OA11494A - Method for making 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline. - Google Patents
Method for making 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline. Download PDFInfo
- Publication number
- OA11494A OA11494A OA1200000268A OA1200000268A OA11494A OA 11494 A OA11494 A OA 11494A OA 1200000268 A OA1200000268 A OA 1200000268A OA 1200000268 A OA1200000268 A OA 1200000268A OA 11494 A OA11494 A OA 11494A
- Authority
- OA
- OAPI
- Prior art keywords
- trifluoromethyl
- ethyl
- dihydro
- quinoline
- carboxylic acid
- Prior art date
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- -1 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline Chemical class 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims abstract description 9
- NFZTWYOOPXLSLR-MJGOQNOKSA-N ethyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methylamino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylate Chemical compound N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 NFZTWYOOPXLSLR-MJGOQNOKSA-N 0.000 claims abstract description 8
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 14
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 14
- 239000002002 slurry Substances 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- CMIBUZBMZCBCAT-HZPDHXFCSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000004494 ethyl ester group Chemical group 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- AZFYCLSCZLWMBW-UHFFFAOYSA-N ethyl 4-amino-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylate Chemical compound FC(F)(F)C1=CC=C2N(C(=O)OCC)C(CC)CC(N)C2=C1 AZFYCLSCZLWMBW-UHFFFAOYSA-N 0.000 claims description 7
- LDWLIXZSDPXYDR-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC(C=O)=CC(C(F)(F)F)=C1 LDWLIXZSDPXYDR-UHFFFAOYSA-N 0.000 claims description 6
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 6
- HVOAACKKZXUIKP-UHFFFAOYSA-N n-[1-(benzotriazol-1-yl)propyl]-4-(trifluoromethyl)aniline Chemical compound N1=NC2=CC=CC=C2N1C(CC)NC1=CC=C(C(F)(F)F)C=C1 HVOAACKKZXUIKP-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 5
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 claims description 5
- AZFYCLSCZLWMBW-PWSUYJOCSA-N ethyl (2r,4s)-4-amino-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylate Chemical compound FC(F)(F)C1=CC=C2N(C(=O)OCC)[C@H](CC)C[C@H](N)C2=C1 AZFYCLSCZLWMBW-PWSUYJOCSA-N 0.000 claims description 4
- GZVVNAWGGPWOOK-UHFFFAOYSA-N ethyl 2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OCC)CC=CC2=C1 GZVVNAWGGPWOOK-UHFFFAOYSA-N 0.000 claims description 2
- NFZTWYOOPXLSLR-UHFFFAOYSA-N ethyl 4-[[3,5-bis(trifluoromethyl)phenyl]methylamino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylate Chemical compound C12=CC(C(F)(F)F)=CC=C2N(C(=O)OCC)C(CC)CC1NCC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 NFZTWYOOPXLSLR-UHFFFAOYSA-N 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 29
- 239000000203 mixture Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
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- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical group CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 9
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 7
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- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 6
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- 108010010234 HDL Lipoproteins Proteins 0.000 description 6
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
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- 239000003112 inhibitor Substances 0.000 description 6
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- 239000012267 brine Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
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- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 208000032928 Dyslipidaemia Diseases 0.000 description 3
- 108010023302 HDL Cholesterol Proteins 0.000 description 3
- 108010007622 LDL Lipoproteins Proteins 0.000 description 3
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- 208000017170 Lipid metabolism disease Diseases 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
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- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- XRHSGPZKFZCFQU-ZFNKBKEPSA-N ethyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methylamino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylate;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 XRHSGPZKFZCFQU-ZFNKBKEPSA-N 0.000 description 3
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
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- 238000002844 melting Methods 0.000 description 3
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
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- 239000003826 tablet Substances 0.000 description 3
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- QOTDBJKZKHHPCY-SCZZXKLOSA-N (2r,4s)-4-amino-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylic acid Chemical compound FC(F)(F)C1=CC=C2N(C(O)=O)[C@H](CC)C[C@H](N)C2=C1 QOTDBJKZKHHPCY-SCZZXKLOSA-N 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 2
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
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- 125000000217 alkyl group Chemical group 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
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- FIBLYQZJDNLKSS-UHFFFAOYSA-N ethyl 2-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OCC)C(C(F)(F)F)CCC2=C1 FIBLYQZJDNLKSS-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (15)
- -21- 011494 CLAIMS 1. 4-(3,5-Bis-trifluoromethylbenzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl acid ethyl ester, 4-toluene-sulfonate.
