CN114957163B - 一种n-甲基高哌嗪的制备方法 - Google Patents
一种n-甲基高哌嗪的制备方法 Download PDFInfo
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- CN114957163B CN114957163B CN202210144295.4A CN202210144295A CN114957163B CN 114957163 B CN114957163 B CN 114957163B CN 202210144295 A CN202210144295 A CN 202210144295A CN 114957163 B CN114957163 B CN 114957163B
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- homopiperazine
- benzyl
- methyl
- sodium
- potassium
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- FXHRAKUEZPSMLJ-UHFFFAOYSA-N 1-methyl-1,4-diazepane Chemical compound CN1CCCNCC1 FXHRAKUEZPSMLJ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- JTJTYCPQUOROFM-UHFFFAOYSA-N 1-benzyl-1,4-diazepane Chemical compound C=1C=CC=CC=1CN1CCCNCC1 JTJTYCPQUOROFM-UHFFFAOYSA-N 0.000 claims abstract description 11
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000007069 methylation reaction Methods 0.000 claims abstract description 5
- VIMRHNNRKUWOIZ-UHFFFAOYSA-N n-(1-benzylpiperidin-4-ylidene)hydroxylamine Chemical compound C1CC(=NO)CCN1CC1=CC=CC=C1 VIMRHNNRKUWOIZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006237 Beckmann rearrangement reaction Methods 0.000 claims abstract description 3
- 238000006264 debenzylation reaction Methods 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 8
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 2
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- PMWKIHOURGCZOJ-UHFFFAOYSA-N n-(1-methylpiperidin-4-ylidene)hydroxylamine Chemical compound CN1CCC(=NO)CC1 PMWKIHOURGCZOJ-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 1
- LLSQPTFEBHVGMF-UHFFFAOYSA-N 2,2,2-trifluoro-n-[2-(methylamino)ethyl]acetamide Chemical compound CNCCNC(=O)C(F)(F)F LLSQPTFEBHVGMF-UHFFFAOYSA-N 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000006923 Schmidt rearrangement reaction Methods 0.000 description 1
