NO791943L - PROCEDURES FOR THE PREPARATION OF PYRROLIDIN-2-ONES FROM 3-PYRROLIN-2-ONES, AND PROCEDURES OF 3-PYRROLIN-2-ONES - Google Patents
PROCEDURES FOR THE PREPARATION OF PYRROLIDIN-2-ONES FROM 3-PYRROLIN-2-ONES, AND PROCEDURES OF 3-PYRROLIN-2-ONESInfo
- Publication number
- NO791943L NO791943L NO791943A NO791943A NO791943L NO 791943 L NO791943 L NO 791943L NO 791943 A NO791943 A NO 791943A NO 791943 A NO791943 A NO 791943A NO 791943 L NO791943 L NO 791943L
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- aryl
- substituted
- hydrogen
- pyrrolin
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 125000003107 substituted aryl group Chemical group 0.000 claims description 16
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 14
- CDCHBOQVXIGZHA-UHFFFAOYSA-N 1,2-dihydropyrrol-5-one Chemical compound O=C1NCC=C1 CDCHBOQVXIGZHA-UHFFFAOYSA-N 0.000 claims description 12
- 238000007363 ring formation reaction Methods 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 150000003235 pyrrolidines Chemical class 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- -1 bromine compound Chemical class 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 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 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- HEQOJEGTZCTHCF-UHFFFAOYSA-N 2-amino-1-phenylethanone Chemical compound NCC(=O)C1=CC=CC=C1 HEQOJEGTZCTHCF-UHFFFAOYSA-N 0.000 description 3
- PDTLMKLERGEENQ-UHFFFAOYSA-N 4-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one Chemical compound C1=CC(C(F)(F)F)=CC=C1C1CC(=O)NC1 PDTLMKLERGEENQ-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 150000003951 lactams Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- PXBGQFYGVFUKNE-UHFFFAOYSA-N phosphanium;acetate Chemical compound [PH4+].CC([O-])=O PXBGQFYGVFUKNE-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- GNWOFDWOUZXQPD-UHFFFAOYSA-N 3,4-diphenyl-1,2-dihydropyrrol-5-one Chemical compound O=C1NCC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 GNWOFDWOUZXQPD-UHFFFAOYSA-N 0.000 description 2
- KCUJZQHVIDHUQU-UHFFFAOYSA-N 3,4-diphenylpyrrolidine Chemical compound C1NCC(C=2C=CC=CC=2)C1C1=CC=CC=C1 KCUJZQHVIDHUQU-UHFFFAOYSA-N 0.000 description 2
- VNGGQUXNILKHIE-UHFFFAOYSA-N 3-[4-(trifluoromethyl)phenyl]-1,2-dihydropyrrol-5-one Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=CC(=O)NC1 VNGGQUXNILKHIE-UHFFFAOYSA-N 0.000 description 2
- XWWQNFOFKPPMHY-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,5-dimethylpyrrolidin-2-one Chemical compound C1C(=O)N(C)C(C)C1C1=CC=C(Cl)C=C1 XWWQNFOFKPPMHY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 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 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- PIJXRNNCIJAUOX-UHFFFAOYSA-N butanoic acid;hydrochloride Chemical compound Cl.CCCC(O)=O PIJXRNNCIJAUOX-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001734 carboxylic acid salts Chemical class 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- RHNBWZZWDAOBQY-UHFFFAOYSA-N 1,2,4-trimethyl-3-phenyl-2h-pyrrol-5-one Chemical compound CC1N(C)C(=O)C(C)=C1C1=CC=CC=C1 RHNBWZZWDAOBQY-UHFFFAOYSA-N 0.000 description 1
- JWUYOFJPYSNYFC-UHFFFAOYSA-N 1,2-dimethyl-3,4-diphenyl-2h-pyrrol-5-one Chemical compound CC1N(C)C(=O)C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 JWUYOFJPYSNYFC-UHFFFAOYSA-N 0.000 description 1
- QLCPYHKRCGVOOA-UHFFFAOYSA-N 1,2-dimethyl-3-phenyl-2h-pyrrol-5-one Chemical compound CC1N(C)C(=O)C=C1C1=CC=CC=C1 QLCPYHKRCGVOOA-UHFFFAOYSA-N 0.000 description 1
- WPPVBSYWZWZVTN-UHFFFAOYSA-N 1,3,5-trimethyl-4-phenylpyrrolidin-2-one Chemical compound CC1C(=O)N(C)C(C)C1C1=CC=CC=C1 WPPVBSYWZWZVTN-UHFFFAOYSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- HOEWCGCSKILLPY-UHFFFAOYSA-N 1,5-dimethyl-4-(4-nitrophenyl)pyrrolidin-2-one Chemical compound C1C(=O)N(C)C(C)C1C1=CC=C([N+]([O-])=O)C=C1 HOEWCGCSKILLPY-UHFFFAOYSA-N 0.000 description 1
- QCZVVNIEASUBIS-UHFFFAOYSA-N 1,5-dimethyl-4-phenylpyrrolidin-2-one Chemical compound C1C(=O)N(C)C(C)C1C1=CC=CC=C1 QCZVVNIEASUBIS-UHFFFAOYSA-N 0.000 description 1
- IRVWTVRIFOKBIL-UHFFFAOYSA-N 1-benzyl-4-methyl-3-[4-(trifluoromethyl)phenyl]-2h-pyrrol-5-one Chemical compound O=C1C(C)=C(C=2C=CC(=CC=2)C(F)(F)F)CN1CC1=CC=CC=C1 IRVWTVRIFOKBIL-UHFFFAOYSA-N 0.000 description 1
- DHMVUKFVGBQDDA-UHFFFAOYSA-N 1-methyl-3-(4-methylphenyl)-4-phenyl-2h-pyrrol-5-one Chemical compound O=C1N(C)CC(C=2C=CC(C)=CC=2)=C1C1=CC=CC=C1 DHMVUKFVGBQDDA-UHFFFAOYSA-N 0.000 description 1
- NKWHNVBHFHODDU-UHFFFAOYSA-N 2-[4-(trifluoromethyl)phenyl]butanoic acid;hydrochloride Chemical compound Cl.CCC(C(O)=O)C1=CC=C(C(F)(F)F)C=C1 NKWHNVBHFHODDU-UHFFFAOYSA-N 0.000 description 1
- APBKZMJARWKEJO-UHFFFAOYSA-N 2-amino-1-[4-(trifluoromethyl)phenyl]ethanone;hydrochloride Chemical compound Cl.NCC(=O)C1=CC=C(C(F)(F)F)C=C1 APBKZMJARWKEJO-UHFFFAOYSA-N 0.000 description 1
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 1
- NJBMZYSKLWQXLJ-UHFFFAOYSA-N 3,4-dihydro-2h-pyrrol-5-amine Chemical class NC1=NCCC1 NJBMZYSKLWQXLJ-UHFFFAOYSA-N 0.000 description 1
- KEMCZWYPWCUGPE-UHFFFAOYSA-N 3-(4-chlorophenyl)-4-phenyl-1,2-dihydropyrrol-5-one Chemical compound C1=CC(Cl)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)NC1 KEMCZWYPWCUGPE-UHFFFAOYSA-N 0.000 description 1
- XIAMSSUQNNNXMH-UHFFFAOYSA-N 3-(4-fluorophenyl)-4-phenyl-1,2-dihydropyrrol-5-one Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)NC1 XIAMSSUQNNNXMH-UHFFFAOYSA-N 0.000 description 1
- SYUHPEZHTMIRMJ-UHFFFAOYSA-N 3-(4-fluorophenyl)-4-phenylpyrrolidin-2-one Chemical compound C1=CC(F)=CC=C1C1C(=O)NCC1C1=CC=CC=C1 SYUHPEZHTMIRMJ-UHFFFAOYSA-N 0.000 description 1
- LXZAVFHIIYGLTF-UHFFFAOYSA-N 3-(4-methoxyphenyl)-4-phenyl-1,2-dihydropyrrol-5-one Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)NC1 LXZAVFHIIYGLTF-UHFFFAOYSA-N 0.000 description 1
- QPGLUEKHBNOAHG-UHFFFAOYSA-N 3-carboxypropylazanium;chloride Chemical class Cl.NCCCC(O)=O QPGLUEKHBNOAHG-UHFFFAOYSA-N 0.000 description 1
- USRGHTBNRODIGQ-UHFFFAOYSA-N 3-phenyl-4-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one Chemical compound C1=CC(C(F)(F)F)=CC=C1C1C(C=2C=CC=CC=2)C(=O)NC1 USRGHTBNRODIGQ-UHFFFAOYSA-N 0.000 description 1
- JBIVTGWLCSEZEU-UHFFFAOYSA-N 4-(4-aminophenyl)-1,5-dimethylpyrrolidin-2-one Chemical compound C1C(=O)N(C)C(C)C1C1=CC=C(N)C=C1 JBIVTGWLCSEZEU-UHFFFAOYSA-N 0.000 description 1
- QZSANDZKAKLRPX-UHFFFAOYSA-N 4-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]-1,2-dihydropyrrol-5-one Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CC(=CC=2)C(F)(F)F)CNC1=O QZSANDZKAKLRPX-UHFFFAOYSA-N 0.000 description 1