- 2. The stereoisomer (-)-(2R,4S)-4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl acid ethyl ester or salts thereof.
- 3. The stereoisomer as recited in claim 2 wherein the sait is the 4-toluene-sulfonate.
- 4. The (-)di-p-toluoyl-L-tartaric acid sait of c/s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
- 5. The (-)di-benzoyl-L-tartrate sait ofc/s-4-amino-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1 -carboxylic acid ethyl ester.
- 6. (-) (2R,4S)- 4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or salts thereof.
- 7. The stereoisomer as recited in claim 6 wherein the sait is the (-)di-benzoyl-L- 15 tartrate sait.
- 8. The stereoisomer as recited in claim 6 wherein the sait is the (-)di-p-toluoyl-L-tartaric acid sait.
- 9. A process for preparing (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- 20 carboxylic acid ethyl ester comprising combining (-)-(2R,4S)-4-(3,5-bis- trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, tosylate sait, sodium carbonate and methyl chloroformatein tetrahydrofuran at a température of about 20°C to about 25°C.
- 10. A process for preparing (-)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2- 25 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester, 4- toluene-sulfonate comprising a. combining 4-amino-2-ethyl-6-trifiuoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylicacid ethyl ester and (-) dibenzoyl-L-tartaric acid or((-)di-p-toluoyl-L-tartaric acid toform the (-) dibenzoyl-L-tartaric acid sait or di-p-toluoyl-L-tartaric acid sait thereof; 30 b. combining the resulting sait, 1,2-dichloroethane and an aqueous base with 3,5-bis(trifluoromethyl)benzaldehyde, followed by the addition of sodiumtriacetoxyborohydride; and c. adding 4-toluene sulfonic acid monohydrate. -22- 011494
- 11. The process as recited in claim 10 wherein 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) dibenzoyl-L-tartaric acid(anhydrous) are combined.
- 12. A process for preparing c/'s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-5 quinoline-1-carboxylic acid ethyl ester comprising combining cis-4- benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium/carbonto form a slurry and heating the resulting slurry at a température of about 35°C toabout 60°C for about 30 minutes to about 3 hours. 10
- 13. A process for preparing cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin- 4-yl)-carbamic acid-R1-esterwherein R1 is benzyl.t-butyl or (CrC^alkyl comprising:combining vinyl-carbamic acid-R1, (1-benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine and 4-toluene-sulfonic acid monohydrate in toluene at a températureof about 50°C to about 90°C.
- 14. The process as recited in claim 13 with the additional step of combining the resulting cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R1-esterwith pyridine and ethyl chloroformate indichloromethane in to préparé cis-4-R1-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. 20
- 15. A process for preparing (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)- methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising a. combining vinyl-carbamic acid-R1, wherein R1 is benzyl, (1-benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine and 4-toluene-sulfonic acid 25 monohydrate in toluene at a température of about 50°C to about 90°C topréparé cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R1-ester wherein R1 is benzyl; b. combining the resulting cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R1-ester with pyridine and ethyl chloroformate in 30 dichloromethane to préparé cis-4-R1-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; c. combining cis-4-R1oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate inmethanol with palladium/carbon to form a slurry and heating the resulting - -23- 011494 slurry at a température of about 35°C to about 60°C for about 30 minutes toabout 3 hours to prépare 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; d. combining 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-5 carboxylic acid ethyl ester and (-)dibenzoyl-L-tartaric acid or (-)di-p-toluoyl-L- tartaric acid to form the (-)dibenzoyl-L-tartaric acid sait or (-)di-p-toluoyl-L-tartaric acid sait thereof; e. combining the resulting sait, 1,2-dichloroethane and an aqueous base with 3,5-bis(trifluoromethyl)benzaldehyde, followed by the addition of sodium 10 triacetoxyborohydride to form a product; f. combining said product and 4-toluene sulfonic acid monohydrate toprépare (-)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 4-toluene-sulfonate; and 15 g. combining (-)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, tosylatesait, sodium carbonate and methyl chloroformate in tetrahydrofuran at atempérature of about 20°C« to about 25°C.
