EP0830362A1 - Process for the synthesis of vinyl sulfenic acid derivatives - Google Patents
Process for the synthesis of vinyl sulfenic acid derivativesInfo
- Publication number
- EP0830362A1 EP0830362A1 EP96918314A EP96918314A EP0830362A1 EP 0830362 A1 EP0830362 A1 EP 0830362A1 EP 96918314 A EP96918314 A EP 96918314A EP 96918314 A EP96918314 A EP 96918314A EP 0830362 A1 EP0830362 A1 EP 0830362A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- compound
- hydrogen
- formula
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 45
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 21
- SLAWTOLLPNIOGD-UHFFFAOYSA-N hydroxysulfanylethene Chemical class OSC=C SLAWTOLLPNIOGD-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims abstract description 19
- -1 silyl ester Chemical class 0.000 claims description 134
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 44
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 39
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 34
- 239000002585 base Substances 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 31
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 150000001412 amines Chemical class 0.000 claims description 21
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- 125000001843 C4-C10 alkenyl group Chemical group 0.000 claims description 16
- 239000003377 acid catalyst Substances 0.000 claims description 15
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical group C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 29
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 7
- 229930192474 thiophene Natural products 0.000 abstract description 11
- 150000003577 thiophenes Chemical class 0.000 abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 66
- 239000000243 solution Substances 0.000 description 59
- 239000000203 mixture Substances 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 16
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 12
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 12
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 12
- 239000007859 condensation product Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000002841 Lewis acid Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- LUFPJJNWMYZRQE-UHFFFAOYSA-N benzylsulfanylmethylbenzene Chemical compound C=1C=CC=CC=1CSCC1=CC=CC=C1 LUFPJJNWMYZRQE-UHFFFAOYSA-N 0.000 description 8
- 229940093499 ethyl acetate Drugs 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 150000007517 lewis acids Chemical class 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 150000002019 disulfides Chemical class 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 239000007800 oxidant agent Substances 0.000 description 7
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- HRWAGCVMOGWQJF-UHFFFAOYSA-N 6-methoxy-2-(4-methoxyphenyl)-1-benzothiophene Chemical compound C1=CC(OC)=CC=C1C1=CC2=CC=C(OC)C=C2S1 HRWAGCVMOGWQJF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 235000013877 carbamide Nutrition 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 150000003460 sulfonic acids Chemical class 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 150000003462 sulfoxides Chemical class 0.000 description 5
- 150000003672 ureas Chemical class 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 4
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- HTMQZWFSTJVJEQ-UHFFFAOYSA-N benzylsulfinylmethylbenzene Chemical compound C=1C=CC=CC=1CS(=O)CC1=CC=CC=C1 HTMQZWFSTJVJEQ-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 4
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 4
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 4
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- 150000004965 peroxy acids Chemical class 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000002178 crystalline material Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- XDBOBNVQEBSKFO-UHFFFAOYSA-N magnesium;di(propan-2-yl)azanide Chemical compound CC(C)N(C(C)C)[Mg]N(C(C)C)C(C)C XDBOBNVQEBSKFO-UHFFFAOYSA-N 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 3
- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003450 sulfenic acids Chemical class 0.000 description 3
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- VYWJFFUJSLRRPW-UHFFFAOYSA-N 1,3-bis(triethylsilyl)urea Chemical compound CC[Si](CC)(CC)NC(=O)N[Si](CC)(CC)CC VYWJFFUJSLRRPW-UHFFFAOYSA-N 0.000 description 2
- BAOIWIMUZBFBAE-UHFFFAOYSA-N 1,3-bis(triphenylsilyl)urea Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)NC(=O)N[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BAOIWIMUZBFBAE-UHFFFAOYSA-N 0.000 description 2
- PYYWHNBEBYFKEZ-UHFFFAOYSA-N 1,3-bis[dimethyl(propan-2-yl)silyl]urea Chemical compound CC(C)[Si](C)(C)NC(=O)N[Si](C)(C)C(C)C PYYWHNBEBYFKEZ-UHFFFAOYSA-N 0.000 description 2
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- 239000011521 glass Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- MDGWZLQPNOETLH-UHFFFAOYSA-N raloxifene core Chemical class C1=CC(O)=CC=C1C1=CC2=CC=C(O)C=C2S1 MDGWZLQPNOETLH-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- RVEZZJVBDQCTEF-UHFFFAOYSA-N sulfenic acid Chemical compound SO RVEZZJVBDQCTEF-UHFFFAOYSA-N 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical class [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/16—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/08—Sulfenic acids; Derivatives thereof
- C07C313/18—Sulfenamides
- C07C313/20—Sulfenamides having sulfur atoms of sulfenamide groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0834—Compounds having one or more O-Si linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention is directed to a novel vinyl sulfenic acid derivatives and a new process for their synthesis. These compounds are useful for the synthesis of benzo [b] thiophenes, in particular 2-aryl-benzo [b] thiophenes .
- Benzo fb] thiophenes have been prepared by a number of different synthetic routes.
- One of the most widely used methods is the oxidative cyclization of o-mercaptocinnamic acids. This route is limited to the preparation of benzo[b] - thiophene-2-carboxylates .
- 2-Phenylbenzo[b] thiophenes are prepared by acid-catalyzed cyclization of 2-phenylthioacetal- dehyde dialkyl acetals .
- Unsubstituted benzo[b]thiophenes are prepared by catalytic condensation of styrene and sulfur.
