MX2008009914A - Process for preparing dibenzothiazepine compounds - Google Patents
Process for preparing dibenzothiazepine compoundsInfo
- Publication number
- MX2008009914A MX2008009914A MXMX/A/2008/009914A MX2008009914A MX2008009914A MX 2008009914 A MX2008009914 A MX 2008009914A MX 2008009914 A MX2008009914 A MX 2008009914A MX 2008009914 A MX2008009914 A MX 2008009914A
- Authority
- MX
- Mexico
- Prior art keywords
- acid
- compound
- group
- formula
- nitro
- Prior art date
Links
- 150000008509 dibenzothiazepines Chemical class 0.000 title description 18
- 238000004519 manufacturing process Methods 0.000 title description 6
- -1 dibenzothiazepine compound Chemical class 0.000 claims abstract description 68
- 239000002904 solvent Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229960003703 Sodium thiosalicylate Drugs 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 229940103494 thiosalicylic acid Drugs 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims abstract description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 36
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 16
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N Thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 13
- 229910052763 palladium Inorganic materials 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 229910052697 platinum Inorganic materials 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 2-Nitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003377 acid catalyst Substances 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- 238000010533 azeotropic distillation Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- DUYABCZVWKPIBJ-UHFFFAOYSA-N O=C1CC=CC2=C1CNC1=C(S2)C=CC=C1 Chemical compound O=C1CC=CC2=C1CNC1=C(S2)C=CC=C1 DUYABCZVWKPIBJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006297 dehydration reaction Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 230000001376 precipitating Effects 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 12
- 239000005711 Benzoic acid Substances 0.000 claims 6
- 235000010233 benzoic acid Nutrition 0.000 claims 6
- RMNTUOAOPRWVLP-UHFFFAOYSA-N 2-(2-aminophenyl)sulfanylbenzoic acid Chemical compound NC1=CC=CC=C1SC1=CC=CC=C1C(O)=O RMNTUOAOPRWVLP-UHFFFAOYSA-N 0.000 claims 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N Allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 claims 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- 239000001632 sodium acetate Substances 0.000 claims 1
- 235000017281 sodium acetate Nutrition 0.000 claims 1
- 230000002378 acidificating Effects 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 description 26
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- 229910000564 Raney nickel Inorganic materials 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- BAUYGSIQEAFULO-UHFFFAOYSA-L Iron(II) sulfate Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-Dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L Barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 description 3
- XGRXETKKISMBSZ-UHFFFAOYSA-N 5-methoxy-2-sulfanylbenzoic acid Chemical compound COC1=CC=C(S)C(C(O)=O)=C1 XGRXETKKISMBSZ-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000011790 ferrous sulphate Substances 0.000 description 3
- 235000003891 ferrous sulphate Nutrition 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000001184 potassium carbonate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000001187 sodium carbonate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinone Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- JMJXGUKTJQNSBR-UHFFFAOYSA-N 1,4-thiazepine 1-oxide Chemical compound O=S1C=CC=NC=C1 JMJXGUKTJQNSBR-UHFFFAOYSA-N 0.000 description 2
- NRIYGZKSJPQMTR-UHFFFAOYSA-N 11-chlorobenzo[d][1,2]benzothiazepine Chemical class C1=NSC2=CC=CC=C2C2=C1C=CC=C2Cl NRIYGZKSJPQMTR-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- WCFDCIHBQQEPFF-UHFFFAOYSA-N 8-methoxy-5H-benzo[b][1,4]benzothiazepin-6-one Chemical compound N1C(=O)C2=CC(OC)=CC=C2SC2=CC=CC=C21 WCFDCIHBQQEPFF-UHFFFAOYSA-N 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N Benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- KAAZGXDPUNNEFN-UHFFFAOYSA-N Clotiapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2SC2=CC=C(Cl)C=C12 KAAZGXDPUNNEFN-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive Effects 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- 230000000561 anti-psychotic Effects 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- JSRLURSZEMLAFO-UHFFFAOYSA-N 1,3-dibromobenzene Chemical compound BrC1=CC=CC(Br)=C1 JSRLURSZEMLAFO-UHFFFAOYSA-N 0.000 description 1
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 1
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-Dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-Dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- HUTXVUPGARJNHM-UHFFFAOYSA-N 1-(2-chloroethoxy)ethanol Chemical compound CC(O)OCCCl HUTXVUPGARJNHM-UHFFFAOYSA-N 0.000 description 1
- YFVOFFKNHQTQQE-UHFFFAOYSA-N 1-(4-bromo-3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C([N+]([O-])=O)=C1 YFVOFFKNHQTQQE-UHFFFAOYSA-N 0.000 description 1
- YEVPHFIFGUWSMG-UHFFFAOYSA-N 1-(4-chloro-3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 YEVPHFIFGUWSMG-UHFFFAOYSA-N 0.000 description 1
- PTCNZDJJIOLIKQ-UHFFFAOYSA-N 1-(4-fluoro-3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C([N+]([O-])=O)=C1 PTCNZDJJIOLIKQ-UHFFFAOYSA-N 0.000 description 1
- KRMMBFKHHSNERO-UHFFFAOYSA-N 1-(4-iodo-3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 KRMMBFKHHSNERO-UHFFFAOYSA-N 0.000 description 1
- NVBGNJFLYDTGTN-UHFFFAOYSA-N 1-bromo-2-nitro-4-phenylbenzene Chemical compound C1=C(Br)C([N+](=O)[O-])=CC(C=2C=CC=CC=2)=C1 NVBGNJFLYDTGTN-UHFFFAOYSA-N 0.000 description 1
- UPBUTKQMDPHQAQ-UHFFFAOYSA-N 1-bromo-4-methyl-2-nitrobenzene Chemical compound CC1=CC=C(Br)C([N+]([O-])=O)=C1 UPBUTKQMDPHQAQ-UHFFFAOYSA-N 0.000 description 1
- FIQBDKFALPAHOK-UHFFFAOYSA-N 1-chloro-2-nitro-4-phenylbenzene Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC(C=2C=CC=CC=2)=C1 FIQBDKFALPAHOK-UHFFFAOYSA-N 0.000 description 1
- HISHUMDTGXICEZ-UHFFFAOYSA-N 1-chloro-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(Cl)C([N+]([O-])=O)=C1 HISHUMDTGXICEZ-UHFFFAOYSA-N 0.000 description 1
- NWESJZZPAJGHRZ-UHFFFAOYSA-N 1-chloro-4-methyl-2-nitrobenzene Chemical compound CC1=CC=C(Cl)C([N+]([O-])=O)=C1 NWESJZZPAJGHRZ-UHFFFAOYSA-N 0.000 description 1
- FCHZACFMGHJGEE-UHFFFAOYSA-N 1-fluoro-2-nitro-4-phenylbenzene Chemical compound C1=C(F)C([N+](=O)[O-])=CC(C=2C=CC=CC=2)=C1 FCHZACFMGHJGEE-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- ZRIKJXDEJYMBEJ-UHFFFAOYSA-N 1-fluoro-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(F)C([N+]([O-])=O)=C1 ZRIKJXDEJYMBEJ-UHFFFAOYSA-N 0.000 description 1