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| HN2000000203A (es) * | 1999-11-30 | 2001-06-13 | Pfizer Prod Inc | Procedimiento para la obtencion de 1,2,3,4-tetrahidroquinolinas 4-carboxiamino-2- sustituidas. |
| MXPA04005864A (es) * | 2001-12-19 | 2004-10-29 | Atherogenics Inc | Derivados de charcona y su uso para tratar enfermedades. |
| WO2003053359A2 (fr) | 2001-12-19 | 2003-07-03 | Atherogenics, Inc. | 1,3-bis-(phenyl-substitue)-2-propyne-1-ones et leur utilisation pour le traitement d'affections |
| CA2480439C (fr) * | 2002-04-11 | 2012-08-21 | Roar Holding Llc | Procede ex vivo permettant de determiner l'activite de cetp et l'efficacite d'un traitement d'une cardiopathie |
| US7504508B2 (en) * | 2002-10-04 | 2009-03-17 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
| US20090181966A1 (en) * | 2002-10-04 | 2009-07-16 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
| MXPA05003456A (es) * | 2002-10-04 | 2005-07-05 | Millennium Pharm Inc | Antagonistas del receptor de pgd2 para el tratamiento de enfermedades inflamatorias. |
| US7223870B2 (en) * | 2002-11-01 | 2007-05-29 | Pfizer Inc. | Methods for preparing N-arylated oxazolidinones via a copper catalyzed cross coupling reaction |
| AU2003303239A1 (en) * | 2002-12-19 | 2004-07-14 | Atherogenics, Inc. | Process of making chalcone derivatives |
| ATE407670T1 (de) | 2002-12-20 | 2008-09-15 | Pfizer Prod Inc | Dosierungsform enthaltend einen cetp-hemmer und einen hmg-coa reduktase hemmer |
| US20040132771A1 (en) * | 2002-12-20 | 2004-07-08 | Pfizer Inc | Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors |
| EP1601655A2 (fr) * | 2003-03-04 | 2005-12-07 | Takasago International Corporation | Procede de production d'amines optiquement actives |
| CA2519458A1 (fr) * | 2003-03-17 | 2004-09-30 | Japan Tobacco Inc. | Procede pour accroitre la biodisponibilite orale de s- 2-( '1-(2-ethylbutyl)cyclohexyl!carbonyl!amino)phenyl!-2-methylpropanethioate |
| PL1603553T3 (pl) * | 2003-03-17 | 2012-04-30 | Japan Tobacco Inc | Kompozycje farmaceutyczne inhibitorów CETP |
| TWI494102B (zh) * | 2003-05-02 | 2015-08-01 | Japan Tobacco Inc | 包含ｓ-〔２（〔〔１-（２-乙基丁基）環己基〕羰基〕胺基）苯基〕２-甲基丙烷硫酯及ｈｍｇ輔酶ａ還原酶抑制劑之組合 |
| BRPI0414186A (pt) * | 2003-10-08 | 2006-10-31 | Lilly Co Eli | compostos, métodos de antagonizar a atividade de cetp, de tratar ou prevenir uma doença, de diminuir o colesterol ldl plasmático em um mamìmero, de tratar e/ou prevenir seqüelas patológicas, formulação farmacêutica, e, uso de um composto |
| UA90269C2 (ru) * | 2004-04-02 | 2010-04-26 | Мицубиси Танабе Фарма Корпорейшн | Тетрагидрохинолиновые производные и способ их получения |
| CA2570688A1 (fr) * | 2004-06-24 | 2006-02-02 | Eli Lilly And Company | Composes et procedes destines a traiter la dyslipidemie |
| DOP2005000123A (es) * | 2004-07-02 | 2011-07-15 | Merck Sharp & Dohme | Inhibidores de cetp |
