MXPA99004067A - Synthesis of benzo[f]quinolinones - Google Patents
Synthesis of benzo[f]quinolinonesInfo
- Publication number
- MXPA99004067A MXPA99004067A MXPA/A/1999/004067A MX9904067A MXPA99004067A MX PA99004067 A MXPA99004067 A MX PA99004067A MX 9904067 A MX9904067 A MX 9904067A MX PA99004067 A MXPA99004067 A MX PA99004067A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- compound
- formula
- alkyl
- isoquinolinyl
- Prior art date
Links
- 230000015572 biosynthetic process Effects 0.000 title description 15
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 230000002194 synthesizing Effects 0.000 title description 8
- YYWLMFCICDCVKT-UHFFFAOYSA-N 2H-benzo[f]quinolin-1-one Chemical class C1=CC=CC2=C3C(=O)CC=NC3=CC=C21 YYWLMFCICDCVKT-UHFFFAOYSA-N 0.000 title description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- -1 2-nitrophenyl Chemical group 0.000 claims description 310
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 177
- 150000001875 compounds Chemical class 0.000 claims description 115
- 125000000217 alkyl group Chemical group 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 23
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 23
- 239000011541 reaction mixture Substances 0.000 claims description 23
- WQOXQRCZOLPYPM-UHFFFAOYSA-N Dimethyl disulfide Chemical group CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- IHNINSVQYKIZIC-UHFFFAOYSA-N 2H-quinolin-3-one Chemical compound C1=CC=CC2=CC(=O)CN=C21 IHNINSVQYKIZIC-UHFFFAOYSA-N 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- 125000003282 alkyl amino group Chemical group 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000001589 carboacyl group Chemical group 0.000 claims description 15
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 15
- 238000007792 addition Methods 0.000 claims description 14
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 9
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 230000001603 reducing Effects 0.000 claims description 9
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 8
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 8
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 8
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 8
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000006604 di(C1-C3 alkyl) aminosulfonyl group Chemical group 0.000 claims description 7
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 claims description 7
- 239000003444 phase transfer catalyst Substances 0.000 claims description 7
- BLRPTPMANUNPDV-UHFFFAOYSA-N silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 7
- 229910000077 silane Inorganic materials 0.000 claims description 7
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000005977 Ethylene Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 150000001266 acyl halides Chemical class 0.000 claims description 6
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 6
- 239000012039 electrophile Substances 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 239000001184 potassium carbonate Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching Effects 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K Aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 claims description 5
- 238000006778 Pummerer Sulfoxide rearrangement reaction Methods 0.000 claims description 5
- 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 230000001035 methylating Effects 0.000 claims description 4
- DVSDBMFJEQPWNO-UHFFFAOYSA-N Methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 3
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 5
- 230000001590 oxidative Effects 0.000 claims 3
- 125000004429 atoms Chemical group 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims 1
- FQAWBGAIOYWONH-UHFFFAOYSA-N 3-chloroperoxybenzoic acid Chemical compound OC(=O)C1=CC=CC(OOCl)=C1 FQAWBGAIOYWONH-UHFFFAOYSA-N 0.000 claims 1
- 230000003197 catalytic Effects 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000003638 reducing agent Substances 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract 2
- YEXWPTQVHNJMNW-UHFFFAOYSA-N 2H-benzo[h]quinolin-3-one Chemical compound C1=CC=C2C=CC3=CC(=O)CN=C3C2=C1 YEXWPTQVHNJMNW-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- WALVUGBRQYPZFQ-UHFFFAOYSA-N 6-methyl-3,4-dihydro-1H-naphthalene-2-thione Chemical compound C1C(=S)CCC2=CC(C)=CC=C21 WALVUGBRQYPZFQ-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000008079 hexane Substances 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000005804 alkylation reaction Methods 0.000 description 9
- 238000004949 mass spectrometry Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000002808 molecular sieve Substances 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 230000002829 reduced Effects 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 150000003462 sulfoxides Chemical class 0.000 description 8
- NQOWVESUHAQWMO-UHFFFAOYSA-N 2-chloro-4-ethyl-1,3-benzothiazole Chemical group CCC1=CC=CC2=C1N=C(Cl)S2 NQOWVESUHAQWMO-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 238000005755 formation reaction Methods 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 7
- AHMLFHMRRBJCRM-UHFFFAOYSA-N 2-(4-methylsulfanylphenyl)acetic acid Chemical compound CSC1=CC=C(CC(O)=O)C=C1 AHMLFHMRRBJCRM-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 6
- BYHKDUFPSJWJDI-UHFFFAOYSA-N 6-bromo-3,4-dihydro-1H-naphthalen-2-one Chemical compound C1C(=O)CCC2=CC(Br)=CC=C21 BYHKDUFPSJWJDI-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 230000001808 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 229940043279 diisopropylamine Drugs 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001351 alkyl iodides Chemical class 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N methyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- AIOOZZBWFLYJPI-UHFFFAOYSA-N 1,3-bis(trimethylsilyloxy)propane-1,1-diol Chemical compound C[Si](C)(C)OCCC(O)(O)O[Si](C)(C)C AIOOZZBWFLYJPI-UHFFFAOYSA-N 0.000 description 3
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-Tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N Acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 150000002642 lithium compounds Chemical class 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-Propanediol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- RMCPATRJLNBKEZ-UHFFFAOYSA-N 2-(4-methylthiophen-2-yl)acetyl chloride Chemical compound CC1=CSC(CC(Cl)=O)=C1 RMCPATRJLNBKEZ-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N 2-Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N Bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 229910013131 LiN Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N Nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M Tetra-n-butylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N Trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- HPGGPRDJHPYFRM-UHFFFAOYSA-J Tin(IV) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
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- 150000001412 amines Chemical class 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
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- 238000004458 analytical method Methods 0.000 description 1
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- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 description 1
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- HCAUQPZEWLULFJ-UHFFFAOYSA-N benzo[f]quinoline Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=N1 HCAUQPZEWLULFJ-UHFFFAOYSA-N 0.000 description 1
- WZJYKHNJTSNBHV-UHFFFAOYSA-N benzo[h]quinoline Chemical compound C1=CN=C2C3=CC=CC=C3C=CC2=C1 WZJYKHNJTSNBHV-UHFFFAOYSA-N 0.000 description 1
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- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
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- HQABUPZFAYXKJW-UHFFFAOYSA-O butylazanium Chemical compound CCCC[NH3+] HQABUPZFAYXKJW-UHFFFAOYSA-O 0.000 description 1
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- 239000000460 chlorine Substances 0.000 description 1
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- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
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- 230000014509 gene expression Effects 0.000 description 1
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- DZVVLBSDPBGJEM-UHFFFAOYSA-N heptane;hydrate Chemical compound O.CCCCCCC DZVVLBSDPBGJEM-UHFFFAOYSA-N 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
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- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
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- 238000010583 slow cooling Methods 0.000 description 1
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Abstract
A process for preparing intermediates and benzoquinolin-3-one pharmaceuticals, such pharmaceuticals are effective in treating conditions consequent on 5&agr;-reductase.
Description
SYNTHESIS OF BENZO [F] QUINOLINONAS
DESCRIPTION OF THE INVENTION
The present invention pertains to the fields of organic chemistry, pharmaceutical chemistry and the manufacture of chemical products, and provides a convenient and economical process for preparing benzo-F] quinolinones which are useful as inhibitors of 5a-reductase, and provides intermediates for the preparation of such pharmaceutical products. A currently active pharmaceutical research field is the inhibition of 5-a-reductase, the enzyme that converts testosterone to dihydro-testosterone, a more powerful androgen. It has been shown that inhibitors of 5-a-reductase can block the formation of dihydrotestosterone and improve a number of highly undesirable conditions, including male pattern baldness and benign prosthetic hypertrophy. Audia et al. Have described a series of benzo [f] quinolinone compounds which are inhibitors of 5-a reductase. See U.S. Patents 5,239,075 and 5,541,190; I do not. Le t. , 44, 7001 (1993); J. REF .: 30137 Med. Chem. , 36, 421 (1993); and European Patent Publication 0703221. The present invention provides a novel process for preparing beta-reductase inhibitors which are effective inhibitors of 5a-reductase. The present process is more efficient than previous processes, is suitable for large-scale synthesis, and avoids the formation of unwanted byproducts. This invention also provides intermediates for the preparation of such pharmaceutical products. The present invention provides a novel process for preparing benzo [f] quinolinones, and provides intermediates useful in the preparation of benzoff] quinolinones. More specifically, the present invention is directed to a process for preparing a compound of the formula I
S-Rj
wherein R 1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanofeayl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1 isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3-1,2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, -naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [gl isoquinolinyl, 8-benz [g] isoquinolinyl, 5-lH-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1, 4-benzodioxinyl, 2-triazine , 2-benzoxazine, 4-benzoxacin, 2-purine or 8-purine; wherein the above R1 groups are unsubstituted or substituted with 1 to 3 functional groups selected from the group consisting of trifluoromethyl, tri-fluoroethoxy, alkyl of 1 to 4 carbon atoms, trifluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms, nitro, alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino, alkylamino of 1 to 3 carbon atoms diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms) carbon, or cycloalkylalkyl of 4 to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), alkanoylamino of 2 to 6 carbon atoms, benzoylamino, diphenylmethylamino (al 1 to 3 carbon atoms), aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminocarbonyl, halo- (C 1 -C 6 alkanoyl), aminosulfonyl, alkylaminosulfonyl from 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminosulfonyl, phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), (halo, C 1 -C 3 alkyl) or C 1 -C 3 alkoxy) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) amino) (alkyl of 1 to 3 carbon atoms).
One aspect of the invention comprises: the conversion of a ketone of the formula
where R is halogen, preferably bromine or iodine; to a protected ketal, preferably using trimethylsilyltrifluoromethanesulfonate and 1,3-bistrimethylsilyloxypropanediol in methylene chloride; reacting the protected ketal with a reactive alkyl lithium compound, such as, n-butyllithium and a sulfur transfer reagent, such as dimethyl disulfide, to provide an S-methylated ketal compound; and deprotecting the S-methylated ketal compound to provide a methyl-thiotetralone compound of the formula II.
