CN114591220A - 一种普芦卡必利中间体1-(3-甲氧基丙基)-4-哌啶胺的制备方法 - Google Patents
一种普芦卡必利中间体1-(3-甲氧基丙基)-4-哌啶胺的制备方法 Download PDFInfo
- Publication number
- CN114591220A CN114591220A CN202011411308.7A CN202011411308A CN114591220A CN 114591220 A CN114591220 A CN 114591220A CN 202011411308 A CN202011411308 A CN 202011411308A CN 114591220 A CN114591220 A CN 114591220A
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- China
- Prior art keywords
- reaction
- methoxypropyl
- preparation
- finished
- hydroxypiperidine
- Prior art date
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- HIXAJGFVNMKLML-UHFFFAOYSA-N 1-(3-methoxypropyl)piperidin-4-amine Chemical compound COCCCN1CCC(N)CC1 HIXAJGFVNMKLML-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- ZPMNHBXQOOVQJL-UHFFFAOYSA-N prucalopride Chemical compound C1CN(CCCOC)CCC1NC(=O)C1=CC(Cl)=C(N)C2=C1OCC2 ZPMNHBXQOOVQJL-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 229960003863 prucalopride Drugs 0.000 title claims abstract description 14
- -1 3-substituted propyl methyl ether Chemical class 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 25
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims description 87
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- 235000011181 potassium carbonates Nutrition 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000001408 amides Chemical group 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical class N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- 238000001914 filtration Methods 0.000 description 41
- 238000001035 drying Methods 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 29
- 238000001514 detection method Methods 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000005406 washing Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- 239000012065 filter cake Substances 0.000 description 14
- YLWUSMHZABTZGP-UHFFFAOYSA-N n-piperidin-4-ylacetamide Chemical compound CC(=O)NC1CCNCC1 YLWUSMHZABTZGP-UHFFFAOYSA-N 0.000 description 14