| WO2006033001A1 (fr) * | 2004-09-23 | 2006-03-30 | Pfizer Products Inc. | Composes de quinoline |
| US7700774B2 (en) * | 2004-12-20 | 2010-04-20 | Dr. Reddy's Laboratories Ltd. | Heterocyclic compounds and their pharmaceutical compositions |
| AU2006216713A1 (en) * | 2005-02-24 | 2006-08-31 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
| TW200808731A (en) | 2006-03-30 | 2008-02-16 | Tanabe Seiyaku Co | A process for preparing tetrahydroquinoline derivatives |
| AR065670A1 (es) | 2007-03-09 | 2009-06-24 | Indigene Pharmaceuticals Inc | Combinacion de metformina r-(+) lipoato y agentes antihiperlipidemicos para el tratamiento de hiperglucemia diabetica y complicaciones diabeticas |
| CN101429160B (zh) * | 2007-11-06 | 2011-10-19 | 上海药明康德新药开发有限公司 | 一种1-r-4-氨基-1,2,3,4-四氢喹啉的合成方法 |
| TWI450896B (zh) * | 2009-06-30 | 2014-09-01 | Lilly Co Eli | 反式－４－〔〔（５ｓ）－５－〔〔〔３，５－雙（三氟甲基）苯基〕甲基〕（２－甲基－２ｈ－四唑－５－基）胺基〕－２，３，４，５－四氫－７，９－二甲基－１ｈ－１－苯并氮呯－１－基〕甲基〕－環己基羧酸 |
| MA71399A (fr) | 2022-07-05 | 2025-04-30 | Newamsterdam Pharma B.V. | Sels d'obicetrapib et leurs procédé de fabrication et leurs intermédiaires |
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|---|---|---|---|---|
| FR7870M (fr) * | 1968-11-08 | 1970-04-27 | ||
| US3971789A (en) | 1972-10-21 | 1976-07-27 | John Wyeth & Brother Limited | O-(4-Quinolylamino)benzamides |
| GB8432091D0 (en) | 1984-12-19 | 1985-01-30 | Wyeth John & Brother Ltd | 4-aminoquinoline derivatives |
| US4839368A (en) | 1986-05-02 | 1989-06-13 | Mochida Pharmaceutical Co., Ltd. | 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives |
| GB8804444D0 (en) | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| US5231102A (en) | 1989-03-08 | 1993-07-27 | Merck Sharp & Dohme, Ltd. | Tetrahydroquinoline derivatives useful for neurodegenerative disorders |
| PT100905A (pt) * | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem |
| US6140342A (en) | 1998-09-17 | 2000-10-31 | Pfizer Inc. | Oxy substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines |
| US6147089A (en) | 1998-09-17 | 2000-11-14 | Pfizer Inc. | Annulated 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines |
| US6197786B1 (en) * | 1998-09-17 | 2001-03-06 | Pfizer Inc | 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines |
| HN2000000203A (es) * | 1999-11-30 | 2001-06-13 | Pfizer Prod Inc | Procedimiento para la obtencion de 1,2,3,4-tetrahidroquinolinas 4-carboxiamino-2- sustituidas. |
-
2000
- 2000-09-14 HN HN2000000203A patent/HN2000000203A/es unknown
- 2000-09-27 PA PA20008503801A patent/PA8503801A1/es unknown
- 2000-09-29 OA OA1200000268A patent/OA11494A/en unknown
- 2000-10-10 US US09/684,830 patent/US6313142B1/en not_active Expired - Fee Related
- 2000-11-03 GT GT200000190A patent/GT200000190A/es unknown