II
Yet another aspect of the invention comprises the preparation of the compound of the formula II
II
by reacting a compound of the formula
Br
with lithium diisopropylamide, n-butyl lithium and dimethyl disulfide, or by conversion of a compound of the formula XI
XI
to an acid halide, for example, an acid chloride; by reacting the acid chloride with a Lewis acid and ethylene to provide the compound of formula II. According to still another aspect, the invention comprises the conversion of the compound of the formula II to a compound of the formula I. A preferred process of this type comprises the reaction of the compound of the formula II with (R) - (+) - phenylethylamine to provide a compound of formula III.
I I I
by reacting the compound of formula III with a strong lithium base to provide a lithium-enamine compound of formula IV
IV
methylating the resulting lithioenamine of formula IV to a compound of formula V, for example, by reacting the resulting lithioenamine with methyl iodide in an ether solvent to prepare the compound of formula V
V by reacting the compound of the formula V with an acyl halide or an acrylic acid anhydride to prepare a compound of the formula VI
SAW
quenching the reaction with base, and combining the residue comprising the compound of formula VI with an appropriate silane and trifluoroacetic acid in the absence of a solvent, to prepare a compound of formula VII
VII
by reacting the compound of the formula VII with a methyl halide, for example, methyl iodide in a reaction mixture comprising an organic solvent and a strong base, to provide an arylmethylsulfide compound of the formula VIII
VIII Oxidating the compound of the formula VIII to a sulfoxide compound of the formula IX
IX
reacting the sulfoxide compound of formula IX with an acylating agent to provide a rearrangement product of Pummerer; reacting the Pummerer rearrangement product with an electrophile selected from the group consisting of A-R1 where A is a leaving group and R1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3-1, 2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9- anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [g] isoquinolinyl, 8-benzfg] isoquinolinyl, 5-lH-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4, 5-b] pyridinyl, 4-10H- pyridazinof3, 2-b] -2-quinazolinyl, 2-1, 4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxacin, 2-purine or 8-purine; wherein the above R1 groups which are unsubstituted or substituted with 1 to 3 functional groups chosen from the group consisting of tri fluoromethyl, trifluoroethoxy, alkyl of 1 to 4 carbon atoms, trifluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms , nitro, alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino, alkylamino of 1 to 3 carbon atoms, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (alkyl), 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or cycloalkylalkyl of 4 to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo ) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), alkanoylamino of 2 to 6 carbon atoms, benzoylamino, diphenylmethylamino (alkyl of 1 to 3 carbon atoms), aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (alkyl) from 1 to 3 carbon atoms) aminocarbonyl, halo- (C 1-6 -alkanoyl), aminosulfonyl, alkylaminosulfonyl of 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminosulfonyl, phenyl (oxy) or thio) (alkyl of 1 to 3 carbon atoms), (halo, alkyl of 1 to 3 carbon atoms or C 1 -C 3 alkoxy) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) amino) (alkyl of 1 to 3 carbon atoms); in the presence of a phase transfer catalyst, a hydride reducing reagent and a base, for preparing a compound of the formula I. According to yet another aspect of the invention, the compound of the formula VIII
VIII
is prepared by the process comprising reacting a compound of formula XII
XII
with a reaction mixture comprising a base, such as lithium diisopropylamide or lithium hexamethyldisilazide, and an ether solvent to provide an amide-enolate solution;
reacting the amide-enolate solution with an alkyl lithium compound to provide a dianionic compound of the formula
reacting the dianionic compound with dimethyl disulfide to provide an arylmethyl sulfide compound of the formula VIII. The preferred intermediates of the present invention have the formulas II, VI, and VIII:
II VI VI I I
or the salts thereof. The starting materials for the compounds in the claimed process are either commercially available, known in the art, or can be prepared by methods known in the art, for example, see Audia et al. In U.S. Patent 5,239,075, issued August 24. of 1993 and European Patent Publication 0703221. Throughout this document, all temperatures will be described in degrees Celsius, and all expressions of concentration, percentage and proportion will be expressed in units of weight, except for mixtures of solvents, which will be described in units of volume, unless otherwise stated. References to the compounds herein include the pharmaceutically acceptable salts of such compounds, unless stated otherwise. The various positions on the benzo [f] quinoline ring are indicated below.
The spatial configuration of the group in 10b and the hydrogen atom in 4a are required. The reader will understand that many of the compounds may exist in two or more stereochemical forms, and that all stereochemical forms are included in the present invention. In some of the compounds prepared or described below, the simple enantiomers are prepared in pure form and are identified by the nomenclature (+) or (-). In other cases, the mixture of diastereoisomers is prepared. The group S-R1 occupies position 8. The terms "halogen" and "halo" include chlorine, bromine, fluorine and iodine. The various alkyl groups, such as alkyl of 1 to 4 carbon atoms and the like include groups such as methyl, ethyl, propyl, isopropyl, t-butyl, n-butyl and isobutyl. The alkenyl and alkynyl groups constitute linking groups which are bivalent and are linked to two other groups. For example, alkenyl of 2 to 4 carbon atoms includes ethenyl, 2-propenyl, 3-butenyl and 2-butenyl; and alkynyl of 2 to 4 carbon atoms includes, for example, ethynyl, 2-propynyl, 2-butynyl and iso-2-butynyl. The alkanoyl group of 1 to 6 carbon atoms includes groups such as formyl, acetyl, propionyl, isobutyryl 2-ethylpropionyl and hexanoyl.
The cycloalkyl group of 3 to 6 carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the cycloalkylalkyl group of 4 to 8 carbon atoms includes, for example, cyclopropylmethyl, cyclohexylethyl, cyclobutyl butyl and cyclohexylmethyl. Terms such as halo-alkanoyl of 1 to 6 carbon atoms, halophenyl or alkylphenyl of 1 to 3 carbon atoms refer to the indicated basic group having substituted on it 1, 2, or 3 halo or alkyl groups of 1 to 3 carbon atoms, as can be described in the individual case. The present process prepares compounds of the formula I having all the benzoff] quinoline nucleus, on the benzo ring of which is substituted a cyclic group R1 linked to the benzoquinoline through a sulfur linker. The R1 groups may be substituted with additional organic groups, and may possess as many as three of the indicated substituent groups. The multiple substituents may be the same or they may be different. Certain aspects of the process are preferred, and will be mentioned later specifically. It will be understood that the following aspects are each individually important, and also that preferred aspects can be combined to create additional, more limited or more extensive, preferred aspects.
Synthesis of 6-methylthio-2-tetralone
The initial material for the synthesis of 6-methylthio-2-tetralone is the acid. .4-methylthiophenylacetic acid. 4-Methylthiophenylacetic acid is commercially available (Aldrich Catalog Manual of Fine Chemicals 1994-5, page 1000) or can be prepared by methods well known to those of skill in the art. For example, 4-methylthiophenylacetic acid can be prepared via a Kindler modification or the illgerodt reaction. The 4-methylthioacetophenone is combined with the sulfur and a primary or secondary amine, preferably morpholine followed by hydrolysis (Scheme I). Alternatively, 4-methylthiophenylacetic acid can be prepared by hydrolysis of the corresponding nitrile or in two steps from benzyl alcohol (Scheme II).
SCHEME I
SCH,
SCHEME I I
6-Methylthio-2-tetralone is prepared by reaction of 4-methylthiophenylacetic acid with thionyl chloride, phosphorus trichloride, oxalyl chloride or phosphorus pentachloride, under conditions known to those skilled in the art, to provide the chloride of 4-methylthiophenacetyl (Scheme III). Preference is given to using thionyl chloride and N, N-dimethylformamide to provide 4-methylthiophenacetyl chloride. By a Friedel-Crafts acylation reaction of 4-methylthiophenacetyl chloride with ethylene gas in the presence of a Lewis acid catalyst and an inert solvent or substantially inert solvent or solvent mixture, ring closure is performed to provide the tetralone II.
SCHEME III
Suitable Lewis acid catalysts include AlBr3, A1C13, A1I3, GaCl3, FeCl3, SbCl5, ZrCl, SnCl4, BC13, BF3, SbCl3 and the like, preferably AlBr3. The solvents used for this reaction include carbon disulfide, methylene chloride, 1,2-dichloroethane nitromethane, nitrobenzene, and the like, preferably methylene chloride. Cyclization of thiomethyltetralone requires stringent conditions and is difficult to isolate. Improved yields of 6-methylthio-2-tetralone are achieved under stringent conditions and by using AlBr3 as Lewis acid. The cyclization is carried out at temperatures from about -78 ° C to about 25 ° C, preferably less than 0 ° C. The addition of ethylene is exothermic in nature and temperatures of about -78 ° C to about 30 ° C are employed using standard cooling procedures. Significantly improved yields of 6-methylthio-2-tetralone were observed after the simultaneous addition of 4-methylthiopheneacetylhalide and ethylene to methylene chloride and AlBr 3 at temperatures of about 5 ° C to about -15 ° C. Alternatively, the preparation of 6-methylthio-2-tetralone can be provided according to the following Scheme IV.
SCHEME IV
BuLi eSS e
where R is halogen, preferably bromine. The ketone group of the tetralone is first protected as a ketal. Preferably, the ketalization is provided by the slow addition of the 1,3-bis-trimethylsilyloxy-propanediol to a solution of trifluoromethanesulfonate in methylene chloride. Temperatures of about -70 ° C to about -60 ° C are employed using standard cooling procedures. For example, 6-bromo-2-tetralone is slowly added to a solution of 1,3-trimethylsilyloxy-propanediol and trifluoromethanesulfonate in methylene chloride to produce 6-bromo-2-tetralone-propylene-ketal.