- Sulfenic acids have been postulated as key intermediates in a variety of chemical reactions; however, very few examples exist of the isolation of these compounds. See Shelton and Davis, J. Am . Chem . Soc , 89(3), 718-719 (1968) and Davis et al . , J. Am . Chem. Soc , 100, 2844 (1978) . Sulfenic acids have been generated in si tu, and intramolecularly or intermolecularly cyclyzed with olefins and acetylenes. See Mazzanti et al . , J. Chem. Soc , Perkin Trans . I, 3299-3004 (1944) and Davis et al . , J.
- the present invention is directed to novel vinyl sulfenic acid derivatives: novel sulfenate silylesters, sulfenamides, and disulfides, and to a process for the synthesis of vinyl sulfenic acid derivatives. Specifically, the present invention is directed to a compound of the formula
- R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
- R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
- R 4 is OSi(R) 3 , NR5R6, or SRg; each R is independently C 1 -C 6 alkyl, aryl, or arylalkyl;
- R 5 and R ⁇ are independently hydrogen, -C ⁇ , alkyl, arylalkyl, or aryl, or R 5 and R ⁇ , together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine, or hexamethylimine; and
- R 8 is C 1 -C 6 alkyl, aryl, or arylalkyl.
- the present invention includes individually the E and Z isomers, or mixtures thereof, of the formula III compounds. These E and Z regioisomers are represented by the following structures:
- Another aspect of the present invention is a process for preparing sulfenate silyl esters, sulfenamides, and disulfides.
- the present invention is directed to a process for preparing a compound of the formula
- R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino;
- R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino;
- R 4 is OSi(R) 3 , NR5R6, or SRs; each R is independently C 1 -C 6 alkyl, aryl, or arylalkyl; R 5 and R ⁇ are independently hydrogen, C 1 -C 6 alkyl, arylalkyl, or aryl; or R 5 and Re together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine, or hexamethylimine; and
- Rs is Ci-C ⁇ alkyl, aryl, or arylalkyl; which comprises :
- Ri and R 2 are as defined above, and
- R 3 is a thermally-labile or acid-labile C 2 -C 10 alkyl, C 4 -C 10 alkenyl, or aryl (C ⁇ -C ⁇ o alkyl) group; with a silylating reagent to produce a sulfenate silyl ester of the formula
- R l and R 2 are as defined above;
- R 7 is OSi (R) 3 ; and each R is independently C 1 -C 6 alkyl, aryl, -or arylalkyl;
- One aspect of the present invention is a process for the synthesis of the sulfenate silyl esters, the formula IV compounds.
- the present invention relates to a process for preparing a compound of the formula
- R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
- R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
- R 7 is OSi(R) 3 ,- and each R is independently Ci-C ⁇ alkyl, aryl, or arylalkyl; which comprises reacting a compound of the formula
- R l and R 2 are as defined above, and
- R 3 is a thermally-labile or acid-labile C 2 -C 10 alkyl, C 4 -C 10 alkenyl, or aryl(C ⁇ C o alkyl) group; with a silylating reagent .
- Another aspect of the present invention is a process for the synthesis of the sulfenamides, the formula V compounds.
- the present invention relates to a process for preparing a compound of the formula
- R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, amino;
- R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, amino; and R5 and R ⁇ , are independently hydrogen, Ci-C ⁇ alkyl, arylalkyl, or aryl, or R 5 and R ⁇ together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine, or hexamethyli ine; comprising the steps of: (1) reacting a compound of the formula
- Ri and R 2 are as defined above, and
- R 3 is a thermally-labile or acid-labile C 2 -C 10 alkyl, C 4 -C 10 alkenyl, or aryl (C 1 -C 10 alkyl) group; with a silylating reagent to produce a sulfenate silyl ester of the formula
- R l and R 2 are as defined above;
- R 7 is OSi(R) 3 ,- and each R is independently Ci-Cg alkyl, aryl, or arylalkyl;
- Another aspect of the present invention is a process for the synthesis of the disulfides, the formula XIV compounds.
- the present invention relates to a process for preparing a compound of the formula
- R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, amino;
- R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, amino
- Rs is Ci-Cg alkyl, aryl, or arylalkyl
- R l and R 2 are as defined above, and
- R3 is a thermally-labile or acid-labile C 2 -C 10 alkyl, C4-C10 alkenyl, or aryl (C1-C10 alkyl) group; with a silylating reagent to produce a sulfenate silyl ester of the formula
- R l and R 2 are as defined above;
- R 7 is OSi(R) 3 ,- and each R is independently Ci-C alkyl, aryl, or arylalkyl;
- Another aspect of the present invention is a process for the synthesis of a compound of the formula
- Rg is hydrogen, halo, amino, or hydroxyl
- Rio is hydrogen, halo, amino, or hydroxyl
- R ll and R 2 are independently C 1 -C 4 alkyl, or Rn and R 12 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
- HX is HCl or HBr; comprising the steps of:
- R l is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
- R 2 is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino
- R 4 is OSi(R) 3 , NR5Rg, or SRs; each R is independently Ci-Cg alkyl, aryl, or arylalkyl;
- R 5 and Rg are independently hydrogen, Ci-Cg alkyl, or aryl, or R 5 and Rg together with the nitrogen atom form a ring selected from piperidine, pyrrolidine, morpholine, and hexamethylimine; and
- Rs is Ci-Cg alkyl, aryl, or arylalkyl; to prepare a benzothiophene compound of the formula
- R and R2 are as defined above;
- R l l R 12/ an d HX are as defined previously; and R1 3 is chloro, bromo, or hydroxyl; in the presence of BX' 3 , wherein X' is chloro or bromo;
- the term "acid catalyst” represents a Lewis acid or a Br ⁇ nsted acid.
