anticancer drugs, and can be used for pertinently treating congenital migraine, angina, epilepsy, hypertension, partial arrhythmia, obesity and other diseases (WO2007071035A1,WO2004032874A2,US2009124620A1,WO2013103973A1,Acs Chemical Biology,2013,8(7):1590-1599.),, and are heterocyclic compounds with wide application and huge potential. However, with the deep application of the compounds in the field of medicine, the reduction of the efficacy of the medicine and the side effects of the medicine are more and more obvious, and the continuous development of new benzhydryl piperazine compounds as pharmaceutically active molecules or active molecular building blocks to meet the high-quality development of the medicine is normal.
Based on the activity of the linear olefin compounds in the existing medicines (Journal of MEDICINAL CHEMISTR Y,2003, 46:623-633.) and the unique properties of the linear olefin compounds, the introduction of the linear olefin on the benzene ring can improve the fat solubility of medicine molecules, and is expected to further promote the release of the medicine effect of the medicine molecules in organisms and improve the biological activity of the medicines, thereby providing potential high-quality active molecular building blocks for the development of corresponding medicines.
Since the synthesis of the novel benzhydryl piperazine compound containing the linear olefin is not reported in the prior art, the research on the synthesis route is necessary.
Disclosure of Invention
Therefore, the embodiment of the invention provides a benzhydryl piperazine compound containing linear olefin and a preparation method thereof, so as to solve the technical problems.
In order to achieve the above object, the embodiment of the present invention provides the following technical solutions:
According to the first aspect of the embodiment of the invention, the benzhydryl piperazine compound containing the linear olefin is provided, and a new potential active molecule or molecular building block is provided for the research and development of antihistamine drugs and opioid analgesic drugs, so that the application of the drugs with high activity and low side effect in medical treatment is expected. The structural general formula of the benzhydryl piperazine compound containing the linear olefin is shown as the following formula (1):
Wherein,
R 1 is selected from hydrogen;
R 2 is selected from hydrogen;
r 3 is selected from one of C2-C6-alkenyl, C1-C6-aldehyde, C1-C6-alkyloxyacyl, C1-C6-alkylcarbonyl, C1-C6-alkylamino, C1-C6-alkylaminosulfonyl, C1-C6-alkylhydroxy, aminocyano, di (cyano) -C1-C6-alkyl, C2-C6-haloalkenyl, C1-C6-haloalkylaldehyde, C1-C6-haloalkylcarbonyl containing up to 4 identical or different halogen atoms.
Further, the C1-C6-alkylaminosulfonyl is substituted with a plurality of identical or different R 4 substituents; r 4 is selected from at least one of C1-C6-alkane, C2-C6-alkene, C2-C6-alkyne, C3-C6-cycloalkane, C1-C6-haloalkane/C2-C6-haloalkene/C3-C6-haloalkane containing up to 4 identical or different halogen atoms.
Preferably, the R3 is selected from-COH, -CH 2OH、-CH2OCOCH3 or-ch=ch 2.
According to a second aspect of the embodiment of the present invention, there is provided a method for preparing a benzhydryl piperazine compound containing a linear olefin, the method comprising the steps of:
step one: dissolving a compound SM 1in a first solvent, adding a compound SM2 and alkali, carrying out reflux reaction on the system until the reaction is complete, filtering after the system is cooled to room temperature, spin-drying, and purifying to obtain a compound A;
step two: dissolving the compound A in a second solvent, sequentially adding 1-alkenyl hexyl boric acid, alkali, a catalyst and a ligand, carrying out reflux reaction under the protection of nitrogen until the reaction is complete, and spin-drying the system to obtain a target compound;
The structural general formula of the target compound is shown as the following formula (1):
The structural general formula of the compound SM1 is shown as the following formula (2):
The structural general formula of the compound SM2 is shown as the following formula (3):
The structural general formula of the compound A is shown as the following formula (4):
Wherein,
R 1 is selected from hydrogen;
R 2 is selected from hydrogen;
r 3 is selected from one of C2-C6-alkenyl, C1-C6-aldehyde, C1-C6-alkyloxyacyl, C1-C6-alkylcarbonyl, C1-C6-alkylamino, C1-C6-alkylaminosulfonyl, C1-C6-alkylhydroxy, aminocyano, di (cyano) -C1-C6-alkyl, C2-C6-haloalkenyl, C1-C6-haloalkylaldehyde, C1-C6-haloalkylcarbonyl containing up to 4 identical or different halogen atoms.