The halogen-metal exchange is then provided by reaction of the protected ketal with a reactive organolithium compound, preferably n-butyllithium. Alkylation of the resulting lithium species with an appropriate sulfur transfer reagent, for example, a sulfenyl halide or dimethyl sulfide, provides a 6-methylthio-2-tetralone-propylene-ketal compound. Deprotection of the S-methylated ketal compound is provided by treatment with an aqueous acid, preferably hydrochloric acid, to provide the desired compound of 6-methylthio-2-tetralone.
Alkylation and Aza-nullification
A preliminary synthesis for the intermediate compound of formula VII
VII was shown in U.S. Patent No. 5,239,075 and in U.S. Application Serial No. 08 / 443,994, each of which is incorporated by reference herein. Yet another synthesis of the compounds of formula VII, of which this invention constitutes an improvement, was shown in European Patent Application No. 0564193. The methylthio group of the compound of formula VII is located at position 8. This process Preferred of the preparation of the compound of the formula VII, described below, can be carried out without purification or isolation of the intermediates. The 6-thiomethyl-2-tetralone is reacted with (R) - (+) - phenethylamine to prepare the intermediate of formula III
The reaction is conveniently carried out at elevated temperature, particularly the reflux temperature, in toluene in the presence of a strong acid such as p-toluenesulfonic acid. Water must be removed as it forms in this reaction, and the absence of water that forms is an indication of the completion of the reaction. A slight excess of phenethylamine should be used such as from about 1.05 to 1.10 equivalents. Alternatively, tetrahydrofuran can be used as the solvent, and it is particularly convenient in that case to use molecular sieves to dehydrate the reaction mixture, using at least twice the weight of the molecular sieves compared to the amount of water that will be released by the process. The above phenethylamino compound is lithiated with, for example, n-butyllithium or with lithium diisopropylamide to provide a compound of the formula IV
IV When the reaction is carried out, as is preferred, with lithium diisopropylamide, the best results are obtained if the lithium diisopropylamide is generated fresh from diisopropylamine and n-butyllithium immediately before use in the process. A substantial excess of approximately 15-25% of the lithium diisopropylamide should be used for better results. The reaction of lithium diisopropylamide is best carried out in tetrahydrofuran at a low temperature in the range from about -100 ° C to about 0 ° C, preferably from about -78 ° C to about -10 ° C. The phenethylamino compound does not need to be purified or isolated, but the first reaction mixture must be evaporated in vacuo and the residue collected in tetrahydrofuran. It is preferred to add the phenethylamino material, in solution, to a solution of lithium diisopropylamide in cold tetrahydrofuran; the opposite way of addition is operable but provides lower returns. In general, the reaction can be carried out in less than one hour. The lithium compound is difficult to isolate and purify, and therefore must be introduced into the process of the present invention as a solution in the lithiation reaction mixture.
Alkylation
The lithium compound is methylated, for example by reaction of the resulting lithioenamine with methyl iodide to provide the compound of the formula V
V
They can be employed to methylate the lithioenamine, in dimethyl sulfate, methyl bromide, methyl chloride, methyl iodide, and the like. It is advisable to use approximately 15-25% excess methyl iodide, and carry out the process in a solvent, preferably an ether-type solvent, such as diethyl ether, methyl tert-butyl ether or, preferably, tetrahydrofuran. The reaction is very rapid at low temperatures in the range of about -100 ° C to about -50 ° C, more preferably, about -80 ° C to about -60 ° C. Reaction times in the range of about a few minutes to about an hour are suitable, and a reaction time of 20 minutes is preferred. If the lithium compound is in the form of the reaction mixture from lithiation with lithium diisopropylamide, and the reaction mixture therefore contains residual diisopropylamine, that amine must be neutralized before methylation. More conveniently, the mixture of methyl iodide is allowed to warm to a temperature close to 0 °, and a sufficient amount of methanesulfonic acid is added to neutralize the diisopropylamine. Other strong acids can be used, but methanesulfonic acid is particularly convenient and preferred, because the resulting methanesulfonate salt of the resulting diisopropylamine is only slightly soluble and therefore can be easily removed by simple filtration or centrifugation.
Passage of Aza-Annulment
The reaction mixture comprising the compound of the formula V is combined with an acyl halide or an acrylic acid anhydride or acryloyl chloride, or the like, to initiate the aza-nullification reaction which forms the compound of the formula VI
SAW
It is better to generate the acrylic anhydride, the preferred reagent, immediately before use by reacting acryloyl chloride and acrylic acid, using triethylamine and a stabilizer, such as hydroquinone and butylated hydroxytoluene, in tetrahydrofuran. The aza-nullification is best carried out by the addition of the acrylic anhydride or the acryloyl chloride at a very low temperature, such as from about -100 ° C to about -70 ° C, and allowing the mixture to warm up very slowly with stirring at a temperature in the range of about -20 ° C to about 0 °, or even up to about 10-20 °. A period of 12 to 15 hours is a reasonable period of time to allow. Let the mixture warm up. When the reaction has gone to completion, as desired, the reaction is quenched by the addition of solid sodium bicarbonate. It is preferred to use from about 1.5 to about 4 equivalents of the base, more preferably about 2 equivalents. The base can be added as a solution, for example, in water or in an aqueous solvent such as water / dimethylaminopyridine, but it is preferred to add the base in solid form. The reaction mixture is stirred with the quenching base for a short period, and then the mixture is filtered, the volatile materials are removed, and the solvent can be replaced with an ethereal solvent, preferably diethyl ether, and the organic solution can be worked by washing with aqueous base and aqueous acid, and perhaps with additional purification steps such as washing with a saturated saline solution. If such working steps are used, the solution is then dehydrated and evaporated in vacuo to obtain the nonvolatile portions of the reaction mixture, which contain the final intermediate of formula VI. On the other hand, the residue of the quenched reaction mixture can be treated as such, if desired.
Reduction-Excision Step
The residue of the aza-nulling step is cooled, and a cooled mixture of an appropriate silane and trifluoroacetic acid is added. A suitable silane is a soluble silane, for example, a dialkylsilane or trialkylsilane, or the like. The addition should take place at a low temperature in the range of about -40 ° C to about 0 ° C, and no other solvent is used. A large amount of trifluoroacetic acid is used in the range of about 10 to 50 equivalents, more preferably about 20 to 30 equivalents. The preferred trialkylsilane is triethylsilane, although trimethylsilane, tripropylsilane and the like may also be used. A substantial excess of the trialkylsilane is used, in the range of about 50 to 20 equivalents, more preferably of about 7 to 15 equivalents. The mixture is stirred for about 10 to 20 hours while allowing it to slowly warm to about 30 ° C, and then the mixture is slowly heated to an elevated temperature, preferably at reflux temperature, and stirred at that temperature for a few hours. hours, such as about 2 to 6 hours to complete the formation of the compound of formula VII
VII Purification
The residue containing the product of formula VII can be dissolved, preferably in a haloalkane such as dichloromethane, washed with base, such as aqueous sodium bicarbonate and concentrated in vacuo. The residue can be washed thoroughly with, for example, an ether solvent, preferably diethyl ether, to obtain the purified compound of formula VII.
N-alkylation process
It is necessary in methylation synthesis nitrogen in position 4 on benzoff ring] quinoline. The American Patent 5, 239,075 shows such alkylation by reaction with an alkyl iodide in the presence of a strong base such as sodium hydride. Further alkylation is shown in EPO publication 0703221. N-methylation comprises the reaction of a compound of formula VII with a methyl halide, for example, methyl iodide in a reaction mixture comprising an organic solvent, for example a solvent selected from the group consisting of tetrahydrofuran, dimethoxyethane, diethoxyethane and methyl t-butyl ether, and a base, for example, aqueous sodium or potassium hydroxide, to provide a compound of formula VIII
VIII
This alkylation process allows an effective alkylation, under mild and easily controlled conditions, and allows the easy isolation of the products. The alkylation process is carried out in conventional chemical plant equipment, preferably at ambient pressure and at moderate temperatures. This is preferably started by suspending the. starting material of formula VII in the organic solvent at a temperature close to ambient, such as from about 0 ° C to about 50 ° C, more preferably from about 15 ° C to about 25 ° C. The most preferred organic solvent is tetrahydrofuran, and it is preferred to use about 5 to 15 liters of solvent per kilogram of starting material; the most preferred volume of solvent is about 10 liters per kilogram. The alkyl iodide is then added as a pure liquid. A substantial excess of alkyl iodide is preferably used, such as about 1.2 to 1.8 equivalents, based on the starting material, more preferably about 1.5 equivalents. The aqueous sodium or potassium hydroxide is then added, still at about room temperature, in an amount of about 1 to 4 liters per kilogram of starting material. The amount of aqueous base is somewhat dependent on the concentration of the base and the choice of sodium or potassium hydroxide; when the most preferred base, 50% sodium hydroxide, is used, the most preferred amount thereof is about 2 liters per kilogram of starting material. Subsequently the reaction mixture, consisting of the solid material suspended in two liquid phases, is heated to approximately 25-65 ° C with vigorous stirring, and the reaction is allowed to proceed at about constant temperature with constant stirring. The preferred reaction temperature is about 35 to 40 ° C. As the reaction proceeds to completion, the initial solid material and the alkyl iodide will dissolve and react, so that the disappearance of the solids is a crude indication of termination. The reaction can be followed by high pressure liquid chromatography on a C-18 silica gel column, eluting with acetonitrile: aqueous buffer 1: 1 (5% ammonium acetate) and verifying periodically at 220 nanometers. When the reaction has proceeded as much as desired until completion, the mixture is cooled to about room temperature and the aqueous layer is separated and discarded. The preferred method of purification and isolation proceeds by diluting the organic layer with water, and neutralizing it with aqueous mineral acid. Subsequently, the solution is distilled until the vapor temperature rises to approximately 69-80 ° C, eliminating most of the tetrahydrofuran. Slow cooling to about 5 ° C in a period of about 1 to 14 hours crystallizes the product, which needs only washing with water and drying to be ready for use as an intermediary or as a pharmaceutical product. The alkylation process provides the product in the same stereochemical manner as the starting material, in purity satisfactory to the pharmaceutical industry, and in yields of or greater than 90% when operating according to the preferred forms.