- Representative Lewis acids are zinc chloride, zinc iodide, aluminum chloride, and aluminum bromide.
- Br ⁇ nsted acids include: inorganic acids, such as sulfuric and phosphoric acids; carboxylic acids, such as acetic and trifluorocetic acids; sulfonic acids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1- butanesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic, 1- hexanesulfonic, 1, 5-naphthalenedisulfonic, 1-octanesulfonic, camphorsulfonic, trifluoromethanesulfonic, and p-toluene ⁇ sulfonic acids; and polymeric arylsulfonic acids, such as Nafion®, Amberlyst®, or Amberlite®.
- inorganic acids such as sulfuric and phosphoric acids
- carboxylic acids such as acetic and trifluorocetic acids
- sulfonic acids such as methanesulfonic
- the preferred acids for use in catalyzing the processes of the present invention are sulfonic or polymeric sulfonic acids. More preferably, the acid catalysts are sulfonic acids, such as methanesulfonic acid, benezenesulfonic acid, camphorsulfonic acid, and p- toluenesulfonic acid. The most preferred acid catalyst is p- toluenesulfonic acid.
- C 1 -C 4 alkoxy represents groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, fc-butoxy, and like groups.
- halo refers to fluoro, chloro, bromo, or iodo groups.
- Ci-Cg alkyl represents a straight or branched alkyl chain having from one to six carbon atoms.
- Typical C ⁇ Cg alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, and the like.
- C 1 -C 4 alkyl represents a straight or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, i-butyl, and t-butyl.
- aryl represents groups such as phenyl and substituted phenyl.
- substituted phenyl represents a phenyl group substituted with one or more moieties chosen from the group consisting of halo, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trichloromethyl, and trifluoromethyl.
- Examples of a substituted phenyl group include 4-chloro- phenyl, 2, 6-dichlorophenyl, 2, 5-dichlorophenyl, 3, 4-dichloro- phenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4- dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 4- hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitro- phenyl, 4-nitrophenyl, 2, 4-dinitrophenyl, 4-methylphenyl, 4- ethylphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-butyl- phenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3- difluorophenyl, 2, 6-difluorophenyl, 2, 6-dimethylphenyl, 2- flu
- arylalkyl represents a C 1 -C 4 alkyl group bearing one or more aryl groups. Representatives of this group include benzyl, o-nitrobenzyl, p-nitrobenzyl, p- halobenzyl (such as p-chlorobenzyl, p-bromobenzyl, p- iodobenzyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4- phenylbutyl, 2-methyl-2-phenylpropyl, (2, 6-dichlorophenyl) - methyl, bis (2, 6-dichlorophenyl)methyl, (4-hydroxyphenyl) - methyl, (2, 4-dinitrophenyl)methyl, diphenylmethyl, triphenylmethyl, (p-methoxyphenyl) -diphenylmethyl, bis (p- methoxyphenyl)methyl, bis (2-nitrophenyl)methyl, and the
- arylalkoxy represents a C 1 -C 4 alkoxy group bearing one or more aryl groups. Representatives of this group include benzyloxy, o-nitrobenzyloxy, p-nitrobenzyloxy, p-halobenzyloxy (such as p-chlorobenzyloxy, p-bromobenzyloxy, p-iodobenzyloxy) , 1-phenylethoxy, 2-phenylethoxy, 3- phenylpropoxy, 4-phenylbutoxy, 2-methyl-2-phenylpropoxy, (2, 6-dichlorophenyl)methoxy, bis (2, 6-dichlorophenyl)methoxy, (4-hydroxyphenyl)methoxy, (2, 4-dinitrophenyl) ethoxy, diphenylmethoxy, triphenyl ethoxy, (p-methoxyphenyl) - diphenylmethoxy, bis (p-methoxyphenyl)methoxy,
- thermally-labile or acid-labile C 2 -C 10 alkyl, C 4 -C 10 alkenyl, or aryl(C -C ⁇ o alkyl) group represents a group that is readily removed from the sulfoxide (SO) group under heating or by treatment with the acid catalyst.
- the thermally-labile or acid-labile C 2 -C 10 alkyl groups are straight or branched alkyl chains having from two to ten carbon atoms and having at least one beta-hydrogen atom.
- thermally-labile or acid-labile C 2 -C 10 alkyl groups include ethyl, n-propyl, i-propyl, 1,1- dimethylpropoyl, n-butyl, sec-butyl, t-butyl, 1,1- di ethylbutyl, 2-methylbutyl, 3-methylbutyl, 1-methylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 4-dimethylbutyl, 3,3- dimethylbutyl, n-pentyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, n-hexyl, and the like.
- the thermally-labile or acid-labile C 4 -C 10 alkenyl groups are straight or branched alkenyl chains having from four to ten carbon atoms, at least one site of unsaturation, and either a beta-hydrogen or delta-hydrogen atom.
- thermally-labile or acid-labile C 4 -C 10 alkenyl groups include 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3- pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl- 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like.
- thermally-labile or acid-labile aryl represents thermally-labile or acid-labile C 2 -C 10 alkyl groups additionally containing one or more aryl groups and aryl-substituted methyl groups.
