EA008192B1 - Способ получения (s,s)-цис-2-бензгидрил-3-бензиламинохинуклидина - Google Patents
Способ получения (s,s)-цис-2-бензгидрил-3-бензиламинохинуклидина Download PDFInfo
- Publication number
- EA008192B1 EA008192B1 EA200500650A EA200500650A EA008192B1 EA 008192 B1 EA008192 B1 EA 008192B1 EA 200500650 A EA200500650 A EA 200500650A EA 200500650 A EA200500650 A EA 200500650A EA 008192 B1 EA008192 B1 EA 008192B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- acid
- salt
- organic
- chiral
- isomer
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 150000002466 imines Chemical class 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 20
- 150000007524 organic acids Chemical class 0.000 claims abstract description 19
- 150000002576 ketones Chemical class 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000002841 Lewis acid Substances 0.000 claims abstract description 17
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 150000001412 amines Chemical class 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 3
- 230000003381 solubilizing effect Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 31
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 22
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical group CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 9
- -1 (8) -benzhydryl-3-quinuclidinone Chemical compound 0.000 claims description 8
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical group [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229910000510 noble metal Inorganic materials 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 150000003892 tartrate salts Chemical group 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- 125000003158 alcohol group Chemical group 0.000 claims description 3
- 150000003975 aryl alkyl amines Chemical group 0.000 claims description 3
- 230000002051 biphasic effect Effects 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 150000003608 titanium Chemical class 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000011928 denatured alcohol Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims 2
- 239000003245 coal Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000008520 organization Effects 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000001735 carboxylic acids Chemical class 0.000 abstract 2
- 230000001376 precipitating effect Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000000926 separation method Methods 0.000 description 17
- 238000005755 formation reaction Methods 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- FJXLZNSVOSVTPH-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-2-one Chemical compound C1CN2C(=O)CC1CC2 FJXLZNSVOSVTPH-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 102100024304 Protachykinin-1 Human genes 0.000 description 7
- 101800003906 Substance P Proteins 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 230000006340 racemization Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- PQSXXBSNZJLXMQ-UHFFFAOYSA-N 2-benzhydryl-1-azabicyclo[2.2.2]octan-3-one Chemical compound O=C1C(CC2)CCN2C1C(C=1C=CC=CC=1)C1=CC=CC=C1 PQSXXBSNZJLXMQ-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000005932 reductive alkylation reaction Methods 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 150000008584 quinuclidines Chemical class 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- 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 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- ZKMZPXWMMSBLNO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one Chemical compound C1CC2C(=O)CN1CC2 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SVHVLAGNGAWUQU-UHFFFAOYSA-N 2-benzhydryl-n-benzyl-1-azabicyclo[2.2.2]octan-3-amine Chemical compound C=1C=CC=CC=1CNC1C(CC2)CCN2C1C(C=1C=CC=CC=1)C1=CC=CC=C1 SVHVLAGNGAWUQU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 229940075894 denatured ethanol Drugs 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012035 limiting reagent Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QWLISCJHYITNQF-UHFFFAOYSA-N n-methoxy-1-phenylmethanamine Chemical compound CONCC1=CC=CC=C1 QWLISCJHYITNQF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003890 substance P antagonist Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41905102P | 2002-10-16 | 2002-10-16 | |
| PCT/US2003/032275 WO2004035575A1 (en) | 2002-10-16 | 2003-10-10 | Process for the preparation of (s,s)-cis-2-benzhydryl-3-benzylaminoquinuclidine |