- LIOVPXGQAPGNNY-UHFFFAOYSA-N 4-(4-fluorophenyl)-3-phenyl-1,2-dihydropyrrol-5-one Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CC=CC=2)CNC1=O LIOVPXGQAPGNNY-UHFFFAOYSA-N 0.000 description 1
- SSNGRNRNPOYPGF-UHFFFAOYSA-N 4-(4-methylphenyl)-3-phenylpyrrolidin-2-one Chemical compound C1=CC(C)=CC=C1C1C(C=2C=CC=CC=2)C(=O)NC1 SSNGRNRNPOYPGF-UHFFFAOYSA-N 0.000 description 1
- MUJPZGGZLAHFFQ-UHFFFAOYSA-N 4-(methylamino)-3-phenylpentanoic acid hydrochloride Chemical compound Cl.CNC(C)C(CC(O)=O)C1=CC=CC=C1 MUJPZGGZLAHFFQ-UHFFFAOYSA-N 0.000 description 1
- CMLJIUSFVCLSEZ-UHFFFAOYSA-N 4-amino-2,3-diphenylbutanoic acid hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CN)C(C(O)=O)C1=CC=CC=C1 CMLJIUSFVCLSEZ-UHFFFAOYSA-N 0.000 description 1
- MDJNQOXQCIGQTJ-UHFFFAOYSA-N 4-amino-2-phenyl-3-[4-(trifluoromethyl)phenyl]butanoic acid;hydrochloride Chemical compound Cl.C=1C=C(C(F)(F)F)C=CC=1C(CN)C(C(O)=O)C1=CC=CC=C1 MDJNQOXQCIGQTJ-UHFFFAOYSA-N 0.000 description 1
- MGNLMDDRHLWILY-UHFFFAOYSA-N 4-amino-3-(4-fluorophenyl)-2-phenylbutanoic acid Chemical compound C=1C=C(F)C=CC=1C(CN)C(C(O)=O)C1=CC=CC=C1 MGNLMDDRHLWILY-UHFFFAOYSA-N 0.000 description 1
- FTSJDURWVUMKDO-UHFFFAOYSA-N 4-amino-3-[4-(trifluoromethyl)phenyl]butanoic acid Chemical compound OC(=O)CC(CN)C1=CC=C(C(F)(F)F)C=C1 FTSJDURWVUMKDO-UHFFFAOYSA-N 0.000 description 1
- DQOSOTIKDZAXKT-UHFFFAOYSA-N 4-phenyl-3-[4-(trifluoromethyl)phenyl]-1,2-dihydropyrrol-5-one Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)NC1 DQOSOTIKDZAXKT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Description
Pyrrolidin-2-oner (I) av formel: og deres tilsvarende pyrrolidiner (II) av formel: Pyrrolidin-2-ones (I) of formula: and their corresponding pyrrolidines (II) of formula:
hvori R = hydrogen, alkyl, substituert alkyl, aryl, substituert aryl, acyl eller åroyl; R 3 = hydrogen, alkyl, substituert alkyl, aryl eller substituert aryl; R 4= aryl, substituert aryl, alkyl eller substituert alkyl; R 5 = hydrogen, alkyl, substituert alkyl, aryl eller substituert aryl; og R 5 1= hydrogen, a]kyl eller substituert alkyl; innbefatter mange kjente forbindelser som utviser 'interessant CNS aktivitet (Archivum Immunologiae et Therapies Experimentalis 1975, 23, 733-751). Mange av forbindelsene av formel I utviser prostaglandin-lignende aktivitet (Cer. Offen. 2.527.989) . wherein R = hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or aroyl; R 3 = hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R 4 = aryl, substituted aryl, alkyl or substituted alkyl; R 5 = hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and R 5 1 = hydrogen, alkyl or substituted alkyl; includes many known compounds exhibiting 'interesting CNS activity (Archivum Immunologiae et Therapies Experimentalis 1975, 23, 733-751). Many of the compounds of formula I exhibit prostaglandin-like activity (Cer. Offen. 2,527,989).
Pyrrolidin-2-onene (I) er generelt blitt fremstilt ved ringslutning av den tilsvarende 4-aminosmørsyre eller ester (III) av formel: The pyrrolidin-2-ones (I) have generally been prepared by cyclization of the corresponding 4-aminobutyric acid or ester (III) of formula:
og 4-halogeno-butyramid, ved omsetning av lactoner med aminer, eller hydrolyse av 2-imino-pyrrolidiner (britisk patentskrift nr. 1.350.582 og US patentskrift nr. 4.012.495). and 4-halogeno-butyramide, by reaction of lactones with amines, or hydrolysis of 2-imino-pyrrolidines (British patent no. 1,350,582 and US patent no. 4,012,495).
Disse metoder for fremstilling av forbindelser av formel I og II er begrenset når det gjelder effektivitet, type av substituenter i de forskjellige stillinger og vanskelighet med å fremstille rene stereo- og optisk aktive isomerer. These methods for preparing compounds of formula I and II are limited in terms of efficiency, type of substituents in the different positions and difficulty in preparing pure stereo- and optically active isomers.
I henhold til oppfinnelsen fremstilles 3-4-cis-substituerte, eventuelt optisk aktive, pyrrolidin-2-oner av formel I, nem-lig : According to the invention, 3-4-cis-substituted, possibly optically active, pyrrolidin-2-ones of formula I are produced, namely:
eller efter isomerisering ved hydrogenering av 3-pyrrolin-2-oner (V) av formel: or after isomerization by hydrogenation of 3-pyrrolin-2-ones (V) of formula:
rhvori R 1 , R 3 , R 4 , R 5 og R 5' har de ovenfor angitte betydninger, under anvendelse av den egnede katalysator, eventuelt optisk aktiv [Angew. Chem. 8_3 , 956 (1971)] eller et innebygget asymmetrisk sen-ter i C-5 av (V), under hydrogenering. rhvori R 1 , R 3 , R 4 , R 5 and R 5' have the meanings given above, using the suitable catalyst, optionally optically active [Angew. Chem. 8_3 , 956 (1971)] or a built-in asymmetric center in C-5 of (V), during hydrogenation.
En av hoVedvanskelighetene ved fremstilling av pyrrolidin-2-oner (I) ved hydrogenering av 3-pyrrolin-2-oner (V) er van-skeligheten ved å fremstille 3-pyrrolin-2-oner (V). One of the main difficulties in preparing pyrrolidin-2-ones (I) by hydrogenating 3-pyrrolin-2-ones (V) is the difficulty in preparing 3-pyrrolin-2-ones (V).
Foreliggende oppfinnelse angår derfor ennvidere generel-le metoder.for fremstilling av forbindelser av formel V, og dette utføres ifølge oppfinnelsen ved ringslutning av N-aroylmethylacet-amider (IV) av formel: under dannelse av den tilsvarende forbindelse av formel V. Denne ringslutning utføres ifølge oppfinnelsen under basiske betingelser, f.eks. i t-butanol med kalium t-butoxyd som base under nitrogen efterfulgt av surgjøring med en uorganisk syre slik som HC1 og fortynning med vann eller ved ringslutning av det tilsvarende fosfoniumbromid (XIII) av formel: The present invention therefore also relates to general methods for the production of compounds of formula V, and this is carried out according to the invention by cyclization of N-aroylmethylacetamides (IV) of formula: while forming the corresponding compound of formula V. This cyclization is carried out according to the invention under basic conditions, e.g. in t-butanol with potassium t-butoxide as base under nitrogen followed by acidification with an inorganic acid such as HCl and dilution with water or by cyclization of the corresponding phosphonium bromide (XIII) of formula:
hvor ringslutningen utføres i basisk medium til den tilsvarende forbindelse av formel V. where the cyclization is carried out in basic medium to the corresponding compound of formula V.