- Representative aryl (Ci- C 10 alkyl) groups include benzyl, diphenylmethyl, triphenylmethyl, p-methoxybenzyl, 2-phenylethyl, 2-phenyl- propyl, 3-phenylpropyl, and the like.
- One group of products of the present invention are sulfenate silyl esters.
- the formula III compounds, where R 4 is OSi(R) 3 and each R is independently C ⁇ Cg alkyl, aryl, or arylalkyl and the formula IV compounds are silyl esters of sulfenic acids.
- the preferred sulfenate silyl esters are abbreviated using nomenclature well recognized in the chemical arts, as shown in the following table.
- silylating reagent represents a compound, or a combination of compounds, used to convert the intermediate sulfenic acid to a sulfenate silyl ester.
- Representative silylating reagents include bis (trialkylsilyl)ureas, such as 1,3-bis (trimethylsilyl)urea, 1, 3-bis (triethylsilyl)urea, 1,3- bis (dimethylisopropylsilyl)urea, 1,3-bis (triisopropyl- silyDurea, 1, 3-bis (diethylisopropylsilyl)urea, 1,3- bis (dimethylhexylsilyl)urea, and 1, 3-bis ( -butyldimethyl- silyl)urea; bis (triarylsilyl)ureas, such as 1,3-bis- (triphenylsilyl)urea; bis (diarylalkylsilyl)ureas, such 1,3
- E and Z The formula III compounds exist in two regioisomeric forms, E and Z. These E and Z regioisomers are represented by the following structures:
- a formula VII compound is converted to a styryl sulfide by reaction with a mercaptan of the formula HSR 3 in the presence of a Lewis acid.
- the formula VIII compound is then oxidized to a styryl sulfoxide, a compound of formula II.
- a formula VII compound wherein Ri and R 2 are as defined above, is treated with a Lewis acid, such as titanium(IV) chloride.
- a Lewis acid such as titanium(IV) chloride.
- This reaction is carried out in an anhydrous organic solvent, such as dry tetrahydrofuran, at a temperature of about 0°C to about 35°C.
- an amine base and a mercaptan of the formula HSR 3 , where R 3 is a thermally-labile or acid labile C ⁇ -C ⁇ o alkyl, C 4 -C 10 alkenyl, or aryl(C ⁇ -C o alkyl) group.
- the mercaptan and amine base are added as a solution in the reaction solvent.
- a representative amine base is triethylamine. After the addition of the mercaptan and amine base, the reaction is generally heated to a temperature of about 35°C to about 65°C, preferably at about 50°C. The products of this reaction can be purified using techniques well known in the chemical arts, such as by crystallization or chromatography.
- the formula VIII compound where Ri, R 2 , and R 3 are as defined above, is then oxidized to produce the formula II compounds.
- Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m-chloroperoxybenzoic acid, and hydrogen peroxide.
- This oxidation reaction is typically run in an organic solvent, such as toluene, methylene chloride, chloroform, or carbontetrachloride.
- the reaction is generally carried out at a temperature of about -30°C to about 15°C, preferably at about -20°C.
- the products of the reaction are easily purified by recrystallization.
- R 3 is t-butyl
- the crystalline product of this reaction sequence is the E regioisomer of formula II.
- the Z regioisomer of the formula II compounds can be prepared selectively by a second route as shown in Scheme II.
- a benzyl alcohol, a formula IX compound is reacted with a mercaptan of the formula R 3 SH to produce a benzyl sulfide, a formula X compound.
- This benzyl sulfide is reacted with a strong base, forming a benzylic anion, which is condensed with a benzaldehyde.
- This condensation product is reacted with an acid chloride and the resulting intermediate treated with a second strong base to produce a styryl sulfide, a formula VIIIZ compound.
- This styryl sulfide is then oxidized with an oxidizing agent to produce the formula HZ compound.
- the first step in the synthesis of the Z styryl sulfoxide compounds is the conversion of a benzyl alcohol to a benzyl sulfide, formula X compound.
- Suitable Lewis acids for this transformation are zinc bromide, zinc chloride, zinc iodide, ferric chloride, titanium(IV) chloride, aluminum trichloride, and aluminum tribromide, preferably zinc iodide.
- the reaction is generally carried out in an organic solvent, such as 1, 2-dichloroethane or methylene chloride. When the reaction is carried out at room temperature, the reaction is complete after about 18 hours.
- the benzyl sulfide is reacted with a strong base to form a benzylic anion.
- Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; and alkyllithiums, such as n- butyllithium, t-butyllithium, sec-butyllithium, and methyllithium.
- the preferred strong base for this reaction is n-butyllithium.
- the preferred solvent for this reaction is dry tetrahydrofuran.
- the benzylic anion is condensed with a benzaldehyde to prepare an intermediate condensation product.
- the benzaldehyde has the general formula p-Ri (CgH 4 )CHO, wherein Ri is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino.
- Ri is hydrogen, C 1 -C 4 alkoxy, arylalkoxy, halo, or amino.
- the benzylic anion is prepared and the condensation product is formed in si tu by adding the benzaldehyde to the cold solution of the benzylic anion.
- the condensation product is treated with an acid chloride to produce an intermediate compound.
- Representative acid chlorides include acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1- butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N, N-dimethylaminocarbonyl chloride; preferably a sulfonyl chloride.
- methanesulfonyl chloride is added to the reaction mixture shortly after formation of the condensation product.
- This intermediate compound is reacted with a second strong base to produce a styryl sulfide, a formula VIIIZ compound where Ri, R 2 , and R 3 are as defined above.
- Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec- butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide.
- the preferred strong base for this reaction is potassium t-butoxide. Generally, this reaction is carried out at about 15°C to about room temperature, preferably at room temperature.
- the styryl sulfide is oxidized to prepare the corresponding styryl sulfoxide.
- Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and m- chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide; and hydrogen peroxide.
- the oxidizing agent is peracetic acid.
- This oxidation is typically carried out in an organic solvent, such as toluene, benzene, xylene, methanol, ethanol, methylacetate, ethylacetate, methylene chloride, 1, 2-dichloroethane, or chloroform; preferably methylene chloride.
- This oxidation can be carried out at a temperature of about -40°C to about 0°C.
- the benzyl sulfide intermediate (formula X compound) can be used to produce a mixture of E and Z isomers of the styryl sulfoxides, the formula II compounds. This synthesis is outlined is Scheme 3.
- the benzyl sulfide prepared as described above, is oxidized to produce the corresponding benzyl sulfoxide.
- This benzyl sulfoxide is reacted with a strong base, and the resulting anion condensed with a benzaldehyde.
- the condensation product is reacted with an acid chloride and the resulting intermediate compound reacted with a second strong base to produce the styryl sulfoxide.
- the benzyl sulfide the formula X compound, wherein R 2 is as defined above and R 3 is a thermally-labile or acid- labile C2-C10 alkyl, C4-C10 alkenyl, or aryl (C1-C1 0 alkyl) group having a tertiary carbon atom adjacent to the sulfur atom, is oxidized to produce the corresponding benzyl sulfoxide, formula XI compound.
- Suitable oxidizing agents for this reaction are peracids, such as peracetic acid and J ⁇ - chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide; and hydrogen peroxide.
- the oxidizing agent is peracetic acid.
- This oxidation is typically carried out in an organic solvent, such as toluene, benzene, xylene, methanol, ethanol, methylacetate, ethylacetate, methylene chloride, 1, 2-dichloroethane, or chloroform; preferably at a temperature of about -30°C to about 5°C.
- organic solvent such as toluene, benzene, xylene, methanol, ethanol, methylacetate, ethylacetate, methylene chloride, 1, 2-dichloroethane, or chloroform
- Suitable strong bases for this reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide.
- the preferred base for this transformation is n-butyllithium.
- This deprotonation reaction is carried out in a dry organic solvent, such as tetrahydrofuran or 1, 2-dimethoxyethane, at a temperature of about -25°C.
- the benzylic anion is condensed, without isolation, with a benzaldehyde compound of the formula p-Ri (CgH 4 ) CHO, wherein Ri is as defined above.
- Ri is as defined above.
- about one equivalent of the benzaldehyde is added to the cold solution prepared as described in the preceding paragraph.
- the resulting diastereomeric mixture of condensation products may be isolated, or preferably used in the next step without isolation.
- the condensation product is reacted with an acid chloride to produce an intermediate compound.
- the condensation product is optionally treated with a base, such as n-butyllithium, and reacted with an acid chloride.
- Representative acid chlorides include acyl chlorides, such as acetyl chloride and benzoyl chloride; sulfonyl chlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as methoxycarbonyl chloride and benzyloxycarbonyl chloride; and dialkylaminocarbonyl chlorides, such as N/ N-dimethylaminocarbonyl chloride; preferably a sulfonyl chloride.
- the acid chloride is added to the cold reaction mixture, then the resulting mixture is allowed to warm to room temperature.
- methanesulfonyl chloride is added to the reaction mixture shortly after formation of the condensation product, which eliminates the need to add additional base.
- the resulting intermediate compound is reacted with a second strong base to produce the E and Z styryl sulfoxides, formula II compounds where Ri, R 2 , and R 3 are as defined above.
- second strong bases for this elimination reaction include metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithium t- butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums, such as n-butyllithium, t-butyllithium, sec- butyllithium, and methyllithium; and metal amides, such as sodium amide, magnesium diisopropylamide, and lithium diisopropylamide.
- the preferred base for this transformation is potassium t-butoxide.
- a 20% excess, such as 1.2 equivalents, of the second base are added.
- this reaction is carried out at a temperature of about 15°C to about room temperature, preferably at room temperature.
- the compounds of the present invention can be prepared from the formula II compounds.
- the novel sulfenate silyl esters are prepared from the styryl sulfoxides as shown in Scheme 4.
- the sulfenate silyl esters where Ri, R 2 , and R 7 are as defined above and R 3 is a thermally-labile or acid labile C 1 -C 10 alkyl, C 4 -C 10 alkenyl, or aryl (C 1 -C 10 alkyl) group, are prepared by reacting a formula II compound with a silylating reagent.
- Suitable solvents for this reaction include benzene, toluene, xylene, and high-boiling, halogenated hydrocarbon solvents, having a boiling point greater than or equal to 80°C, such as 1, 1, 2-trichloroethane.
- Suitable silylating reagents include bis (trialkylsilyl)ureas, such as 1,3-bis (trimethylsilyl)urea, 1,3-bis (triethylsilyl) - urea, 1, 3-bis (dimethylisopropylsilyl) -urea, 1,3-bis (t-butyl- dimethylsilyl)urea; bis (triarylsilyl) -ureas, such as 1,3- bis (triphenylsilyl)urea; bis (dialkylaryl-silyl) ureas, such 1, 3-bis (diphenylmethylsilyl)urea; and hexaalkyldisilylzanes, such as hexamethyldisilylzane; or combination of a hexaalkyldisilylzane and a catalytic amount of a chlorotrialkylsilane, such as chlorotrimethylsilane.