Thioalkylation
The compound of formula VIII can also be prepared via the thiomethylation of (+) - (4aR) - (lObR) - (lObR) -4-methyl-8-halo-1 Ob-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinoli-3-one. Preferably, the amide enolate is provided by the combination of (+) - (4aR) - (lObR) -4-methyl-8-bromo-10b-methyl-1, 2, 3, 4, a, 5, 6, 10b-octahydrobenzoff] quinolin-3-one with a lithium salt, for example, lithium chloride in an organic solvent, preferably tetrahydrofuran. A weak base, such as lithium hexamethyldisilazide (LiN (TMS) 2) is added slowly and the mixture is stirred at room temperature. Methyl lithium can be added to facilitate the deprotonation of hexamethyldisilazide. The reaction is then cooled to -70 ° C and an alkyl lithium compound is employed, for example n-butyl-lithium to aid in the formation of the dianion. The amide-enolate solution can also be provided by the sequential treatment of (+) - (4aR) - (1 ObR) - (lObR) -4-methyl-8-halo-10b-methyl-1, 2, 3 , 4, 4a, 5, 6, 1 Ob-octahydrobenzo [f] quinolin-3-one with a strong base, for example, lithium diisopropylamide in an ethereal solvent, preferably tetrahydrofuran, followed by the exchange of lithium-halogen with the n-butyl-li io, sec-butyl-lithium or the like, aged (Scheme V). The dianionic compound is then reacted with dimethyl sulfide to provide an arylmethyl sulfide compound of the formula VIII. A very high degree of chemoselectivity of dianion with dimethyl disulfide was observed.
E S BURNING V
VIII
er. where R is halogen, preferably bromine
Coupling E I ect rofí 1 i co
The electrophilic coupling of the substitute R to the sulfur group on the annulus [i; q r.cl ir.cr.a can be provided in accordance with the following schema VI.
SCHEME VI
vrp IX
where R- is as defined above in the formula? . The . { +) - (4aR) - (lObR) - -methi -8-methyl-1-io-10b-metii-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzoJf] quinolin-3-one is oxidized to a sulfoxide compound. M-chloroperoxybenzoic acid is a preferred oxidizing agent. With or without isolation, the sulphoxid compound is subjected to a Pummerer reaction as shown by Young et al., Tetrahedron l.ett. 25, ~ O, (1934), such that the sulfoxide is reacted with an acylating agent, such as, trifluoroacetic anhydride to provide a trifluoroacetyloxymethylene sulfide compound. The trifluoroacetyloxymethylene sulfide compound is reacted with an electrophilic reagent, a hydride reducing reagent, such as sodium borohydride, potassium borohydride, lithium borohydride or the like, and a base, preferably a hydroxide or carbonate, more preferably, potassium carbonate, to prepare a compound of the formula X. For purposes of this reaction, suitable acylating agents include acyl halides such as acetyl chloride, sulfonic acid halides, reactive anhydrides, such as trichloroacetic anhydride, anhydride phosphoric acid, sulfonic acid anhydride and similar agents capable of producing a Pummerer rearrangement product. By methods known in the art, the electrophilic reagent is replaced with a leaving group, such as a halogen, sulfate, sulfonate or the like. The electrophilic reagent is then coupled to the sulfur on the benzo [f] quinolinone ring. A preferred electrophilic reagent is 2-chloro-4-ethylbenzothiazole and this reagent is coupled to the compound of the formula X to provide the (+) - (4aR) - (lObR) -4-methyl-8- (4-ethyl2- benzothiazolylthio-1-methyl-1, 2, 3, 4, 4a, 5 ^ 6 ^ 10 -octahydrobenzoff] quinolin-3-one Preferably, a catalyst, for example tetrabutylammonium acid sulfate, is used to direct the coupling of Trifluoroacetyloxymethylene sulfide with the electrophilic reagent Sodium borohydride has been found to induce the reduction of the trifluoroacetyloxymethylene sulfide compound.Furthermore, formaldehyde is generated in itself, which is environmentally and pharmaceutically unacceptable. formaldehyde to methanol as the former is formed.Also, according to the present process, the disulfides that are formed from the oxidation with air are reduced in. This process step allows the initial materials to be more completely used. The rigorous exclusion of oxygen, or impurities that promote oxidation, is unnecessary. The addition of base to the mixture is not essential to promote the coupling. However, the decomposition of borohydride is delayed, and the speed of the relative coupling is accelerated, with the base added.
The following preparations further illustrate the present inventive process. The preparations are not intended to be limiting for the scope of the invention in any aspect, and should not be considered as such. Unless stated otherwise, the initial materials were obtained from commercial suppliers and used without further purification. Toluene, dimethylformamide and methylene chloride were stored on 4Á molecular sieves. The tetrahydrofuran was distilled from sodium cetyl benzophenone. The reactions using the organometallic reagents were run under a nitrogen atmosphere. The reactions were checked periodically by high pressure liquid chromatography using the compositions specified below. Thin layer chromatography was performed using Merck 60 silica gel plates with a fluorescent indicator (F254). The 1H and 13C NMR spectra were recorded on a General Electric QE or Bruker spectrophotometer at 300 MHz at room temperature using CDC13 as solvent, unless otherwise specified. The chemical shifts of nuclear magnetic resonance (NMR) were recorded in ppm with solvent as the internal standard in the scale d and the J values are in Hertz. The IR, UV and mass spectrometry (MS) analyzes were carried out by the Eli Lilly Physical Chemistry Laboratory. Conditions of high pressure liquid chromatography: Hitachi Intelligent Pump model L-6200A with a D-2500 chromatointegrator. Column Zorbax RX C-18 25 cm CH3CN / H20 60:40, 1.0 ml / minute, 275 nm, Injection - 10 μl. Gas chromatography (GC) conditions: HP 5890A GC with DB1 column of 0.25 μ x 25 m; injection temperature 300 ° C; detection at 300 ° C (FID); column at 5 ° C (5 minutes), 18 ml / minute at 250 ° C, then at 250 ° C for 20 minutes. The terms "NMR", "MS" "IR" and / or "GC" indicate that the spectrum of the product was analyzed and was consistent with the desired structure.
Preparation 1
Propylene-ketal of 6-bromo-2-tetralone
The 1,3-bis-trimethylsilyloxypropanediol (38.5 grams, 175 mmol, prepared from 1,3-propanediol, triethylamine and chlorotrimethylsilane in tetrahydrofuran) was slowly added to a stirred solution of trimethylsilyl trifluoromethanesulfonate (0.5 ml, 2.6 mmol) in Methylene chloride (100 ml, -70 ° C), maintaining the reaction temperature between -70 ° C and -60 ° C. The solution was allowed to stir for 10 minutes at -70 ° C. A solution of 6-bromo-2-tetralone (35.5 grams, 158 mmol) in methylene chloride (100 ml) was added slowly over a period of 10 minutes. The resulting reaction mixture was allowed to warm slowly to 15 ° C in 15 hours, after which thin layer chromatography (diethyl ether: hexanes 55:45) and high pressure liquid chromatography showed complete consumption of the initial tetralone. The reaction was quenched with saturated sodium bicarbonate (200 ml) and the layers separated. The aqueous layer was extracted with methylene chloride (50 ml). The combined methylene chloride solution was washed with (200 mL) of brine, dried with sodium sulfate and concentrated under reduced pressure to provide a golden residue. This was filtered through 300 grams of silica gel and eluted with hexanes / ethyl acetate 3: 1. The filtrate was concentrated under reduced pressure and the product was recrystallized from hexanes to obtain 33.5 grams (75% yield) of the propylene ketal of 6-bromo-2-tetralone as white crystals (NMR, MS). Calculated for C? H? 502Br: C, 55.14; H, 5.34. Found C, 55.05; H, 5.52.
Preparation 2
Propylene-ketal of 6-methylthio-2-tetralone.
To a stirring solution of the propylene ketal of 6-bromo-2-tetralone (0.511 grams 1.81 mmol) in tetrahydrofuran (5 ml, -75 ° C), 2.5 M n-butyl lithium (0.76 g) was added dropwise. mi, 1.90 mmol) while maintaining the temperature between -73 ° C and -70 ° C. The resulting solution was allowed to stir at -70 ° C for 15 minutes or until more initial material was no longer evident by thin layer chromatography (hexanes / ethyl acetate 70:30) after quenching an aliquot of the reaction mixture with benzaldehyde After 15 minutes, dimethyl disulfide (0.18 ml, 2.00 mmol) was added dropwise at -75 ° C. After stirring at -75 ° C for 20 minutes, the reaction was diluted with ethyl acetate (25 ml) and quenched with saturated ammonium chloride (10 ml). The organic layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography on silica gel (50 grams), eluted with hexanes / ethyl acetate 3: 1 to obtain 0.39 grams (87%) of the propylene ketal of 6-methylthio-2-tetralone as a clear viscous oil (IR, NMR, MS). Calculated for C? H18025: C, 67.17; H, 7.25. Found C, 67.04; H, 7.20.
Preparation 3
6-methylthio-2-tetralone
A solution of the propylene ketal of 6-methylthio-2-tetralone (29.7 grams, 118 mmol) in tetrahydrofuran (50 mL) was treated with 6N hydrochloric acid (9 mL, 54 mmol) and stirred at room temperature for 3 hours. hours or until thin layer chromatography (methylene chloride / hexanes 80:20) indicated the complete consumption of the initial material. The reaction was diluted with ethyl acetate (60 ml) and saturated aqueous sodium bicarbonate (110 ml). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 ml). The combined organic solution was stirred with brine (100 mL), dried with sodium sulfate, and concentrated under reduced pressure to obtain an off white solid. The crude product was purified by flash chromatography on silica gel (400 grams) and eluted with hexanes / ethyl acetate 5: 1 to obtain 19.5 grams (85%) of the 6-methylthio-2-tetralone as a white solid ( IR, NMR, MS). Calculated for CnH? 0S: C, 68.71; H, 6.29. Found C, 68.60; H, 6.31.
