CN112266349A - 一种制备2-氨基-4-甲基-1-丙基-1h-吡咯-3-甲腈的方法 - Google Patents
一种制备2-氨基-4-甲基-1-丙基-1h-吡咯-3-甲腈的方法 Download PDFInfo
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- CN112266349A CN112266349A CN202011285039.4A CN202011285039A CN112266349A CN 112266349 A CN112266349 A CN 112266349A CN 202011285039 A CN202011285039 A CN 202011285039A CN 112266349 A CN112266349 A CN 112266349A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- YXHGHIPMRPOBRH-UHFFFAOYSA-N 2-amino-4-methyl-1-propylpyrrole-3-carbonitrile Chemical compound CCCN1C=C(C)C(C#N)=C1N YXHGHIPMRPOBRH-UHFFFAOYSA-N 0.000 title claims abstract description 17
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000006239 protecting group Chemical group 0.000 claims abstract description 10
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 235000011181 potassium carbonates Nutrition 0.000 claims description 8
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- WZWSOGGTVQXXSN-UHFFFAOYSA-N cyclohexanone;toluene Chemical compound CC1=CC=CC=C1.O=C1CCCCC1 WZWSOGGTVQXXSN-UHFFFAOYSA-N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 150000002334 glycols Chemical class 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 5
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- 238000001035 drying Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 3
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- -1 heterocyclic ketone Chemical class 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical class C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RXMDFMQMRASWOG-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound CCCN1C=C(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 RXMDFMQMRASWOG-UHFFFAOYSA-N 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种制备2‑氨基‑4‑甲基‑1‑丙基‑1H‑吡咯‑3‑甲腈的方法,属于有机合成技术领域。本发明制备方法步骤如下:采用环氧丙烷与正丙胺为原料;保护氮原子上的氢后,经氧化、脱保护基,再与丙二腈成环制得2‑氨基‑4‑甲基‑1‑丙基‑1H‑吡咯‑3‑甲腈。本发明产品收率高、纯度高,并且原料易得,操作简单,有利于工业化生产。
Description
技术领域
本发明属于有机化学合成领域,具体涉及一种制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的方法。
背景技术
优克那非(Yonkenafil)是一种环磷酸鸟苷(Cyclic Guanosine monophosphate,cGMP)的五元并六元杂环酮类结构类似物,是我国科研工作者独立研发的具有自主知识产权的一种新型磷酸二酯酶(Phosphodiesterase,PDE)V抑制剂。前期药效学试验研究表明,该化合物对PDE V具有很好的选择性抑制作用,明显优于市场上现有的PDE V抑制剂类药物西地那非和伐地那非。药理学实验表明优克那非在动物体内的耐受剂量很高,安全性良好,毒副作用明显低于市场上现有药物,有望成为一种新的男性性功能障碍的治疗药物。