- 238000000605 extraction Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- QFWBXLYVHOMANN-UHFFFAOYSA-N 1-(3-methoxypropyl)piperidin-4-one Chemical compound COCCCN1CCC(=O)CC1 QFWBXLYVHOMANN-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 229910001385 heavy metal Inorganic materials 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 150000002497 iodine compounds Chemical class 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QZRSNVSQLGRAID-UHFFFAOYSA-N 4-amino-5-chloro-n-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide;butanedioic acid Chemical compound OC(=O)CCC(O)=O.C1CN(CCCOC)CCC1NC(=O)C1=CC(Cl)=C(N)C2=C1OCC2 QZRSNVSQLGRAID-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 238000005642 Gabriel synthesis reaction Methods 0.000 description 2
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- RWIXVBSTSIXRQL-UHFFFAOYSA-N n-piperidin-4-ylpropanamide Chemical compound CCC(=O)NC1CCNCC1 RWIXVBSTSIXRQL-UHFFFAOYSA-N 0.000 description 2
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- LVKFNRKLHWNBFB-UHFFFAOYSA-N (4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-yl)methanol Chemical compound NC1=C(C=C(C2=C1CCO2)CO)Cl LVKFNRKLHWNBFB-UHFFFAOYSA-N 0.000 description 1
- ZJHUFUNDFQXUFX-UHFFFAOYSA-N 1-(3-methoxypropyl)piperidin-4-ol Chemical compound COCCCN1CCC(O)CC1 ZJHUFUNDFQXUFX-UHFFFAOYSA-N 0.000 description 1
- BQLHMMQUVJCTAN-UHFFFAOYSA-N 1-chloro-3-methoxypropane Chemical compound COCCCCl BQLHMMQUVJCTAN-UHFFFAOYSA-N 0.000 description 1
- KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FRQCAZXFZRBMRX-UHFFFAOYSA-N 3-methoxypropyl methanesulfonate Chemical compound COCCCOS(C)(=O)=O FRQCAZXFZRBMRX-UHFFFAOYSA-N 0.000 description 1
- FYGQHKJGZDCCRG-UHFFFAOYSA-N 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carbaldehyde Chemical compound C1COC2=C1C(=C(C=C2C=O)Cl)N FYGQHKJGZDCCRG-UHFFFAOYSA-N 0.000 description 1
- KRMUVKSAOVLXLF-UHFFFAOYSA-N 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid Chemical compound C1=C(Cl)C(N)=C2CCOC2=C1C(O)=O KRMUVKSAOVLXLF-UHFFFAOYSA-N 0.000 description 1
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- PURGEZDXACYNBT-UHFFFAOYSA-N O(C)CCCN1CCC(CC1)NCC1=CC=CC=C1 Chemical compound O(C)CCCN1CCC(CC1)NCC1=CC=CC=C1 PURGEZDXACYNBT-UHFFFAOYSA-N 0.000 description 1
- WSEYRYIQSMUYMG-UHFFFAOYSA-N [3-iodo-2-(2,2,2-trifluoroacetyl)oxyphenyl] 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OC1=CC=CC(I)=C1OC(=O)C(F)(F)F WSEYRYIQSMUYMG-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- HTWQUGILRGGBDZ-UHFFFAOYSA-N methanol;thionyl dichloride Chemical compound OC.ClS(Cl)=O HTWQUGILRGGBDZ-UHFFFAOYSA-N 0.000 description 1