Følgende definisjoner og uttrykk anvendes: The following definitions and expressions are used:
Aroyl = Aryl-CO- Aroyl = Aryl-CO-
Acyl = Alkyl(minus 1 C)-C0- Acyl = Alkyl(minus 1 C)-C0-
Aryl = fenyl, pyridyl, furyl, thienyl, N-alkyl- eller N-aryl-pyrrolyl, og de tilsvarende benzoderivater, dvs. nafthyl, Aryl = phenyl, pyridyl, furyl, thienyl, N-alkyl- or N-aryl-pyrrolyl, and the corresponding benzo derivatives, i.e. naphthyl,
kinolyl, etc. quinolyl, etc.
Alkyl = til C16hydrocarboner Alkyl = to C16 hydrocarbons
Substituenter (opp til 5, lik eller blandet) = Substituents (up to 5, equal or mixed) =
alkyl, haloalkyl (f.eks. F3C), O-alkyl, N-dialkyl (lik og forskjellig), S-alkyl, halogen, O-benzyl, N-dibenzyl, N-alkyl/benzyl, S-benzyl, O-aryl, S-aryl, N-diaryl, N-alkyl/ alkyl, haloalkyl (e.g. F3C), O-alkyl, N-dialkyl (same and different), S-alkyl, halogen, O-benzyl, N-dibenzyl, N-alkyl/benzyl, S-benzyl, O- aryl, S-aryl, N-diaryl, N-alkyl/
benzyl/aryl>OH, NI-^, SH (de sistnevnte tre er beskyttet under den basiske ringslutning). benzyl/aryl>OH, NI-^, SH (the latter three are protected during the basic cyclization).
Visse 3-pyrrolin-2-oner (V) er krevet i US patentskrift nr. 3.272.842, og fremstilles efter følgende.reaksjonsligning: Certain 3-pyrrolin-2-ones (V) are claimed in US Patent No. 3,272,842, and are prepared according to the following reaction equation:
5 5' 4 Imidlertid utelukker R og R hydrogen, og R er alltid S-CH-- (S = substituent). Denne ringslutning av VI med R 4= aryl eller substituert aryl og R 5 og/eller R 51 = hydrogen, i henhold til eksemplene i US patentskrift nr. 3.272.842 forløper enten ik-ke, eller gir gule forbindelser (sannsynligvis dimerer), som er resultat at forskjellen i substituenter, dvs. at de angitte metoder ikke var anvendbare på foreliggende forbindelser. 3-pyrrolin-2-oner (V) er blitt fremstilt (G. Stork and R. Matthews, Chemical Communications 1970, 445-6) efter følgende reaksjonsskjema: 5 5' 4 However, R and R exclude hydrogen, and R is always S-CH-- (S = substituent). This cyclization of VI with R 4 = aryl or substituted aryl and R 5 and/or R 51 = hydrogen, according to the examples in US Patent No. 3,272,842 either does not proceed, or gives yellow compounds (probably dimers), which is the result that the difference in substituents, i.e. that the specified methods were not applicable to the present compounds. 3-pyrrolin-2-ones (V) have been prepared (G. Stork and R. Matthews, Chemical Communications 1970, 445-6) according to the following reaction scheme:
Imidlertid er anvendelsen av dicyclohexylcarbodiimid . (DCC) for kondensasjonen av aminoketonderivatet (VI) med ustabil fosfoniumeddiksyre (VII) uegnet for syntese i stor skala. I til-legg er prisen på DCC ganske høy, og N,N<1->dicyclohexylurea er et biprodukt som er vanskelig å fjerne, hvilket gjør prosessen ytterligere uøkonomisk. However, the application of dicyclohexylcarbodiimide. (DCC) for the condensation of the aminoketone derivative (VI) with unstable phosphonium acetic acid (VII) unsuitable for large-scale synthesis. In addition, the price of DCC is quite high, and N,N<1->dicyclohexylurea is a by-product that is difficult to remove, making the process even more uneconomical.
En lignende ringslutningsreaksjon [T.W. Guntert et al. Heiv. Chim. Acta 60, 334-9 (1977)] er blitt foreslått som følger: A similar ring closure reaction [T.W. Guntert et al. Hooray. Chim. Acta 60, 334-9 (1977)] has been proposed as follows:
men denne prosess krever imidlertid gjentatte kromatografiske separasjoner for isolering av 3-pyrrolin-2-on (V) med R 4 = 170-steroidyl i 10 %'s utbytte, slik at denne prosess er uegnet for syntese i stor skala, og man var ikke istand til å fremstille brom-moderforbindelsen av formel IX (svarende til foreliggende forbindelse av formel XII). however, this process requires repeated chromatographic separations for the isolation of 3-pyrrolin-2-one (V) with R 4 = 170-steroidyl in a 10% yield, so that this process is unsuitable for large-scale synthesis, and one was unable to prepare the bromine parent compound of formula IX (corresponding to the present compound of formula XII).
Ifølge oppfinnelsen kan direkte ringslutning av forbindelser av formel IV være effektiv, selv for syntese av substituerte 3-pyrrolin-2-oner (V) mest hensiktsmessig hvor substituentene R 1 og - R 3 i forbindelser av formel (IV) oppfyller følgende to kriterier: (1) at enten rVh, dvs. R"*" = alkyl, substituert alkyl, aryl, substituert aryl, acyl eller aroyl, eller (2) hvis R = H, at R^ er en gruppe som stabiliserer anioner ved C-3 og er stabile overfor baser, dvs. aryl, substituert aryl, ;.carbonyl etc, men ikke alkyl eller hydrogen. ;For fremstilling av forbindelser av formel V ved ring- ;1 3 slutning i det tilfelle hvor R = hydrogen og R = hydrogen, alkyl eller substituert alkyl, er det blitt funnet best å gå frem efter ef-terfølgende reaksjonsligning . Hvor således R 4 = .arylsubstituert 5 5' aryl, R = hydrogen, alkyl eller substituert alkyl og R = hydro gen, alkyl eller substituert alkyl, er det mulig å omsette 2-ami-noacetofenon (XI) av formel: ;med et 2-brom-acylklorid eller bromid under dannelse av den tilsvarende bromforbindelse (XII) åv formel: ;i praktisk talt kvantitativt utbytte. Bromforbindelsen av formel XII reagerer i motsetning til klorforbindelsen av formel IX mellom romtemperatur og 50°C med trifenylfosfin, f.eks. i benzen eller klorbenzenoppløsning, uten spaltning, under dannelse av det tilsvarende fosfoniumbromid (XIII) av formel: ; som er tilstrekkelig oppløselig i alkoholer og vann for ringslut-ningsreaks. jonen til den tilsvarende forbindelse av formel V, f.eks. med 2N NaOH oppløsning. ;I henhold til denne metode er utgangsaminoketonene (XI) hvori R 4= aryl, substituert aryl, alkyl eller substituert alkyl, ;5 51 ;R = hydrogen, alkyl eller substituert alkyl, og R = hydrogen eller alkyl, generelt lettilgjengelige forbindelser som kan acyl-eres i praktisk talt kvantitativt utbytte i svakt basiske media, f.eks. natriumbicarbonat i en vann-etherblanding, med 2-bromacyl-klorider eller bromider til det tilsvarende N-(2-bromacyl)-amino-keton (XII) hvori R 3 = hydrogen, aryl, substituert aryl, alkyl eller substituert alkyl. ;Ketonene av formel XII som ovenfor angitt reagerer ved romtemperatur med trifenylfosfin, f.eks. i benzenoppløsning, under dannelse av det tilsvarende fosfoniumbromid XIII som utfelles og kan oppsamles ved enkel filtrering. Oppløsningen av forbindelsen av formel XIII i alkohol (fortrinnsvis methanol) eller vann, og behandling med mer enn én ekvivalent base (fortrinnsvis 2N NaOH oppløsning) ved romtemperatur gir raskt det ønskede 3-pyrrolin-2-one (V) og trifenylfosfinoxyd i praktisk talt kvantitativt utbytte, som utfelles fra oppløsningen. Efter fortynning med vann og fordampning av alkoholen, oppsamles blandingen og skilles ved ekstraksjon, f.eks. méd methylenklorid som fjerner trifenylfosfin-oxydet. ;3-pyrrolin-2-on (V) fremstilt på hvilken som helst av de ovenfor angitte måter, kan lett hydrogeneres med f.eks. Pd/C, Pt, eller chirale rhodiumkomplekser som katalysator i alkohol ;(fortrinnsvis methanol) oppløsning til de CNS-aktive substituerte pyrrolidin-2-oner (I-cis). Denne reaksjon har den fordel at de- ;rivatene erholdes hvori R 3 og R 4utelukkende dannes som cis-substituenter. I-cis-forbindelsene kan omdannes til de tilsvarende I-traris-forbindelser ved base eller syrebehandling. ;Pyrrolidin-2-onene av formel (I) kan hydrolyseres ved sterk syre- eller basebehandling til de tilsvarende 4-amino-smør-syrederivater av formel III ledsaget av partiell isomerisering av R 