- OORBDHOQLZRIQR-UHFFFAOYSA-N 1-fluoro-4-methyl-2-nitrobenzene Chemical compound CC1=CC=C(F)C([N+]([O-])=O)=C1 OORBDHOQLZRIQR-UHFFFAOYSA-N 0.000 description 1
- KDGJAPMZHIQXIS-UHFFFAOYSA-N 1-iodo-2-nitro-4-phenylbenzene Chemical compound C1=C(I)C([N+](=O)[O-])=CC(C=2C=CC=CC=2)=C1 KDGJAPMZHIQXIS-UHFFFAOYSA-N 0.000 description 1
- JWZODIRSJJQOKY-UHFFFAOYSA-N 1-iodo-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(I)C([N+]([O-])=O)=C1 JWZODIRSJJQOKY-UHFFFAOYSA-N 0.000 description 1
- AQFAXYGURHOSPN-UHFFFAOYSA-N 11-piperazin-1-ylbenzo[d][1,2]benzothiazepine Chemical class C1CNCCN1C1=CC=CC2=C1C1=CC=CC=C1SN=C2 AQFAXYGURHOSPN-UHFFFAOYSA-N 0.000 description 1
- RROSHIIMNNWHFW-UHFFFAOYSA-N 2-(2-aminophenyl)sulfanylbenzonitrile Chemical compound NC1=CC=CC=C1SC1=CC=CC=C1C#N RROSHIIMNNWHFW-UHFFFAOYSA-N 0.000 description 1
- WOEQJEQPTQHJIF-UHFFFAOYSA-N 2-(2-nitrophenyl)sulfonylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1S(=O)(=O)C1=CC=CC=C1[N+]([O-])=O WOEQJEQPTQHJIF-UHFFFAOYSA-N 0.000 description 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminobenzenethiol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 1
- QZYHIOPPLUPUJF-UHFFFAOYSA-N 3-Nitrotoluene Chemical compound CC1=CC=CC([N+]([O-])=O)=C1 QZYHIOPPLUPUJF-UHFFFAOYSA-N 0.000 description 1
- HIOOFBBNJCVVJZ-UHFFFAOYSA-N 5-methyl-2-sulfanylbenzoic acid Chemical compound CC1=CC=C(S)C(C(O)=O)=C1 HIOOFBBNJCVVJZ-UHFFFAOYSA-N 0.000 description 1
- XLJRROMOQCRLJI-UHFFFAOYSA-N 5-phenyl-2-sulfanylbenzoic acid Chemical compound C1=C(S)C(C(=O)O)=CC(C=2C=CC=CC=2)=C1 XLJRROMOQCRLJI-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N Bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- XUPYJHCZDLZNFP-UHFFFAOYSA-N Butyl butyrate Chemical compound CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N Cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N Cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N Ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L Iron(II) chloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N Methyl butyrate Chemical compound CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910003310 Ni-Al Inorganic materials 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N Quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical class [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- BAQGCWNPCFABAY-UHFFFAOYSA-N methyl 2-sulfanylbenzoate Chemical class COC(=O)C1=CC=CC=C1S BAQGCWNPCFABAY-UHFFFAOYSA-N 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000005181 nitrobenzenes Chemical class 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Abstract
A dibenzothiazepine compound is suitably prepared by subjecting a 2-amino-2'-carboxy-diphenylsulfide compound to dehydration-condensation reaction in the presence of an acidic catalyst;the 2-amino-2'-carboxy-diphenylsulfide compound is suitably prepared by reducing a 2-nitro-2'-carboxy-diphenylsulfide compound in a lower aliphatic ester solvent;and the 2-nitro-2'-carboxy-diphenylsulfide compound is suitably prepared by reacting a nitrobenzene compound with a thiosalicylic acid compound in a mixture of a lower aliphatic alcohol and water.
Description
PROCEDURE FOR THE PREPARATION OF DIBENZOTIAZEPINE COMPOUNDS FIELD OF THE INVENTION The present invention is directed, in part, to methods for the preparation of a dibenzothiazepine derivative. In particular, the invention relates to methods for the preparation of a dibenzothiazepine derivative which can be used as an intermediate for the preparation of 11- [4- (2- (2-hydroxyethoxy) -ethyl] -1-piperadinyl -dibenzothiazepine and its derivatives, which is known to be effective as an antipsychotic pharmaceutical BACKGROUND OF THE INVENTION EP 0282236-A1 reports that a dibenzothiazepine derivative can be processed to generate an 11- [4- (2- ( 2-hydroxyethoxy) ethyl-l-piperadinidibenzothiazepine, which is valuable as, for example, an antipsychotic pharmaceutical, in more detail, dibenzo- [b, f] [1,4] -thiazepin-l-one, which is a compound representative of the dibenzothiazepine derivatives reported there, reacted with phosphorous oxychloride to produce an 11-chloro-dibenzothiazepine derivative. To the 11-chloro-dibenzothiazepine derivative piperazine is added to produce an 11-piperazinyl-dibenzothiazepine derivative, and Which is subsequently reacted with 2-chloroethoxyethanol under Ref. 195087
basic conditions to give the desired 11- [4- (2- (2-hydroxyethoxy) -ethyl] -1-piperadinidibenzothiazepine EP 0282236-Al further reports that dibenzo- [b, f] [1,4] thiazepin- ll-one is prepared from phenyl 2- (phenylthio) phenylcarbamate or its analogous compounds by cyclization in the presence of polyphosphoric acid Helv. Chim. Acta., 1959, 42, 1263 reports that a dibenzothiazepine derivative can be prepared by heating a methyl thiosalicylate derivative with a halogenated 2-nitro-benzene derivative in the presence of sodium to give a 2-nitro-2'-carboxy-diphenylsulfide derivative, which is then reduced using a Raney nickel catalyst to produce a 2-amino-2'-carboxy-diphenylsulfide derivative, which is finally heated to give a dibenzothiazepine derivative, Org. Prep. Int. Procedure, 1974, 287 reports that a dibenzothiazepine derivative can be prepared by heating a derivative of thiosalicylic acid ester and 2-iodo-nitr derivative obencene, in the presence of sodium methylate and copper, treating the resulting compound successively with an alkaline solution and an acid solution to give a derivative of 2-nitro-2'-carboxy-diphenylsulfide, reducing the derivative by means of ferrous sulfate in a solution aqueous ammonia to give a derivative of 2-amino-2'-carboxy-diphenylsulfide, and heating the resulting derivative under
reduced pressure. WO 92/19607 reports that a dibenzothiazepine derivative can be prepared by means of the steps of reacting 2-aminothiophenol with 2-fluorobenzonitrile to give 2- (2-aminophenylthio) benzonitrile, hydrolyzing the resulting compound to give 2- (2-carboxyphenylthio) ) aniline, and finally generating in cycles the aniline derivative. As described above, various methods are known for the preparation of a dibenzothiazepine derivative. However, the known processes have several disadvantageous characteristics, such as low production, high temperature reaction conditions, the use of starting compounds which are not readily available and / or complicated after-treatments. These disadvantageous characteristics are naturally unfavorable in the industrial preparation of the desired dibenzothiazepine derivative. EP 1201663A1 and WO 2004/047722 A2 also report the preparation of dibenzothiazepine derivatives. BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods for the preparation of dibenzothiazepine compounds in good production without complicated back treatment, using readily available materials such as, for example, a nitrobenzene compound and thiosalicylic acid compound.