- XAVNWNCTXQDFLF-UHFFFAOYSA-N methyl piperidin-1-ium-4-carboxylate;chloride Chemical compound Cl.COC(=O)C1CCNCC1 XAVNWNCTXQDFLF-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical compound Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229950010671 prucalopride succinate Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Abstract
本发明属于药物合成技术领域,具体涉及一种普芦卡必利中间体1‑(3‑甲氧基丙基)‑4‑哌啶胺的制备方法。本方法以4‑羟基哌啶为起始原料,与取代氰反应引入酰胺官能团,再与3‑取代丙基甲基醚对接后水解制得1‑(3‑甲氧基丙基)‑4‑哌啶胺。与现有技术相比,本方法可有效避免现有技术中操作危险的催化氢化技术,操作简便、安全,条件温和,通过本工艺制得的目标产品具有较高的收率及纯度。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种普芦卡必利中间体1-(3-甲氧基丙基)-4-哌啶胺的制备方法。
背景技术
琥珀酸普芦卡必利(Prucalopride Succinate),化学名为4-氨基-5-氯-2,3-二氢-N-[1-(3-甲氧基丙基)-4-哌啶基]-7-苯并呋喃甲酰胺丁二酸盐,是比利时Movetis公司开发的新一代高选择性、高亲和力的5-羟色胺4(5-HT4)受体激动药,它通过对肠道壁的直接作用恢复受损的肠道活动能力。2009年10月欧盟批准其用于治疗慢性便秘,2010年1月在德国上市,同年3月在英国上市,2012年10月经FDA批准上市,临床研究表明该药对严重慢性便秘患者疗效恒定且安全。其化学结构式如下:
目前关于普芦卡必利的制备公开的方法较多,如专利CN1164233A(CN1071332C)、CN103664912B及文献普卡必利的合成,药学与临床研究,2011,Aug;19(4):306-307等中,以4-氨基-5-氯-2,3-二氢苯并呋喃-7-羧酸为起始物料或关键中间体和1-(3-甲氧基丙基)-4-哌啶胺经酰胺化反应制得。
专利CN108976216A通过多步反应制得4-氨基-5-氯-2,3-二氢苯并呋喃-7-甲醛后,与1-(3-甲氧基丙基)-4-哌啶胺经氧化脱氢偶联制得目标产品。
类似的,专利CN109232544A通过多步反应制得(4-氨基-5-氯-2,3-二氢苯并呋喃-7-基)甲醇后,与1-(3-甲氧基丙基)-4-哌啶胺经氧化脱氢偶联制得目标产品。
由上可知,1-(3-甲氧基丙基)-4-哌啶胺在多种合成策略中均被用作制备普芦卡必利的关键中间体,因此1-(3-甲氧基丙基)-4-哌啶胺直接影响该药品的生产、市场供应和质量问题。具体结构式如下:
目前关于1-(3-甲氧基丙基)-4-哌啶胺的制备方法主要包括以下几种:
其中,专利CN102295594B中以N-保护氨基哌啶为起始物料,与1-取代-3-甲氧基丙烷在碱性条件下反应后,脱保护[苄氧羰基(Cbz)的脱保护条件一般为氢解或酸解裂解(HBt或TMSI);乙酰基、丙酰基通常以碱解或酸解脱除]制得目标产品。但此方法起始原料价格较高,工业生产成本高。
专利CN102898356B则以4-哌啶酮盐酸盐一水合物为起始物料,在碱性条件下与1-取代-3-甲氧基丙烷反应制得1-(3-甲氧基丙基)-4-哌啶酮,然后在氨气的有机溶液中,在氢气以及催化剂(Raney Ni和/或Pd/C)的作用下,反应制得目标产品。该路线第一步反应的反应时间较长(>15小时),第二步反应采用高压氢化,条件较为难控,且需使用高成本重金属催化剂钯碳或易燃高毒性的Raney Ni,给原料药普卡必利带来重金属残留的风险。
专利CN103193699B则以4-哌啶酮为起始物料,在K2CO3的碱性条件下与1-溴-3-甲氧基丙烷反应制得1-(3-甲氧基丙基)-4-哌啶酮,然后在甲酸/甲酸铵体系中,110℃回流反应8h制得目标产品。该工艺高温反应时间长,能耗较高,同时由于目标产品的极性非常大,而该方法的最后一步反应不完全,很难除去中间体及副产物,纯化难度较大。
文献Tetrahedron Lett,2001,42(25):4257-4259以Pd/C为催化剂、甲酸铵作氮源及氢源,直接将羰基还原为氨基。文献琥珀酸普卡必利的合成,中国医药工业杂志,2012,43(1):5-8中以饱和氨气的甲醇溶液作溶剂,经10%Pd/C催化氢化直接将羰基转化为氨基得到目标产品。
专利CN103508939A则以上述工艺中的关键中间体1-(3-甲氧基丙基)-4-哌啶酮为起始物料,与盐酸羟胺加热回流脱水制得关键中间体1-(3-甲氧基丙基)-4-哌啶肟,最后通过催化(Raney Ni)氢化制得目标产品。该工艺起始原料昂贵,且应用强毒性的Raney Ni催化剂,不适合工业生产。
此外,专利CN1143858(US6479487)同样沿用上述策略制备关键中间体1-(3-甲氧基丙基)-4-哌啶肟后,采用四氢铝锂还原得到相应产品。四氢铝锂在实验操作时需要严格无氧无水的环境,后处理复杂,不容易过滤,因此,该方法的工业化难度较大。