- the final concentration, after complete addition, of the formula II compound is about 0.001 M to about 0.5 M.
- a slight excess, such as ten percent, of the silylating reagent is used. This reaction can be carried out at about 80°C to about 140°C for about ten minutes to about two hours. Because the Z isomer reacts much faster than the corresponding E isomer, the use of only the Z isomer as the starting compound requires less time for complete transformation.
- the sulfenate silyl ester where Ri, R 2 , and R 7 are as defined above, is prepared from the styryl sulfoxide and, preferably without isolation or purification, reacted with an amine of the formula HNRsRg, wherein R 5 and Rg as defined above.
- the sulfenate silyl ester is prepared,- the reaction solution cooled to about 0°C to about 50°C, and treated with the amine.
- one to two equivalents of the amine are used.
- the conversion from the silyl ester to the sulfenamide is typically complete after about two hours to about eight hours.
- the resulting sulfenamides can be purified using standard organic techniques, such as silica-gel chromatography.
- novel disulfides are prepared from the sulfenate silyl esters as shown in Scheme 6.
- the sulfenate silyl ester where Ri, R 2 , and R 7 are as defined above, is prepared from the styryl sulfoxide and, preferably without isolation or purification, reacted with a mercaptan of the formula HSRs, where Rs is as defined above, in the presence of an amine base.
- the sulfenate silyl ester is prepared, the reaction solution allowed to cool to room temperature, and the reaction mixture treated with a solution containing the mercaptan and amine base.
- the solvent for this mercaptan/amine solution is the same as the solvent for the sulfenate silyl ester-containing mixture.
- Representative amine bases include triethylamine, diisopropylethylamine, pyridine, morpholine, N-methyl ⁇ morpholine, and collidine.
- the conversion of the sulfenate silyl ester is typically complete after about one to about eight hours.
- the resulting disulfides can be purified using standard organic techniques, such as silica-gel chroma ⁇ tography.
- the sulfenate silyl esters, sulfenamides, or disulfides are treated with acid catalysts to produce the formula I compounds.
- Suitable acid catalysts for this reaction include Lewis acids or Br ⁇ nsted acids.
- Representative Lewis acids include zinc chloride, zinc iodide, aluminum chloride, and aluminum bromide.
- Br ⁇ nsted acids include inorganic acids, such as sulfuric and phosphoric acids; carboxylic acids, such as acetic and trifluoroacetic acids; sulfonic acids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1- butanesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic, 1- hexanesulfonic, 1, 5-naphthalenedisulfonic, 1-octanesulfonic, camphorsulfonic, trifluoromethanesulfonic, and p-toluene- sulfonic acids; and polymeric arylsulfonic acids, such as Nafion®, Amberlyst®, or Amberlite®.
- the more preferred acid catalysts are sulfonic acids, such as methanesulfonic acid, benezene-sulfonic acid, camphorsulfonic, and p- toluenesulfonic acid.
- the most preferred acid catalyst is p- toluenesulfonic acid.
- a solution of the acid catalyst in an organic solvent such as toluene, benzene, xylene, or a high-boiling halogenated hydrocarbon solvent, such as 1, 1, 2-trichloroethane, is heated to about 80°C to about 140°C, and treated with a solution of the sulfenate silyl ester, sulfenamide, or disulfide in the same solvent.
- an excess amount of the acid catalyst is used, preferably three equivalents of the acid.
- the final concentration of the starting compound is about 0.01 M to about 0.2 M, preferably 0.05 M.
- best yields are obtained when the sulfenate silyl ester is slowly added to the heated acid solution over a period of about 15 minutes to about three hours.
- residual water is removed from the reaction solution by the use of a Dean-Stark trap or Soxhlet extractor.
- styryl sulfoxides are also useful for the preparation of a benzothiophene styryl sulfide as shown in Scheme 8.
- benzothiophene styryl sulfides where Ri and R 2 are as defined above, are prepared from the styryl sulfoxides.
- a solution of the styryl sulfoxide, where Ri and R 2 are as defined above and R 3 is a thermally- labile or acid labile C 1 -C 10 alkyl, C 4 -C 10 alkenyl, or aryl(C ⁇ -C ⁇ o alkyl) group is added to a solution of an acid catalyst at a temperature of about 100°C to about 140°C, where the acid catalyst is defined above.
- the concentration of acid catalyst is dependent on the final concentration of the formula II compound and the rate of addition of the formula II compound.
- the acid concentration is about 0.002 M.
- the acid concentration is about 0.05 M and is added over 30 minutes.
- the Formula I compound wherein Ri and R 2 are hydrogen, C 1 -C 4 alkoxy, or arylalkoxy, is acyiated with the formula XII compound, wherein R 13 is chloro or hydroxy, in the presence of boron trichloride or boron tribromide; boron trichloride is preferred.
- the reaction can be carried out in a variety of organic solvents, such as chloroform, methylene chloride, 1, 2-dichloroethane, 1, 2, 3-dichloropropane, 1, 1, 2, 2-tetra- chloroethane, 1, 2-dichlorobenzene, chlorobenzene, and fluorobenzene.
- the preferred solvent for this synthesis is 1, 2-dichloroethane.
- the reaction is carried out at a temperature of about -10°C to about 25°C, preferably at 0°C.