Further, the C1-C6-alkylaminosulfonyl is substituted with a plurality of identical or different R 4 substituents; r 4 is selected from at least one of C1-C6-alkane, C2-C6-alkene, C2-C6-alkyne, C3-C6-cycloalkane, C1-C6-haloalkane/C2-C6-haloalkene/C3-C6-haloalkane containing up to 4 identical or different halogen atoms.
Further, in the first step, the first solvent is at least one selected from acetonitrile, dichloroethane, tetrahydrofuran, and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, sodium carbonate, potassium acetate, sodium acetate and N, N-diisopropylethylamine; the molar ratio of the compound SM1 to the compound SM2 to the alkali is 1 (0.8-1.2): 1.5-3.5); the reaction time is 4-8h.
Further, in the second step, the second solvent is at least one selected from toluene, dimethyl sulfoxide, N-dimethylformamide, and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, cesium carbonate and sodium carbonate; the catalyst is selected from Pd 2(dba)3、Pd(OAc)2、NiCl2(PCy3)2; the ligand is selected from tricyclohexylphosphine or 1, 3-bis (dicyclohexylphosphino) propane; the mol ratio of the compound A to the 1-alkenyl hexyl boric acid, the alkali, the catalyst and the ligand is 1 (1.1-1.5) (3-5) (0.05-0.15); the reaction time is 8-15h.
According to a third aspect of the embodiment of the present invention, there is provided a method for preparing a benzhydryl piperazine compound containing a linear olefin, the method comprising the steps of:
step one: dissolving a compound SM 1in a first solvent, adding a compound SM2 and alkali, carrying out reflux reaction on the system until the reaction is complete, filtering after the temperature of the system is cooled to room temperature, spin-drying, and purifying to obtain a compound B1;
Step two: dissolving the compound B1 in a second solvent, sequentially adding 1-alkenyl hexyl boric acid, alkali, a catalyst and a ligand, carrying out reflux reaction under the protection of nitrogen until the reaction is complete, and spin-drying the system to obtain a compound B2;
Step three: dissolving the compound B2 in a third solvent, adding alkali under ice water bath, heating to room temperature after adding alkali for reaction for 2-4h, filtering, spin-drying the solvent, dissolving with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain a compound B3;
step four: dissolving the compound B3 in a fourth solvent, adding an oxidant under ice water bath, heating to room temperature after adding, reacting for 1-2h, quenching, extracting a water layer with dichloromethane, combining an organic layer, washing with saturated saline water, drying, filtering, and concentrating a filtrate to obtain a compound B4;
Step five: dissolving methyl triphenylphosphine bromide in a fifth solvent, dropping alkali at-5-0 ℃, keeping the temperature after dropping, stirring, adding a solution of the compound B4 dissolved in the fifth solvent, keeping the temperature, reacting until the reaction is complete, quenching the reaction by saturated ammonium chloride, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated common salt, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing silica gel column chromatography to obtain a target compound;
The structural general formula of the target compound is shown as the following formula (1):
The structural general formula of the compound SM1 is shown as the following formula (2):
the structural general formula of the compound SM2 is shown as the following formula (5):
the structural general formula of the compound B1 is shown as the following formula (6):
The structural general formula of the compound B2 is shown as the following formula (7):
the structural general formula of the compound B3 is shown as the following formula (8):
the structural general formula of the compound B4 is shown as the following formula (9):
Wherein,
R 1 is selected from hydrogen;
R 2 is selected from hydrogen;
r 3 is selected from-ch=ch 2.
Further, in the first step, the first solvent is at least one selected from acetonitrile, dichloroethane, tetrahydrofuran, and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, sodium carbonate, potassium acetate, sodium acetate and N, N-diisopropylethylamine; the molar ratio of the compound SM1 to the compound SM2 to the alkali is 1 (0.8-1.2): 1.5-3.5); the reaction time is 4-8h.
Further, in the second step, the second solvent is at least one selected from toluene, dimethyl sulfoxide, N-dimethylformamide, and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, cesium carbonate and sodium carbonate; the catalyst is selected from Pd 2(dba)3、Pd(OAc)2、NiCl2(PCy3)2; the ligand is selected from tricyclohexylphosphine or 1, 3-bis (dicyclohexylphosphino) propane; the mol ratio of the compound B1 to the 1-alkenyl hexyl boric acid, the alkali, the catalyst and the ligand is 1 (1.1-1.5) (3-5) (0.05-0.15); the reaction time is 8-15h.