Preparation 4
6-methylthio-2-tetralone
A solution of 4-methylthiophenylacetic acid (10 grams, 54.8 mmol) and dimethylformamide (0.1 grams, 1.37 mmol) in methylene chloride (50 ml) at 35 ° C was treated with thionyl chloride (4.4 ml, 60.25 mmol). The solution was maintained at 35 ° C for 30 minutes, after which the solvent was removed by distillation under reduced pressure and replaced with fresh methylene chloride (50 ml). The solution of acid chloride and ethylene (4.6 grams, 164 mmol) was introduced simultaneously in 25 minutes to a stirred mixture of aluminum bromide (36.5 grams, 137 mmol) in methylene chloride (450 ml) at -15 to -10. ° C. The resulting reaction mixture was stirred for 2.5 hours at -10 to 0 ° C. 200 ml of water (temperature <25 ° C) was slowly added and the layers separated. The organic layer was washed successively with 5% sodium bicarbonate (200 ml) and brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure to produce a dark colored oil. The oil was dissolved in alcohol 3A (12 mL) and treated with a solution of sodium bisulfite (22.8 grams) in water (40 mL) and alcohol 3A (12 mL). After 30 minutes at 20 ° C and 1 hour at 0 ° C, the precipitated bisulfite addition complex was filtered, washed with cold 3A alcohol (15 ml) and then ether (50 ml). The filtered solid was added to a mixture of ether (100 ml) and potassium carbonate (22.7 grams, 164 mmol), dissolved in 75 ml of water, and stirred vigorously at 22 ° C until the solid dissolved completely. The organic layer was separated, washed with 100 ml of 1N hydrochloric acid, then with 200 ml of water, dried over sodium sulfate and concentrated under reduced pressure to yield 5.8 grams (48%) of the 6-methylthio- 2-tetralone as a beige solid (88% purity by high pressure liquid chromatography.
Preparation 5
(+) - (4aR) - (lObR) -8-methylthio-lOb-methyl-1, 2, 3, 4, 4a, 5, 6, 1 Ob-octahydrobenzo [f-quinolin-3-one.
A solution of 6-methylthio-2-tetralone (1 gram, 5.2 mmol, 1 equivalent) in 18 ml of anhydrous toluene was treated with (R) - (+) - phenethylamine (0.72 ml, 5.7 mmol, 1.1 equivalent) and p-TsOH (6 mg). The solution was degassed 3 times with light vacuum / nitrogen and a positive nitrogen pressure was maintained. The solution was heated to reflux under Dean-Stark conditions to remove the water. The progress of imine formation was periodically verified by NMR. After 2.5 hours of reflux, the initial ketone could not be detected by XH NMR. The toluene was distilled in a light vacuum and under a nitrogen atmosphere, taking care not to expose the mixture to the air. Anhydrous tetrahydrofuran (14 mL) was added to obtain a clear purple solution which was maintained at -70 ° C under nitrogen atmosphere. Lithium diisopropylamide was generated by dropwise addition of 2.5 M hexanes solution of n-butyllithium (2.4 mL, 6.0 mmol, 1.15 equivalent) to a solution of diisopropylamine (0.78 mL, 6.0 mmol, 1.15 equivalent) in tetrahydrofuran. my at -45 ° C. The temperature was maintained between -45 ° C and -30 ° C during the addition. After the addition, the solution was stirred for 10 minutes at -45 ° C. After cooling the lithium diisopropylamide solution to -75 ° C, the imine solution was added dropwise in 15 minutes by means of a cannula while maintaining the temperature between -70 ° C and -75 ° C. The resulting yellowish-orange solution was allowed to warm to -20 ° C in 20 minutes and then cooled again to -75 ° C. Iodomethane (0.36 ml, 5.8 mmol, 1.15 equivalents) was added between -75 ° C and -72 ° C. The solution was heated (with the aid of an acetone bath) in a period of 15 minutes at 0 ° C. After re-cooling to -5 ° C, methanesulfonic acid was added
(0.43 mL, 6.6 mmol, 1.3 equivalents) in 2 minutes between -5 ° C and 1 ° C. After 5 minutes at 0 ° C, a gray heterogeneous mixture resulted. The mixture was re-cooled to -75 ° C. A 1,125 M solution of tetrahydrofuran of acrylic anhydride (11 ml) was quickly added, 12.5 mmol, 2.4 equivalents). The mixture was kept in the cooling bath for 15 hours, during which time it was heated to 13 ° C. The reaction was allowed to warm to 15 ° C. 2 ml of water was added and the mixture was stirred while the mixture was warmed to room temperature. The solution was diluted with 50 ml of diethyl ether and washed successively with 20 ml of 1 N sodium hydroxide, 20 ml of 1N hydrochloric acid, 20 ml of water, 40 ml of saturated aqueous sodium bicarbonate, and 20 ml of brine. The sodium sulfate solution was dried, concentrated and subjected to flash chromatography on silica gel (120 grams), eluting with hexanes / ethyl acetate 70:30 to obtain 1.3 grams (69% yield) of (+) - (lObR) -4- (2- (R) -phenethyl) -8-methylthio-lOb-methyl- 1, 2, 3, 4, 6, 10b-hexahydrobenzo [f] quinolin-3-one (NMR).
A mixture of triethylsilane (12 ml, 75 mmol) and tifluoroacetic acid (14.5 ml, 188 mmol) was pre-cooled to -15 ° C under nitrogen atmosphere and added to the (+) - (10BR) -4- (2- (R) -phenethyl) -8-methylthio-lOb-methyl-l, 2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one (2.76 grams, 7.6 mmol) precooled in a -15 bath ° C. the mixture was stirred for 15 hours, during which time it was heated to 13 ° C. Thin layer chromatography (hexanes / ethyl acetate 70:30) and high pressure liquid chromatography showed complete disappearance of (+) - (lObR) -4- (2- (R) -phenethyl) -8-methylthio- 10b-methyl-l, 2, 3,4,6, 10b-hexahydrobenzo [f] quinolin-3-one and the appearance of a new product, indicating complete reduction of the double bond. The mixture was then heated to reflux for 2 hours to remove the chiral auxiliary. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in methylene chloride (50 ml) and washed twice with 35 ml of saturated sodium bicarbonate solution and 50 ml of brine. The crude product dried with sodium sulfate and concentrated was purified by flash chromatography on silica gel (100 grams), eluting first with hexanes / ethyl acetate 3: 1 to remove the triethylsilane and then with 14% methanol in methylene chloride. with 1% acetic acid to obtain a foamy solid. Recrystallization from hot ethyl acetate gave 1.6 grams (82%) of the (+) - (4aR) - (10BR) -8-methylthio-10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (92% ee, IR, NMR, MS).
Calculated for C15H? 9NOS: C, 68.93; H, 7.33. Found C, 69.05; H, 7.44.
Preparation 6
(+) - (4aR) - (lObR) -4-methyl-8-methylthio-10b-methyl-1,2, 3, 4, 4a, 5, 6, 1 Ob-octahydrobenzo [f] quinolin-3-one .
(+) - (4aR) - (lObR) -8-methylthio-10b-methyl-1,2,3,4, 4a, 5, 6, 1 Ob-octahydrobenzo [f] quinolin-3-one
(0.423 grams, 1.62 mmol, 1.0 equivalents) was treated with potassium t-butoxide (1.86 mL as a 1.0 M solution in tetrahydrofuran, 1.15 equivalents) in dimethylformamide (1.6 mL) at about 0 ° C. After stirring 5 minutes, methyl iodide (0.116 ml, 1.15 equivalents) was added and the mixture was allowed to stir for 2 hours at 0 ° C. The mixture was then treated with about 100 mg of acetic acid and the solvents were removed in a stream of nitrogen. The solid was dissolved in about 50 ml of methylene chloride and washed twice with water. The extracts were dried (4 molecular sieves) and filtered on silica gel (2 grams, washed with ethyl acetate containing 2% methanol). The solid from the evaporation of the methylene chloride extracts was subjected to chromatography on silica gel with methylene chloride, ethyl acetate and methanol (50: 50: 1) as the eluent. (GC).
Preparation 7
(+) - (4aR) - (lObR) -4-methyl-8-methylthio-lOb-methyl-1,2, 3, 4, 4a, 5, 6,1 Ob-octahydrobenzo [f] quinolin-3-one .
(+) - (4aR) - (lObR) -4-methyl-8-bromo-10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (20.0 grams, 64.9 mmol, in 150 ml of tetrahydrofuran) was added to a freshly prepared solution of lithium diisopropylamide in 500 ml of tetrahydrofuran at -20 ° C. After standing 90 minutes in an ice bath, the resulting amide-enolate solution was cooled to -70 ° C and added via a cannula in a period of 10 minutes to a freshly mixed solution of n-butyl-lithium (60.0 ml = 2.54 M in hexane, 152 mmol, 2.34 equivalents) at -72 to -75 ° C in 300 ml of tetrahydrofuran. The homogeneous solution was allowed to stir at about -75 ° C for 45 minutes and quenched with dimethyl disulfide (11.0 ml, 123 mmol, 1.9 equivalents) at about -75 ° C. After 30 minutes at -75 ° C, the mixture was treated with acetic acid (18 ml) and all volatile materials were removed in vacuo. The resulting white solid was treated with 300 ml of heptane-water (1: 1 v / v) and the pH was adjusted to 3 with 1 N hydrogen sulfate. The two-phase mixture was filtered and the wet filter cake was washed with water. 1% aqueous sodium bicarbonate (2 portions of 50 ml) and 200 ml of water. The material was dried at 50 ° C under vacuum to provide (+) - (4aR) - (lObR) -4-methyl-8-methylthio-10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-Octahydrobenzo [f] quinolin-3-one (IR, NMR, MS). Calculated for C? 6H2? NOS: C, 69.77; H, 7.69; N, 5.09. Found C, 69.70; H, 7.62; N, 5.06.