- the reaction is best carried out at a concentration of the benzothiophene formula I compound of about 0.2 M to about 1.0 M.
- the acylation reaction is generally complete after about two hours to about eight hours.
- the acyiated benzothiophene preferably is converted to a formula XIII compound, wherein R 5 and/or Rg are hydroxy, without isolation of the product from the acylation reaction.
- This conversion is performed by adding additional boron trichloride or boron tribromide and heating the reaction mixture.
- two to five molar equivalents of boron trichloride are added to the reaction mixture, most preferably three molar equivalents .
- This reaction is carried out at a temperature of about 25°C to about 40°C, preferably at 35°C. The reaction is generally complete after about 4 hours to about 48 hours.
- the acylation reaction or acylation/dealkylation reaction is quenched with an alcohol or a mixture of alcohols.
- Suitable alcohols for use in quenching the reaction include methanol, ethanol, and isopropanol.
- the acylation/dealkylation reaction mixture is ⁇ added to a 95:5 mixture of ethanol and methanol (3A ethanol) .
- the 3A ethanol can be at room temperature or heated to reflux, preferably at reflux.
- the quench is performed in this manner, the Formula XIII compound conveniently crystallizes from the resulting alcoholic mixture.
- Proton nuclear magnetic resonance ( 1 H NMR) spectra and 13 C nuclear magnetic resonance ( 13 C NMR) spectra were obtained on a Bruker AC-300 FTNMR spectrometer at 300.135 MHz or at 75.469 MHz for proton and carbon, respectively, or a GE QE-300 spectrometer at 300.15 MHz.
- Silica-gel flash chromatography was performed as described by Still et al . using Silica Gel 60 (230-400 mesh, E. Merck) .
- Still et al . J. Org. Chem. , 43, 2923 (1978) .
- Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer.
- Elemental analyses for sulfur were determined on a Brinkman Colorimetric Elemental Analyzer. Melting points were determined in open glass capillaries on a Mel-Temp II melting point apparatus or a Mettler FP62 Automatic instrument, and are uncorrected.
- Field desorption mass spectra were obtained using a Varian Instruments VG 70-SE or VG ZAB-3F mass spectrometer.
- High resolution free atom bombardment mass spectra were obtained using a Varian Instruments VG ZAB-2SE mass spectrometer.
- % potency peak area - b sample volume (mL; m sample weight (mg)
- the amount (percentage) of solvent, such as 1,2- dichloroethane, present in the crystalline material was determined by gas chromatography.
- a sample of the crystalline solid (50 mg) was weighed into a 10-mL volumetric flask, and dissolved in a solution of 2-butanol (0.025 mg/mL) in dimethylsulfoxide.
- a sample of this solution was analyzed on a gas chromatograph using a DB Wax column (30 m x 0.53 mm ID, 1 m particle) , with a column flow of 10 mL/min and flame ionization detection.
- the column temperature was heated from 35°C to 230°C over a 12 minute period.
- the amount of solvent was determined by comparison to the internal standard (2- butanol) .
- a solution of desoxyanisoin (12.82 g) in tetrahydrofuran (100 mL) was treated with titanium (IV) chloride (10.43 g) .
- titanium (IV) chloride 10.43 g
- the reaction mixture was cooled to maintain the temperature below 35°C.
- the resulting mixture was stirred at 30°C.
- this mixture was treated with a solution of 2-methyl-2-propane- thiol (6.76 mL) and triethylamine (16.70 mL) in tetrahydro- furan (15 mL) .
- the resulting mixture was stirred at 50°C.
- Example IIA The crystalline compound prepared as described in Example IA was dissolved in toluene (150 mL) , and the resulting solution cooled to about -20°C. The cold solution was treated with peracetic acid (32% w/w in dilute acetic acid, 1.24 g) over ten minutes. The resulting mixture was extracted with saturated sodium sulfite and brine. The organic phase was concentrated in vacuo . The residue was recrystallized from ethyl acetate/heptane to give 14.11 g of the title compound. Melting point 104°C (dec) .
- Example 2A (2.51 g) in tetrahydrofuran (50 mL) was cooled to about -20°C. This cold solution was treated with a solution of n-butyllithium in hexane (1.6 M, 7.47 L) over ten minutes. The resulting solution was allowed to warm to about 0°C over 35 minutes. This cold solution was treated with p- anisaldehyde (1.46 mL) . After an additional 15 minutes, the reaction solution was treated with methanesulfonyl chloride (0.95 mL) . The resulting reaction was allowed to warm to room temperature.
- reaction mixture was treated with a solution of potassium t- butoxide in tetrahydrofuran (1.0 M, 12.0 L) .
- reaction was quenched by the addition of IN hydrochloric acid (12.0 mL) .
- the organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to an oil (4.4 g) .
- Example 2B The compound from Example 2B was converted to the title compound using the procedure substantially as described in Example IB.
- Example 3B (10.0 g) in tetrahydrofuran (140 mL) was cooled to about -30° to -25°C (dry ice/acetone bath) . This cold solution was treated with n-butyllithium in cyclohexane (1.6 M, 27.65 mL) over 25 minutes. After stirring for 35 minutes, the reaction mixture was treated with p-anisaldehyde (5.4 mL) . The dry ice/acetone bath was removed and the reaction allowed to warm to about 20°C. This mixture was treated with methanesulfonyl chloride (3.5 mL) . The temperature of the reaction rose from about 20° to about 35°C upon addition of the methanesulfonyl chloride.