Each of the compounds and methods, and the steps thereof, are useful in, for example, the preparation of pharmaceuticals such as, for example, quetiapine. The present invention also provides, inter alia, the improved isolation of the nitro acid compound, as well as improved quality of the isolated lactam compound. The invention lies, in part, in a method for the preparation of a dibenzothiazepine compound of the Formula
(I) in which each R1, R2, R3, R4, R5, R6, R7 and R8, independently, represents a hydrogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group or an arylcarbonyl group, each group being optionally substituted, which comprises a step of subjecting a 2-amino-2'-carboxy-diphenylsulfide compound of Formula V:
wherein each R1, R2, R3, R, R, R6, R7 and R8 is the same as defined above, to a dehydration-condensation reaction, in the presence of an acid catalyst. The 2-amino-21-carboxy-diphenylsulfide of Formula V can be prepared by a known method. However, 2-amino-2'-carboxy-diphenylsulfide can be appropriately prepared by the method described below. The invention further lies, in part, in a method for the preparation of 2-amino-2'-carboxy-diphenylsulfide compound of the aforementioned Formula V, which comprises a step of reducing a 2-nitro-2 'compound. -carboxy-diphenylsulfide of the Formula IV:
wherein each R1, R2, R3, R, R5, R6, R7 and R8 is the same as defined above, in an aliphatic ester of an aliphatic alcohol having from 1 to 6 carbon atoms and an aliphatic carboxylic acid which has from 1 to 6 carbon atoms. The 2-nitro-2'-carboxy-diphenylsulfide compound of Formula IV can be prepared by a known method. However, the 2-nitro-2'-carboxy-diphenylsulfide compound is properly prepared by the method described below. The invention also lies, in part, in a method for the preparation of the above-mentioned 2-nitro-2'-carboxy-diphenylsulfide compound of Formula IV, which comprises a step of reacting a nitrobenzene compound of Formula II :
wherein each R1, R2, R3 and R4 is the same as defined above, with a thiosalicylic acid compound of Formula III:
wherein each R5, R6, R7 and R8 is the same as defined above, in a mixture of an aliphatic alcohol having from 1 to 6 carbon atoms and water. The method for the preparation of the dibenzothiazepine compounds of Formula I according to the invention is illustrated by means of Reaction Scheme 1:
DETAILED DESCRIPTION OF THE INVENTION In the formulas of the compounds involved in the methods described herein, an "alkyl group" means a branched chain or straight chain alkyl group of 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 5 carbon atoms, without any substituent, or a branched chain alkyl group or
straight chain of 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 5 carbon atoms, comprising one or more substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl, and including all isomers of each of the foregoing. Suitable alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. Also suitable are methyl, ethyl, propyl, butyl and pentyl. The substituent of the branched chain or straight chain alkyl group mentioned above, comprising one or more substituents can be attached at any position of the alkyl portion. Examples of substituents include, but are not limited to, straight or branched chain alkoxy groups comprising from 1 to 10 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy, and including all the isomers of each of the foregoing, and all subgroups thereof; alkylcarbonyl groups comprising from 2 to 6 carbon atoms and containing a branched chain or straight chain, comprising from 1 to 5 carbon atoms, such as acetyl, propionyl, butanoyl and pentanoyl, and including all the isomers of each of the previous ones, and all the subgroups of these; phenylcarbonyl groups
which may comprise one or more substituents; and phenyl, which may comprise one or more substituents. As used herein, a "phenylcarbonyl group" means a phenylcarbonyl group that does not comprise any substituent or phenylcarbonyl group comprising one or more substituents. As used herein, a "phenyl group" means phenyl group which does not comprise any substituent or phenyl group comprising one or more substituents. The substituent for the phenylcarbonyl group and the phenyl group may be phenyl, phenylcarbonyl or one of the alkyl, alkoxy and alkylcarbonyl groups mentioned above. As used herein, an "alkoxy group" means an alkoxy group comprising from 1 to 10 carbon atoms and containing a branched or straight chain alkyl portion which does not comprise any substituent and which comprises from 1 to 10 carbon atoms , or an alkoxy group having 1 to 10 carbon atoms and containing a branched chain or straight chain alkyl portion, which comprises one or more substituents and comprising from 1 to 10 carbon atoms. Examples of an "alkoxy group" include, but are not limited to, the alkyl groups mentioned above, an alkylcarbonyl group comprising from 2 to 6 carbon atoms, a phenylcarbonyl group which comprises one or more substituents and a phenyl which comprises one or more substituents.