目前优克那非已经在中国和美国申请了专利保护(中国申请号:CN03142399.X;中国公开号:CN1552714;美国申请号:PCT/CN2004/000487;美国公开号:WO2004/108726),同时也在国内进行新药的申报工作(优克那非属于化学药品1.1类)。临床前药效、药理、毒理、药代及毒代研究工作均已完成,现国家药品评审中心正对此品种进入临床研究进行技术审评。2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈是合成优克那非的关键中间体,结构式如下:
目前无相关文献报道制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的方法,仅有相似的结构被文献报道,相似的文献报道是以硝基环氧化物为原料制备苯取代2-氨基-3-氰基吡咯。[Indian Journal of Chemistry-Section B Organic and MedicinalChemistry,1990,vol.29,#1,p.47-52]中报道的合成路线如下:
目前无文献报道制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的方法,因此有必要开发一种制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的方法。
发明内容
本发明目的在于提供一种制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的新方法,以解决上述背景技术中提出的问题。
一种制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的方法,采用如下所示的合成路线:
具体包括以下步骤:
步骤1:环氧丙烷与正丙胺在碱作用下于溶剂中反应制得如式(I)所示的化合物;
步骤2:将如式(I)所示的化合物与含保护基R试剂反应制得如式(II)所示的化合物;
步骤3:将如式(II)所示的化合物氧化制得如式(III)所示的化合物;
步骤4:将如式(III)所示的化合物脱保护基制得如式(IV)所示的化合物;
步骤5:将如式(IV)所示的化合物与丙二睛在碱的作用下于溶剂中成环制得如式(V)所示的2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈。
作为本发明再进一步的方案:步骤1中,所述碱可选用氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、N,N-二异丙基乙基胺、吡啶、4-二甲氨基吡啶、醋酸钾、醋酸钠等,优选三乙胺;所述溶剂可选用甲苯、甲醇、乙醇、二氯甲烷等其中一种或几种的混合溶剂,优选二氯甲烷;
作为本发明再进一步的方案:步骤2中,所述含保护基R试剂可选用氯甲酸苄酯、Boc酸酐等,优选Boc酸酐;
作为本发明再进一步的方案:步骤2中,所述含保护基R的试剂摩尔量与式(I)所示的化合物摩尔量之比可选(1~5):1,优选1.5:1;反应温度可选-10~100℃,优选-5~5℃;
作为本发明再进一步的方案:步骤3中,所述氧化剂可选用浓硫酸、高锰酸钾、臭氧、高碘酸、双氧水、次氯酸钠、氯气、硝酸、高铁酸钠、氟气、间氯过氧苯甲酸、过氧化物等,优选次氯酸钠;
作为本发明再进一步的方案:步骤3中,所述氧化剂摩尔量与式(II)所示的化合物摩尔量之比可选(1~10):1,优选3:1;反应温度可选-10~100℃,优选-10~0℃;
作为本发明再进一步的方案:步骤4中,所述脱保护基试剂可选用盐酸水溶液,盐酸乙酸乙酯溶液,盐酸甲醇溶液,盐酸乙醇溶液,盐酸二氧六环溶液,柠檬酸,TFA,MeSiI,氯化氢气体等,优选盐酸水溶液;
作为本发明再进一步的方案:步骤4中,所述脱保护试剂摩尔量与式(III)所示的化合物摩尔量之比可选(1~5):1,优选2:1;反应温度可选-10~100℃,优选-10~0℃;
作为本发明再进一步的方案:步骤5中,所述碱可选用氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、N,N-二异丙基乙基胺、吡啶、4-二甲氨基吡啶、醋酸钾、醋酸钠等,优选碳酸钾;
作为本发明再进一步的方案:步骤5中,所述溶剂可选用苯、甲苯、二甲苯、戊烷、己烷、辛烷、环己烷、环己酮、甲苯环己酮、氯苯、二氯苯、二氯甲烷、甲醇、乙醇、异丙醇、乙醚、醋酸甲酯、醋酸乙酯、醋酸丙酯、丙酮、四氢呋喃、甲基四氢呋喃、二醇衍生物、乙二醇单甲醚、乙二醇单乙醚、乙二醇单丁醚、乙腈、吡啶、苯酚、N,N-二甲基甲酰胺、N,N-二甲基甲酰胺、二甲基亚砜等,优选乙醇。
作为本发明再进一步的方案:步骤5中,所述碱摩尔量与式(IV)所示的化合物摩尔量之比可选(1~10):1,优选3.5:1。
本发明的有益效果为:
选用环氧丙烷与正丙胺作为原料,原料易得,操作简单,并且产品收率高、纯度高,有利于工业化生产。