Further, in the third step, the third solvent is at least one selected from methanol, ethanol, isopropanol, tetrahydrofuran, and 1, 4-dioxane; the alkali is at least one selected from potassium carbonate, sodium hydroxide and potassium hydroxide; the molar ratio of the compound B2 to the alkali is 1 (2.5-4); the reaction time is 2-4h.
Further, in the fourth step, the fourth solvent is at least one selected from dichloromethane, dichloroethane, tetrahydrofuran, and chloroform; the oxidant is at least one selected from dess-martin oxidant, pyridinium dichromate and 2-iodiyl benzoic acid; the mol ratio of the compound B3 to the oxidant is 1 (1.5-3); the reaction time is 1-2h.
Further, in the fifth step, the fifth solvent is at least one selected from tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide; the alkali is at least one selected from n-butyllithium, sodium ethoxide, sodium tert-butoxide and dimethyl sulfoxide salt; the molar ratio of the compound B4 to the methyl triphenylphosphine bromide and the alkali is 1 (1.5-2.5): 1.5-2.5); adding alkali, and stirring for 10-50min; and the compound B4 is dissolved in the solution of the fifth solvent, and the reaction is carried out for 0.5 to 1.5 hours at the temperature.
The embodiment of the invention has the following advantages:
The embodiment of the invention provides a benzhydryl piperazine compound containing linear olefin and a preparation method thereof, which are expected to directly act on focus or be used as molecular building blocks to participate in the research and development of new drugs. The preparation method of the novel benzhydryl piperazine compound containing the linear olefin takes 1-bromo-2- (bromo (phenyl) methyl) benzene as a raw material, and the target compound is obtained through nucleophilic substitution and carbon-carbon coupling two-step reaction. The whole preparation route has stable reaction, mild used condition and simple operation, and the carbon-carbon coupling reaction obviously improves the reaction activity through a preferential catalytic system, has high reaction yield and can provide reliable reference for the synthesis of the compounds.
Detailed Description
Other advantages and advantages of the present invention will become apparent to those skilled in the art from the following detailed description, which, by way of illustration, is to be read in connection with certain specific embodiments, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The present invention will be described in detail with reference to the following specific examples, but is not limited thereto.
The embodiment of the invention discloses a linear-olefin-containing benzhydryl piperazine compound, which has a structural general formula of the following formula (1):
Wherein,
R 1 is selected from hydrogen;
R 2 is selected from hydrogen;
r 3 is selected from one of C2-C6-alkenyl, C1-C6-aldehyde, C1-C6-alkyloxyacyl, C1-C6-alkylcarbonyl, C1-C6-alkylamino, C1-C6-alkylaminosulfonyl, C1-C6-alkylhydroxy, aminocyano, di (cyano) -C1-C6-alkyl, C2-C6-haloalkenyl, C1-C6-haloalkylaldehyde, C1-C6-haloalkylcarbonyl containing up to 4 identical or different halogen atoms.
Wherein, the C1-C6-alkyl amino sulfonyl can be substituted by a plurality of identical or different R 4 substituents; r 4 is selected from at least one of C1-C6-alkane, C2-C6-alkene, C2-C6-alkyne, C3-C6-cycloalkane, C1-C6-haloalkane/C2-C6-haloalkene/C3-C6-haloalkane containing up to 4 identical or different halogen atoms.
As the use of the benzhydryl piperazine medicines is deeper and deeper, the problems of reduced efficacy, obvious side effects and the like are more and more prominent, and the active molecular spectrum of the benzhydryl piperazine compounds is required to be updated continuously, so that the benzhydryl piperazine compounds are the normal state of medicine development. The benzhydryl piperazine compound provided by the invention can be used as a potential active molecule for various diseases, and as the piperazine ring part of the benzhydryl piperazine compound acts as an active group in the treatment of a plurality of diseases, the biological activity of branched olefins in modern medicines is combined, and the linear olefins are introduced into the benzene ring part by splicing fragments of one of the medicine design strategies, so that the release degree of the medicine in organisms is expected to be improved, and the medicine effect of the medicine is further improved; meanwhile, in order to obtain bioactive molecules with high bioavailability, a plurality of different groups are introduced on the piperazine ring, and the balance degree of water solubility and fat solubility is selected and removed through synergistic effect, so that the active intermediate of the active drug with high potential is obtained.