An "alkylcarbonyl group" means an alkylcarbonyl group comprising from 2 to 11 carbon atoms and containing a branched chain or straight chain alkyl portion, which does not comprise any substituent and which comprises from 1 to 10 carbon atoms, or a alkylcarbonyl group comprising from 2 to 11 carbon atoms and containing a branched chain or straight chain alkyl portion, which comprises one or more substituents and comprising from 1 to 10 carbon atoms. Examples of alkyl portions of the "alkylcarbonyl group" include, but are not limited to those described above. An "aryl group" means an aryl group that does not comprise any substituent or an aryl group that comprises one or more substituents. Examples of "aryl groups" include, but are not limited to phenyl, naphthyl and antoryl, and any subgroup thereof. The appropriate groups are phenyl and naphthyl. An appropriate group is phenyl. Examples of the "aryl group" include, but are not limited to those described above for the alkyl groups. An "aryloxy group" means an aryloxy group comprising an aryl moiety that does not comprise any substituent or an aryloxy group comprising an aryl moiety comprising one or more substituents. Examples of aryl groups of an "aryloxy group" include, but are not limited to the substituents described above for the
alkyl group. An "arylcarbonyl group" means an arylcarbonyl group comprising an aryl moiety that does not comprise any substituent, or an arylcarbonyl group comprising an aryl moiety comprising one or more substituents. Examples of aryl groups of an "arylcarbonyl group" include, but are not limited to, the substituents described above for the alkyl group. The groups of R1 to R8 could be the same or different from each other, and each can be a hydrogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group or an arylcarbonyl group. Also suitable is a hydrogen atom, an alkyl group, an alkoxy group and an alkylcarbonyl group. The halogen atom for X of Formula II can be fluorine, chlorine, bromine or iodine. Also suitable are fluorine, chlorine and bromine. Also appropriate is chlorine. Each of the steps of the method for preparing the dibenzothiazepine compounds according to the invention is described in more detail below. In the first step of the method for the preparation of the dibenzothiazepine compounds of the invention, a nitrobenzene compound of the Formula II and a thiosalicylic acid compound of the Formula III are reacted in a solvent, in the presence of a base, to prepare a
composed of 2-nitro-2'-carboxy-diphenylsulfide of Formula IV. Examples of the nitrobenzene compounds of Formula II employed in the first step include, but are not limited to, 2-chloronitrobenzene, 2-bromonitrobenzene, 2-fluoronitrobenzene, 2-iodoitrobenzene, 2-chloro-5-methoxynitrobenzene, 2- bromine-5-methoxynitrobenzene, 2-fluoro-5-methoxynitrobenzene, 2-iodo-5-methoxynitrobenzene, 2-chloro-5-methylnitrobenzene, 2-bromo-5-methylnitrobenzene, 2-fluoro-5-methylnitrobenzene, 2-iodine 5-methylnitrobenzene, 2-chloro-5-phenylnitrobenzene, 2-bromo-5-phenylnitrobenzene, 2-fluoro-5-phenylnitrobenzene, 2-iodo-5-phenylnitrobenzene, 2-chloro-5-acetylnitrobenzene, 2-bromo-5- acetylnitrobenzene, 2-fluoro-5-acetylnitrobenzene and 2-iodo-5-acetylnitrobenzene, or any subset of these. Suitable are 2-halonitrobenzenes such as, for example, 2-chloronitrobenzene and 2-bromonitrobenzene. Also suitable is 2-chloronitrobenzene. Examples of thiosalicylic acid compounds of Formula III employed in the first step include, but are not limited to, thiosalicylic acid, 5-methoxy thiosalicylic acid, 5-methylthiosalicylic acid, 5-phenyl-thiosalicylic acid and 5-acetyl acid -salicylic, or any subgroup of these. Suitable are thiosalicylic acid and 5-methoxythiosalicylic acid. Also suitable is thiosalicylic acid.
The nitrobenzene compound of Formula II is generally employed in an amount of 0.7 to 10 moles, or 1.0 to 5 moles, per one mole of the thiosalicylic acid of Formula III. In some modalities it is used from 1.0 to 1.32, or from 1.1 to 1.32 or from 1.2 to 1.32 equivalents of 2-chloronitrobenzene. The first stage mentioned above is generally carried out in a solvent. There are no specific limitations in the solvents, as long as the solvents do not participate in the reaction. Examples of the solvents include, but are not limited to, water; amide solvents such as N, -dimethylformamide, N, -dimethylacetamide, N-methylpyrrolidone and dimethylimidazolidone; aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and 1-pentanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile and benzonitrile; or any combination of these. Appropriate are water, amides and aliphatic alcohols. More suitable are mixtures of lower aliphatic alcohols (ie, aliphatic alcohols having 1 to 6 carbon atoms) and water. Suitably, the mixture comprises the lower aliphatic alcohol and water in a volume ratio of 10/1 to 1/10 (also appropriately 5/1 to 1/10), in terms of the above for the latter. In the mixture, the aliphatic alcohol also appropriate is alcohol
isopropyl In some embodiments, the nitrobenzene compound of Formula II, such as 2-chloronitrobenzene, and the thiosalicylic acid compound of Formula III, such as thiosalicylic acid, are charged to a reactor at 20-25 ° C, followed by isopropanol. and water. The reactor containing the nitrobenzene compound of Formula II and the thiosalicylic acid of Formula III can be inactivated with, for example, nitrogen. The solvent in the first step can be employed in such a way that a weight ratio of the amount of thiosalicylic acid against the amount of the solvent (such as a water / isopropyl mixture) is in the range of 0.08 to 0.31, 0.12 to 0.27. or 0.16 to 0.23. The reaction of the first stage is generally carried out in the presence of a base. Examples of the appropriate bases include, but are not limited to, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium methylate, or any subset thereof. Also suitable are potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and sodium methylate or any subgroup thereof. The base is generally employed in a corresponding amount of 1 to 10 moles, or 1.5 to 5 moles, or 2.0 to 2.3 moles or 2.1 to 2.27 moles per one mole of the
total amounts of the starting compounds. The reaction in the first step is generally carried out at a temperature not higher than the boiling temperature of the solvent used, such as a temperature of 0 to 150 ° C, or of 20 to 100 ° C, or 70 to 84 ° C or from 79 to 84 ° C. The reaction period of the first stage depends mostly on the reaction temperature, but the reaction is generally completed in 20 hours. In some embodiments, the reaction mixture is heated to reflux (approximately 84 ° C) and maintained at this temperature for 6 hours. In the reaction of the first stage, additives may be added to accelerate the reaction, which is not the base. Examples of the additives include, but are not limited to, potassium iodide and N, N-dimethylaminopyridine. The additive can be used in an amount of 0.0005 to 0.5 mole (mole of additive / mole of nitrobenzene compound), or 0.001 to 0.1 mole, per one mole of nitrobenzene compound of Formula II. The chemical structure of the 2-nitro-2'-carboxydiphenylsulfide compound of Formula IV obtained in the first step of the invention depends on the chemical structure of the nitrobenzene compound of Formula II, as well as on the chemical structure of the acid compound thiosalicylic of the Formula III. Examples of the 2-nitro-2'-carboxydiphenylsulfide derivatives include, but are not limited to, 2-