3-substituenten, resulterende i en diastereoisomer blanding som kan isoleres som salter (f.eks. HC1 eller natrium og magnesium etc.) eller som frie aminosyrer. Hydrolysen med R"^ = alkyl er ufullstendig på grunn av dannelse av en likevekt mellom I og III som kan separeres ved ekstraksjon. ;En ytterligere fordel ved oppfinnelsen er at reduksjonen av de nye pyrrolidin-2-oner (I), f.eks. med B9H, eller LiAlH. fø-rer til dannelse av nye pyrrolidiner (II-cis (R 3 og R 4= cis) eller II-trans (R 3 og R 4 = trans) avhengig av utgangsmaterialet. ;Reduksjonen av C=C dobbeltbindingen i V utføres lett med hydrogen og ca. 5 - 15 % 10 %'s palladium på carbon som katalysator. Asymmetrisk hydrogenering erholdes med chirale rhodiumkata-lysatorer (f.eks. J. Am. Chem. -Soc. 1977, 99, 5946-52). Filtrering og fordampning av oppløsningsmidlet, fortrinnsvis methanol, gir direkte de ønskede lactamer I-cis i kvantitativt utbytte. I det tilfelle hvor R"'" = benzyl i formel V, kan forbindelsen av I-cis hvorR"<*>"= hydrogen, erholdes ved hydrogenolyse, dvs. at N-benzylgruppen har en funksjon som en beskyttende gruppe i det tilfelle hvor R 3 = hydrogen, alkyl, eller substituert alkyl. According to the invention, direct cyclization of compounds of formula IV can be effective, even for the synthesis of substituted 3-pyrrolin-2-ones (V) most appropriately where the substituents R 1 and - R 3 in compounds of formula (IV) fulfill the following two criteria: (1) that either rVh, i.e., R"*" = alkyl, substituted alkyl, aryl, substituted aryl, acyl, or aroyl, or (2) if R = H, that R^ is a group that stabilizes anions at C-3 and are stable to bases, ie aryl, substituted aryl, ;.carbonyl etc, but not alkyl or hydrogen. ;For the preparation of compounds of formula V by ring- ;1 3 conclusion in the case where R = hydrogen and R = hydrogen, alkyl or substituted alkyl, it has been found best to proceed according to the following reaction equation. Thus where R 4 = .aryl substituted 5 5' aryl, R = hydrogen, alkyl or substituted alkyl and R = hydro gene, alkyl or substituted alkyl, it is possible to react 2-amino-acetophenone (XI) of formula: ;with a 2-bromo-acyl chloride or bromide to form the corresponding bromine compound (XII) of formula: ;in practically quantitative dividend. The bromine compound of formula XII reacts in contrast to the chlorine compound of formula IX between room temperature and 50°C with triphenylphosphine, e.g. in benzene or chlorobenzene solution, without cleavage, to form the corresponding phosphonium bromide (XIII) of formula: ; which is sufficiently soluble in alcohols and water for ring closure reactions. the ion of the corresponding compound of formula V, e.g. with 2N NaOH solution. ;According to this method, the starting aminoketones (XI) in which R 4= aryl, substituted aryl, alkyl or substituted alkyl, ;5 51 ;R = hydrogen, alkyl or substituted alkyl, and R = hydrogen or alkyl, are generally readily available compounds which can is acyl-erized in practically quantitative yield in weakly basic media, e.g. sodium bicarbonate in a water-ether mixture, with 2-bromoacyl chlorides or bromides to the corresponding N-(2-bromoacyl)-amino ketone (XII) in which R 3 = hydrogen, aryl, substituted aryl, alkyl or substituted alkyl. The ketones of formula XII as indicated above react at room temperature with triphenylphosphine, e.g. in benzene solution, forming the corresponding phosphonium bromide XIII which precipitates and can be collected by simple filtration. The dissolution of the compound of formula XIII in alcohol (preferably methanol) or water, and treatment with more than one equivalent base (preferably 2N NaOH solution) at room temperature rapidly gives the desired 3-pyrrolin-2-one (V) and triphenylphosphine oxide in practically quantitative yield, which is precipitated from the solution. After dilution with water and evaporation of the alcohol, the mixture is collected and separated by extraction, e.g. with methylene chloride, which removes the triphenylphosphine oxide. ;3-pyrrolin-2-one (V) prepared in any of the above ways can be easily hydrogenated with e.g. Pd/C, Pt, or chiral rhodium complexes as catalyst in alcohol (preferably methanol) solution to the CNS-active substituted pyrrolidin-2-ones (I-cis). This reaction has the advantage that the derivatives are obtained in which R 3 and R 4 are formed exclusively as cis-substituents. The I-cis compounds can be converted into the corresponding I-traris compounds by base or acid treatment. ;The pyrrolidin-2-ones of formula (I) can be hydrolyzed by strong acid or base treatment to the corresponding 4-aminobutyric acid derivatives of formula III accompanied by partial isomerization of the R 3 substituent, resulting in a diastereoisomeric mixture which can be isolated as salts (e.g. HC1 or sodium and magnesium etc.) or as free amino acids. The hydrolysis with R"^ = alkyl is incomplete due to the formation of an equilibrium between I and III which can be separated by extraction. A further advantage of the invention is that the reduction of the new pyrrolidin-2-ones (I), e.g. . with B9H, or LiAlH. leads to the formation of new pyrrolidines (II-cis (R 3 and R 4 = cis) or II-trans (R 3 and R 4 = trans) depending on the starting material. ;The reduction of C= The C double bond in V is easily carried out with hydrogen and about 5 - 15% 10% palladium on carbon as catalyst. Asymmetric hydrogenation is obtained with chiral rhodium catalysts (eg J. Am. Chem. -Soc. 1977, 99 , 5946-52). Filtration and evaporation of the solvent, preferably methanol, gives directly the desired lactams I-cis in quantitative yield. In the case where R"'" = benzyl in formula V, the compound of I-cis where R"< *>"= hydrogen, obtained by hydrogenolysis, i.e. that the N-benzyl group has a function as a protecting group in the case where R 3 = hydrogen, alkyl, or subs titrated alkyl.
Hydrolyse av forbindelser av formel I i tilbakeløpskok-ende konsentrert (15-35 %) uorganiske syrer (f.eks. saltsyre) et-terfulgt av fordampning, leder direkte til dannelse av tilsvarende 4-amino-smørsyrehydroklorider av formel III når det gjelder HC1. Med svovelsyre kan sulfater fjernes med bariumhydroxydoppløsning under dannelse av de frie aminosyrer av forme] III som kan omdannes til et ønsket carbonsyresalt (f.eks. magnesium) eller til et ammoniumsalt med en terapeutisk akseptabel syre. På den annen side leder hydrolyse med base til de tilsvarende carbonsyresalter (f.eks. natrium, kalium). Hydrolysis of compounds of formula I in refluxing concentrated (15-35%) inorganic acids (e.g. hydrochloric acid) followed by evaporation leads directly to the formation of corresponding 4-amino-butyric acid hydrochlorides of formula III in the case of HCl . With sulfuric acid, sulfates can be removed with barium hydroxide solution to form the free amino acids of form] III which can be converted to a desired carboxylic acid salt (eg magnesium) or to an ammonium salt with a therapeutically acceptable acid. On the other hand, hydrolysis with base leads to the corresponding carboxylic acid salts (e.g. sodium, potassium).
Reduksjon av carbonylgruppen i lactamer av formel I med f.eks. lithiumaluminiumhydrid eller borhydrid fører til dannelse . av de tilsvarende pyrrolidiner av formel II som kan omdannes til et ammoniumsalt med en terapeutisk akseptabel syre. Reduction of the carbonyl group in lactams of formula I with e.g. lithium aluminum hydride or borohydride leads to the formation of . of the corresponding pyrrolidines of formula II which can be converted to an ammonium salt with a therapeutically acceptable acid.
De etterfølgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
EKSEMPEL. I 3, 4- difenyl- 3- pyrrolin- 2- on ( Va) EXAMPLE. In 3, 4- diphenyl- 3- pyrrolin- 2- one (Va)
En oppløsning av 12,6 g (50 mmol) 2-fenylacetamido-aceto-fenon i 200 ml t-butanol ble tilsatt til en tilbakeløpskokende oppløsning av kalium t-butoxyd fremstillet av 6,5 g kalium (166 mmol) og 200 ml t-butanol under nitrogen. Efter 40 minutters til-bakeløpskokning ble oppløsningen avkjølt til 40°C og surgjort med 2N HC1 (ca. 120 ml) til pH 6 til 5. Den dannede suspensjon ble helt over i 3 liter isvann. Bunnfallet ble oppsamlet og vasket med vann. Efter tørking ble der erholdt 9,85 g (84,1 %) av Va med smeltepunkt 183 - 90°C. Ekstråksjon av vannet med kloroform ga ytterligere 1,3 g (11,1 %) av Va. En omkrystallisert prøve fra benzen utviste et smeltepunkt ved 177 - 9°C. De etterfølgen-de forbindelser av formel V ble fremstilt på analog måte: 3-fenyl-4-(4'-klorfenyl)-3-pyrrolin-2-on (Vb), smp. '204- 10°C 3-(2<1->carboxyfenyl)-4-fenyl-3-pyrrolin-2-on (Vc), smp. 238- 41°C 3-fenyl-4-(4'-fluorfenyl)-3-pyrrolin-2-on (Vd), smp. 200- 2°C 3-(4'-fluorfenyl)-4-fenyl-3-pyrrolin-2-on (Ve), smp. 199-209°C 3-fenyl-4-(4<1->methylfenyl)-3-pyrrolin-2-on (Vf), smp. 210- 20°C 3-fenyl-4-(4'-trifluormethylfenyl)-3-pyrrolin-2-on (Vg), smp. 195- 8°C 3-(21-fluorfenyl)-4-(4'-trifluormethylfenyl)-3- pyrrolin-2-on (Vh), smp. 165- 6 C 1,3,5-trimethyl-4-fenyl-3-pyrrolin-2-on (Vi), smp. 79- 81°C l-benzyl-4-(4<1->trifluormethylfenyl)-3-pyrrolin-2-on (Vk), gummi l-benzyl-3-methyl-4- (4 ' -trif luormethylf enyl) -3-pyrrolin-2-on (VI) , A solution of 12.6 g (50 mmol) of 2-phenylacetamido-aceto-phenone in 200 ml of t-butanol was added to a refluxing solution of potassium t-butoxide prepared from 6.5 g of potassium (166 mmol) and 200 ml of t -butanol under nitrogen. After refluxing for 40 minutes, the solution was cooled to 40°C and acidified with 2N HCl (ca. 120 ml) to pH 6 to 5. The resulting suspension was poured into 3 liters of ice water. The precipitate was collected and washed with water. After drying, 9.85 g (84.1%) of Va with melting point 183 - 90°C were obtained. Extraction of the water with chloroform gave an additional 1.3 g (11.1%) of Va. A recrystallized sample from benzene showed a melting point of 177 - 9°C. The following compounds of formula V were prepared in an analogous manner: 3-phenyl-4-(4'-chlorophenyl)-3-pyrrolin-2-one (Vb), m.p. '204- 10°C 3-(2<1->carboxyphenyl)-4-phenyl-3-pyrrolin-2-one (Vc), m.p. 238- 41°C 3-phenyl-4-(4'-fluorophenyl)-3-pyrrolin-2-one (Vd), m.p. 200- 2°C 3-(4'-fluorophenyl)-4-phenyl-3-pyrrolin-2-one (Ve), m.p. 199-209°C 3-phenyl-4-(4<1->methylphenyl)-3-pyrrolin-2-one (Vf), m.p. 210- 20°C 3-phenyl-4-(4'-trifluoromethylphenyl)-3-pyrrolin-2-one (Vg), m.p. 195- 8°C 3-(21-fluorophenyl)-4-(4'-trifluoromethylphenyl)-3- pyrrolin-2-one (Vh), m.p. 165- 6 C 1,3,5-trimethyl-4-phenyl-3-pyrrolin-2-one (Vi), m.p. 79- 81°C 1-benzyl-4-(4<1->trifluoromethylphenyl)-3-pyrrolin-2-one (Vk), gum 1-benzyl-3-methyl-4-(4'-trifluoromethylphenyl) -3-pyrrolin-2-one (VI),
gummi 1,5-dimethyl-3,4-difenyl-3-pyrrolin-2-on (Vm), smp. 95-103°C 1,5-dimethyl-4-fenyl-3-pyrrolin-2-on (Vn), smp. 130- 5°C l-methyl-3-fenyl-4-(4'-methylfenyl)-3-pyrrolin-2-on (Vo), smp. 123- 4°C 3-fenyl-4-(4'-methoxyfenyl)-3-pyrrolin-2-on (Vp), smp. 179- 81°C 3-fenyl-4-(31,4'-dimethoxyfenyl)-3-pyrrolin-2-on (Vq), smp. 202- 4°C 3-(4'-fluorfenyl)-4-(4'-trifluormethylfenyl)-3-pyrrolin-2-on (Vu), smp. 212- 3 C gum 1,5-dimethyl-3,4-diphenyl-3-pyrrolin-2-one (Vm), m.p. 95-103°C 1,5-dimethyl-4-phenyl-3-pyrrolin-2-one (Vn), m.p. 130-5°C 1-methyl-3-phenyl-4-(4'-methylphenyl)-3-pyrrolin-2-one (Vo), m.p. 123- 4°C 3-phenyl-4-(4'-methoxyphenyl)-3-pyrrolin-2-one (Vp), m.p. 179- 81°C 3-phenyl-4-(31,4'-dimethoxyphenyl)-3-pyrrolin-2-one (Vq), m.p. 202- 4°C 3-(4'-fluorophenyl)-4-(4'-trifluoromethylphenyl)-3-pyrrolin-2-one (Vu), m.p. 212-3C
EKSEMPEL II cis- 3, 4- difenyl- pyrrolidin- 2- on ( cis- Ia) EXAMPLE II cis-3,4-diphenyl-pyrrolidin-2-one (cis-Ia)
En oppløsning av 9,00 g 3,4-difenyl-3-pyrrolin-2-on (Va) i 200 ml methanol og 0,90 g 10 %'s palladium på carbon ble anbragt i en 500 ml's hydrogeneringskolbe, og hydrogenert 16 timer ved romtemperatur. Katalysatoren ble filtrert fra, og methanolen fordampet i vakuum. Krystallisering fra benzen-petroleumether (1:1) ga krystaller med smeltepunkt 154 - 5°C. De følgende forbindelser ble fremstilt på tilsvarende måte. A solution of 9.00 g of 3,4-diphenyl-3-pyrrolin-2-one (Va) in 200 ml of methanol and 0.90 g of 10% palladium on carbon was placed in a 500 ml hydrogenation flask, and hydrogenated 16 hours at room temperature. The catalyst was filtered off, and the methanol was evaporated in vacuo. Crystallization from benzene-petroleum ether (1:1) gave crystals with melting point 154 - 5°C. The following compounds were prepared in a similar manner.