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明涉及药物化学及医药技术领域,具体是一种N‑甲基高哌嗪的制备方法。采用N‑苄基‑4‑哌啶酮为起始原料与盐酸羟胺反应,制备得到N‑苄基‑4‑哌啶酮肟,再发生贝克曼重排,制备得到N‑苄基高哌嗪‑5‑酮,N‑苄基高哌嗪‑5‑酮经还原反应得到N‑苄基高哌嗪,N‑苄基高哌嗪再经甲基化反应得到1‑苄基‑4‑甲基‑1,4‑高哌嗪,1‑苄基‑4‑甲基‑1,4‑高哌嗪经脱苄基,制备得到N‑甲基高哌嗪。本发明反应条件温和,操作简便,后处理简单,对环境污染小,纯度高,收率好,适合工业化生产。
Description
一.技术领域
本发明涉及药物化学及医药技术领域,具体是一种N-甲基高哌嗪的制备方法。
二.背景技术
N-甲基高哌嗪及其衍生物是药物合成中的重要中间体,在化学药物的结构修饰和改造中具有极其重要的作用,是抗组胺药物、治疗心血管药物、抗高血压药物的重要中间体。其结构式如下:
N-甲基高哌嗪现有的制备方法主要有以下两种:
(1)该路线以N-甲基-4-哌啶酮为原料,溶于硫酸后加入叠氮酸经Schmidt重排生成酰胺,最后氢化铝锂还原得到N-甲基高哌嗪。文献J.Am.Chem.Soc.,1954,76,5805-5805.采用此方法制备N-甲基高哌嗪,但是此方法使用剧毒原料,反应剧烈,易爆炸,危险性高,后处理复杂,产品不易提纯,可操作性低,不适应于工业化生产的需求。
(2)该路线以2-卤代乙胺化合物为原料,与三氟乙酸乙酯反应得到N-(2-卤代乙基) 三氟乙酰胺,后与甲胺反应得到N-甲基-N’-三氟乙酰基乙二胺,再与1,3-二取代丙烷化合物反应得到N-甲基-N’-三氟乙酰基高哌嗪,最后与氯化氢的乙醇溶液反应得到N-甲基高哌嗪。专利CN107382883采用此方法制备N-甲基高哌嗪,该方法收率低,反应路线长,产品不易提纯,不适合工业化生产。
三.发明内容:
本发明克服了上述现有技术的不足,提供了一种N-甲基高哌嗪的制备方法,该方法反应条件温和,操作简便,对环境污染小,适合工业化生产。
本发明涉及一种N-甲基高哌嗪的制备方法,其中包括如下步骤:
采用N-苄基-4-哌啶酮为原料,与盐酸羟胺反应,制备得到N-苄基-4-哌啶酮肟,其经贝克曼重排制备得到N-苄基高哌嗪-5-酮,N-苄基高哌嗪-5-酮经还原反应得到N-苄基高哌嗪, N-苄基高哌嗪经甲基化反应得到1-苄基-4-甲基-1,4-高哌嗪,再经脱苄基反应,制备得到N- 甲基高哌嗪。
优选的,在步骤1中,
所述的溶剂包括甲醇、乙醇、异丙醇、正丁醇、叔丁醇、乙腈中的一种或几种;
所述的N-苄基-4-哌啶酮和盐酸羟胺的摩尔质量比为1∶1~1∶5;
所述反应温度范围为0~150℃。
优选的,步骤2中
所述的酸催化剂包括无水氯化锌、无水氯化铝、硫酸、苯磺酰氯、五氯化磷、三氯氧磷中的一种或几种;
所述溶剂包括甲醇、乙醇、异丙醇、正丁醇、叔丁醇、乙酸乙酯、乙酸丁酯、苯、甲苯、乙醚、四氢呋喃、丙酮、DMSO中的一种或几种;
所述的碱包括甲醇钠、甲醇钾、乙醇钠、乙醇钾、氢氧化锂、氢氧化钠、氢氧化钾中的一种或几种;
所述的N-甲基-4-哌啶酮肟和苯磺酰氯的摩尔质量比为1∶0.5~1∶5;
所述的反应温度范围为-10~100℃。
优选的,步骤3中,
所述的还原剂包括硼氢化钠、硼氢化钾、氢化铝锂、硼烷-四氢呋喃、硼烷-二甲硫醚、三乙基硼氢化锂中的一种或几种;
所述的溶剂包括乙醚、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、乙二醇二乙醚、二乙二醇二甲醚、DMSO中的一种或几种;
所述的N-苄基高哌嗪-5-酮和还原剂的摩尔质量比为1∶1~1∶5;
所述的反应温度范围为-10~100℃。
优选的,步骤4中,
所述的溶剂包括N,N-二甲基甲酰胺、二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲醇、乙醇、甲苯、N-甲基吡咯烷酮、DMSO中的一种或几种。
所述的碱包括甲醇钠、甲醇钾、乙醇钠、乙醇钾、氢化钠、氢化钾、异丙醇钠、叔丁醇钠、叔丁醇钾、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、碳酸钾、碳酸氢钾中的一种或几种;
所述的甲基化试剂包括硫酸二甲酯、碘甲烷、对甲苯磺酸甲酯、三氟甲磺酸甲酯中的一种或几种;
所述的N-苄基高哌嗪与碱试剂的摩尔质量比为1∶0.5~1∶5;
所述的N-苄基高哌嗪与甲基化试剂的摩尔质量比为1∶0.5~1∶5;