附图说明
图1为实例1制备的2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的核磁谱图。
图2为实例1制备的2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的高效液相色谱图。
具体实施方式
下面将结合实施例对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
下述中,如无特殊说明,所有的原料均来自于商购或者通过本领域的常规方法制备而得。下述中,次氯酸钠溶液是指质量百分含量为10%的次氯酸钠水溶液。
所述制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的方法,采用如下的合成路线:
实施例1
步骤1:在500ml三口瓶中加入环氧丙烷30g(0.516mol),二氯甲烷160ml搅拌10min,冰水浴冷却。控温0~10℃,滴加三乙胺0.5g(5mmol)。搅拌30min,控温0~10℃,滴加正丙胺32.06g(0.542mol)。控温反应3h。浓缩干,减压蒸馏。得到55g式(I)所示的化合物,摩尔收率90.8%;
步骤2:在500ml三口瓶中加入式(I)所示的化合物20g(0.170mol),甲醇200ml,控温-10-0℃,滴加Boc酸酐74.5g(0.341mol),滴完继续搅拌6h。浓缩干,减压蒸馏。得到35g式(II)所示的化合物,摩尔收率94.0%。
步骤3:在500ml三口瓶中加入式(II)所示的化合物5.45g(0.025mol),二氯甲烷50ml,控制温度回流,滴加30%双氧水11.3g(0.1mol)。滴完回流8h。冰水浴冷却,滴加10%亚硫酸钠溶液。分层,水层萃取有机相,合并有机相。浓缩,减压蒸馏。得到4.9g式(III)所示的化合物,摩尔收率90.5%;
步骤4:在100ml三口瓶中加入式(III)所示的化合物5.58g(0.025mol),二氯甲烷50ml,搅拌10min。控制温度5~15℃,滴加盐酸水溶液。保温1h。分层,水萃取二氯甲烷层一次。合并水层。旋蒸,得到3.7g式(IV)所示的化合物,摩尔收率94.1%。
步骤5:在100ml三口瓶中加入式(IV)所示的化合物2g(0.013mol),乙醇20ml,丙二腈0.871g(0.013mol),回流反应5h。加入碳酸钠4.13g(0.039mol)。保温10h,降至室温,过滤,浓缩,加入二氯甲烷10ml和水5ml,搅拌10min,分层,干燥,浓缩,柱层析,得到的产品加入乙醇10ml,控制0~10℃,滴加1mol/L盐酸溶液,pH=2~3。浓缩干得到2.35g式(V)所示的化合物,摩尔收率91.0%。纯度99.7%,1HNMR(400MHz,CDCl3):δppm5.95-5.96(CH),3.83(NH2),3.62-3.65(CH2),2.10-2.11(CH3),1.72-1.79(CH2),0.95-0.99(CH3)。
实施例2
步骤1:在500ml三口瓶中加入环氧丙烷30g(0.516mol),四氢呋喃200ml搅拌10min,控温10~20℃,滴加正丙胺59.09g(1mol)。控温反应3h。浓缩干,减压蒸馏。得到55.6g式(I)所示的化合物,摩尔收率91.8%;
步骤2:在500ml三口瓶中加入式(I)所示的化合物13g(0.111mol),乙醇130ml,控温20~30℃,滴加Boc酸酐72.6g(0.333mol),滴完继续搅拌8h。滴加碳酸氢钠饱和溶液,浓缩,减压蒸馏。得到22.1g式(II)所示的化合物,摩尔收率91.7%。
步骤3:在500ml三口瓶中加入式(II)所示的化合物5.45g(0.025mol),二氯甲烷50ml,饱和碳酸氢钠溶液50ml,冰水浴下,滴加10%次氯酸钠74.4g(0.1mol)。保温2h。冰水浴下,滴加10%亚硫酸钠溶液。分层,水层萃取有机相,合并有机相。浓缩,减压蒸馏。得到4.97g式(III)所示的化合物,摩尔收率92%;
步骤4:在100ml三口瓶中加入式(III)所示的化合物5.58g(0.025mol),二氯甲烷50ml,搅拌10min。控制温度5-15℃,滴加盐酸二氧六环溶液。保温1h。分层,水萃取二氯甲烷层一次。合并水层。旋蒸,得到3.6g式(IV)所示的化合物,摩尔收率91.6%。
步骤5:在100ml三口瓶中加入式(IV)所示的化合物8g(0.052mol),甲醇80ml,丙二腈0.871g(0.013mol),回流反应8h。加入碳酸钾14.37g(0.104mol)。保温8h,降至室温,过滤,浓缩,加入二氯甲烷40ml和水40ml,搅拌10min,分层,干燥,浓缩,柱层析,得到的产品加入甲醇10ml,控制0~10℃,滴加1mol/L盐酸溶液,pH=2-3。浓缩干得到9.37g式(V)所示的化合物,摩尔收率90.6%。
实施例3
步骤1:在500ml三口瓶中加入环氧丙烷64g(1.1mol),四氢呋喃400ml搅拌10min,控温10~20℃,滴加正丙胺130g(2.2mol)。控温反应3h。浓缩干,减压蒸馏。得到220.4g式(I)所示的化合物,摩尔收率90.9%;