nitro-2 '-carboxydiphenylsulfide, 2-nitro-4-methoxy-2'-carboxydiphenylsulfide, 2-nitro-4-methyl-2'-carboxydiphenylsulfide, 2-nitro-4-phenyl-2'-carboxydiphenylsulfide, 2-nitro- 4-acetyl-2 '-carboxydiphenylsulfide and 2-nitro-2'-carboxy-4'-methoxy-diphenylsulfide or any subgroup thereof. Also suitable are 2-nitro-2 '-carboxydiphenylsulfide and 2-nitro-2'-carboxy-4'-methoxydiphenylsulfide. The 2-nitro-2'-carboxy-phenylsulfide compound of Formula IV, prepared in the first step, can be recovered by means of a combination of a conventional washing process and a conventional separation process, such as a combination of adding a acid to make the acid reaction mixture and filtration of the precipitated crystalline product to obtain a crude product, or a combination of addition of water and an extraction solvent (organic solvent) to the reaction mixture and the addition of an acid to make acid the aqueous phase of the reaction mixture. Otherwise, the crude product can be recovered by placing the organic solvent portion under reduced pressure. Accordingly, the obtained crude product can be used in the next step. The crude product can also be purified, if necessary, by column or re-crystallization. The process for purification can be selected depending on each compound to be
purified. The acid used can be hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, or any subgroup of these. In the second step of the process of the invention, the 2-nitro-2'-carboxyphenylsulfide compound of Formula IV is reduced to give a 2-amino-2'-carboxydiphenylsulfide compound of Formula V. The reduction procedure carried out in the second stage it is not limited, and known methods for reducing the nitro group can be employed. Suitable methods include, for example, the Raney nickel method (hereinafter referred to as "Reaction A"), the ferrous salt method (hereinafter referred to as "Reaction B") and a method employing palladium, platinum. or its compounds (hereinafter referred to as "Reaction C"). In the reduction process, hydrogen gas is used as a source of hydrogen supply. Reaction A: Raney nickel method Raney nickel can be employed in the method in an amount of 1.0 to 80% by weight (in terms of nickel), or from 5.0 to 40% by weight, by the amount of compound of 2- nitro-2 '-carboxidiphenylsulfide of Formula IV. Examples of Raney nickels that can be used in the reaction include, but are not limited to, 10-60% Ni-Al alloy and one containing Cr and Mo. It can also be used
stabilized. Production is not heavily influenced by the Raney nickel development method. In the case of using the Raney nickel method, the reaction is generally carried out in the presence of hydrogen gas under pressure. Accordingly, the reaction is generally carried out in an autoclave. The pressure of the hydrogen gas can be as high as possible. Generally, the pressure of the hydrogen gas is in the range of 5 to 100 barg. The reaction could be carried out under atmospheric pressure. In this case, the reaction is carried out in the flow of hydrogen gas. There are no specific limitations on the solvents used in Reaction A, as long as the solvents do not participate in the reaction. Examples of the solvents include, but are not limited to, aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol. The volume of the solvent is selected such that the volume of the 2-nitro-2'-carboxy-diphenylsulfide compound of Formula IV would be 0.05 to 0.6 volume, or 0.1 to 0.6 volume per one volume of the solvent (volume of 2-nitro-2 '-carboxydiphenyl-sulfide compound of the formula / volume of solvent). Reaction A can be carried out at a temperature up to the boiling point of the solvent. The reaction is generally carried out at a temperature of 20 to 200 ° C or 25 to 150 ° C. The reaction period depends on the
temperature and pressure of hydrogen gas. The reaction is usually completed in 20 hours. After Reaction A is complete, the 2-amino-2'-carboxy diphenylsulfide compound of Formula V produced in the reduction, can be recovered by means of a conventional combination of a washing process and a separation process, such as a combination of filtration of the reaction mixture and concentration of the filtrate under reduced pressure. The product obtained before, by itself, can be used in the next stage. If desired, the product can be purified by column chromatography or re-crystallization. The purification process can be selected depending on the product to be purified. Reaction B: Ferrous Salt Method Examples of ferrous salts that can be used in the reaction include, but are not limited to, ferrous sulfate and ferrous chloride. These salts can be used in the hydrate or anhydride form. The appropriate ones are ferrous sulfate hydrates 7, ferrous salt anhydrides, ferrous salt hydrates 4 and ferrous salt hydrates n. The salt can be used in a volume of 0.1 to 30 (in terms of iron atom), or 0.5 to 10, by a volume of 2-nitro-2'-carboxy-diphenylsulfide of Formula IV. The mixture of water and aqueous ammonia is generally
used as a solvent for Reaction B. Aqueous ammonia can be prepared using concentrated aqueous ammonia (concentration of ammonia: from 25 to 28% by weight). Aqueous ammonia of lower concentration or water containing ammonia gas can also be used, as long as the ammonia content is sufficient. Water may be employed, such that the volume of 2-nitro-2'-carboxy-phenylsulfide derivative of Formula IV would be 0.01 to 0.4 equivalents per one volume of water (volume of 2-nitro-2'-derivative). carboxy-diphenylsulfide / volume of water), or from 0.02 to 0.2 equivalents (the same as before). The volume of ammonia is selected so that the volume of 2-nitro-2'-carboxy diphenylsulfide derivative would be 0.005 to 0.5 equivalents, or 0.01 to 0.5 equivalents, per one volume of ammonia (volume of 2-nitro derivative). 2'-carboxydiphenylsulfide / volume of ammonia). Reaction B can be carried out at a temperature up to the boiling point of the solvent. The reaction is generally carried out at a temperature of 20 to 100 ° C or 40 to 90 ° C. The reaction period depends on the temperature. The reaction is usually complete in 2 hours. After Reaction B is complete, the 2-amino-2'-carboxy diphenylsulfide compound of Formula V produced in the reduction, can be recovered by means of a conventional combination of a washing procedure and
a separation procedure. For example, the reaction mixture is filtered, and an acid (for example, hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid) is added to the filtrate, in such a way that its pH is placed on the acid side. The obtained filtrate is concentrated under reduced pressure to obtain a crude compound. The product obtained before, by itself, can be used in the next stage. If desired, the product can be purified by means of column chromatography or re-crystallization. The purification process can be selected depending on the product to be purified. Reaction C: Method employing palladium or platinum (or its compounds) The reaction may be carried out in the presence of a reduction catalyst (ie, hydrogenation catalyst), selected from the group consisting of palladium (Pd), platinum (Pt), a palladium compound and a platinum compound, or any combination or subgroup thereof. The reduction catalyst is appropriately deposited on a carrier such as carbon (C) or barium sulfate. Suitable are Pt / C, Pd / C, Pd / barium sulfate, Pd-Pt / C (or Pd, Pt / C), and platinum oxide. Pd-Pt / C is also appropriate. The reduction catalyst comprising palladium or platinum can be used in a corresponding amount of?,, ?? to 30% by weight (in terms of palladium metal or