另外,该专利CN1143858(US6479487)还采用4-甲酰胺哌啶为原料,与1-甲氧基-3-溴丙烷发生烷基化反应后,在高价碘化合物二(三氟乙酰氧)碘苯[PhI(O2CCF3)2]作用下,通过Hofmann重排生成目标产物。但该工艺中原料以及高价碘化合物价格均较高,同时高价碘化合物存在的稳定性与安全性问题一直都制约其大规模用于工业化生产。
专利CN106146386A及文献琥珀酸普芦卡必利的合成,中国医药工业杂志,2015,46(11):1158-1160以价廉易得的4-哌啶甲酸为原料,在氯化亚砜-甲醇中酯化得4-哌啶甲酸甲酯盐酸盐;然后与1-甲氧基-3-溴丙烷经烷基化反应制得1-(3-甲氧基丙基)哌啶-4-甲酸甲酯;之后在氨水中氨解获得1-(3-甲氧基丙基)哌啶-4-甲酰胺;最后与二溴海因在碱性条件下反应发生Hofmann重排得到粗品后再经精馏即可获得纯度大于99.5%的目标产品。但该工艺总收率仅有56%,且需要精馏提纯,操作繁琐。
专利CN103351329A同样以1-(3-甲氧基丙基)-4-哌啶酮为起始物料,在氨的甲醇溶液或甲酸铵盐的条件下,经三乙酰氧基硼氢化钠还原制得目标产品。
专利CN103804281A同样以1-(3-甲氧基丙基)-4-哌啶酮为起始物料,羰基先经NaBH4还原得到1-(3-甲氧基丙基)-4-哌啶醇,然后经对甲苯磺酰氯酯化得1-(3-甲氧基丙基)-4-对甲基苯磺酸酯哌啶,最后与邻苯二甲酰亚胺反应再在碱性条件下肼解得到目标产品。但该工艺应用基因毒性物质对甲苯磺酰氯活化羟基,同时采用Gabriel反应制备伯胺基,原子经济性较差,肼解法生成的邻苯二甲酰肼极性大,后处理困难,此外应用剧毒物质水合肼,操作安全性较差。
专利CN103848777A(WO2015139332)同样以1-(3-甲氧基丙基)-4-哌啶酮为起始物料,与取代或未取代的苄胺在还原剂的作用下反应生成N-(3-甲氧基丙基)-4-苄胺基哌啶,最后经钯碳催化还原得到目标产品。
综上可知,目前制备1-(3-甲氧基丙基)-4-哌啶胺的工艺主要存在以下问题:
1.所采用的起始原料以及多种试剂价格较高,使得生产成本增加,基本不具有市场竞争力的问题。
2.采用催化氢化制备目标产品,相关高压反应条件较难控制,需使用高成本重金属催化剂钯碳或易燃高毒性催化剂Raney Ni,给原料药普卡必利带来重金属残留的风险。
3.需要高温长时间反应,使得能耗较高的问题。
4.反应需要无水无氧或者目标产品的获得需要精馏提纯,使得操作繁琐的问题。
5.反应需要对甲苯磺酰氯活化羟基,以及采用Gabriel反应制备伯胺基,使得原子经济性较差的问题。
6.采用水合肼以及催化氢化或者氢化物进行还原,使得操作安全性较低的问题。
鉴于目前制备1-(3-甲氧基丙基)-4-哌啶胺时存在许多不足,因此,研究寻找一条操作简便、安全,反应条件温和,产品收率高、纯度高的适合工业化生产1-(3-甲氧基丙基)-4-哌啶胺的制备工艺仍是目前需要解决的问题。
发明内容
针对现有技术中制备普芦卡必利中间体1-(3-甲氧基丙基)-4-哌啶胺时存在的诸多问题,本发明提供了一种新的1-(3-甲氧基丙基)-4-哌啶胺的制备方法。该方法反应条件温和,操作过程安全、简便,所制得的目标产品具有较高的纯度、收率。
本发明具体通过如下技术方案实现:
一种普芦卡必利中间体1-(3-甲氧基丙基)-4-哌啶胺的制备方法,以4-羟基哌啶为起始原料,与RCN经催化剂催化反应得中间体I-1,中间体I-1与3-取代丙基甲基醚发生取代反应制得中间体I-2,中间体I-2经水解反应得到化合物1-(3-甲氧基丙基)-4-哌啶胺,反应式如下:
一种如式I所示的普芦卡必利关键中间体1-(3-甲氧基丙基)-4-哌啶胺的制备方法,具体步骤如下:
步骤1.将4-羟基哌啶、催化剂加入RCN中,控温至反应结束,经后处理制得中间体I-1;
步骤2.将I-1、3-取代丙基甲基醚、碱加入有机溶剂A中,控温至反应结束后,经后处理制得中间体I-2;
步骤3.将中间体I-2、酸加入有机溶剂B中,控温至反应结束,经后处理制得化合物I。
优选地,步骤1中所述的催化剂包括但不限于Mg(HSO4)2、Ca(HSO4)2、NaHSO4、NH4HSO4中的一种或其组合,优选Ca(HSO4)2。
优选地,步骤1中所述的4-羟基哌啶与催化剂的投料摩尔比为1:0.8~2.4,优选1:1.2,其中,催化剂以HSO4 -计。
优选地,步骤1中所述的4-羟基哌啶与RCN的质量体积比为1:1~10,g/ml;优选1:4,g/ml。
优选地,步骤1中所述的反应温度为所用溶剂的回流温度。
在一优选方案中,步骤1中所述后处理步骤为:将反应液降至室温,过滤,滤液减压浓缩至干后,加入纯化水,有机溶剂萃取,有机相经饱和食盐水洗涤,干燥,过滤,滤液减压浓缩至干即为中间体I-1;优选地,所述萃取溶剂包括但不限于二氯甲烷、氯仿、乙酸乙酯、甲基叔丁基醚中的一种或其组合,优选二氯甲烷。
优选地,步骤2中所述的碱包括但不限于碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、三乙胺、N,N-二异丙基乙基胺、吡啶中的一种或其组合,优选碳酸钾。
优选地,步骤2中所述的有机溶剂A包括但不限于乙腈、丁酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜中的一种或其组合,优选乙腈。
优选地,步骤2中所述的I-1与3-取代丙基甲基醚、碱的投料摩尔比1:1.1~2.5:1.2~3.0。
