WO2007017544A2 - Procedimiento para la obtención de 3,3-difenilpropilaminas - Google Patents
Procedimiento para la obtención de 3,3-difenilpropilaminas Download PDFInfo
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- WO2007017544A2 WO2007017544A2 PCT/ES2006/000458 ES2006000458W WO2007017544A2 WO 2007017544 A2 WO2007017544 A2 WO 2007017544A2 ES 2006000458 W ES2006000458 W ES 2006000458W WO 2007017544 A2 WO2007017544 A2 WO 2007017544A2
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- WIPO (PCT)
- Prior art keywords
- acid
- formula
- compound
- alkyl
- mixtures
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 98
- KISZTEOELCMZPY-UHFFFAOYSA-N 3,3-diphenylpropylamine Chemical class C=1C=CC=CC=1C(CCN)C1=CC=CC=C1 KISZTEOELCMZPY-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 150000003839 salts Chemical class 0.000 claims abstract description 89
- 239000000203 mixture Substances 0.000 claims abstract description 60
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical group 0.000 claims abstract description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 5
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 73
- 230000008569 process Effects 0.000 claims description 44
- 239000002253 acid Substances 0.000 claims description 39
- 150000007524 organic acids Chemical class 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 150000007522 mineralic acids Chemical class 0.000 claims description 28
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 21
- -1 2-methoxy-5- methylphenyl Chemical group 0.000 claims description 19
- 239000012429 reaction media Substances 0.000 claims description 19
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 18
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 15
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 14
- 239000002841 Lewis acid Substances 0.000 claims description 13
- 150000004677 hydrates Chemical class 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 150000007517 lewis acids Chemical class 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 235000005985 organic acids Nutrition 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 229940095064 tartrate Drugs 0.000 claims description 9
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
- 229910002651 NO3 Inorganic materials 0.000 claims description 5
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- CCXFTVHDCYNKJH-OAQYLSRUSA-N (3r)-3-(2-methoxy-5-methylphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine Chemical compound COC1=CC=C(C)C=C1[C@H](CCN(C(C)C)C(C)C)C1=CC=CC=C1 CCXFTVHDCYNKJH-OAQYLSRUSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- FWUJIDZFUQSGOI-ZMBIFBSDSA-N 2,3-dihydroxybutanedioic acid;(3r)-3-(2-methoxy-5-methylphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine Chemical compound OC(=O)C(O)C(O)C(O)=O.COC1=CC=C(C)C=C1[C@H](CCN(C(C)C)C(C)C)C1=CC=CC=C1 FWUJIDZFUQSGOI-ZMBIFBSDSA-N 0.000 claims 2
- QDQUJHUKAQWAQM-ZMBIFBSDSA-N (3r)-3-(2-methoxy-5-methylphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine;hydrobromide Chemical compound Br.COC1=CC=C(C)C=C1[C@H](CCN(C(C)C)C(C)C)C1=CC=CC=C1 QDQUJHUKAQWAQM-ZMBIFBSDSA-N 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 abstract description 19
- 229960004045 tolterodine Drugs 0.000 abstract description 18
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 abstract description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 abstract description 5
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 abstract description 2
- 206010046543 Urinary incontinence Diseases 0.000 abstract description 2
- 208000013403 hyperactivity Diseases 0.000 abstract description 2
- 208000024891 symptom Diseases 0.000 abstract description 2
- 210000003932 urinary bladder Anatomy 0.000 abstract description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 22
- 150000001412 amines Chemical class 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 11
- 238000007796 conventional method Methods 0.000 description 10
- 238000007336 electrophilic substitution reaction Methods 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229940043279 diisopropylamine Drugs 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 6
- OOGJQPCLVADCPB-FQEVSTJZSA-N 2-[(1s)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound C1([C@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-FQEVSTJZSA-N 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- OOGJQPCLVADCPB-UHFFFAOYSA-N 2-[3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound C=1C(C)=CC=C(O)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 OOGJQPCLVADCPB-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 238000001640 fractional crystallisation Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- CCXFTVHDCYNKJH-UHFFFAOYSA-N 3-(2-methoxy-5-methylphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine Chemical compound COC1=CC=C(C)C=C1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 CCXFTVHDCYNKJH-UHFFFAOYSA-N 0.000 description 3