3-fenyl-4-(4<1->fluorfenyl)-pyrrolidin-2-on ( cis- Id), smp. 198-200°C 3-(4'-fluorfenyl)-4-fenyl-pyrrolidin-2-on ( cis- Ie), smp. 167- 8°C 3-fenyl-4-(4'-methylfenyl)-pyrrolidin-2-on( cis- If), smp. 190- 1°C 3-fenyl-4-(4'-trifluormethylfenyl)-pyrrolidin-2-on 3-phenyl-4-(4<1->fluorophenyl)-pyrrolidin-2-one (cis-Id), m.p. 198-200°C 3-(4'-fluorophenyl)-4-phenyl-pyrrolidin-2-one (cis-Ie), m.p. 167- 8°C 3-phenyl-4-(4'-methylphenyl)-pyrrolidin-2-one (cis-If), m.p. 190- 1°C 3-phenyl-4-(4'-trifluoromethylphenyl)-pyrrolidin-2-one
( cis- Ig), smp. 149- 51°C 3- (2'-fluorfenyl)-4-(41-trifluormethylfenyl)- (cis-Ig), m.p. 149- 51°C 3-(2'-fluorophenyl)-4-(41-trifluoromethylphenyl)-
pyrrolidin-2-on ( cis - Ih ), smp. 154- 6°C 1,3,5-trimethyl-4-fenyl-pyrrolidin-2-on ( cis- Ii), gummi 4- (4'-trifluormethylfenyl)-pyrrolidin-2-on ( Ik), smp. 121- 22°C 3-methyl-4-(4'-trifluormethylfenyl)-pyrro- pyrrolidin-2-one (cis-Ih), m.p. 154- 6°C 1,3,5-trimethyl-4-phenyl-pyrrolidin-2-one ( cis- Ii ), gum 4-(4'-trifluoromethylphenyl)-pyrrolidin-2-one ( Ik ), m.p. 121- 22°C 3-methyl-4-(4'-trifluoromethylphenyl)-pyrro-
1id in-2-on( cis- Il) , 1,5-dimethyl-4-fenyl-pyrrolidin-2-on ( In), gummi l-methyl-3-fenyl-4-(4'-methylfenyl)-pyrrolidin-2-on ( cis - Io ), smp. 113- 4 C 3-fenyl-4-(4<1->methoxyfenyl)- 1id in-2-one (cis-Il), 1,5-dimethyl-4-phenyl-pyrrolidin-2-one (In), gum l-methyl-3-phenyl-4-(4'-methylphenyl)-pyrrolidine -2-one (cis-Io), m.p. 113- 4 C 3-phenyl-4-(4<1->methoxyphenyl)-
pyrrolidin-2-on ( cis- Ip), smp. 156- 9°C 3-fenyl-4-(31,4'-dimethoxyfenyl)-pyrrolidin-2-on ( cis - Iq ), smp. 144- 6 C 3-(4'-fluorfenyl)-4-(41-trifluormethyl-fenyl)-pyrrolidin-2-on ( cis - Iu ), smp. 203- 4°C pyrrolidin-2-one (cis-Ip), m.p. 156- 9°C 3-phenyl-4-(31,4'-dimethoxyphenyl)-pyrrolidin-2-one ( cis - Iq ), m.p. 144- 6 C 3-(4'-fluorophenyl)-4-(41-trifluoromethyl-phenyl)-pyrrolidin-2-one ( cis - Iu ), m.p. 203-4°C
EKSEMPEL III 1, 5- dimethyl- 4-( 4'- nitrofenyl)- pyrrolidin- 2- on ( Ir) EXAMPLE III 1,5-dimethyl-4-(4'-nitrophenyl)-pyrrolidin-2-one (Ir)
4,32 gin ble gradvis tilsatt til 30 ml rykende salpeter-syre ved -5 til 0°C. Efter 1 time ved -10°C ble oppløsningen helt over i 300 ml vann. Ekstraksjon med ethylacetat og vasking med 4.32 gin was gradually added to 30 ml of fuming nitric acid at -5 to 0°C. After 1 hour at -10°C, the solution was poured into 300 ml of water. Extraction with ethyl acetate and washing with
bicarbonatoppløsning og vann gå éfter fordampning av oppløsnings-midlet 4,89 g (91,6 %) Ir. Krystallisasjon fra acetonether (1:3) ga krystaller med smeltepunkt 94 - 5°C. bicarbonate solution and water leave after evaporation of the solvent 4.89 g (91.6%) Ir. Crystallization from acetone ether (1:3) gave crystals with a melting point of 94 - 5°C.
EKSEMPEL IV 1, 5- dimethy1- 4-( 4'- klorfenyl)- pyrrolidin- 2- on ( It) EXAMPLE IV 1,5-dimethyl-4-(4'-chlorophenyl)-pyrrolidin-2-one (It)
En oppløsning av 4,89 g (20,9 mmol) I_r i 50 ml methanol og 0,49 g 10 %'s palladium på carbon ble anbragt i en 250 ml's hydrogeneringskolbe og hydrogenert ved romtemperatur i 30 timer'. Katalysatoren ble filtrert fra, og methanolen fordampet i vakuum. A solution of 4.89 g (20.9 mmol) I_r in 50 ml of methanol and 0.49 g of 10% palladium on carbon was placed in a 250 ml hydrogenation flask and hydrogenated at room temperature for 30 hours. The catalyst was filtered off, and the methanol was evaporated in vacuo.
Det resulterende 1,5-dimethyl-4-(4'-aminofenyl)-pyrrolidin-2-on ( Is), isolert i 100 % utbytte, ble oppløst i 12 ml 18 %'s saltsyre i et 250 ml's begerglass og dråpevis behandlet med 5,23 ml 4N nat-riumnitritoppløsning ved 0 - 5°C. Efter 5 minutter ved 0°C ble overskuddet av nitrit ødelagt med urea. Efter 10 minutter ved 0 - 5°C ble diazoniumoppløsningen dråpevis tilsatt til en friskt fremstillet oppløsning av CuCl (20,9 mmol) i 8 ml 37 %'s saltsyre ved 0°C. Et brunt bunnfall ble umiddelbart dannet, som ble oppvarmet til 60°C i 1 time. Ekstraksjon med kloroform og vasking med vann ga 4,30 g urent reaksjonsprodukt efter fordampning. Efter filtrering gjennom 130 g silicagel ble der erholdt 3,80 g (81 %) It som en gummi. The resulting 1,5-dimethyl-4-(4'-aminophenyl)-pyrrolidin-2-one ( Is ), isolated in 100% yield, was dissolved in 12 ml of 18% hydrochloric acid in a 250 ml beaker and treated dropwise with 5.23 ml of 4N sodium nitrite solution at 0 - 5°C. After 5 minutes at 0°C, the excess nitrite was destroyed with urea. After 10 minutes at 0-5°C, the diazonium solution was added dropwise to a freshly prepared solution of CuCl (20.9 mmol) in 8 ml of 37% hydrochloric acid at 0°C. A brown precipitate immediately formed, which was heated to 60°C for 1 hour. Extraction with chloroform and washing with water gave 4.30 g of impure reaction product after evaporation. After filtration through 130 g of silica gel, 3.80 g (81%) of It were obtained as a gum.
EKSEMPEL V 4-amino-2-fenyl-3-(4'-trifluormethylfenyl)-smørsyre-hydroklorid ( IIIg- HCl) EXAMPLE V 4-Amino-2-phenyl-3-(4'-trifluoromethylphenyl)-butyric acid hydrochloride (IIIg-HCl)
9,15 g cis- Ig ble suspendert i 300 ml 25 %'s HC1 oppløs-ning i en 500 ml's kolbe og kokt under tilbakeløpskjøling i 13 timer. Fortynning med 3 00 ml vann og fordampning i vakuum til tørr-het ga et krystallinsk hvitt residuum som ble suspendert i ether over natten for å fjerne ethvert lactam. Filtrering og vasking med ether ga 9,65 g (89,4 %) IIIg- HCl med smeltepunkt 182 - 3°C. 9.15 g of cis-Ig was suspended in 300 ml of 25% HCl solution in a 500 ml flask and refluxed for 13 hours. Dilution with 300 ml of water and evaporation in vacuo to dryness gave a crystalline white residue which was suspended in ether overnight to remove any lactam. Filtration and washing with ether gave 9.65 g (89.4%) IIIg-HCl with melting point 182 - 3°C.