步骤2:在500ml三口瓶中加入式(I)所示的化合物26g(0.222mol),乙醇260ml,控温20~30℃,滴加Boc酸酐145.2g(0.666mol),滴完继续搅拌8h。滴加碳酸氢钠饱和溶液,浓缩,减压蒸馏。得到44.6g式(II)所示的化合物,摩尔收率92.5%。
步骤3:在500ml三口瓶中加入式(II)所示的化合物10.9g(0.05mol),二氯甲烷100ml,饱和碳酸氢钠溶液100ml,冰水浴下,滴加10%次氯酸钠148.8g(0.2mol)。保温2h。冰水浴下,滴加10%亚硫酸钠溶液。分层,水层萃取有机相,合并有机相。浓缩,减压蒸馏。得到10.1g式(III)所示的化合物,摩尔收率93.5%;
步骤4:在100ml三口瓶中加入式(III)所示的化合物11.16g(0.05mol),二氯甲烷100ml,搅拌10min。控制温度5-15℃,滴加盐酸水溶液。保温1h。分层,水萃取二氯甲烷层一次。合并水层。旋蒸,得到7.3g式(IV)所示的化合物,摩尔收率92.9%。
步骤5:在100ml三口瓶中加入式(IV)所示的化合物16g(0.106mol),甲醇160ml,丙二腈1.742g(0.026mol),回流反应8h。加入碳酸钾28.74g(0.208mol)。保温8h,降至室温,过滤,浓缩,加入二氯甲烷80ml和水80ml,搅拌10min,分层,干燥,浓缩,柱层析,得到的产品加入甲醇20ml,控制0~10℃,滴加1mol/L盐酸溶液,pH=2~3。浓缩干得到18.8g式(V)所示的化合物,摩尔收率91.7%。
Claims (10)
1.一种制备2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈的方法,其特征在于,采用如下合成路线:
所述方法包括如下步骤:
步骤(1):环氧丙烷与正丙胺在碱作用下于溶剂中反应制得如式(I)所示的化合物;
步骤(2):将如式(I)所示的化合物与含保护基R试剂反应制得如式(II)所示的化合物;
步骤(3):将如式(II)所示的化合物与氧化剂反应制得如式(III)所示的化合物;
步骤(4):将如式(III)所示的化合物脱保护基制得如式(IV)所示的化合物;
步骤(5):将如式(IV)所示的化合物与丙二睛在碱的作用下于溶剂中成环制得如式(V)所示的2-氨基-4-甲基-1-丙基-1H-吡咯-3-甲腈。
2.根据权利要求1所述的方法,其特征在于,所述步骤(1)中碱可选用氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、N,N-二异丙基乙基胺、吡啶、4-二甲氨基吡啶、醋酸钾、醋酸钠等,优选三乙胺;所述溶剂可选用甲苯、甲醇、乙醇、二氯甲烷等其中一种或几种的混合溶剂,优选二氯甲烷。
3.根据权利要求1所述的方法,其特征在于,所述步骤(2)中含保护基R试剂可选用氯甲酸苄酯、二碳酸二叔丁酯等,优选二碳酸二叔丁酯。
4.根据权利要求1所述的方法,其特征在于,所述步骤(2)中含保护基R的试剂摩尔量与式(I)所示的化合物摩尔量之比可选(1~5):1,优选1.5:1;反应温度可选-10~100℃,优选-5~5℃。
5.根据权利要求1所述的方法,其特征在于,所述步骤(3)中氧化剂可选用浓硫酸、高锰酸钾、臭氧、高碘酸、双氧水、次氯酸钠、氯气、硝酸、高铁酸钠、氟气、间氯过氧苯甲酸、过氧化物等,优选次氯酸钠。
6.根据权利要求1所述的方法,其特征在于,所述步骤(3)中氧化剂摩尔量与式(II)所示的化合物摩尔量之比可选(1~10):1,优选3:1;反应温度可选-10~100℃,优选-10~0℃。
7.根据权利要求1所述的脱保护试剂,其特征在于,所述步骤(4)中脱保护基试剂可选用氯化氢水溶液,氯化氢乙酸乙酯溶液,氯化氢甲醇溶液,氯化氢乙醇溶液,氯化氢二氧六环溶液,柠檬酸,TFA,MeSiI,氯化氢气体等,优选氯化氢水溶液。
8.根据权利要求1所述的方法,其特征在于,所述步骤(4)中脱保护试剂摩尔量与式(III)所示的化合物摩尔量之比可选(1~5):1,优选2:1;反应温度可选-10~100℃,优选-10~0℃。
9.根据权利要求1所述的方法,其特征在于,所述步骤(5)中碱可选用氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、N,N-二异丙基乙基胺、吡啶、4-二甲氨基吡啶、醋酸钾、醋酸钠等,优选碳酸钾;所述碱摩尔量与式(IV)所示的化合物摩尔量之比可选(1~10):1,优选3.5:1。
10.根据权利要求1所述的方法,其特征在于,所述步骤(5)中的溶剂可选用苯、甲苯、二甲苯、戊烷、己烷、辛烷、环己烷、环己酮、甲苯环己酮、氯苯、二氯苯、二氯甲烷、甲醇、乙醇、异丙醇、乙醚、醋酸甲酯、醋酸乙酯、醋酸丙酯、丙酮、四氢呋喃、甲基四氢呋喃、二醇衍生物、乙二醇单甲醚、乙二醇单乙醚、乙二醇单丁醚、乙腈、吡啶、苯酚、N,N-二甲基甲酰胺、N,N-二甲基甲酰胺、二甲基亚砜等,优选乙醇。
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