platinum), or from 0.05 to 10% by weight, by the amount of the 2-nitro-2 '-carboxydisulfide derivative of Formula IV. If the catalyst is deposited on a conveyor, the catalyst can be deposited in an amount of 1 to 10% by weight (in terms of palladium metal or platinum), by the amount of carrier. If Pd / C, Pt / C or Pd-Pt / C is used, a dry catalyst having a water content of not more than 5% can be used, as well as a wet catalyst containing water component in a larger amount . The wet catalyst could contain from 10 to 70% by weight (amount of water by the total amount of catalyst and transporter). When platinum oxide is used in Reaction C as the reduction catalyst, it can be used in an amount of 0.1 to 50% by weight, or 1 to 30% by weight, by the amount of 2-nitro derivative 2 '-carboxydisulfide of Formula IV. Reaction C is generally carried out in the presence of hydrogen gas under pressure. Accordingly, the reaction is generally carried out in an autoclave or other reaction vessel. The pressure of the hydrogen gas can be as high as possible. Generally, the pressure of the hydrogen gas is in the range of 2 to 100 barg or 4 to 6 barg. The reaction could be carried out under atmospheric pressure. In this case, the reduction (or hydrogenation) is
can carry out in the flow of hydrogen gas. In some embodiments, hydrogen is introduced into the recent up to 5 barg and stirring is initiated, and the hydrogen pressure is maintained at 5 barg. Reaction C is generally carried out in a solvent. There are no specific limitations in the solvent used, as long as the solvents do not participate in the reaction. Examples of the solvents include, but are not limited to, aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol, ethers such as methyl acetate, ethyl acetate, isopropyl acetate and n-acetate. butyl, and amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and dimethylimidazolidone, or any combination thereof, or any subgroup thereof. The esters of an aliphatic alcohol having 1 to 6 carbon atoms and an aliphatic carboxylic acid having 1 to 6 carbon atoms are suitable, because the use of the ester solvent can reduce the production of by-products ( that is, impurities). The solvent can be used in an amount of 2 to 70% by weight, or 5 to 50% by weight, for the amount of 2-nitro-21-carboxy-phenylsulfide derivative of Formula IV. In some embodiments, an appropriate solvent is ethyl acetate. Reaction C is generally carried out at a
temperature from 10 to 200 ° C, or from 20 to 150 ° C. The reaction period depends on the reaction temperature and the pressure of the hydrogen gas, but generally it does not last more than 30 hours. In some embodiments, the reaction suspension is heated to 50 ° C and maintained at this temperature and under pressure of 5 barg of hydrogen for 5 hours. The 2-amino-2'-carboxy diphenylsulfide derivative of Formula V produced in Reaction C (hydrogenation) can be recovered by means of a conventional combination of a washing process and a separation process, such as a filtration combination of the reaction mixture and concentration of the filtrate under reduced pressure. The product obtained before, by itself, can be used in the next stage. If desired, the product can be purified by column chromatography or re-crystallization. The purification process can be selected depending on the product to be purified. In some embodiments, at the end of the reaction, the reaction mixture is cooled to 20-25 ° C and filtered to remove the catalyst residue. The ethyl acetate solution of the amino acid is washed with water. The material can be used directly in the next stage without further purification or isolation. The chemical structure of the 2-amino-2'-carboxydifhenylsulfide compound of Formula V prepared in the second step (reduction step) depends on the structure
2-nitro-2 '-carboxydiphenylsulfide chemistry of Formula IV used in the second stage as starting material. Examples of 2-amino-2'-carboxyphenylsulfide compounds of Formula V include, but are not limited to, 2-amino-2'-carboxydiphenylsulfide, 2-amino-4-methoxy-2'-carboxylfhenyl sulfide, -amino-4-methyl-2 '-carboxidiphenylsulfide, 2-amino-4-phenyl-2' -carboxydiphenylsulfide, 2-amino-4-acetyl-2 '-carboxydiphenylsulfide and 2-amino-2' -carboxy-4 '- methoxydifhenylsulfide or any subset of these. Suitable are 2-amino-2 '-carboxydiphenylsulfide and 2-amino-2'-carboxy-4'-methoxydiphenylsulfide. In the third step of the invention, the 2-amino-2'-carboxy diphenylsulfide compound of Formula V is condensed by dehydration to prepare the dibenzothiazepine compound of Formula I. The reaction of the third step can be carried out using no solvent. However, the reaction can be carried out in a hydrophobic organic solvent, which does not participate in the reaction. Examples of the organic solvents include, but are not limited to, aromatic hydrocarbons such as toluene, xylene, eumeno and benzene; halogenated aromatic hydrocarbons such as chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, bromobenzene, 1,2-dibromobenzene, 1,3-dibromobenzene and 1,4-dibromobenzene; Aliphatic hydrocarbons
cyclics such as cyclohexane, cycloheptane and cyclooctane; and aliphatic esters such as ethyl acetate, butyl acetate, methyl butyrate, ethyl butyrate and butyl butyrate; or other solvents such as ethanol, 1-pentanol or methyl isobutyl ketone; or any combination or subgroup of these. Suitable are toluene, xylene, eumeno and 1,2-dichlorobenzene. There is no specific limitation of the amount of solvent used in the third stage. However, it is appropriate that the solvent be used in an amount to give a ratio of the weight amount of the 2-amino-2'-carboxydiphenylsulfide compound against the volume amount of the solvent (% of P / V) of not less than of 3%, or in the range of 4 to 40%. The reaction in the third stage can be carried out in a Dean-Stark apparatus to perform the azeotropic dehydration (to reflux with the elimination of the water produced in the reaction), in order to accelerate the reaction rate and the coefficient of conversion. There is no specific limitation on the reaction temperature of the third stage. Appropriate is a temperature of 100 to 200 ° C or 120-140 ° C. In addition, the reaction of the third step can take place in the presence of an acid catalyst such as, for example, sulfonic acid, para-toluene, benzene sulfonic acid, methane sulfonic acid, sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, nitric
formic acid. The use of an acid catalyst is effective to accelerate the reaction rate. Other suitable catalysts are para-toluenesulfonic acid, benzenesulfuric acid, methanesulfonic acid, sulfuric acid and phosphoric acid. Generally, 0.01-20% mol or 0.05-10% mol of the acid catalyst is used (based on the amount of amino acid, ie, composed of 2-amino-2'-carboxydiphenylsulfide). In some embodiments, the amino acid and 0.1-0.2% mol of para-toluenesulfonic acid are heated at reflux for 10 hours with azeotropic removal of water. The chemical structure of the dibenzothiazepine compound of Formula I obtained in the third step depends on the chemical structure of the 2-amino-2'-carboxydiphenylsulfide derivative of Formula IV. Examples of the dibenzothiazepine derivatives of Formula I include, but are not limited to, dibenzo [b, f] [1,4] thiazepin-1-one, 8-methyl-dibenzo [b, f] [1,] thiazepin-ll-one, 8-phenyl-dibenzo [b, f] [1,4] -thiazepin-l-one, 8-methoxy-dibenzo [b, f] [1,4] thiazepin-l-one and 2 -methoxy-dibenzo [b, f] [1,4] -thiazepin-ll-one. Appropriate are dibenzo [b, f] [1,4] -thiazepin-ll-one and 2-methoxy-dibenzo [b, f] [1,4] -thiazepin-ll-one, or any subgroup thereof. The dibenzothiazepine compound of Formula I produced in the third stage can be easily recovered