Publications (2)
| Publication Number | Publication Date |
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| EA200500650A1 EA200500650A1 (ru) | 2005-10-27 |
| EA008192B1 true EA008192B1 (ru) | 2007-04-27 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA200500650A EA008192B1 (ru) | 2002-10-16 | 2003-10-10 | Способ получения (s,s)-цис-2-бензгидрил-3-бензиламинохинуклидина |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US6861526B2 (https=) |
| EP (1) | EP1551833A4 (https=) |
| JP (1) | JP2006506368A (https=) |
| KR (1) | KR100739901B1 (https=) |
| CN (1) | CN100418964C (https=) |
| AP (1) | AP2005003288A0 (https=) |
| AR (1) | AR041587A1 (https=) |
| AU (1) | AU2003277353B2 (https=) |
| BR (1) | BR0315335A (https=) |
| CA (1) | CA2500635A1 (https=) |
| EA (1) | EA008192B1 (https=) |
| HR (1) | HRP20050328A2 (https=) |
| IS (1) | IS7755A (https=) |
| MX (1) | MXPA05004058A (https=) |
| PA (1) | PA8586601A1 (https=) |
| PE (1) | PE20040777A1 (https=) |
| PL (1) | PL376218A1 (https=) |
| TN (1) | TNSN05111A1 (https=) |
| UY (1) | UY28024A1 (https=) |
| WO (1) | WO2004035575A1 (https=) |
| ZA (1) | ZA200502411B (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| JP5021318B2 (ja) * | 2004-01-30 | 2012-09-05 | ファイザー・プロダクツ・インク | β−シクロデキストリンを液体投薬形態に用いて多用量製剤を達成するための抗菌性防腐剤 |
| KR100812046B1 (ko) * | 2004-02-02 | 2008-03-10 | 화이자 프로덕츠 인크. | 1-(2ｓ,3ｓ)-2-벤즈히드릴-ｎ-(5-삼급-부틸-2-메톡시벤질)퀴누클리딘-3-아민의 제조 방법 |
| DE102004054054A1 (de) * | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| EP2540725A1 (de) | 2006-05-04 | 2013-01-02 | Boehringer Ingelheim International GmbH | Polymorphe von 1-((4-Methyl-chinazolin-2-yl)methyl)-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-amino-piperidin-1-yl)xanthin |
| PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
| PE20091730A1 (es) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
| UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
| BRPI0916997A2 (pt) | 2008-08-06 | 2020-12-15 | Boehringer Ingelheim International Gmbh | Inibidor de dpp-4 e seu uso |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| CN102256976A (zh) | 2008-12-23 | 2011-11-23 | 贝林格尔.英格海姆国际有限公司 | 有机化合物的盐形式 |
| AR074990A1 (es) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
| KR20240090632A (ko) | 2009-11-27 | 2024-06-21 | 베링거 인겔하임 인터내셔날 게엠베하 | 리나글립틴과 같은 ｄｐｐ－ｉｖ 억제제를 사용한 유전자형 검사된 당뇨병 환자의 치료 |
| CN102946875A (zh) | 2010-05-05 | 2013-02-27 | 贝林格尔.英格海姆国际有限公司 | 组合疗法 |
| WO2011161161A1 (en) | 2010-06-24 | 2011-12-29 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
| AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
| US8883800B2 (en) | 2011-07-15 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| JP6218811B2 (ja) | 2012-05-14 | 2017-10-25 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ｓｉｒｓ及び／又は敗血症の治療に用いるｄｐｐ−４阻害薬としてのキサンチン誘導体 |
| JP6224084B2 (ja) | 2012-05-14 | 2017-11-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 糸球体上皮細胞関連障害及び／又はネフローゼ症候群の治療に用いるｄｐｐ−４阻害薬としてのキサンチン誘導体 |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| EP3110449B1 (en) | 2014-02-28 | 2023-06-28 | Boehringer Ingelheim International GmbH | Medical use of a dpp-4 inhibitor |
| CN109310697A (zh) | 2016-06-10 | 2019-02-05 | 勃林格殷格翰国际有限公司 | 利格列汀和二甲双胍的组合 |
| CN108341812A (zh) * | 2017-01-23 | 2018-07-31 | 科贝源(北京)生物医药科技有限公司 | 一种含奎宁环化合物的制备方法 |
| CN108341811A (zh) * | 2017-01-23 | 2018-07-31 | 科贝源(北京)生物医药科技有限公司 | 马罗皮坦杂质的制备方法 |
| CN106977512B (zh) * | 2017-05-04 | 2019-01-01 | 海门慧聚药业有限公司 | 制备马罗匹坦游离碱的方法 |
| WO2025172911A1 (en) * | 2024-02-16 | 2025-08-21 | Teadus Pharmaceuticals Pvt. Ltd | A process for the preparation of (2s,3s)-2-benzhydryl- n-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine and pharmaceutically acceptable salts thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162339A (en) * | 1988-11-23 | 1992-11-10 | Pfizer Inc. | Quinuclidine therapeutic agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3560510A (en) * | 1969-03-05 | 1971-02-02 | Aldrich Chem Co Inc | 2-benzhydrylquinuclidines |
| US4680283A (en) | 1984-09-26 | 1987-07-14 | Merck & Co., Inc. | Analogs of substance P and eledoisin |
| US5138060A (en) | 1991-01-03 | 1992-08-11 | Pfizer Inc. | Process and intermediates for preparing azabicyclo(2.2.2)octan-3-imines |
| PL171921B1 (pl) | 1991-05-22 | 1997-06-30 | Pfizer | Sposób wytwarzania nowych pochodnych podstawionej 3-aminochinuklidyny PL PL PL PL PL |