Analyse beregnet for C17H17ClF3N02-0,5 H20 (368,8) Analysis calculated for C17H17ClF3N02-0.5 H20 (368.8)
Funnet: C 55.84 %, H 4.96 %, N 3.79 % Found: C 55.84%, H 4.96%, N 3.79%
Beregnet: C 55.37 %, H 4,85 %, N 3.80 % Calculated: C 55.37%, H 4.85%, N 3.80%
De etterfølgende syrehydroklorider ble fremstilt på tilsvarende måte: 4-amino-2, 3-dif enyl-smørsyre - HC1 ( IIIa- 1- ICl) , smp. 210- 22°C 4-amino-3-(4'-fluorfenyl)-2-fenyl-smørsyre- The following acid hydrochlorides were prepared in a similar way: 4-amino-2, 3-diphenyl-butyric acid - HCl (IIIa-1-ICl), m.p. 210- 22°C 4-amino-3-(4'-fluorophenyl)-2-phenyl-butyric acid-
HC1 ( IIId- HCl), smp. 190- 5°C 4-amino-2-(41-fluorfenyl)-3-fenyl-smørsyre-HC1 ( IIIe - HCl ), smp. 170- 5°C 4-amino-3-(4'-methylfenyl)-2-fenyl-smørsyre-HC1 ( IIIf - HCl ) , smp.- 210- 6°C 4-amino-2-(21-fluorfenyl)-3-(4'-trifluor- ' HC1 (IIId-HCl), m.p. 190-5°C 4-amino-2-(41-fluorophenyl)-3-phenyl-butyric acid-HC1 ( IIIe - HCl ), m.p. 170- 5°C 4-amino-3-(4'-methylphenyl)-2-phenyl-butyric acid-HC1 ( IIIf - HCl ), m.p.- 210- 6°C 4-amino-2-(21-fluorophenyl) -3-(4'-trifluoro-'
methylf enyl)-smørsyre HC1 ( IIIh - HCl ) , smp. 182- 5°C methylphenyl)-butyric acid HC1 ( IIIh - HCl ), m.p. 182-5°C
4-amino-2-(41-fluorfenyl)-3-, (4'-trifluormethyl-fenyl)-smørsyre-HCl (IIIu-HCl)., smp. 200- 3°C 4-amino-3-(4'-trifluormethylfenyl)-smørsyre HC1 ( IIIk- HCl), smp. 175- 77°C 4-amino-2-methyl-3-(4'-trifluormethylfenyl)- 4-amino-2-(41-fluorophenyl)-3-, (4'-trifluoromethyl-phenyl)-butyric acid-HCl (IIIu-HCl)., m.p. 200-3°C 4-amino-3-(4'-trifluoromethylphenyl)-butyric acid HCl (IIIk-HCl), m.p. 175- 77°C 4-amino-2-methyl-3-(4'-trifluoromethylphenyl)-
smørsyre-HCl ( III- HC1) butyric acid-HCl (III- HC1)
4-methylamino-4-methyl-3-fenyl-smørsyre-HC1 ( IIIn- HCl), smp. 165- 75°C 4-amino-3-(4'-methoxyfenyl-2-fenyl)-smørsyre-HCl (IIIp-HCl), smp. 190-210°C 4-amino-3-(3<1>,4<1->dimethoxyfenyl)-2-fenyl- 4-methylamino-4-methyl-3-phenyl-butyric acid-HCl (IIIn-HCl), m.p. 165-75°C 4-amino-3-(4'-methoxyphenyl-2-phenyl)-butyric acid-HCl (IIIp-HCl), m.p. 190-210°C 4-amino-3-(3<1>,4<1->dimethoxyphenyl)-2-phenyl-
smørsyre-HCl (IIIq-HCl), smp. 230- 3°C. butyric acid-HCl (IIIq-HCl), m.p. 230-3°C.
EKSEMPEL VI 3, 4- difenyl- pyrrolidin ( Ila) EXAMPLE VI 3,4-diphenylpyrrolidine (IIa)
En oppløsning av 1,185 g cis-3,4-difenyl-pyrrolidin-2-on (Ia) i 30 ml tetrahydrofuran (THF) ble langsomt tilsatt til en suspensjon av 0,950 g lithiumaluminiumhydrid (LAH) og kokt under tilbakeløpskjøling 7 timer. Efter avkjøling ble 5 ml ethylacetat tilsatt for å ødelegge overskuddet av LAH, og 7 ml vann for å dan-ne hydroxyder. Suspensjonen ble filtrert og vasket med THF. THF ble fjernet i vakuum, og residuet ble tatt opp i kloroform og eks-trahert to ganger med 50 ml 2N-svovelsyre. Vannfasen ble behandlet med 2N NaOH oppløsning inntil denne ble alkalisk og ekstra-hert med kloroform. Krystallisering av residuet fra methylenklorid ga krystaller med smp. 169-72°C. 0,05 m 37 %'s saltsyreopp-løsning ble tilsatt til en oppløsning av 0,100 g Ila oppløst i 3 ml methanol. Fordampning og suspensjon i ether ga 0,111 g Ila-HC1 med smp. 74-84°C. A solution of 1.185 g of cis-3,4-diphenyl-pyrrolidin-2-one (Ia) in 30 ml of tetrahydrofuran (THF) was slowly added to a suspension of 0.950 g of lithium aluminum hydride (LAH) and refluxed for 7 hours. After cooling, 5 ml of ethyl acetate was added to destroy the excess of LAH, and 7 ml of water to form hydroxides. The suspension was filtered and washed with THF. The THF was removed in vacuo, and the residue was taken up in chloroform and extracted twice with 50 ml of 2N sulfuric acid. The water phase was treated with 2N NaOH solution until it became alkaline and extracted with chloroform. Crystallization of the residue from methylene chloride gave crystals with m.p. 169-72°C. 0.05 m of 37% hydrochloric acid solution was added to a solution of 0.100 g of Ila dissolved in 3 ml of methanol. Evaporation and suspension in ether gave 0.111 g of Ila-HCl with m.p. 74-84°C.
EKSEMPEL VII N-[(4'-trifluormethylbenzoy1)methyl]-2-brom-acetamid ( Xllk) EXAMPLE VII N-[(4'-trifluoromethylbenzoyl)methyl]-2-bromoacetamide (Xllk)
En oppløsning av 51,16 g (0,609 mol) natriumbicarbonat i 550 ml vann ble tilsatt under nitrogen ved 0 til 10°C til en to-faseoppløsning av 48,5 g (0,203 mol) 2-amino-4'-trifluormethyl-acetofenonhydroklorid (Xlk) i 250 ml vann og 250 ml ether. En annen oppløsning av 18,41 ml (0,223 mol) bromacetylklorid i 200 ml tørr ether ble tilsatt ved 0 til 5°C innen 15 minutter til den ovenfor omrørte suspensjon. Den umiddelbart tykke suspensjon ble tynnere. Efter 2 timers omrøring ble ethylacetat tilsattinntil en klar to-faseoppløsning ble erholdt. Vannet ble fraskilt, og ethylacetat-etheroppløs-ningen ble vasket med vann inntil den var nøytral. Fordampning i vakuum ga 62,3 g (95 %) av Xllk. En omkrystallisert prøve hadde smp. på 201 - 11°C. A solution of 51.16 g (0.609 mol) of sodium bicarbonate in 550 mL of water was added under nitrogen at 0 to 10°C to a two-phase solution of 48.5 g (0.203 mol) of 2-amino-4'-trifluoromethyl-acetophenone hydrochloride (Xlk) in 250 ml of water and 250 ml of ether. Another solution of 18.41 ml (0.223 mol) of bromoacetyl chloride in 200 ml of dry ether was added at 0 to 5°C within 15 minutes to the above stirred suspension. The immediately thick suspension became thinner. After stirring for 2 hours, ethyl acetate was added until a clear two-phase solution was obtained. The water was separated and the ethyl acetate-ether solution was washed with water until neutral. Evaporation in vacuo gave 62.3 g (95%) of Xllk. A recrystallized sample had m.p. at 201 - 11°C.
EKSEMPEL VIII N-[4 »-trifluormethylbenzoyl)methy1]-2-trifenylfosfoniumbromid) - acetamid ( XHIk) EXAMPLE VIII N-[4'-trifluoromethylbenzoyl)methyl]-2-triphenylphosphonium bromide)-acetamide (XHIk)
70,5 g (0,269 mol) trifenylfosfin ble tilsatt til en suspensjon av 62,36 g.(0,192 mol) XITk i 600 ml benzen. Efter 4 dagers omrøring ved romtemperatur ble det faste materiale oppsamlet og suspendert i 250 ml aceton i 3 timer. Filtrering ga 77, 66 g (69 %) XHIk med smp. 250 - 1°C. 70.5 g (0.269 mol) of triphenylphosphine was added to a suspension of 62.36 g (0.192 mol) of XITk in 600 ml of benzene. After 4 days of stirring at room temperature, the solid material was collected and suspended in 250 ml of acetone for 3 hours. Filtration gave 77.66 g (69%) of XHIk with m.p. 250 - 1°C.
EKSEMPEL IX 4-( 4'- trifluormethylfenyl)- 3- pyrrolin- 2- on( Vk) EXAMPLE IX 4-(4'-trifluoromethylphenyl)-3-pyrrolin-2-one (Vk)
72,5 ml 2N NaOH oppløsning ble langsomt tilsatt under nitrogen til en oppløsning av 77,6 g (0,132 mol) XHIk i 780 ml methanol for. å holde temperaturen under 40°C. Efter 1 times om-røring ble 15 ml 2N HC1 oppløsning tilsatt inntil en pH på 6,5. Methanolén ble delvis fordampet i vakuum, og efter tilsetning av 200 ml vann fjernet fullstendig. Bunnfallet ble oppsamlet og vasket med vann. Efter tørking ble residuet som veiet 67,25 g, suspendert i 200 ml methylenklorid i 2 timer. Filtrering ga 27,3 g (91 %) Vk med smp. 208 - 20°C (spaltning). 72.5 ml of 2N NaOH solution was slowly added under nitrogen to a solution of 77.6 g (0.132 mol) XHIk in 780 ml of methanol. to keep the temperature below 40°C. After stirring for 1 hour, 15 ml of 2N HCl solution was added until a pH of 6.5. The methanol was partially evaporated in vacuo, and after the addition of 200 ml of water removed completely. The precipitate was collected and washed with water. After drying, the residue weighing 67.25 g was suspended in 200 ml of methylene chloride for 2 hours. Filtration yielded 27.3 g (91%) Vk with m.p. 208 - 20°C (decomposition).