cooling the reaction mixture to precipitate it to a crystalline product of the dibenzothiazepine compound. The precipitated crystallized product is then collected by filtration to give the dibenzothiazepine compound of high purity. If more purification is required, re-crystallization or column chromatography can be used. Otherwise, the reaction mixture is made alkaline by the addition of an aqueous alkaline solution and then the aqueous portion is removed, before precipitating the resulting product. The remaining organic portion is then cooled to precipitate a crystalline product of the dibenzothiazepine compound. The aqueous alkaline solution can be produced by the use of hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, or any subgroup thereof. The alkaline compound in the alkaline solution can be in a concentration of 0.5 to 30% by weight. There is no limitation on the amount of alkaline solution, but the alkaline solution can be used in an amount of 0.05 to 0.4 parts by weight, based on the weight part of the product of the third stage (ie, dibenzothiazepine compound of the Formula I). In some embodiments, after heating for ten hours at 140 ° C, the contents of the vessel are cooled to 55 ° C and the resulting suspension is filtered. The lactam filtration product of dibenzothiazepine is washed with methanol and dried
to the vacuum The appropriate embodiments of the invention are described below. 1) The nitrobenzene compound of Formula II is a halonitrobenzene such as 2-chloronitrobenzene or 2-bromo-nitrobenzene. 2) The thiosalicylic acid compound of Formula III is thiosalicylic acid or 5-methoxythiosalicylic acid. 3) In the first step of the method for the preparation of dibenzothiazepine compounds, a base such as potassium hydroxide is used. 4) The 2-nitro-2 '-carboxydiphenylsulfide derivative of Formula IV is 2-nitro-2'-carboxy-phenylsulfide or 2-nitro-21-carboxy-4'-methoxydiphenylsulfide. 5) In the reduction of the second step of the method for preparing a dibenzothiazepine compound, the Pd-Pt / C catalyst is used and ethyl acetate is used as the solvent. 6) In the condensation stage of the dehydration of the method for the preparation of dibenzothiazepine, para-toluenesulfonic acid or another acid is used. A dibenzothiazepine compound, represented by Formula I and of value as an intermediate compound for preparing pharmaceuticals, can be easily produced at
high production with easy procedures according to the methods described above. So that the invention presented here could be understood more efficiently, examples are provided later. It should be understood that these examples are for illustrative purposes only and will not be construed as limiting the invention in any way. EXAMPLES Example 1 for Step -1 Thiosalicylic acid (20 g, 0.126 moles, 96.9%) and 2-chloronitrobenzene (24.6 g, 0.156 moles, 99.7%) were added to an appropriate vessel, followed by IPA (50 ml) and water (10 ml) at 20-25 ° C. The reactor was activated (nitrogen), the suspension was heated to 30-35 ° C and an aqueous KOH solution (30.9 g, 0.273 moles, 49.51% w / w) was added, followed by water wash (24.4 ml). The reaction mixture was heated to reflux and kept at this temperature for 6 hours. Upon completion of the reaction, the solution was cooled to 65 ° C and water (50 ml) was added. The solution was maintained at 65 ° C and c.HCl (20 g) was added, leading to precipitation of the crude Nitro Acid. The suspension was refluxed and stirred at this temperature for 1 hour. The solution was then cooled to 25-30 ° C. After stirring for 30 minutes at 25-30 ° C, the suspension was filtered and the filtrate was washed with water (2 x 40 ml) and toluene (2 x 40 ml) and left on the filter under vacuum
1 hour to give 2- (2-nitrophenylsulfuryl) benzoic acid (31. lg at 100% w / w, 90%). Example 2 for Step -2 Nitro acid (43.0 g, 145 mmol, 93%), Pd-Pt / C catalyst (8 g wet, 0.076% w / w, dry) and ethyl acetate (400 ml) were charged. in a suitable reactor at 20-25 ° C. Hydrogen was introduced into the vessel up to 5 barg. The reaction suspension was heated to 50 ° C and the suspension was heated to 50 ° C at 5 barg hydrogen pressure for 5 hours. At the end of the reaction, the contents of the container were filtered. The ethyl acetate solution was washed with water (120 ml). Example 3 for Step-3 Para-toluenesulfonic acid (41 mg, 0.2175 mmol) was added to the ethyl acetate solution obtained in Example 2, and about 50% of the ethyl acetate was removed by distillation. Xylene (320 ml) was added to the reactor and distillation was continued until batch temperature of 125 ° C was achieved. The reaction was then heated for 10 hours with azeotropic removal of water. The contents of the vessel were cooled to 55 ° C and the resulting suspension was filtered. The filtrate was washed with methanol (120 ml), isolated and dried in vacuo to give 10, 11-dihydrodibenzo- [b, f] [1,4] thiazepin-1-one (28.4 g, 86%). Various modifications of the invention, in addition to
those described herein will be apparent to those skilled in the art from the foregoing description. It is also intended that the modifications fall within the scope of the appended claims. Each reference (including, but not limited to, newspaper articles, US patents and non-US patents, patent application publications, international patent application publications, and the like) cited in the present application, are incorporated herein for reference in its entirety. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (2)
- CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A method for the preparation of a dibenzothiazepine compound of Formula I: (i) characterized in that each R1, R2, R3, R4, R5, R6, R7 and R8, independently, represents a hydrogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group and an aryl group, an aryloxy group, or an arylcarbonyl group, each optionally substituted group, comprising a step of subjecting a 2-amino-2'-carboxy-diphenylsulfide compound of Formula V: wherein each R1, R2, R3, R4, R5, R6, R7 and R8 is the same as defined above, for the dehydration-condensation reaction in the presence of an acid catalyst. 2. - The method according to claim 1, characterized in that the acid catalyst is at least one compound selected from the group consisting of para-toluenesulfonic acid, benzenesulfuric acid, methanesulfonic acid and phosphoric acid. 3. The method according to claim 1, characterized in that the following step is performed before the dehydration-condensation reaction step: a step of reducing a 2-nitro-2'-carboxy-diphenylsulfide compound from the Formula IV: (IV) wherein each R1, R2, R3, R4, R5, R6, R7 and R8 is the same as defined above, in an aliphatic ester of an aliphatic alcohol having from 1 to 6 carbon atoms and a carboxylic acid aliphatic having 1 to 6 carbon atoms to obtain the 2-amino-2'-carboxy compound diphenylsulfide of Formula V. 4. - The method according to claim 3, characterized in that the aliphatic ester is at least one aliphatic ester selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate and sodium acetate. -butyl. 