优选地,步骤2中所述的I-1与3-取代丙基甲基醚的投料摩尔比为1:1.1~2.5,优选1:1.2。
优选地,步骤2中所述的I-1与碱的投料摩尔比为1:1.2~3.0,优选1:1.4。
优选地,步骤2中所述的反应温度为60~90℃;优选75~80℃。
在一优选方案中,步骤2所述后处理步骤如下:反应完毕,过滤,滤液减压浓缩至干,加入二氯甲烷,用0.5~2M稀盐酸洗涤1~2次,收集有机层干燥,减压浓缩,制得中间体I-2。
优选地,步骤3中所述的有机溶剂B选自甲醇、乙醇、异丙醇、正丁醇、四氢呋喃、1,4-二氧六环、***中的一种或其组合,更优选为甲醇或乙醇。
优选地,步骤3中所述的酸选自氢氯酸、氢溴酸、氢碘酸、硫酸、磷酸、甲酸、醋酸、三氟乙酸中的一种或其组合,优选氢氯酸。
优选地,步骤3中所述的中间体I-2与酸的投料摩尔比为1:1.2~3.0,优选1:1.8。
优选地,步骤3中所述的反应温度为0~30℃,优选20~25℃。
在一优选方案中,步骤3所述后处理步骤如下:a.将反应液过滤,滤饼经二氯甲烷洗涤,干燥后即为化合物I的盐酸盐固体,易于保存和使用;b.将反应液过滤,滤饼加入饱和碳酸钠溶液中,搅拌,有机溶剂萃取,合并有机相,干燥,过滤,滤液减压浓缩至干后,所得黄色油状物即为化合物I;优选地,步骤b中所述的萃取溶剂选自二氯甲烷、氯仿、乙酸乙酯、甲基叔丁基醚中的一种或其组合,优选二氯甲烷。
本发明的有益效果:
本发明提供了一条简便高效的制备普芦卡必利关键中间体1-(3-甲氧基丙基)-4-哌啶胺的方法,以廉价易得的4-羟基哌啶为起始原料,与腈反应引入酰胺官能团,再与3-取代丙基甲基醚对接后水解制得化合物I。整个合成方法操作简便,条件温和,环境友好;与现有技术相比,可有效避免现有技术中操作危险的催化氢化技术,操作安全;通过本工艺制得的目标产品具有较高的收率及纯度,适合工业大规模生产。
具体实施方式
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属于本发明要求保护的范围。
以下各实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
I-1的合成:
实施例1
将4-羟基哌啶(20.23g,0.20mol)、Ca(HSO4)2(56.21g,0.24mol)加入乙腈(R=Me,80ml)中,控温80~85℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),二氯甲烷(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)乙酰胺。
将上述所得N-(哌啶-4-基)乙酰胺(28.44g,0.20mol)、3-溴丙基甲基醚(X=Br,36.72g,0.24mol)、碳酸钾(38.70g,0.28mol)加入乙腈(200ml)中,控温75~80℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率94.5%,纯度99.2%。
实施例2
将4-羟基哌啶(20.22g,0.20mol)、Ca(HSO4)2(37.47g,0.16mol)加入乙腈(R=Me,80ml)中,控温80~85℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),氯仿(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)乙酰胺。
将上述所得N-(哌啶-4-基)乙酰胺(28.45g,0.20mol)、3-溴丙基甲基醚(X=Br,33.65g,0.22mol)、碳酸钠(29.68g,0.28mol)加入N,N-二甲基甲酰胺(200ml)中,控温85~90℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率91.3%,纯度99.3%。
实施例3
将4-羟基哌啶(20.25g,0.20mol)、Ca(HSO4)2(113.28g,0.48mol)加入乙腈(R=Me,80ml)中,控温80~85℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),乙酸乙酯(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)乙酰胺。
将上述所得N-(哌啶-4-基)乙酰胺(28.47g,0.20mol)、3-溴丙基甲基醚(X=Br,30.50g,0.20mol)、碳酸氢钾(28.05g,0.28mol)加入N,N-二甲基乙酰胺(200ml)中,控温85~90℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率88.5%,纯度99.1%。
实施例4
将4-羟基哌啶(20.21g,0.20mol)、Mg(HSO4)2(52.42g,0.24mol)加入乙腈(R=Me,20ml)中,控温80~85℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),甲基叔丁基醚(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)乙酰胺。