- 2000-11-09 CO CO00085289A patent/CO5261552A1/es not_active Application Discontinuation
- 2000-11-13 AT AT00310064T patent/ATE315028T1/de not_active IP Right Cessation
- 2000-11-13 DE DE60025317T patent/DE60025317T2/de not_active Expired - Fee Related
- 2000-11-13 ES ES00310064T patent/ES2254109T3/es not_active Expired - Lifetime
- 2000-11-13 DK DK00310064T patent/DK1125929T3/da active
- 2000-11-13 EP EP00310064A patent/EP1125929B1/fr not_active Expired - Lifetime
- 2000-11-16 YU YU71500A patent/YU71500A/sh unknown
- 2000-11-17 IS IS5715A patent/IS5715A/is unknown
- 2000-11-22 HR HR20000804A patent/HRP20000804A2/hr not_active Application Discontinuation
- 2000-11-23 IL IL139849A patent/IL139849A/en not_active IP Right Cessation
- 2000-11-23 AU AU71789/00A patent/AU784694B2/en not_active Ceased
- 2000-11-24 TW TW089125066A patent/TW591016B/zh not_active IP Right Cessation
- 2000-11-24 SK SK1779-2000A patent/SK17792000A3/sk unknown
- 2000-11-27 ID IDP20001022D patent/ID28489A/id unknown
- 2000-11-27 CZ CZ20004407A patent/CZ20004407A3/cs unknown
- 2000-11-27 UY UY26451A patent/UY26451A1/es not_active Application Discontinuation
- 2000-11-27 ZA ZA200006947A patent/ZA200006947B/xx unknown
- 2000-11-28 SG SG200006869A patent/SG102603A1/en unknown
- 2000-11-28 PE PE2000001266A patent/PE20010913A1/es not_active Application Discontinuation
- 2000-11-28 CN CNB001283820A patent/CN1173953C/zh not_active Expired - Fee Related
- 2000-11-28 UA UA2000116782A patent/UA65615C2/uk unknown
- 2000-11-28 CA CA002327029A patent/CA2327029C/fr not_active Expired - Fee Related
- 2000-11-29 JP JP2000362153A patent/JP3579345B2/ja not_active Expired - Fee Related
- 2000-11-29 AR ARP000106287A patent/AR029775A1/es unknown
- 2000-11-29 HU HU0004747A patent/HUP0004747A3/hu unknown
- 2000-11-29 NZ NZ508509A patent/NZ508509A/en unknown
- 2000-11-29 DZ DZ000153A patent/DZ3079A1/fr active
- 2000-11-29 EA EA200001129A patent/EA003668B1/ru not_active IP Right Cessation
- 2000-11-29 KR KR10-2000-0071527A patent/KR100408177B1/ko not_active Expired - Fee Related
- 2000-11-29 TN TNTNSN00230A patent/TNSN00230A1/fr unknown
- 2000-11-29 MA MA26112A patent/MA25223A1/fr unknown
- 2000-11-29 NO NO20006039A patent/NO20006039L/no not_active Application Discontinuation
- 2000-11-30 GE GEAP20005651A patent/GEP20022798B/en unknown
- 2000-11-30 EE EEP200000659A patent/EE200000659A/xx unknown
- 2000-11-30 PL PL00344208A patent/PL344208A1/xx not_active Application Discontinuation
- 2000-11-30 BR BR0005636-7A patent/BR0005636A/pt not_active Application Discontinuation
- 2000-11-30 AP APAP/P/2000/002011A patent/AP2000002011A0/en unknown
- 2000-11-30 BG BG105009A patent/BG105009A/xx unknown
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2006
- 2006-03-01 CY CY20061100287T patent/CY1104989T1/el unknown
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