The embodiment of the invention also discloses a preparation method of the benzhydryl piperazine compound containing the linear olefin. The synthesis of the benzhydryl piperazine compound with the structural general formula (1) adopts the following synthesis route:
the preparation method of the benzhydryl piperazine compound containing the linear olefin specifically comprises the following steps:
step one: dissolving a compound SM 1in a first solvent, adding a compound SM2 and alkali, carrying out reflux reaction on the system until the reaction is complete, filtering after the system is cooled to room temperature, spin-drying, and purifying to obtain a compound A;
Step two: and dissolving the compound A in a second solvent, sequentially adding 1-alkenyl hexyl boric acid, alkali, a catalyst and a ligand, carrying out reflux reaction under the protection of nitrogen until the reaction is complete, and spin-drying the system to obtain the target compound.
In the first step, the first solvent is at least one selected from acetonitrile, dichloroethane, tetrahydrofuran and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, sodium carbonate, potassium acetate, sodium acetate and N, N-diisopropylethylamine; the molar ratio of the compound SM1 to the compound SM2 to the base is 1: (0.8-1.2): (1.5-3.5) the reaction time is 4-8h.
In the second step, the second solvent is at least one selected from toluene, dimethyl sulfoxide, N-dimethylformamide and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, cesium carbonate and sodium carbonate; the catalyst is selected from Pd 2(dba)3、Pd(OAc)2、NiCl2(PCy3)2; the ligand is selected from tricyclohexylphosphine or 1, 3-bis (dicyclohexylphosphino) propane; the reaction time is 8-15h. Further, the mol ratio of the compound A to the 1-alkenyl hexyl boric acid, the alkali, the catalyst and the ligand is 1 (1.1-1.5): (3-5): (0.05-0.15): (0.05-0.15).
In addition, in the embodiment of the invention, when R3 is selected from C2-C6 thin radical, C1-C6 aldehyde radical, C1-C6 alkyloxyacyl radical and C1-C6 alkyl hydroxyl radical; the R3 is selected from-COH, -CH 2OH、-CH2OCOCH3 or-CH=CH 2.
Hereinafter, R 1 is selected from hydrogen; r 2 is selected from hydrogen; r 3 is selected from-CH=CH 2, and illustrates a preparation method of the linear olefin-containing benzhydryl piperazine compound in the embodiment of the invention, wherein the following synthetic route can be adopted:
the method specifically comprises the following steps:
step one: dissolving a compound SM 1in a first solvent, adding a compound SM2 and alkali, carrying out reflux reaction on the system until the reaction is complete, filtering after the temperature of the system is cooled to room temperature, spin-drying, and purifying to obtain a compound B1;
Step two: dissolving the compound B1 in a second solvent, sequentially adding 1-alkenyl hexyl boric acid, alkali, a catalyst and a ligand, carrying out reflux reaction under the protection of nitrogen until the reaction is complete, and spin-drying the system to obtain a compound B2;
Step three: dissolving the compound B2 in a third solvent, adding alkali under ice water bath, heating to room temperature after adding alkali for reaction for 2-4h, filtering, spin-drying the solvent, dissolving with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain a compound B3;
step four: dissolving the compound B3 in a fourth solvent, adding an oxidant under ice water bath, heating to room temperature after adding, reacting for 1-2h, quenching, extracting a water layer with dichloromethane, combining an organic layer, washing with saturated saline water, drying, filtering, and concentrating a filtrate to obtain a compound B4;
Step five: dissolving methyl triphenylphosphine bromide in a fifth solvent, dropping alkali at-5-0 ℃, keeping the temperature and stirring after dropping, adding a solution of the compound B4 dissolved in the fifth solvent, keeping the temperature and reacting until the reaction is complete, quenching the reaction by saturated ammonium chloride, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated common salt, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing silica gel column chromatography to obtain the target compound.
Because of the lack of reports on methods of synthesis of linear benzhydryl piperazine in the prior art, the present invention provides a reliable synthesis method with respect to the synthesis of the compound. Nucleophilic substitution is carried out by taking compound SM1 1-bromo-2- (bromo (phenyl) methyl) benzene and compound SM2 tert-butyl piperazine-1-carboxylic ester derivative with corresponding groups as raw materials, and a benzhydryl piperazine framework is constructed in one step, so that the difficulty of adding a modification group on a piperazine ring in the benzhydryl piperazine framework is reduced; then, on the frame, the olefination is carried out, and the olefination of benzene derivatives in the prior art is realized by a format reagent, and due to the characteristics of the Grignard reagent, strict water and oxygen removal are needed in the reaction, the operation of the reaction process is complicated, and meanwhile, the large-scale expansion production has a plurality of inconveniences, so that the application of the compounds is limited to a certain extent; according to the invention, the (E) -1-hexenyl dihydroxyborane is adopted to treat the obtained benzhydryl piperazine derivative, the target compound is obtained by carbon-carbon coupling reaction and linear olefin is added, the catalyst used in the reaction and the preferable high-activity ligand are subjected to metal transfer and catalytic reaction, so that the activation energy required by the reaction is reduced, the reaction activity is improved, the reaction is realized in high yield, the tolerance of the reaction to groups is high, strict deoxidization is not needed in the reaction process, the reaction is convenient to control, the operation is simpler and more convenient, and the method is suitable for synthesizing various linear benzhydryl piperazine compounds.