所述的反应温度范围为0~80℃。
优选的,步骤5中,
所述的溶剂包括甲醇、乙醇、异丙醇、正丁醇、叔丁醇、四氢呋喃中的一种或几种;
所述的催化剂包括钯碳、硝酸铈铵、2,3-二氯-5,6-二氰对苯醌、钠的液氨溶液、三氟乙酸中的一种或几种;
所述压力范围为0.1~5MPa;
所述的反应温度范围为0~100℃。
本发明的优势主要体现在:1)操作简便,反应条件更加温和,产生的杂质较少;2)三废少,对环境污染小;3)产率和纯度较高,适合工业化大生产。
四.附图说明
图1是N-甲基高哌嗪核磁图
五.具体实施方式
以下以具体实施例来说明本发明的技术方案,但本发明的保护范围不限与此:
实施例1
称取盐酸羟胺(51.47g,740.4mmol),加入到1L三口瓶中,并量取乙醇600ml,溶解,并保温在20-25℃下,分批加入碳酸氢钠(139.37g,1.659mol),加入完毕后降温到0-5℃,滴加N-苄基-4-哌啶酮(105.36g,556.7mmol),滴加完毕后升温到20-25℃保温搅拌3h,TLC 监控反应,反应完全加水300ml,加压浓缩掉乙醇,用300ml乙酸乙酯萃取2次,无水硫酸钠干燥,浓缩至干,得到白色固体为94.95g,收率为83.5%。
称取N-苄基-4-哌啶酮肟(95.62g,468.1mmol),并量取丙酮450ml加入到反应瓶中,降温到0-5℃,称取苯磺酰氯(99.22g,561.72mmol)缓慢滴加入反应液中,滴加完毕后,保温0-5℃搅拌30min,称取氢氧化钠(22.47g,561.72mmol)溶解于240ml水中,并在0-5℃下缓慢滴加入反应液中,1h内滴加完毕,滴加完毕后,升温至20-30℃,保温搅拌18h,TLC 监控反应,反应完全后用10N的氢氧化钠溶液调节pH值至11-12,减压浓缩至干,加水500ml 稀释,再用500ml*2乙酸乙酯萃取,无水硫酸钠干燥,抽滤浓缩至干,制备得到产品98.98g,收率103.5%,再用乙醇500ml重结晶,制备得到纯品90.10g,收率94.2%。
称取N-苄基高哌嗪-5-酮(31.87g,156.0mmol),加入到2L三口瓶中,并加入四氢呋喃1L,氮气保护并降温至20℃,称取四氢铝锂(14.80g,390.0mmol),分批缓慢加入到反应液中,30分钟加完,升温20-30℃,保温搅拌过夜,TLC监控,反应完全,加入50ml淬灭反应,反应完全加碳酸钾100g,搅拌,抽滤,减压浓缩掉溶剂,再加入甲醇100ml重结晶,得到产品15.18g,收率51.2%。
称取N-苄基高哌嗪(12.08g,63.6mmol),并量取N,N-二甲基甲酰胺60ml加入到反应瓶中,加入碳酸钾(26.37g,190.8mmol),再称取碘甲烷(18.05g,127.2mmol)缓慢滴加入反应液中,升温至80℃,保温搅拌3h,TLC监控反应,反应完全后减压浓缩至干,残留物加入水100ml溶解,用200ml*3乙酸乙酯,浓缩至干,再加入75ml甲醇重结晶,得到产品 10.72g,收率为82.5%。
称取1-苄基-4-甲基-1,4-高哌嗪(8.05g,39.4mmol),并量取甲醇50mL加入到反应瓶中,称取1.6g 10%Pd/C加入到反应液中,并通氢气压力在1MPa,反应4h,反应完全后,抽滤,减压浓缩至干,再经减压蒸馏,得到产品4.12g,收率为91.6%。
实施例2
称取盐酸羟胺(51.47g,740.4mmol),加入到1L三口瓶中,并量取乙醇600ml,溶解,并保温在20-25℃下,分批加入碳酸钠(175.84g,1.659mol),加入完毕后降温到0-5℃,滴加N-苄基-4-哌啶酮(105.36g,556.7mmol),滴加完毕后升温到20-25℃保温搅拌3h,TLC 监控反应,反应完全加水300ml,加压浓缩掉乙醇,用300ml乙酸乙酯萃取2次,无水硫酸钠干燥,浓缩至干,得到白色固体为95.95g,收率为84.5%。
称取N-苄基-4-哌啶酮肟(95.62g,468.1mmol),并量取四氢呋喃450ml加入到反应瓶中,降温到0-5℃,称取苯磺酰氯(99.22g,561.72mmol)缓慢滴加入反应液中,滴加完毕后,保温0-5℃搅拌30min,称取氢氧化钠(22.47g,561.72mmol)溶解于240ml水中,并在0-5℃下缓慢滴加入反应液中,1h内滴加完毕,滴加完毕后,升温至20-30℃,保温搅拌18h,TLC监控反应,反应完全后用10N的氢氧化钠溶液调节pH值至11-12,减压浓缩至干,加水500ml稀释,再用500ml*2乙酸乙酯萃取,无水硫酸钠干燥,抽滤浓缩至干,制备得到产品98.98g,收率103.5%,再用乙醇500ml重结晶,制备得到纯品90.10g,收率94.2%。