- Example 1 (1.74 g) and 1, 3-bis (trimethylsilyl)urea (578 mg) in toluene (54 mL) was heated to reflux. After 1.5 hours, the reaction was allowed to cool to room temperature, and treated with dimethylamine (2.80 mL, 2.0 M in tetrahydro- furan) . After an additional two hours, the reaction solution was evaporated to dryness to give a 7:1 mixture of E/Z regio ⁇ isomers of the title compounds.
- Late-elutmg Isomer i H NMR (CDCI 3 ) d 7.90 (d, IH) , 7.62 (d, 2H) , 7.24 (IH), 7.08 (d, 2H) , 7.02 (dd, IH) , 6.96 (d, 2H) , 6.74-6.71 (d, 2H) , 6.70 (d, 2H) , 6.55 (d, 2H) , 6.21 (s, IH) , 3.86 (s, 3H) , 3.85 (s, 3H) , 3.76 (s, 3H) , 3.67 (s, 3H) .
- the compound (early-elutmg isomer) prepared as described in Example 10 (125 mg) was added to a refluxing solution of p-toluenesulfonic acid monohydrate (4.2 mg) m toluene (1.5 mL) . After six hours, methanesulfonic acid (7.5 mL) was added to the reaction mixture. After an additional hour, the reaction mixture was allowed to cool to room temperature. The resulting mixture was diluted with acetonitrile and assayed by HPLC, showing a 71.1% m s tu yield of the title compound.
- Example 12 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-p ⁇ per ⁇ dmoethoxy) - benzoyl]benzo [b] thiophene Hydrochloride 1, 2-D ⁇ chloroethane Solvate A. Preparation of Ethyl 4- (2-P ⁇ per ⁇ dmoethoxy)benzoate A mixture of ethyl 4-hydroxybenzoate (8.31 g) , l-(2- chloroethyl)piperidine monohydrochloride (10.13 g) , potassium carbonate (16.59 g) , and methyl ethyl ketone (60 L) was heated to 80°C.
- Example 12A A solution of the compound prepared as described in Example 12A (about 13.87 g) in methanol (30 mL) was treated with 5 N sodium hydroxide (15 mL) , and heated to 40°C. After 4 1/2 hours, water (40 L) was added. The resulting mixture was cooled to 5-10°C, and concentrated hydrochloric acid
- Example 12B (30.01 g) and dimethylformamide (2 mL) in methylene chloride (500 mL) was treated with oxalyl chloride (10.5 mL) over a 30-35 minute period. After stirring for about 18 hours, the reaction was assayed for completion by HPLC analysis. Additional oxalyl chloride may be added to the reaction if the starting carboxylic acid is present. Upon completion, the reaction solution was evaporated to dryness in vacuo . The residue was dissolved in methylene chloride (200 mL) , and the resulting solution evaporated to dryness. This dissolution/evaporation procedure was repeated to give the title compound as a solid.
- Example 8 or 9 (2.92 g), the compound prepared as described in Example 12C (3.45 g) , and 1,2-dichloroethane (52 L) was cooled to about 0°C. Boron trichloride gas was condensed into a cold graduated cylinder (2.8 mL) , and added to the cold mixture described above. After eight hours at 0°C, the reaction mixture was treated with additional boron trichloride (2.8 L) . The resulting solution was heated to 35°C. After 16 hours, the reaction was complete.
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US08/482,692 US5512701A (en) | 1995-06-07 | 1995-06-07 | Process for the synthesis of vinyl sulfenic acid derivatives |
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US08/483,607 US5514826A (en) | 1995-06-07 | 1995-06-07 | Vinyl sulfenic acid derivatives |
US482692 | 1995-06-07 | ||
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WO2004029046A2 (en) | 2002-09-30 | 2004-04-08 | A/S Gea Farmaceutisk Fabrik | Novel raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these |
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Title |
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G. CAPOZZI, ET AL.: "Phthalimidesulphenyl chloride; part VII: synthesis of 2-sustituted 3-chlorobenzoÄbÜthiophenes and related heteroaromatics" SYNTHESIS, no. 5, May 1994, STUTTGART, DE, pages 521-525, XP002069036 * |
See also references of WO9640693A1 * |
Also Published As
Publication number | Publication date |
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BR9608847A (en) | 1999-06-08 |
CA2224225A1 (en) | 1996-12-19 |
CZ387997A3 (en) | 1998-09-16 |
CN1330071A (en) | 2002-01-09 |
KR19990022503A (en) | 1999-03-25 |
IL122127A (en) | 2001-05-20 |
JPH11507346A (en) | 1999-06-29 |
EA000606B1 (en) | 1999-12-29 |
NZ310241A (en) | 1999-07-29 |
HUP9900923A2 (en) | 1999-07-28 |
HUP9900923A3 (en) | 2000-02-28 |
WO1996040693A1 (en) | 1996-12-19 |
TR199701511T1 (en) | 1998-04-21 |
AU698076B2 (en) | 1998-10-22 |
MX9709130A (en) | 1998-03-31 |
NO975633L (en) | 1998-01-28 |
IL122127A0 (en) | 1998-04-05 |
CN1068883C (en) | 2001-07-25 |
AU6100396A (en) | 1996-12-30 |
EA199800026A1 (en) | 1998-06-25 |
EP0830362A4 (en) | 1998-09-02 |
CN1192215A (en) | 1998-09-02 |
NO975633D0 (en) | 1997-12-04 |
PL323907A1 (en) | 1998-04-27 |
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