Preparation 8
(+) - (4aR) - (lObR) -4-met i 1-8-met il thio-1 Ob-met il- 1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one
Lithium chloride (1.80 grams, 2.46 mmol, 10 equivalents) was weighed quickly and placed in a 500 ml flask equipped with mechanical stirring, pressure equalization addition funnel, thermocouple, septum for injection and nitrogen inlet. (+) - (4aR) - (lObR) -4-methyl-8-bromo-10b-methyl-1,2,3,4, 4a, 5, 6, 1 Ob-octahydrobenzo [f] quinolin-3 ona (13.09 grams, 2.46 mmol, 1.0 equivalents) and 100 ml of anhydrous tetrahydrofuran were added and stirred until dissolved (10-15 minutes). Subsequently, 46.71 ml of lithium hexamethyldisilazide (LiN (TMS) 2 ^ 46.71 mmol, 1.1 equivalents) were added in tetrahydrofuran, by means of a syringe in a period of 40 minutes (exotherm of 1 degree). This resulted in a light yellow solution and was stirred at room temperature for 1 hour. Methyllithium (1.4 M in diethyl ether, 33.36 mL, 46.71 mmol, 1.1 equivalents) was added dropwise by syringe over a period of 50 minutes. Gas evolution was observed and the reaction was exothermic from 23 to 26 degrees. The exothermic reaction was controlled using standard procedures. The reaction mixture was allowed to stir at room temperature for 45 minutes and then cooled to -70 ° C. The n-butyllithium (1.6 M in hexane, 29.2 ml, 46.71 mmol, 1.1 equivalents) by means of a syringe in 25 minutes, while the reaction temperature was maintained at -71 / -70 ° C. The remaining yellow solution was maintained at -70 ° C and stirred for 35 minutes. High pressure liquid chromatography showed almost complete formation of the dianion after 15 minutes. Dimethyl disulfide (4.0 grams, 42.46 mmol, 1.0 equivalents) was dissolved in 25 ml of tetrahydrofuran and added in 50 minutes. The mixture was stirred for 30 minutes (-70 ° C). High pressure liquid chromatography showed that the reaction was complete after 10 minutes. The mixture was quenched with 1 N hydrochloric acid (100 ml, -70 ° C). The reaction was warmed to room temperature and the aqueous layer was extracted with 200 ml of methyl t-butyl ether. The organic layers were combined and washed with 50 ml of brine. The organic layers were dried over magnesium sulfate and filtered and concentrated on a rotary evaporator Rotovap ™ at 35 ° C and domestic vacuum. A white solid formed as the volume decreased. Organic materials were concentrated from 550 ml to approximately 30-40 ml of a white suspension. The suspension was stirred at room temperature for a few hours followed by filtration with small portions of methyl t-butyl ether until the washings were colorless. The white solid was dried and yielded 7.73 grams (66%) of the (+) - (4aR) - (1 ObR) -4-methyl-8-methylthio-10b-methyl- 1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one.
Preparation 9
(+) - (4aR) - (lObR) -4-methy1-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5,6,1 Ob-octahydrobenzo [f] quinolin-3-one.
A solution of the meta-chloroperoxybenzoic acid (potency of about 56%, 6.32 grams as a solution in methylene chloride) was added to a mixture of (+) - (4aR) - (1 ObR) -4-met il- 8- methylthio-10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (5.50 grams in 110 ml of methylene chloride) and sodium bicarbonate (9.4 grams) in 110 ml of water) at 0 to -1 ° C in about an hour. After 8 hours, the layers were separated and the organic extracts were washed twice with aqueous 1% sodium bicarbonate solution, dried (4A molecular sieves) and evaporated to a total weight of 5.90 grams. A portion (2.91 grams) of this unpurified sulfoxide in 10 ml of toluene was treated with 2.20 ml of tifluoroacetic anhydride at 5-10 ° C. After 30 minutes, the XH-NMR analysis of an aliquot of 0.50 ml showed nothing of the initial sulfoxide (singlet of ArSOCH absent at d = 2.25 ppm) and the exclusive formation of the Pummerer product (ArSCH20C0CF3, singlet at d = 5.31 ppm). The reaction mixture was subjected to vacuum (5-10 torr) for 30 minutes, after which the contents were added to a stirred mixture (under nitrogen atmosphere) of 20 ml of water, 0.1 gram of tetrahydric acid sulfate. n-butylammonium, and 7.1 ml of water-boron hydride (12% by weight of sodium borohydride in 14 N sodium hydroxide) at 5-10 ° C in 20 minutes. After an additional 20 minutes, 3.00 grams of 2-chloro-4-ethylbenzothiazole were added with an additional 9.5 ml of toluene-d8 and another portion of more than 0.50 grams of tetra-n-butylammonium acid sulfate. The reaction was stirred at 37-39 ° C during which 4 0.25 ml portions were removed for the 1 H NMR direct assay and high pressure liquid chromatography for analysis of product conversion and distribution. After 26 hours the uppermost layer (toluene containing (+) - (4aR) - (lObR) -4-methy1-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one and excess 2-chloro-4-ethylbenzothiazole) of the three phase mixture was separated and diluted with 25 ml of methylene chloride. This organic layer was washed with 1N aqueous sulfuric acid, 5% aqueous sodium bicarbonate, dried with 4A molecular sieves, and concentrated in vacuo to 5.24 grams. The resulting solid was digested with hot methyl t-butyl ether (30 ml), after which it was concentrated in vacuo at 20 ml and then cooled to 0 ° C. The mixture was filtered and the white solid was dried to give 2.92 grams of (+) - (4aR) - (lObR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -lOb-methyl-1,2, 3, 4, 4a, 5, 6.1 Ob-octahydrobenzo [f] quinolin-3-one (IR, NMR, MS). Calculated for C24H26N2OS2: C, 67.93; H, 6.16; N, 6.83; S, 15.08. Found C, 68.21, H, 6.20; N, 6.63; S, 15.17.
Preparation 10
(+) - (4aR) - (lObR) -4-methy1-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [ f] quinolin-3-one.
A solution of the meta-chloroperoxybenzoic acid (35.2 mmol in 100 ml of methylene chloride) was added to the (+) - (4aR) - (lObR) -methyl-8-methylthio-10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (10.0 grams, 98% purity by standard weighted power test, 35.6 mmol) in a biphasic mixture of methylene chloride (200 ml) and aqueous sodium bicarbonate (8.90 grams in 89 ml of water) at -2 to 0 ° C in a period of 1 hour. The layers were separated and the methylene chloride layers were washed once with sodium metabisulfite (1.00 grams in 25 ml) and three times with sodium bicarbonate (1.00 grams in 100 ml). The dry methylene chloride extract
(4Á molecular sieves) was concentrated to approximately 20 ml and diluted with 100 ml of toluene. The mixture was then concentrated in vacuo at 30-35 ° C. This process was repeated twice with fresh toluene (100 ml portions each) after which the sulfoxide (usually crystalline) was diluted with 100 ml of toluene. The mixture was then treated with trifluoroacetic anhydride (7.30 ml) in 10 minutes at 0-10 ° C. After 30 minutes at 0 ° C, this solution was subjected to vacuum (< 10 torr) for 30 minutes and added in 30 minutes to a degassed (nitrogen) mixture of potassium carbonate (41 grams), 2.88 grams of borohydride of sodium, 2.00 grams of tetra-n-butylammonium acid sulfate and 8.20 grams of 2-chloro-4-ethylbenzothiazole (at a purity of 96.5% dissolved in 5 ml of toluene) and 87 ml of water at 0-5 ° C . This mixture was heated to 40 ° C in a period of one hour and then stirred at 40 ° C for 26 hours. The toluene layer was separated (while hot) and washed with 3 100 ml portions of water. The toluene layer was diluted with 125 ml of ethyl acetate and then washed in sequence with 3 portions of 200 ml of 0.25 N hydrochloric acid, 100 ml of 1% sodium hydrogen carbonate and 100 ml of saturated aqueous solution of chloride of sodium. The organic layer was dried (10 grams of molecular sieves of 4A), concentrated to a total volume of 25 ml and treated with 100 ml of methyl t-butyl ether (heated at reflux for 30 minutes then, 0 ° C by 1 hour) yielding (+) - (4aR) - (lObR) -4-methy1-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5, 6 , 10b-octahydrobenzo [f] quinolin-3-one.
Preparation 11
(+) - (4aR) - (lObR) -4-methi 1-8- (4-ethyl-2-benzothiazolylthio) -1 Ob-methyl-1, 2, 3, 4, 4a, 5, 6, 10b- octahydrobenzo [f] quinolin-3-one.
The anhydrous sulfoxide IX (purity of 96% by gas chromatography, 8.90 grams, corrected 29.4 mmol) as a suspension in toluene (89 ml) was treated dropwise with 5.2 ml of trifluoroacetic anhydride at 0-5 ° C in 20 minutes. (the dissolution occurs). After 30 minutes, the solution was added to a mixture of 32 grams of potassium carbonate, 45 ml of water, 2.25 grams of tetrabutylammonium acid sulfate, 1.0 grams of sodium borohydride, 2-chloro-4-ethylbenzothiazole (7.07 grams). , approximately 96.5% purity by gas chromatography), and 10 ml of toluene at about 5-15 ° C in 30 minutes. The biphasic mixture was then stirred for 20 hours at 43 ° C, after which a small amount of solid was filtered from the reaction mixture. The hot toluene layer was washed once with 400 ml of water (45 ° C) and then evaporated in vacuo yielding 13.86 grams of a white solid consisting mainly of the (+) - (4aR) - (lObR) -4 -methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one and 2-chloro-4 -ethylbenzothiazole. 13.0 grams of this mixture were treated with methyl t-butyl ether (50 ml at reflux then 0 ° C for 2 hours) yielding 11.05 grams of (+) - (4aR) - (lObR) -4-methyl-8- ( 4-ethyl-2-benzothiazolylthio) -10b-methyl- 1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (IR, NMR, MS). Calculated for C, 68.21; H, 6.20; N, 6.63. Found C, 68.29; H, 6.15, N, 6.67.