5. The method according to claim 3, characterized in that the reduction step is carried out in the presence of at least one catalyst selected from the group consisting of Pd / C, Pt / C and Pd-Pt / C. 6. - The method according to claim 3, characterized in that the following step is performed before the reduction step: a step of reacting a nitrobenzene compound of Formula II: (II) wherein each R1, R2, R3 and R4 is the same as defined above, with a thiosalicylic acid compound of Formula III: (III) wherein each R5, R6, R7 and R8 is the same as defined above, in a mixture of aliphatic alcohol having from 1 to 6 carbon atoms and water to obtain the compound of 2-nitro-2 '- carboxy-diphenylsulfide of Formula IV. 7. - The method according to claim 6, characterized in that the mixture comprises the aliphatic alcohol and water in a volume ratio of 10/1 to 1/10, in terms of the first for the latter. 8. The method according to claim 6, characterized in that the aliphatic alcohol is isopropyl alcohol. 9. - The method according to claim 6, characterized in that the reaction stage is carried out under reflux. 10. - The method according to claim 6, characterized in that the reaction is carried out in the presence of a base. 11. - A method for preparing a 2-amino-2'-carboxy-diphenylsulfide compound of Formula V: (V) characterized in that each R1, R2, R3, R, R5, R6, R7 and R8, independently, represents a hydrogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group or an arylcarbonyl group, each optionally substituted group, which comprises a step of reducing a 2-nitro-2'-carboxy-diphenylsulfide compound of Formula IV: (IV) wherein each R1, R2, R3, R4, R5, R6, R7 and R8 is the same as defined above, in an aliphatic ester of an aliphatic alcohol having from 1 to 6 carbon atoms and an aliphatic acid carboxylic having 1 to 6 carbon atoms. 12. The method according to the claim 11, characterized in that the aliphatic ester is at least one ester selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate and n-butyl acetate. 13. The method according to claim 11, characterized in that the reduction step is carried out in the presence of at least one catalyst selected from the group consisting of Pd / C, Pt / C and Pd-Pt / C. 14. - A method for preparing 2-nitro-2'-carboxy-diphenylsulfide compound of Formula IV: (IV) characterized in that each R1, R2, R3, R4, R5, R6, R7 and R8, independently, represents a hydrogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, an aryl group, an aryloxy group or an arylcarbonyl group , each optionally substituted group, which comprises a step of reacting a nitrobenzene compound of Formula II: (?) wherein each R1, R2, R3 and R4 is the same as defined above, with a thiosalicylic acid compound of Formula III: wherein each R5, R6, R7 and R8 is the same as defined above, in a mixture of allylic alcohol having from 1 to 6 carbon atoms and water. 15.- The method according to the claim 14, characterized in that the mixture comprises the aliphatic alcohol and water in a volume ratio of 10/1 to 1/10, in terms of the former for the latter. 16. The method according to claim 14, characterized in that the aliphatic alcohol is alcohol Isopropyl 17. The method according to claim 14, characterized in that the reaction stage is carried out under reflux. 18.- The method of compliance with the claim 14, characterized in that the reaction is carried out in the presence of a base. 19. - A method, characterized in that it comprises: reacting a halonitrobenzene compound with a thiosalicylic acid compound in a solvent in the presence of a base at about 84 SC for about 6 hours to obtain a nitro acid compound; reducing the nitro acid compound with a Pd-Pt / C catalyst in the presence of ethyl acetate at about 50 ° C under a pressure of about 4 to about 6 barg under hydrogen gas for about 5 hours to obtain an amino acid compound; and subjecting the amino acid compound to dehydration-condensation reaction in the presence of an acid and xylene from about 120 to about 140aC for about 10 hours with azeotropic removal of water to produce a lactam compound. 20. - The method according to claim 19, characterized in that the halonitrobenzene compound is
- 2-chloronitrobenzene. 21. The method according to claim 19, characterized in that the thiosalicylic acid compound is thiosalicylic acid. 22. The method according to the claim 19, characterized in that the acid in the dehydration-condensation reaction is para-toluenesulfonic acid, sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid or formic acid. 23.- The method according to the claim 19, characterized in that the solvent is water and isopropanol. 24. The method according to claim 19, characterized in that the base is potassium hydroxide. 25. The method according to claim 19, characterized in that the halonitrobenzene compound and the thiosalicylic compound are brought to reflux at about 84aC for about 6 hours. 26. The method according to claim 19, characterized in that the nitro acid compound formed by the reaction of the halonitrobenzene compound and the thiosalicylic acid compound is recovered by cooling to 65 ° C and precipitating with acid. 27. The method according to claim 26, characterized in that after precipitating with acid, the nitro acid compound is heated to reflux at 79 to 84 ° C. 28. - The method according to claim 27, characterized in that it further comprises cooling the nitro acid compound from 25 to 30 ° C after heating to reflux. 29.- The method of compliance with the claim 19, characterized in that the nitro acid compound is reduced with the Pd-Pt / C catalyst at a pressure of about 5 barg. 30. The method according to claim 19, characterized in that the dehydration-condensation reaction is carried out at approximately 1402C. 31.- A method for the preparation of a dibenzothiazepine compound, characterized in that it comprises: reacting 2-chloronitrobenzene with thiosalicylic acid in water and isopropanol in the presence of potassium hydroxide at approximately 84 eC for about 6 hours to obtain 2 - (2 -nitrophenyl-sulfañilo) benzoico; reduce 2- (2-nitrophenyl-sulfanyl) enzoic acid with a Pd, Pt / C catalyst in the presence of ethyl acetate at about 50 ° C under a pressure of about 5 barg under hydrogen gas for about 5 hours to obtain acid 2 - ( 2-aminophenyl-sulfañilo) benzoico; and subjecting 2- (2-aminophenyl-sulfañilo) benzoic acid to dehydration-condensation reaction in the presence of para-toluenesulfonic acid in xylene at about 1402C for about 10 hours with azeotropic removal of the water to produce 10,11-dihydrodibenzo [b, f] [1,4] thiazepin-1-one. 32. - A method for the preparation of 2 - (2-nitropheni-1-sulphonyl) benzoic acid, characterized in that it comprises: reacting 2-chloro-trobenzene with thiosalicylic acid in water and isopropanol in the presence of potassium hydroxide. about 84SC for about 6 hours to obtain 2- (2-nitrophenyl-sulfañyl) benzoic acid. 33. A method for preparing 2- (2-amino-1-sulphonyl) benzoic acid, characterized in that it comprises: reducing 2 - (2-nitrophenol-1-sulphonyl) benzoic acid with a catalyst Pd, Pt / C in the presence of ethyl acetate at about 50 ° C at a pressure of about 5 barg under hydrogen gas for about 5 hours to obtain 2 - (2 - aminophen - 1 - sulphonyl) benzoic acid. 34. - A method for the preparation of 10,11-dihydrodibenzo [b, f] [1,4] thiazepin-l-one, characterized in that it comprises: subjecting 2- (2-aminophenyl-sulfanyl) benzoic acid to dehydration reaction -condensation in the presence of acid para-toluenesulfonic in xylene at about 140 SC for about 10 hours with azeotropic removal of the water to produce 10,11-dihydrodibenzo [b, f] [1,4] thiazepin-1-one.
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