EKSEMPEL X 4-( 4- trifluormethylfenyl)- pyrrolidin- 2- on( Ik) EXAMPLE X 4-(4-trifluoromethylphenyl)-pyrrolidin-2-one (Ik)
En oppløsning av 27,2 g (0,12 mol) Vk i 500 ml methanol (delvis suspendert) ble hydrogenert 10 timer med 4,1 g 10 %'s Pd på carbon som katalysator. Filtrering og fordampning i vakuum ga 27,5 g (100 %) Ik. En omkrystallisert [acetonether (1:2)] prøve hadde smp. 121. - 2°C. A solution of 27.2 g (0.12 mol) Vk in 500 ml of methanol (partially suspended) was hydrogenated for 10 hours with 4.1 g of 10% Pd on carbon as catalyst. Filtration and evaporation in vacuo gave 27.5 g (100%) Ik. A recrystallized [acetone ether (1:2)] sample had m.p. 121. - 2°C.
Analyse (C,,H,nF.,N0): Beregnet: C 57.64 % H 4.40 % N 6.11 % Analysis (C,,H,nF.,N0): Calculated: C 57.64 % H 4.40 % N 6.11 %
Funnet: C 57.65 % H 4.38 % N 6.35% Found: C 57.65% H 4.38% N 6.35%
EKSEMPEL' XI 4-amino-3- (4 ' -.trif luormethylf enyl) -smørsyre-HC1 ( IIIk- HCl) EXAMPLE' XI 4-Amino-3-(4'-.trifluoromethylphenyl)-butyric acid-HCl (IIIk-HCl)
11,45 g (50 mmol) Ik ble kokt under tilbakeløpskjøling 15 timer i 100 ml 25 %'s HC1 oppløsning. Efter fortynning med vann og ekstraksjon med ether ble vannfasen fordampet i vakuum. Residuet ble suspendert i litt ether og oppsamlet: 13,45 g (95%) IIIk- HCl med smp. 175 - 7°C. 11.45 g (50 mmol) of Ik was refluxed for 15 hours in 100 ml of 25% HCl solution. After dilution with water and extraction with ether, the water phase was evaporated in vacuo. The residue was suspended in a little ether and collected: 13.45 g (95%) IIIk-HCl with m.p. 175 - 7°C.
Analyse (C, , H, -.CIF^NO-) : Beregnet: C 46.57 % H 4.62 % N 4.94 % Analysis (C, , H, -.CIF^NO-) : Calculated: C 46.57 % H 4.62 % N 4.94 %
Funnet: C 46.44 % H 4.67 % N 5.06 % Found: C 46.44% H 4.67% N 5.06%
Claims (8)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US91468278A | 1978-06-12 | 1978-06-12 | |
US1249679A | 1979-02-15 | 1979-02-15 |
Publications (1)
Publication Number | Publication Date |
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NO791943L true NO791943L (en) | 1979-12-13 |
Family
ID=26683628
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO791943A NO791943L (en) | 1978-06-12 | 1979-06-11 | PROCEDURES FOR THE PREPARATION OF PYRROLIDIN-2-ONES FROM 3-PYRROLIN-2-ONES, AND PROCEDURES OF 3-PYRROLIN-2-ONES |
Country Status (19)
Country | Link |
---|---|
AR (1) | AR222997A1 (en) |
AT (1) | ATA386679A (en) |
AU (1) | AU529479B2 (en) |
CA (1) | CA1108628A (en) |
CH (1) | CH650772A5 (en) |
DE (3) | DE2954237C2 (en) |
DK (1) | DK157847C (en) |
ES (1) | ES481315A1 (en) |
FI (1) | FI70209C (en) |
FR (1) | FR2434151A1 (en) |
GB (1) | GB2028307B (en) |
GR (1) | GR68438B (en) |
IL (1) | IL57266A (en) |
IT (1) | IT1116891B (en) |
NL (1) | NL7904584A (en) |
NO (1) | NO791943L (en) |
NZ (1) | NZ190705A (en) |
PT (1) | PT69716A (en) |
SE (1) | SE431644B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US4943640A (en) * | 1983-10-14 | 1990-07-24 | The Dow Chemical Company | Preparation of 5-(1-alkyl-carbonyloxy)alkylpyrrolidin-2-one |
WO1990007499A1 (en) * | 1988-12-27 | 1990-07-12 | Ici Americas Inc. | Process for the preparation of 3-carboalkoxypyrrolidones |
US5021587A (en) * | 1990-01-24 | 1991-06-04 | Petrolite Corporation | Synthesis of N,3,4-trisubstituted-3-azoline-2-ones |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US3272842A (en) * | 1965-06-25 | 1966-09-13 | Lilly Co Eli | Novel pyrrolinones |
GB1350582A (en) * | 1970-07-24 | 1974-04-18 | Ucb Sa | Cerivatives of 2-pyrrolidinone |
DE2413935A1 (en) * | 1974-03-20 | 1975-10-16 | Schering Ag | 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE |
-
1979
- 1979-05-14 IL IL57266A patent/IL57266A/en unknown
- 1979-05-15 GR GR59088A patent/GR68438B/el unknown
- 1979-05-17 AR AR276559A patent/AR222997A1/en active
- 1979-05-28 AT AT793866A patent/ATA386679A/en not_active Application Discontinuation
- 1979-06-01 PT PT69716A patent/PT69716A/en unknown
- 1979-06-01 AU AU47670/79A patent/AU529479B2/en not_active Ceased
- 1979-06-06 ES ES481315A patent/ES481315A1/en not_active Expired
- 1979-06-08 CA CA329,322A patent/CA1108628A/en not_active Expired
- 1979-06-09 DE DE2954237A patent/DE2954237C2/de not_active Expired
- 1979-06-09 DE DE19792923553 patent/DE2923553A1/en active Granted
- 1979-06-09 DE DE2954236A patent/DE2954236C2/de not_active Expired
- 1979-06-11 DK DK241779A patent/DK157847C/en not_active IP Right Cessation
- 1979-06-11 SE SE7905079A patent/SE431644B/en not_active IP Right Cessation
- 1979-06-11 NO NO791943A patent/NO791943L/en unknown
- 1979-06-11 IT IT49373/79A patent/IT1116891B/en active
- 1979-06-11 GB GB7920275A patent/GB2028307B/en not_active Expired
- 1979-06-11 FR FR7914907A patent/FR2434151A1/en active Granted
- 1979-06-12 FI FI791866A patent/FI70209C/en not_active IP Right Cessation
- 1979-06-12 NZ NZ190705A patent/NZ190705A/en unknown
- 1979-06-12 CH CH5496/79A patent/CH650772A5/en not_active IP Right Cessation
- 1979-06-12 NL NL7904584A patent/NL7904584A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
IL57266A (en) | 1982-12-31 |
DE2923553C2 (en) | 1988-06-01 |
FR2434151B3 (en) | 1982-04-30 |
IT7949373A0 (en) | 1979-06-11 |
CH650772A5 (en) | 1985-08-15 |
FI791866A (en) | 1979-12-13 |
DE2923553A1 (en) | 1979-12-20 |
GR68438B (en) | 1981-12-30 |
CA1108628A (en) | 1981-09-08 |
AU4767079A (en) | 1979-12-20 |
SE7905079L (en) | 1979-12-13 |
IL57266A0 (en) | 1979-09-30 |
DK241779A (en) | 1979-12-13 |
GB2028307A (en) | 1980-03-05 |
GB2028307B (en) | 1983-01-19 |
FI70209C (en) | 1986-09-15 |
DK157847C (en) | 1990-09-17 |
NL7904584A (en) | 1979-12-14 |
AR222997A1 (en) | 1981-07-15 |
NZ190705A (en) | 1981-10-19 |
SE431644B (en) | 1984-02-20 |
FR2434151A1 (en) | 1980-03-21 |
DK157847B (en) | 1990-02-26 |
DE2954236C2 (en) | 1988-10-06 |
DE2954237C2 (en) | 1989-09-21 |
PT69716A (en) | 1979-07-01 |
ES481315A1 (en) | 1980-08-16 |
IT1116891B (en) | 1986-02-10 |
ATA386679A (en) | 1983-12-15 |
AU529479B2 (en) | 1983-06-09 |
FI70209B (en) | 1986-02-28 |
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