将上述所得N-(哌啶-4-基)乙酰胺(28.45g,0.20mol)、3-溴丙基甲基醚(X=Br,76.50g,0.50mol)、三乙胺(28.35g,0.28mol)加入乙腈(200ml)中,控温75~80℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率92.2%,纯度98.5%。
实施例5
将4-羟基哌啶(20.23g,0.20mol)、NaHSO4(57.63g,0.48mol)加入乙腈(R=Me,200ml)中,控温80~85℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),二氯甲烷(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)乙酰胺,收率95.8%,纯度97.3%。
将上述所得N-(哌啶-4-基)乙酰胺(28.41g,0.20mol)、3-溴丙基甲基醚(X=Br,79.56g,0.52mol)、吡啶(22.14g,0.28mol)加入乙腈(200ml)中,控温75~80℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率90.0%,纯度98.8%。
实施例6
将4-羟基哌啶(20.23g,0.20mol)、Ca(HSO4)2(56.21g,0.24mol)加入乙腈(R=Me,80ml)中,控温80~85℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),二氯甲烷(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)乙酰胺。
将上述所得N-(哌啶-4-基)乙酰胺(28.42g,0.20mol)、3-氯丙基甲基醚(X=Cl,25.90g,0.24mol)、碳酸钾(33.15g,0.24mol)加入二甲基亚砜(200ml)中,控温80~85℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率92.7%,纯度99.0%。
实施例7
将4-羟基哌啶(20.23g,0.20mol)、Ca(HSO4)2(56.21g,0.24mol)加入乙腈(R=Me,80ml)中,控温80~85℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),二氯甲烷(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)乙酰胺。
将N-(哌啶-4-基)乙酰胺(28.44g,0.20mol)、甲磺酸3-甲氧基丙基酯(X=MsO,40.35g,0.24mol)、碳酸钾(82.90g,0.60mol)加入乙腈(200ml)中,控温70~75℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率93.5%,纯度98.6%。
实施例8
将4-羟基哌啶(20.20g,0.20mol)、NH4HSO4(56.21g,0.48mol)加入乙腈(R=Et,80ml)中,控温95~100℃回流反应,经检测反应完毕后,将反应液降至室温,过滤,滤液减压浓缩至干,加入纯化水(250ml),二氯甲烷(150ml×3)萃取,有机相经饱和食盐水(100ml×2)洗涤,干燥,过滤,滤液减压浓缩至干即为中间体N-(哌啶-4-基)丙酰胺。
将上述所得N-(哌啶-4-基)丙酰胺(31.24g,0.20mol)、3-溴丙基甲基醚(X=Br,36.70g,0.24mol)、碳酸钾(38.70g,0.28mol)加入丁酮(200ml)中,控温75~80℃反应,经检测反应完毕后,过滤,滤液减压浓缩至干,加入二氯甲烷(300ml),用2M盐酸(80ml)洗涤1~2次,有机层干燥,减压浓缩制得中间体N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺,收率93.8%,纯度99.1%。
I的合成:
实施例9
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.72g,0.05mol)加入HCl-甲醇溶液(0.5M,180ml)中,控温20~25℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率96.4%,纯度99.7%。
实施例10
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.70g,0.05mol)加入HCl-甲醇溶液(1.0M,60ml)中,控温25~30℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率92.3%,纯度99.5%。
实施例11
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.73g,0.05mol)加入HCl-甲醇溶液(0.25M,600ml)中,控温10~15℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率93.7%,纯度99.0%。
实施例12
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.75g,0.05mol)加入HCl-乙醇溶液(0.5M,180ml)中,控温20~25℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率95.9%,纯度99.3%。