| UA27776C2 (uk) * | 1991-05-31 | 2000-10-16 | Пфайзер Інк. | Похідні хінуклідину та їх фармацевтично прийнятні солі, що є антагоністами речовини р у ссавців, фармацевтична композиція, що має антагоністичну дію на речовину р у ссавців |
| ATE208376T1 (de) | 1992-08-19 | 2001-11-15 | Pfizer | Substituierte benzylamin-stickstoff enthaltende nichtaromatische heterocyclen |
| US5604241A (en) * | 1992-10-21 | 1997-02-18 | Pfizer Inc. | Substituted benzylaminoquinuclidines as substance P antagonists |
| JP2656699B2 (ja) | 1992-10-21 | 1997-09-24 | ファイザー製薬株式会社 | 置換ベンジルアミノキヌクリジン |
| JP2656700B2 (ja) | 1992-10-28 | 1997-09-24 | ファイザー製薬株式会社 | 置換キヌクリジン誘導体 |
| DK0668863T3 (da) * | 1992-11-12 | 1997-06-30 | Pfizer | Quinuclidinderivat som substans P-antagonist |
| IL109646A0 (en) | 1993-05-19 | 1994-08-26 | Pfizer | Heteroatom substituted alkyl benzylamino-quinuclidines |
| PE8798A1 (es) * | 1995-07-17 | 1998-03-02 | Pfizer | Procedimiento de separacion de los enantiomeros del 1-azabiciclo[2.2.2] octan-3-amina, 2-(difenilmetil) -n- [[2-metoxi-5-(1-metiletil) fenil] metil] |
| MX9706944A (es) | 1996-09-12 | 1998-08-30 | Pfizer | Quinuclidinas sustituidas con tetrazolilo como antagonistas de la sustancia p. |
-
2003
- 2003-10-06 US US10/679,961 patent/US6861526B2/en not_active Expired - Fee Related
- 2003-10-10 BR BR0315335-5A patent/BR0315335A/pt not_active IP Right Cessation
- 2003-10-10 AU AU2003277353A patent/AU2003277353B2/en not_active Ceased
- 2003-10-10 AR ARP030103709A patent/AR041587A1/es unknown
- 2003-10-10 WO PCT/US2003/032275 patent/WO2004035575A1/en not_active Ceased
- 2003-10-10 EA EA200500650A patent/EA008192B1/ru not_active IP Right Cessation
- 2003-10-10 PL PL03376218A patent/PL376218A1/xx not_active Application Discontinuation
- 2003-10-10 AP AP2005003288A patent/AP2005003288A0/xx unknown
- 2003-10-10 CA CA002500635A patent/CA2500635A1/en not_active Abandoned
- 2003-10-10 HR HR20050328A patent/HRP20050328A2/xx not_active Application Discontinuation
- 2003-10-10 EP EP03808986A patent/EP1551833A4/en not_active Withdrawn
- 2003-10-10 CN CNB200380101563XA patent/CN100418964C/zh not_active Expired - Fee Related
- 2003-10-10 JP JP2004544849A patent/JP2006506368A/ja active Pending
- 2003-10-10 MX MXPA05004058A patent/MXPA05004058A/es active IP Right Grant
- 2003-10-10 KR KR1020057006471A patent/KR100739901B1/ko not_active Expired - Fee Related
- 2003-10-14 PE PE2003001050A patent/PE20040777A1/es not_active Application Discontinuation
- 2003-10-15 UY UY28024A patent/UY28024A1/es not_active Application Discontinuation
- 2003-10-16 PA PA20038586601A patent/PA8586601A1/es unknown
-
2004
- 2004-10-27 US US10/974,447 patent/US20050085641A1/en not_active Abandoned
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2005
- 2005-03-17 IS IS7755A patent/IS7755A/is unknown
- 2005-03-23 ZA ZA200502411A patent/ZA200502411B/en unknown
- 2005-04-15 TN TNP2005000111A patent/TNSN05111A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162339A (en) * | 1988-11-23 | 1992-11-10 | Pfizer Inc. | Quinuclidine therapeutic agents |
Non-Patent Citations (1)
| Title |
|---|
| SEWARD, E.M. et al.: Quinuclidine-based NK-1 antagonists I: 3-benzyloxy-l-azabicyclo[2.2.2]octanes. Bioorg. & Medicn. Chem. Lett. 1993, Vol. 3, No. 6, pages 1361-1366, especially compounds 16 and 17 on page 1363. * |
Also Published As
| Publication number | Publication date |
|---|---|
| IS7755A (is) | 2005-03-17 |
| US6861526B2 (en) | 2005-03-01 |
| HK1078087A1 (en) | 2006-03-03 |
| AU2003277353A1 (en) | 2004-05-04 |
| CA2500635A1 (en) | 2004-04-29 |
| EP1551833A4 (en) | 2010-06-02 |
| KR20050083764A (ko) | 2005-08-26 |
| EA200500650A1 (ru) | 2005-10-27 |
| BR0315335A (pt) | 2005-08-16 |
| ZA200502411B (en) | 2006-05-31 |
| UY28024A1 (es) | 2004-05-31 |
| EP1551833A1 (en) | 2005-07-13 |
| AR041587A1 (es) | 2005-05-26 |
| JP2006506368A (ja) | 2006-02-23 |
| PE20040777A1 (es) | 2004-11-20 |
| PA8586601A1 (es) | 2005-02-04 |
| PL376218A1 (en) | 2005-12-27 |
| MXPA05004058A (es) | 2005-06-08 |
| US20040116704A1 (en) | 2004-06-17 |
| CN100418964C (zh) | 2008-09-17 |
| HRP20050328A2 (en) | 2005-06-30 |
| TNSN05111A1 (en) | 2007-05-14 |
| WO2004035575A8 (en) | 2005-05-12 |
| KR100739901B1 (ko) | 2007-07-13 |
| WO2004035575A1 (en) | 2004-04-29 |
| AU2003277353B2 (en) | 2007-08-09 |
| US20050085641A1 (en) | 2005-04-21 |
| AP2005003288A0 (en) | 2005-06-30 |
| CN1705664A (zh) | 2005-12-07 |
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