Preparation 12
(+) - (4aR) - (lObR) -4-methy1-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [ f] quinolin-3-one.
The meta-chloroperoxybenzoic acid (approximately 92 grams, power of approximately 50%, in 1.0 liter of methylene chloride) was added at 0 ° C to a solution of (+) - (4aR) - (lObR) -4-methyl- 8-methylthio) -lOb-methyl-1,2,3,4, 4a, 5, 6,1 Ob-octahydrobenzo [f] quinolin-3-one (79.5 grams, 92.9% strength, 0.269 moles) in 2.2 liters of methylene chloride. The progress of the reaction was checked periodically by high pressure liquid chromatography (240 nm) for the oxidation of (+) - (4aR) - (1 ObR) -4-methyl-8-methylthio-10b-methyl-1, 2, 3,, 4a, 5,6,10b-octahydrobenzoff] quinolin-3-one at a level less than 0.3% per area. The organic solution was stirred with a solution of sodium bisulfite (75 grams in 1 liter of deionized water). The organic layer was separated, and washed with 6% sodium bicarbonate solution (3 x 1 liter). The organic layer was dried over sodium sulfate and concentrated. 1 liter of toluene was added to the intermediate sulfoxide and this solution was concentrated in vacuo. This was repeated twice with fresh toluene (1.1 liter each) after which the sulfoxide was dissolved in 1.1 liter of toluene and cooled in an ice bath. 51 ml of trifluoroacetic anhydride was added dropwise to the sulfoxide at 0 ° C in 15 minutes. After 30 minutes of stirring at 0 ° C, the product of Pummerer (ArSCH2OCOCF3) was added via a cannula to a well-stirred mixture of 414 ml of deionized water, 319 grams of potassium carbonate, 15.2 grams of sodium borohydride. , 65.7 grams of 2-chloro-4-ethylbenzothiazole (purity of approximately 96.5%), 21.6 grams of tetrabutylammonium acid sulfate, and 170 ml of toluene at 10 ° C. The reaction was slowly heated to 42 ° C while the progress was monitored periodically by high pressure liquid chromatography. After 18 hours, an additional volume of 1.0 liter of toluene was added and the toluene layers were washed with deionized water (3 liter, 45 ° C). To the organic layer was added 1 liter of ethyl acetate, and then the organic layer was washed with 0.25 M hydrochloric acid solution (3 x 1 liter), 1 N sulfuric acid solution (3 x 1 liter), bicarbonate solution of sodium at 6% (1.5 liters), and saturated solution of sodium chloride (2 liters). The organic extracts were dried over 4Á molecular sieves (500 grams) and then concentrated. 400 ml of methyl t-butyl ether were added and the mixture was heated to reflux. After 30 minutes of refluxing, the mixture was cooled to 5 ° C. The suspension was filtered and washed with 100 ml of methyl t-butyl ether. The solution was filtered and the product was dried at 50 ° C at approximately 5 mm for 18 hours providing 90.1 grams (80%) of the (+) - (4aR) - (lObR) -4-methyl-8- (4- eti1-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5,6, 10b-octahydrobenzo [f] quinolin-3-one.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned ntion, is that which is clear from the present description of the ntion.
Claims (26)
1. A process for the preparation of a compound of the formula I wherein R 1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1 isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3- 1, 2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, -naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl , 5-lH-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1,4-benzodioxinyl, 2- triazine, 2-benzoxazine, 4-benzoxacin, 2-purine or 8-purine; wherein the above R1 groups "are unsubstituted or substituted with 1 to 3 functional groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, alkyl of 1 to 4 carbon atoms, tri fluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms , nitro, alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino , alkylamino of 1 to 3 carbon atoms diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 atoms) carbon, or cycloalkylalkyl of 4 to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo) (phenyl, phenoxy, phenylthio, phenylsufonyl or phenoxysulfonyl), alkanoylamino of 2 to 6 carbon atoms, benzoylamino, diphenylmethylamino (al 1 to 3 carbon atoms), aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminocarbonyl, halo- (C 1 -C 6 alkanoyl), aminosulfonyl, alkylaminosulfonyl from 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminosulfonyl, phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), (halo, C 1 -C 3 alkyl) or C 1 -C 3 alkoxy) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) carbon) amino) (alkyl of 1 to 3 carbon atoms); characterized the process because it comprises: the conversion of a ketone of the formula wherein R is halogen, to a protected ketal; the reaction of the protected ketal with a reactive alkyllithium compound and a sulfur transfer agent, to provide an S-methylated ketal compound; the deprotection of the S-methylated ketal compound to provide a methyl triotetralone compound of the formula II II by reacting the compound of the formula II with (R) - (+) - phenethylamine to provide a compound of the formula III III by reacting the compound of the formula III with a strong lithium base to provide a lithium-enamine compound of the formula IV IV methylating the resulting lithioenamine of formula IV to a compound of formula V H-: c c6H5 V by reacting the compound of the formula V with an acyl halide or an acrylic acid anhydride to prepare a compound of the formula VI SAW quenching the reaction with base, and combining the residue comprising the compound of formula VI with an appropriate silane and trifluoroacetic acid, in the absence of a solvent, to prepare a compound of formula VII VII 11 reacting the compound of the formula VII with a methyl halide in a reaction mixture comprising an organic solvent and a strong base, to provide an arylmethyl sulfide compound of the formula VIII VIII oxidizing the compound of the formula VIII to a sulfoxide compound of the formula IX IX by reacting the sulfoxide compound of formula IX with an acylating agent to provide a rearrangement product of Pummerer; reacting the Pummerer rearrangement product with an electrophile selected from the group consisting of A-R1, wherein A is a leaving group, in the presence of a phase transfer catalyst, and a hydride reducing reagent and a base, for prepare a compound of formula I.
2. A process for the preparation of the compound of formula II II characterized in that it comprises: the conversion of a ketone of the formula wherein R is halogen; to a protected ketal; the reaction of the protected ketal with a reactive alkyllithium compound and a sulfur transfer agent to provide an S-methylated ketal compound; deprotecting the S-methylated ketal compound to provide the methylthiotetralone compound of the formula II.
3. The process according to claim 2, characterized in that the sulfur transfer agent is dimethyl disulfide and the protected ketal is
4. A process for the preparation of a compound of formula II II characterized in that it comprises: the reaction of a compound of the formula with lithium diisopropylamide, n-butyl lithium and dimethyl disulfide.
5. A process for the preparation of the compound of formula II II characterized in that it comprises: the conversion of a compound of the formula XI XI to an acid halide; reacting the acid halide with a Lewis acid and ethylene to provide the compound of formula II.
6. The process according to claim 5, characterized in that the methylene chloride, the thionyl chloride and a catalytic amount of dimethylformamide are used to provide the acid halide, and the aluminum bromide is used as the Lewis acid.
7. The process according to any of claims 2, 3, 4, 5 or 6, characterized in that it further comprises the conversion of the compound of the formula II II to a compound of the formula I 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl and 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl , 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3-1, 2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-naphtho [2, 3 -d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [g] isoquinolinyl, 8-benzfg] isoquinolinyl, 5- lH-tetrazolyl, -quinazolinyl, 2-thiazolo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolini lo, 2-1, 4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4 -benzoxacin, 2-purine or 8-purine; wherein the above R1 groups are unsubstituted or substituted with 1 to 3 functional groups selected from the group consisting of trifluoromethyl, tri-fluoroethoxy, alkyl of 1 to 4 carbon atoms, trifluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms, nitro, alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino, alkylamino of 1 to 3 carbon atoms diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms) carbon, or cycloalkylalkyl of 4 to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), alkanoylamino from 2 to 6 carbon atoms, benzoylamino, diphenylmethylamino (alkyl) ilo of 1 to 3 carbon atoms), aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (C 1-3 alkyl) aminocarbonyl, halo- (C 1-6) alkanoyl, aminosulfonyl, alkylaminosulfonyl of 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminosulfonyl , phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), (halo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) amino) (alkyl of 1 to 3 carbon atoms).
8. The process according to any of claims 2, 3, 4, 5 or 6, characterized in that it further comprises the conversion of the compound of the formula II II a (+) - (4aR) - (lQbR) -4-methyl-β- (4-ethyl-2-benzothiazolylthio) -l Ob-methyl-1, 2,3,4,4a, 5,6,10b -octahydrobenzo [f] quinolin-3-one.