称取N-苄基高哌嗪-5-酮(31.87g,156.0mmol),加入到2L三口瓶中,并加入四氢呋喃 1L,氮气保护并降温至20℃,称取硼氢化钠(14.75g,390.0mmol),分批缓慢加入到反应液中,30分钟加完,升温20-30℃,保温搅拌过夜,TLC监控,反应完全,加入50ml淬灭反应,反应完全加碳酸钾100g,搅拌,抽滤,减压浓缩掉溶剂,再加入甲醇100ml重结晶,得到产品12.21g,收率39.1%。
称取N-苄基高哌嗪(12.08g,63.6mmol),并量取DMF60ml加入到反应瓶中,加入氢氧化钠(7.63g,190.8mmol),再称取碘甲烷(18.05g,127.2mmol)缓慢滴加入反应液中,升温至80℃,保温搅拌3h,TLC监控反应,反应完全后减压浓缩至干,残留物加入水100ml 溶解,用200ml*3乙酸乙酯,浓缩至干,再加入75ml甲醇重结晶,得到产品10.72g,收率为 82.5%。
称取1-苄基-4-甲基-1,4-高哌嗪(8.05g,39.4mmol),并量取乙醇50mL加入到反应瓶中,称取1.6g 10%Pd/C加入到反应液中,并通氢气压力在1MPa,反应4h,反应完全后,抽滤,减压浓缩至干,再经减压蒸馏,得到产品4.12g,收率为91.6%。
Claims (6)
1.一种N-甲基高哌嗪的制备方法,其特征在于,其合成路线如下:
采用N-苄基-4-哌啶酮为原料,与盐酸羟胺反应,制备得到N-苄基-4-哌啶酮肟,其经贝克曼重排制备得到N-苄基高哌嗪-5-酮,N-苄基高哌嗪-5-酮经还原反应得到N-苄基高哌嗪,N-苄基高哌嗪经甲基化反应得到1-苄基-4-甲基-1,4-高哌嗪,再经脱苄基反应,制备得到N-甲基高哌嗪。
2.根据权利要求1所述的一种N-甲基高哌嗪的制备方法,其特征在于,在步骤1中,
溶剂包括甲醇、乙醇、异丙醇、正丁醇、叔丁醇、乙腈中的一种或几种;
所述的N-苄基-4-哌啶酮和盐酸羟胺的摩尔质量比为1:1~1:5;
反应温度范围为0~150℃。
3.根据权利要求1所述的一种N-甲基高哌嗪的制备方法,其特征在于,在步骤2中,
酸催化剂包括无水氯化锌、无水氯化铝、硫酸、苯磺酰氯、五氯化磷、三氯氧磷中的一种或几种;
溶剂包括甲醇、乙醇、异丙醇、正丁醇、叔丁醇、乙酸乙酯、乙酸丁酯、苯、甲苯、乙醚、四氢呋喃、丙酮、DMSO中的一种或几种;
碱包括甲醇钠、甲醇钾、乙醇钠、乙醇钾、氢氧化锂、氢氧化钠、氢氧化钾中的一种或几种;
所述的N-甲基-4-哌啶酮肟和苯磺酰氯的摩尔质量比为1:0.5~1:5;
反应温度范围为-10~100℃。
4.根据权利要求1所述的一种N-甲基高哌嗪的制备方法,其特征在于,在步骤3中,
还原剂包括硼氢化钠、硼氢化钾、氢化铝锂、硼烷-四氢呋喃、硼烷-二甲硫醚、三乙基硼氢化锂中的一种或几种;
溶剂包括乙醚、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、乙二醇二乙醚、二乙二醇二甲醚、DMSO中的一种或几种;
所述的N-苄基高哌嗪-5-酮和还原剂的摩尔质量比为1:1~1:5;
反应温度范围为-10~100℃。
5.根据权利要求1所述的一种N-甲基高哌嗪的制备方法,其特征在于,在步骤4中,
碱包括甲醇钠、甲醇钾、乙醇钠、乙醇钾、氢化钠、氢化钾、异丙醇钠、叔丁醇钠、叔丁醇钾、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、碳酸钾、碳酸氢钾中的一种或几种;
甲基化试剂包括硫酸二甲酯、碘甲烷、对甲苯磺酸甲酯、三氟甲磺酸甲酯中的一种或几种;
所述的N-苄基高哌嗪与碱试剂的摩尔质量比为1:0.5~1:5;
所述的N-苄基高哌嗪与甲基化试剂的摩尔质量比为1:0.5~1:5;
反应温度范围为0~80℃。
6.根据权利要求1所述的一种N-甲基高哌嗪的制备方法,其特征在于,在步骤5中,
溶剂包括甲醇、乙醇、异丙醇、正丁醇、叔丁醇、四氢呋喃中的一种或几种;
催化剂包括钯碳、硝酸铈铵、2,3-二氯-5,6-二氰对苯醌、钠的液氨溶液、三氟乙酸中的一种或几种;
压力范围为0.1~5MPa;
反应温度范围为0~100℃。
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