- QOHVOTFSKSSADY-UHFFFAOYSA-N 3-phenyl-n,n-di(propan-2-yl)prop-2-en-1-amine Chemical compound CC(C)N(C(C)C)CC=CC1=CC=CC=C1 QOHVOTFSKSSADY-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- TWHNMSJGYKMTRB-KXYUELECSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(1r)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 TWHNMSJGYKMTRB-KXYUELECSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- YCVOIKCPNOVQMV-UHFFFAOYSA-N 3-phenyl-n,n-di(propan-2-yl)prop-2-en-1-amine;hydrochloride Chemical compound Cl.CC(C)N(C(C)C)CC=CC1=CC=CC=C1 YCVOIKCPNOVQMV-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 210000001268 chyle Anatomy 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 description 1
- 150000000093 1,3-dioxanes Chemical class 0.000 description 1
- VESLRNDUOCLYDT-UHFFFAOYSA-N 1-phenylprop-2-en-1-amine Chemical compound C=CC(N)C1=CC=CC=C1 VESLRNDUOCLYDT-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BYNJCCMGUBTMJZ-UHFFFAOYSA-N 3,3-diphenylpropanal Chemical class C=1C=CC=CC=1C(CC=O)C1=CC=CC=C1 BYNJCCMGUBTMJZ-UHFFFAOYSA-N 0.000 description 1
- QDQUJHUKAQWAQM-UHFFFAOYSA-N 3-(2-methoxy-5-methylphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine;hydrobromide Chemical compound Br.COC1=CC=C(C)C=C1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 QDQUJHUKAQWAQM-UHFFFAOYSA-N 0.000 description 1
- OCGTUTJXBDQGKL-UHFFFAOYSA-N 3-(2-methoxy-5-methylphenyl)-3-phenylpropan-1-ol Chemical compound COC1=CC=C(C)C=C1C(CCO)C1=CC=CC=C1 OCGTUTJXBDQGKL-UHFFFAOYSA-N 0.000 description 1
- RUROFEVDCUGKHD-UHFFFAOYSA-N 3-bromoprop-1-enylbenzene Chemical compound BrCC=CC1=CC=CC=C1 RUROFEVDCUGKHD-UHFFFAOYSA-N 0.000 description 1
- RDAFNSMYPSHCBK-UHFFFAOYSA-N 3-phenylprop-2-en-1-amine Chemical compound NCC=CC1=CC=CC=C1 RDAFNSMYPSHCBK-UHFFFAOYSA-N 0.000 description 1
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000007799 cork Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004862 dioxolanes Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/28—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by unsaturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the invention relates to a process for obtaining 3,3-diphenylpropylamines, their enantiomers or mixtures thereof, or their salts, including pharmaceutically acceptable salts.
- 3,3-Diphenylpropylamines are known that act as muscarinic receptor antagonists and are useful in the treatment of urinary incontinence and other symptoms of urinary bladder hyperactivity.
- N N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine, whose enantiomer (R) is tolterodine, the international common denomination of compound (R) - (+) -N, N-diisopiOpil-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine [(R) -tolterodine].
- the invention faces the problem of providing an alternative method for obtaining 3,3-diphenylpropylamines, and in particular of tolterodine, which overcomes the problems existing in the different syntheses of the prior art mentioned above.
- the solution provided by the invention is based on the fact that the inventors have observed that it is possible to obtain 3,3-diphenylpropylamines of formula (I) (defined below), their enantiomers or mixtures thereof, their solvates, hydrates or their salts (including pharmaceutically acceptable salts and pharmaceutically unacceptable salts), from the reaction of a propylenephenylamine of formula (II) (defined below) with a disubstituted aromatic hydrocarbon of formula (III) (defined below), by a reaction of aromatic electrophilic substitution Friedel-Cra ⁇ s type, providing said compounds with very good yields.
- Said compound of formula (II) can be obtained from commercial and economic starting compounds.
- a process such as that provided by the present invention has the advantage that the number of synthetic stages is considerably reduced with respect to prior art procedures, while achieving high yields with very simple steps. Likewise, said process is not toxic and allows starting from very cheap and non-dangerous reagents by providing 3,3-diphenylamines, and, in particular, N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl - amine, its enantiomers or mixtures thereof, its solvates, hydrates or its salts, in particular, its pharmaceutically acceptable salts, with good yield and pharmaceutical quality. All this contributes to reducing the overall cost of the procedure, which makes it commercially interesting and allows its implementation at industrial level.