9. The process according to any of claims 2, 3, 4, 5, or 6, further characterized in that it comprises: the reaction of the compound of the formula II SCH: with (R) - (+) - phenethylamine to provide a compound of the formula III III by reacting the compound of formula III with a strong lithium base to provide a lithium-enamine compound of formula IV IV methylating the resulting lithioenamine of formula IV to a compound of formula V V by reacting the compound of the formula V with an acyl halide or an acrylic acid anhydride to prepare a compound of the formula VI VI quenching the reaction with base, and combining the residue comprising the compound of formula VI with an appropriate silane and trifluoroacetic acid in the absence of a solvent to prepare a compound of formula VII VII
10. The process according to claim 9, characterized in that it further comprises: the reaction of the compound of the formula VII with a methyl halide in a reaction mixture comprising an organic solvent and a strong base, to provide an arylmethyl sulfide compound of the formula VIII VIII oxidizing the compound of the formula VIII to a sulfoxide compound of the formula IX IX reacting the sulfoxide compound of formula IX with an acylating agent to provide a rearrangement product of Pummerer; reacting the rearrangement product of Pummerer with an electrophile selected from the group consisting of A-R1 wherein A is a leaving group and R1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl , 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl , 2-benzoxazolyl, 3-1, 2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, -2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl, 5-lH-tetrazolyl, 2-quinazolinyl, 2-t-azolo [4,5-b] pyridinyl 4-10H-pyridazino [3,2-b] -2 -quinazinyl, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxacin, 2-purine or 8-purine; wherein the above R1 groups - are unsubstituted or substituted with 1 to 3 functional groups selected from the group consisting of tri fluoromethyl, tri-fluoroethoxy, alkyl of 1 to 4 carbon atoms, trifluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms carbon, nitro, alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino, alkylamino of 1 to 3 carbon atoms diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) encyl (oxy or thio), di (alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6) carbon atoms, or cycloalkylalkyl of 4 to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo) (phenyl, phenoxy, phenylthio, phenylsufonyl or phenoxysulfonyl) , alkanoylamino of 2 to 6 carbon atoms, benzoylamino, diphenylmethylamino (a alkyl of 1 to 3 carbon atoms), aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminocarbonyl, halo- (C 1 -C 6 alkanoyl), aminosulfonyl, alkylaminosulfonyl from 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminosulfonyl, phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), (halo, C 1 -C 3 alkyl) or C 1 -C 3 alkoxy) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) amino) (alkyl of 1 to 3 carbon atoms), 'in the presence of a phase transfer catalyst, a hydride reducing reagent and a base, to prepare a compound of the formula I
11. A process for the preparation of a compound of the formula wherein R 1 represents 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphile, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3-1,2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, -naphtho [2,3-d] thiazolyl, 2-naphthoyl, 2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl, -lH-tetrazolyl, 2-quinazolinyl, 2-thiazoo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxacin, 2-purine or 8-purine; wherein the above R1 groups are unsubstituted or substituted with 1 to 3 functional groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, alkyl of 1 to 4 carbon atoms, trifluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms, nitro , alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino, alkylamino from 1 to 3 carbon atoms diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms) , or cycloalkylalkyl of 4 to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), 2 to 6 carbon atoms, benzoylamino, diphenylmethylamino (alkyl) or from 1 to 3 carbon atoms), aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (C1 to C3 alkyl) aminocarbonyl, halo- (C 1 -C 6 alkanoyl), aminosulfonyl, alkylaminosulfonyl from 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminosulfonyl, phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), (halo, C 1 -C 3 alkyl) or C 1 -C 3 alkoxy) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) amino) (alkyl of 1 to 3 carbon atoms). characterized in the process because it comprises the oxidation of an arylmethyl sulfide compound of the formula VIII VIII to a sulfoxide compound of the formula IX IX by reacting the sulfoxide compound of formula IX with an acylating agent to provide a rearrangement product of Pummerer; reacting the Pummerer rearrangement product with an electrophile selected from the group consisting of A-R1 wherein A is a leaving group, in the presence of a phase transfer catalyst, a hydride reducing reagent and a base, to prepare a composed of the formula I.
12. The process according to claim 11, characterized in that the acylating agent is trifluoroacetic anhydride and the rearrangement product of Pummerer is a trifluoroacetyloxymethylene sulfide compound of the formula X X
13. A process for the preparation of (+) - (4aR) - (lObR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,4,4, 4a, 5, 6, 10b-octahydrobenzo-f-quinolin-3-one, characterized in that it comprises: the reaction of a trifluoroacetyloxymethylene sulfide compound of the formula X X with 2-halo-4-ethylbenzothiazole in the presence of a phase transfer catalyst, a hydride reducing reagent and a base.
14. The process according to claim 11 or 12, characterized in that the monoperoxyphthalic acid or the 3-chloroperoxybenzoic acid is the oxidizing agent, the 2-halo-4-ethyl-benzothiazole is the electrophile, the potassium carbonate is the base, the Sodium borohydride is the reducing agent and the prepared compound is (+) - (4aR) - (1 ObR) - 4-methyl-8-j-ethyl-2-benzothiazole ilthio) -1 Ob-methyl-1,2, 3, 4, 4a, 5,6, 1 Ob-octahydrobenzoJfJquinolin-3-one.
15. A process for the preparation of a compound of formula VIII VIII characterized in that it comprises the reaction of a compound of the formula XII XII with a reaction mixture comprising a base and an ether type solvent to provide an amide-enolate solution; the reaction of the amide-enolate solution with an alkyl lithium compound to provide a dianionic compound of the formula reacting the dianionic compound with dimethyl disulfide to provide an arylmethyl sulfide compound of the formula VIII.
16. The process according to claim 15, characterized in that the base is lithium diisopropylamide.
17. The process according to claim 15, characterized in that the base is lithium hexamethyldisilazide.
18. The process according to claim 16 or claim 17, characterized in that it further comprises the addition of a salt of lithium and of methyl-lithium.
19. The process according to any of claims 15, 16, 17 or 18, further characterized in that it comprises the conversion of the compound of the formula VIII to a compound of the formula I wherein R 1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1 isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3-1,2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, -naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [g] isoquinolinyl, 8-benzfg] isoquinolinyl, -lH-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1, 4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxacin, 2-purine or 8-purine; where the previous R1 groups. are unsubstituted or substituted with 1 to 3 functional groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, alkyl of 1 to 4 carbon atoms, trifluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms, nitro, alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino, alkylamino of 1 to 3 carbon atoms carbon diphenylmethylamino, tri phenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or cycloalkylalkyl of 4) to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo) (phenyl, phenoxy, phenylthio, phenylsufonyl or phenoxysulfonyl), alkanoylamino of 2 to 6 carbon atoms carbon, benzoylamino, diphenylmethylamino (alkyl of 1 to 3 carbon atoms), a minocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (alkyl of 1 to 3 carbon atoms) aminocarbonyl, halo- (alkanoyl of 1 to 6 carbon atoms), aminosulfonyl, alkylaminosulfonyl of 1 to 3 carbon atoms, di ( alkyl of 1 to 3 carbon atoms) aminosulfonyl, phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), (halo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) amino) (alkyl of 1 to 3 atoms of carbon).
20. The process according to any of claims 15, 16, 17 or 18, further characterized in that it comprises the oxidation of the compound of the formula VIII VIII to a sulfoxide compound of the formula IX IX reacting the sulfoxide compound of formula IX with an acylating agent to provide a rearrangement product of Pummerer; reacting the Pummerer rearrangement product with an electrophile selected from the group consisting of A-R1 wherein A is a leaving group and R1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, -isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3-1, 2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-naphtho [2, 3-d ] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, l-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl, 5-lH-tetrazolyl, 2 -quinazolinyl, 2-thiazolo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4- benzoxacin, 2-purine or 8-purine; wherein the above R1 groups are unsubstituted or substituted with 1 to 3 functional groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, alkyl of 1 to 4 carbon atoms, trifluoromethoxy, hydroxyl, alkoxy of 1 to 3 carbon atoms, nitro , alkylthio of 1 to 3 carbon atoms, alkanoyl of 1 to 6 carbon atoms, phenyl, oxo, phenoxy, phenylthio, alkylsulfinyl of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, cyano, amino, alkylamino from 1 to 3 carbon atoms diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms) , or cycloalkylalkyl of 4 to 8 carbon atoms) amino, (mono-alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halo) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), 2 to 6 carbon atoms, benzoylamino, diphenylmethylamino (alkyl) 1 to 3 carbon atoms), aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminocarbonyl, halo- (C 1 -C 6 alkanoyl), aminosulfonyl, alkylaminosulfonyl from 1 to 3 carbon atoms, di (C 1 -C 3 alkyl) aminosulfonyl, phenyl (oxy or thio) (C 1 -C 3 alkyl), (halo, C 1 -C 3 alkyl) or alkoxy of 1 to 3 carbon atoms) phenyl (oxy or thio) (alkyl of 1 to 3 carbon atoms), benzoyl or (amino, alkylamino of 1 to 3 carbon atoms or di (alkyl of 1 to 3 carbon atoms) carbon) amino) (alkyl of 1 to 3 carbon atoms); in the presence of a phase transfer catalyst, a hydride reducing reagent and a base for preparing a compound of the formula I
21. A process for the preparation of (+) - (4aR) - (lObR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -1 Ob-methyl-1, 2,3,4,4a, 5,6,10b-octahydrobenzoff] quinolin-3-one, characterized in that it comprises: the reaction of a compound of the formula II II with (R) - (+) - phenethylamine to provide a compound of the formula III III by reacting the compound of formula III with a strong lithium base to provide a lithium-enamine compound of formula IV IV methylating the resulting lithioenamine of formula IV to a compound of formula V V by reacting the compound of the formula V with an acyl halide or an acrylic acid anhydride to prepare a compound of the formula VI VI quenching the reaction with base, and combining the residue comprising the compound of formula VI with an appropriate silane and trifluoroacetic acid in the absence of a solvent to prepare a compound of formula VII VII reacting the compound of the formula VII with a methyl halide in a reaction mixture comprising an organic solvent and a strong base, to provide an arylmethyl sulfide compound of the formula VIII SCH2 11. 0 oxidizing the compound of the formula VIII to a sulfoxide compound of the formula IX IX by reacting the sulfoxide compound of the formula IX with trifluoroacetic anhydride to provide a trifluoroacetyloxymethylene sulfide compound of the formula X X reacting the trifluoroacetyloxymethylene sulfide compound with 2-halo-4-ethylbenzothiazole in the presence of a phase transfer catalyst, sodium borohydride and a base to prepare the (+) - (4aR) - (lObR) -4- methyl-8- (4-ethyl-2-benzothiazolylthio) -1 Ob-methyl-1,2, 3, 4, 4a, 5, 6,1 Ob-octahydrobenzo [f] quinolin-3-one.
22. A process for the preparation of (+) - (4aR) - (lObR) -4-methi 1-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1, 2, 3, 4, 4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one substantially as described in accordance with any of the Examples.
23. A compound of formula II II
24. A process for preparing a compound of formula II II as described in any of Examples
25. A compound of formula VI VI or a salt of it
26. A compound of formula VIII 10 VIII or a salt thereof
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US027868 | 1996-10-30 | ||
US60/027868 | 1996-10-30 |
Publications (1)
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MXPA99004067A true MXPA99004067A (en) | 2000-01-01 |
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