In the first step, the first solvent is at least one selected from acetonitrile, dichloroethane, tetrahydrofuran and 1, 2-dioxane; the alkali is at least one of potassium carbonate, sodium carbonate, potassium acetate, sodium acetate and N, N-diisopropylethylamine; the molar ratio of compound SM1 to compound SM2 to base is 1: (0.8-1.2): (1.5-3.5); the reaction time is 4-8h.
In the second step, the second solvent is selected from at least one of toluene, dimethyl sulfoxide, N-dimethylformamide and 1, 2-dioxane; the alkali is at least one of potassium carbonate, cesium carbonate and sodium carbonate; the catalyst is selected from Pd 2(dba)3、Pd(OAc)2、NiCl2(PCy3)2; the ligand is selected from tricyclohexylphosphine or 1, 3-bis (dicyclohexylphosphino) propane, and the molar ratio of the compound B1 to the 1-alkenylhexylboric acid, the base, the catalyst and the ligand is 1 (1.1-1.5): (3-5): (0.05-0.15): (0.05-0.15), the reaction time is 8-15h.
In the third step, the third solvent is at least one selected from methanol, ethanol, isopropanol, tetrahydrofuran and 1, 4-dioxane; the alkali is at least one of potassium carbonate, sodium hydroxide and potassium hydroxide; the molar ratio of the compound B2 to the alkali is 1 (2.5-4); the reaction time is 2 to 4 hours, more preferably 2 hours.
In the fourth step, the fourth solvent is at least one selected from dichloromethane, dichloroethane, tetrahydrofuran and chloroform; the oxidant is at least one selected from Dess-Martin, pyridinium dichromate (Pyridinium Dichromate) and 2-iodoxybenzoic acid; and further preferably Dess-Martin as oxidizing agent; the mol ratio of the compound B3 to the oxidant is 1 (1.5-3); the reaction time is 1 to 2 hours, and more preferably 1 hour.
In the fifth step, the fifth solvent is at least one selected from tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide; the alkali is at least one selected from n-butyllithium, sodium ethoxide, sodium tert-butoxide and dimethyl sulfoxide salt; the molar ratio of the compound B4 to the methyl triphenylphosphine bromide and the alkali is 1 (1.5-2.5): 1.5-2.5); adding alkali, and stirring for 10-50min; preferably for 20min; after the solution of the compound B4 dissolved in the fifth solvent is dripped, the temperature is kept for reaction for 0.5 to 1.5 hours, preferably 0.5 hour.
In the synthetic route, a compound SM1 1-bromo-2- (bromo (phenyl) methyl) benzene and 3- (acetoxymethyl) -4- ((2-bromophenyl) (phenyl) methyl) piperazine-1-carboxylic acid tert-butyl ester are used as raw materials for nucleophilic substitution, a benzhydryl piperazine framework is directly constructed, then a catalyst and a ligand are optimized, the required activation energy for the reaction is reduced, the reaction activity is greatly improved, the addition of a direct alkenyl group is realized, the tolerance of the reaction group is high, the method can be used for the synthesis of various substrates, the operation of the reaction process is simple and convenient, strict water removal and oxygen removal are not needed, and the large-scale expansion production is facilitated; then the intermediate is hydrolyzed under alkaline condition; oxidizing an alcohol group by using an oxidizing reagent to realize the group conversion from the alcohol group to the aldehyde group, so as to obtain a benzhydryl piperazine compound containing the formaldehyde group, wherein Dess-Martin is preferably used as the oxidizing reagent, and the reagent has the characteristics of short reaction time, mild reaction condition, small consumption of the oxidizing reagent and the like, so that the reaction activity is improved, the reaction time is shortened, and the energy consumption required by the reaction and the material cost for production are reduced; finally olefination is carried out under the action of methyl triphenylphosphine bromide and alkali to obtain a benzhydryl piperazine compound containing vinyl, and the reaction has few byproducts and specificity; the whole synthesis route is used for continuously synthesizing the compound, which is beneficial to further reducing the production cost and improving the feasibility of industrial production, thereby obtaining the production process route with the highest cost performance.