实施例13
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.72g,0.05mol)加入HCl-异丙醇溶液(0.5M,180ml)中,控温20~25℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率93.7%,纯度99.6%。
实施例14
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.72g,0.05mol)加入HCl-四氢呋喃溶液(0.5M,180ml)中,控温20~25℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率93.8%,纯度99.1%。
实施例15
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.71g,0.05mol)加入HBr-甲醇溶液(0.5M,180ml)中,控温15~20℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率92.7%,纯度99.2%。
实施例16
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.74g,0.05mol)加入HI-甲醇溶液(0.5M,180ml)中,控温10~15℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率93.1%,纯度99.5%。
实施例17
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.72g,0.05mol)、H2SO4(6.0g,98%,0.06mol)加入甲醇(180ml)中,控温0~5℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率90.8%,纯度99.0%。
实施例18
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.70g,0.05mol)、HCOOH(5.52g,0.12mol)加入甲醇(180ml)中,控温25~30℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率92.2%,纯度99.0%。
实施例19
将N-(1-(3-甲氧基丙基)哌啶-4-基)乙酰胺(10.75g,0.05mol)、CH3COOH(7.21g,0.15mol)加入甲醇(180ml)中,控温5~10℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥,制得化合物I,收率92.5%,纯度99.3%。
实施例20
将N-(1-(3-甲氧基丙基)哌啶-4-基)丙酰胺(11.42g,0.05mol)、CF3COOH(13.68g,0.06mol)加入甲醇(180ml)中,控温20~25℃反应,经检测反应完毕后,过滤,滤饼以二氯甲烷洗涤,干燥制得化合物I,收率93.0%,纯度99.1%。
Claims (10)
2.根据权利要求1所述的制备方法,其特征在于,具体步骤如下:
步骤1.将4-羟基哌啶、催化剂加入RCN中,回流反应结束后,经后处理制得中间体I-1;
步骤2.将I-1、3-取代丙基甲基醚、碱加入有机溶剂A中,控温至反应结束后,经后处理制得中间体I-2;
步骤3.将中间体I-2、酸加入有机溶剂B中,控温至反应结束,经后处理制得化合物I。
3.根据权利要求2所述的制备方法,其特征在于,步骤1中所述的催化剂包括但不限于Mg(HSO4)2、Ca(HSO4)2、NaHSO4、NH4HSO4中的一种或其组合。
4.根据权利要求2所述的制备方法,其特征在于,步骤1中所述的4-羟基哌啶与催化剂的投料摩尔比为1:0.8~2.4,其中,催化剂以HSO4 -计。
5.根据权利要求2所述的制备方法,其特征在于,步骤1中所述的4-羟基哌啶与RCN的质量体积比为1:1~10,g/ml。
6.根据权利要求2所述的制备方法,其特征在于,步骤2中所述的碱包括但不限于碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、三乙胺、N,N-二异丙基乙基胺、吡啶中的一种或其组合。
7.根据权利要求2所述的制备方法,其特征在于,步骤2中所述的有机溶剂A包括但不限于乙腈、丁酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜中的一种或其组合。
8.根据权利要求2所述的制备方法,其特征在于,步骤2中所述的I-1与3-取代丙基甲基醚、碱的投料摩尔比为1:1.1~2.5:1.2~3.0。
9.根据权利要求2所述的制备方法,其特征在于,步骤3中所述的有机溶剂B选自甲醇、乙醇、异丙醇、正丁醇、四氢呋喃、1,4-二氧六环、***中的一种或其组合。
10.根据权利要求2所述的制备方法,其特征在于,步骤3中所述的中间体I-2与酸的投料摩尔比为1:1.2~3.0。
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