- the invention relates to a process for obtaining 3,3-diphenylpropylamines of formula (I) comprising reacting a propylenephenylamine of formula (II) with a disubstituted aromatic hydrocarbon of formula (III), and , then, if desired, separate the desired (R) or (S) enantiomer, or the mixture of enantiomers, and / or converting the compound of formula (I) into a salt thereof.
- the invention relates to a process for obtaining 3,3-diphenylamines of formula (I) from a compound of formula (II) obtained by a process comprising the reaction between a compound of formula (IV) (defined below) with a primary or secondary amine of formula (V) (defined below) by a nucleophilic substitution reaction.
- the invention relates to acid addition salts of the compound of formula (II).
- the invention relates to a process, hereinafter, method of the invention [11, for obtaining a 3,3-diphenylpropylamine of formula (I):
- Ri is hydrogen, C] -C 6 alkyl, Ci-C 6 haloalkyl or alkoxyalkyl of the formula
- n is an integer between 1 and 3 and R 5 is Ci-C 6 alkyl
- R2 is alkyl Ci-C 6 alkoxy Ci-C 6, halogen, NO 2, CN, CHO or protected free, or COOR CH2OH 6 wherein R 6 is H or an alkyl group Ci-C 6; R 3 and R 4 , independently, are selected from H and Ci-C 8 alkyl or together form a 3- to 7-membered ring with the nitrogen to which they are attached; their enantiomers or mixtures thereof, their solvates, hydrates, or salts, comprising: a) reacting a compound of formula (II)
- haloalkyl refers to an alkyl group, linear or branched, substituted by one or more halogens, such as fluorine, chlorine, bromine or iodine.
- protected CHO refers to a carbonyl group functionalized or protected by groups commonly used to block the functionality of said carbonyl group while other functional groups of the compound react. Such groups can be optionally removed to unmask the carbonyl group.
- Suitable protecting groups of a carbonyl group are known in the state of the art and include those described in Green, TW, "Protective Groups in Organic Synthesis” John Wiley & Sons, New Cork 1999.
- Examples of carbonyl group protecting groups include, among others, an ester such as an alkyl ester, for example, methyl ester, ethyl ester, tert-butyl ester or benzyl ester, an alkoxy group such as dimethoxy, diethoxy or other Ci-C 6 dialkoxy, diphenoxy, cyclic ketals such as dioxolanes, 1,3-dioxanes or catechols.
- the reaction of the propylenephenylamine of formula (II) with the disubstituted aromatic hydrocarbon of formula (III) constitutes an electrophilic substitution reaction of the ortho position of the aromatic ring present in the compound of formula (III), of Friedel-Crafts type, and it is carried out in a reaction medium comprising an acid that acts as a catalyst for said aromatic electrophilic substitution reaction of type
- said acid is an inorganic acid.
- inorganic acids that may be used include hydrobromic, perchloric, sulfuric, hydrochloric, phosphoric acids, etc., and mixtures thereof. Said inorganic acids can be used in the form of aqueous solutions or suspensions.
- said acid is an organic acid, advantageously, a strong organic acid.
- organic acids include sulfonic acids, such as p-toluenesulfonic acid, methanesulfonic acid, etc., acetic acid, trifluoroacetic acid, etc., or mixtures thereof.
- the reaction medium comprises one or more inorganic acids and one or more organic acids.
- the reaction medium comprises an inorganic acid selected from the group consisting of hydrobromic acid, perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid and mixtures thereof and an organic acid, such as, for example, acetic acid.
- said acid is a Lewis acid, such as, for example, AlCl 3 , SnCl 4 , ZnCl 2 , BF 3 , etc., or mixtures thereof.
- the aromatic electrophilic substitution reaction can be carried out under different conditions depending on the reactivity of the compound of formula (III).