Example 1
Hereinafter, R 1 is selected from hydrogen; r 2 is selected from hydrogen; r 3 is selected from the group consisting of-CH 2 OAc; for example, a method for preparing the linear olefin-containing benzhydryl piperazine compound in the embodiment of the present invention is described.
Step one: synthesis of Compound B1
Compound SM1 (20 g,61.34mmol,1 eq) was dissolved in acetonitrile (150 mL), and compound SM2 (15.85 g,61.36mmol,1 eq) and potassium carbonate (17 g,123.0mmol,2 eq) were added and the system was refluxed for 4 hours. After the reaction is finished, the mixture is filtered after the temperature of the system is cooled to room temperature, and the white solid 27.51g is obtained by silica gel column chromatography after the solvent is dried by spin, namely the compound B1 is obtained, the yield is 87.4%, and the purity is 98.1%.
The structural characterization data for compound B1 are as follows:
[M+H]+＝503.16
1H-NMR(300MHz,CDCl3)δ7.79(m,1H),7.48(m,3H),7.28(m,3H),7.20(m,1H),7.06(m,1H),5.42(m,1H),4.28(m,2H),3.95(m,2H),3.08(m,3H),2.61(m,2H),2.00(m,3H),1.43(s,9H).
step two: synthesis of Compound B2
Compound B1 (27.51 g,53.63mmol,1 eq) was dissolved in toluene (300 ml), and 1-alkenylhexylboric acid (8.24 g,64.39mmol,1.2 eq), potassium carbonate (22.24 g,160.91mmol,3 eq), pd 2(dba)3 (4.91 g,5.365mmol,0.1 eq) and 1, 3-bis (dicyclohexylphosphino) propane (2.34 g,5.365mmol,0.1 eq) were added in this order and the system was replaced three times with nitrogen. The reaction was refluxed overnight under nitrogen. The next day, silica gel column chromatography after the system spin-dries the solvent gave 26.09g of pale yellow liquid, namely compound B2, with a yield of 94.00% and a purity of 97.9%.
The structural characterization data for compound B2 are as follows:
[M+H]+＝507.32
1H-NMR(300MHz,CDCl3)δ7.73(q,1H),7.38(d,J＝5.7Hz,2H),7.13-7.35(m,6H),6.80(m,1H),5.91(m,1H),5.20(m,1H),4.30(m,2H),3.95(m,1H),3.0(m,2H),2.57(m,2H),2.22(q,2H),1.97(m,3H),1.49(q,2H),1.43(s,9H),1.38(m,4),0.98(dd,J＝7.8Hz,3H).
step three to step five: synthesis of target Compound
Compound B2 (4.78 g,9.43mmol,1 eq) obtained in step two was dissolved in methanol (50 ml), and potassium carbonate (3.91 g,28.29mmol,3 eq) was added under ice-water bath, after which the ice-water bath was removed and reacted for 2 hours at room temperature. After filtration, the solvent was dried by spin-drying, 60ml of ethyl acetate was dissolved, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent under reduced pressure, 4.45g of a pale yellow liquid, namely compound B3, was obtained in a yield of 93.34% and a purity of 92.00%.
The pale yellow liquid compound B3 (4.09 g,8.10 mmol) obtained in the above step was dissolved in methylene chloride (40 ml), and Dess-Martin oxidant (8.6 g,24.90mmol,2.5 eq) was added three times in an ice-water bath, and after the addition, the ice-water bath was removed and reacted at room temperature for 1 hour. After the reaction was quenched by adding a mixed solution of saturated sodium hydrogencarbonate and sodium thiosulfate, the aqueous layer was extracted with methylene chloride, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent under reduced pressure, 3.68g of a pale yellow liquid was obtained, namely compound B4, in a yield of 89.78% and a purity of 91.30%.
Methyl triphenylphosphine bromide (5.19 g,14.54mmol,2 eq) was dissolved in tetrahydrofuran (120 ml), n-butyllithium (5.80 ml,14.54mmol,2 eq) was slowly added dropwise at 0℃and stirred at 0℃for 20min after the addition, and then a tetrahydrofuran solution (20 ml) of the above-obtained compound B4 (3.68 g,7.27mmol,1 eq) was slowly added dropwise, and the reaction was allowed to stand for 0.5h and then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent under reduced pressure, 2.61g of a pale yellow liquid, i.e., the target compound was obtained by silica gel column chromatography, with a yield of 76.37% and a purity of 98.12%.
The structural characterization data for the target compounds are as follows:
[M+H]+＝461.32
1H-NMR(300MHz,CDCl3)δ7.63(m,1H),7.12-7.34(m,9H),6.77(t,J＝30.3,1H),6.39(m,2H),5.58(m,2H),4.88(s,1H),3.80(m,2H),3.32(m,3H),3.02(brs,1H),2.75(m,2H),1.40(s,9H),1.38(m,4),0.98(m,3H).
Examples 2 to 11 and comparative examples 1 to 5
The steps of examples 2-11 and comparative examples 1-5 were the same as in example 1 above, except that only a portion of the process conditions of step two were changed. The present invention is specifically described in the form of a list in examples 2 to 11 and comparative examples 1 to 5, so that the results are more intuitively clear.
TABLE 1 influence of reaction conditions on the yield of intermediate compound B2
From Table 1, the reaction yields were preferably obtained in a high boiling point solvent, and as shown in examples 1 to 4, toluene, dimethyl sulfoxide, N-dimethylformamide and 1, 2-dioxane were preferably used as the solvents, and when the reaction was carried out using a low boiling point solvent as shown in comparative example 4, the reaction yields were significantly reduced. Because of the partial boron removal effect of the 1-alkenyl hexyl boric acid in the reaction, when the dosage is more than 1eq of theoretical value, the reaction yield is more ideal, and as shown in examples 5-6, the dosage is preferably 1.1-1.5eq, and when the dosage is reduced to 0.7eq in comparative example 5, the raw materials are more remained, and the yield is obviously reduced; the essence of this reaction is carbon-carbon coupling, the result of the reaction is not ideal when Pd (Ph 3P)4、Pd(dppf)Cl2、Pd Cl2(Ph3P)2) as the catalyst in comparative examples 1-3 is used, when the catalytic system is changed to any combination of Pd 2(dba)3、Pd(OAc)2 and ligand 1, 3-bis (dicyclohexylphosphino) propane and tricyclohexylphosphine as shown in examples 1 and 7-9, the reaction yield is obviously improved, and Pd 2(dba)3 and 1, 3-bis (dicyclohexylphosphino) propane catalytic system is preferable, in particular, when Pd 2(PCy3)2 is used as the catalyst in example 10 and tricyclohexylphosphine is used as the ligand, the result of the reaction is slightly inferior to that of Pd 2(dba)3 and 1, 3-bis (dicyclohexylphosphino) propane, but the result of the reaction is also excellent, which provides a reference for carbon-carbon coupling of nickel catalytic similar reactants.
According to the technical scheme, the invention provides a plurality of novel benzhydryl piperazine compounds containing linear olefins, and potential active molecules or active molecular building blocks can be provided for the development of benzhydryl piperazine medicines, so that the candidate molecular spectrum of the active medicines is further expanded. The synthesis preparation method of the benzhydryl piperazine compound containing the linear olefin, provided by the invention, can provide reliable reference for synthesis of the compound, and a reaction strategy is optimized, a benzhydryl piperazine frame is constructed by taking the compound SM2 tert-butyl piperazine-1-carboxylate derivative with corresponding groups as a raw material, so that the synthesis difficulty of a target compound is reduced, the linear olefin is added, a catalyst and a ligand are preferably reacted, the activation energy required by the reaction is reduced, the reaction activity is improved, the side reaction is reduced, the application range is wide, the reaction condition is mild, the operation is simple and convenient, and particularly in the step of the reaction, a nickel catalyst with lower price is adopted to catalyze the reaction with the corresponding ligand, so that the reference is provided for catalyzing carbon-carbon coupling of similar reactants by the nickel catalyst; the whole synthesis process has high reaction yield, no high-toxicity and high-risk reagent is used, the post-reaction treatment is simple, the synthesis steps are short, and the method has the characteristic of green chemistry.
While the invention has been described in detail in the foregoing general description and specific examples, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (5)
1. A preparation method of benzhydryl piperazine compound containing linear olefin is characterized in that,
The specific synthetic route is as follows:
the method comprises the following steps:
step one: dissolving a compound SM 1in a first solvent, adding a compound SM2 and alkali, carrying out reflux reaction on the system until the reaction is complete, filtering after the temperature of the system is cooled to room temperature, spin-drying, and purifying to obtain a compound B1;
Step two: dissolving the compound B1 in a second solvent, sequentially adding 1-alkenyl hexyl boric acid, alkali, a catalyst and a ligand, carrying out reflux reaction under the protection of nitrogen until the reaction is complete, and spin-drying the system to obtain a compound B2; the catalyst is selected from Pd 2(dba)3、Pd(OAc)2、NiCl2(PCy3)2; the ligand is selected from tricyclohexylphosphine or 1, 3-bis (dicyclohexylphosphino) propane; the mol ratio of the compound B1 to the 1-alkenyl hexyl boric acid, the alkali, the catalyst and the ligand is 1 (1.1-1.5) (3-5) (0.05-0.15); the reaction time is 8-15h;
Step three: dissolving the compound B2 in a third solvent, adding alkali under ice water bath, heating to room temperature after adding alkali for reaction for 2-4h, filtering, spin-drying the solvent, dissolving with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain a compound B3;
Step four: dissolving the compound B3 in a fourth solvent, adding an oxidant under ice water bath, heating to room temperature after adding, reacting for 1-2h, quenching, extracting a water layer with dichloromethane, combining an organic layer, washing with saturated saline water, drying, filtering, and concentrating a filtrate to obtain a compound B4; the oxidant is at least one selected from dess-martin oxidant, pyridinium dichromate and 2-iodiyl benzoic acid; the mol ratio of the compound B3 to the oxidant is 1 (1.5-3); the reaction time is 1-2h;
Step five: dissolving methyl triphenylphosphine bromide in a fifth solvent, dropping alkali at-5-0 ℃, keeping the temperature after dropping, stirring, adding a solution of the compound B4 dissolved in the fifth solvent, keeping the temperature, reacting until the reaction is complete, quenching the reaction by saturated ammonium chloride, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated common salt, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing silica gel column chromatography to obtain a target compound;
The structural general formula of the target compound is shown as the following formula (1):
(1)
The structural general formula of the compound SM1 is shown as the following formula (2):
the structural general formula of the compound SM2 is shown as the following formula (5):
the structural general formula of the compound B1 is shown as the following formula (6):
The structural general formula of the compound B2 is shown as the following formula (7):
the structural general formula of the compound B3 is shown as the following formula (8):
the structural general formula of the compound B4 is shown as the following formula (9):
Wherein,
R 1 is selected from hydrogen;
R 2 is selected from hydrogen;
r 3 is selected from-ch=ch 2.
2. The method for producing a linear olefin-containing benzhydryl piperazine compound according to claim 1, wherein in the first step, the first solvent is at least one selected from acetonitrile, dichloroethane, tetrahydrofuran, and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, sodium carbonate, potassium acetate, sodium acetate and N, N-diisopropylethylamine; the molar ratio of the compound SM1 to the compound SM2 to the base is 1: (0.8-1.2): (1.5-3.5); the reaction time is 4-8h.
3. The process for producing a linear olefin-containing benzhydryl piperazine compound according to claim 2, wherein in the second step, the second solvent is at least one selected from toluene, dimethyl sulfoxide, N-dimethylformamide, and 1, 2-dioxane; the alkali is at least one selected from potassium carbonate, cesium carbonate and sodium carbonate.
4. The process for producing a linear olefin-containing benzhydryl piperazine compound according to claim 1, wherein in the third step, the third solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, and 1, 4-dioxane; the alkali is at least one selected from potassium carbonate, sodium hydroxide and potassium hydroxide; the molar ratio of the compound B2 to the alkali is 1: (2.5-4); the reaction time is 2-4h.
5. The process for producing a linear olefin-containing benzhydryl piperazine compound according to claim 4, wherein in the fourth step, the fourth solvent is at least one selected from the group consisting of methylene chloride, ethylene dichloride, tetrahydrofuran, and chloroform;
In the fifth step, the fifth solvent is selected from at least one of tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide; the alkali is at least one selected from n-butyllithium, sodium ethoxide, sodium tert-butoxide and dimethyl sulfoxide salt; the molar ratio of the compound B4 to the methyl triphenylphosphine bromide and the alkali is 1 (1.5-2.5): 1.5-2.5); adding alkali, and stirring for 10-50min; and after the solution of the compound B4 dissolved in the fifth solvent is added, carrying out heat preservation reaction for 0.5-1.5h.
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