- R] in the compound of formula (III) is hydrogen
- the aromatic electrophilic substitution reaction can be carried out in different ways, for example: - using between 4 and 16 equivalents of the alkoxy derived from formula (III) [Rj ⁇ H] per equivalent of compound of formula ( II), in a reaction medium comprising an inorganic acid (with the exception of hydrobromic acid), for example, perchloric, sulfuric, hydrochloric, phosphoric acid or mixtures thereof, generally aqueous, at a temperature between 8O 0 C and the * " reflux temperature, preferably at the reflux temperature; or using between 4 and 16 equivalents of the alkoxy derived from formula (III) [Ri ⁇ H] per equivalent of compound of formula (II), in a reaction medium wherein said compound of formula ( II)
- the compound of formula (I) has a chiral carbon and, therefore, there is either the form of its isolated (R) or (S) enantiomers or in the form of mixtures of said enantiomers.
- the term "enantiomer mixtures" or “enantiomeric mixtures” includes both racemic mixtures and enriched mixtures in any one of the enantiomers.
- the enantiomers (R) and (S) of the compound of formula (I) obtained can be separated by conventional methods of resolving mixtures of enantiomers, for example, by fractional crystallization, conventional chromatographic methods, etc.
- the compound of formula (I) obtained by the process provided by this invention is obtained in the form of a mixture of enantiomers, for example, in the form of a racemic mixture. Therefore, if desired, the mixture of enantiomers obtained can be resolved into their corresponding enantiomers to Obtain the desired enantiomer.
- said enantiomer is the (R) [(+) - N, N-diiso ' propyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpiOpylamine] enantiomer, or tolterodine, also known as ( R) -Tolterodine, pharmaceutically useful.
- said enantiomer is the (S) [(-) - N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine], or (S) -tolterodine enantiomer, which also It presents therapeutic applications.
- the resolution of the mixture of enantiomers can be accomplished by any conventional method, for example, using chiral graphic chromate columns or by fractional crystallization of salts of the corresponding enantiomers with the appropriate optically active (chiral) acids.
- the separation of the enantiomer (R) from the compound of formula (I) is performed by optical resolution by treating the mixture of enantiomers with L-tartaric acid.
- the salt (R) -tolterodine L-tartrate or any other corresponding salt with an appropriate chiral acid can be recrystallized as many times as necessary until obtaining the enantiomer (R) of the compound of formula (I) with the desired purity.
- the enantiomer obtained can be transformed into a salt, such as a pharmaceutically acceptable salt or a pharmaceutically acceptable salt, thereof by conventional procedures known to those skilled in the art.
- the compound of formula (I) is an amine and can form addition salts with organic or inorganic acids when it reacts with the appropriate acids.
- Said salts include both pharmaceutically acceptable salts and salts that are not pharmaceutically acceptable (ie, pharmaceutically acceptable salts), which, on occasion, may be useful in the synthesis, isolation or purification of the compound of formula (I) desired or the pharmaceutically desired salt.
- Illustrative, non-limiting examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate, although not limited thereto.
- Said salts can be obtained by conventional methods by reacting the free amine with the acid in question.
- said salt is a pharmaceutically acceptable salt, for example, hydrobromide or tartrate.
- Said salt can be obtained either by reacting the free amine with hydrobromic acid or as a result of carrying out the addition reaction by treatment with hydrobromic acid in the presence of acetic acid, or by reaction with tartaric acid.
- said addition salt may be transformed into the corresponding free amine by conventional methods, for example, by varying the pH of a solution comprising said salt until the free amine is obtained.
- the compound of formula (I) can be obtained as a free base or salt. In both cases it can be obtained in crystalline form, both as free compounds or as solvates (for example, hydrates), both forms being included within the scope of the present invention. Solvation methods are generally known in the state of the art.
- the process of the invention [1] provides compounds of formula (I), their enantiomers, hydrates, solvates and salts.
- said process provides compounds of formula (I) in which Ri is H or methyl, R 2 is methyl and R 3 and R 4 are both isopropyl, preferably compounds of formula (I) in which Rj is H, R 2 is methyl and R 3 and R 4 are both isopropyl, as well as their enantiomers or mixtures thereof and their salts (including pharmaceutically acceptable salts and pharmaceutically acceptable salts).
- said process provides the compound N, N ⁇ diisopropy-
- the process of the invention [1] provides the compound (R) - (+) - N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine or a salt thereof, such as hydrobromide or tartrate.
- the invention relates to a process for obtaining a 3,3-diphenylpropylamine of formula (F)
- R2 is alkyl Ci-C 6 alkoxy Ci-C 6, halogen, NO 2, CN, CHO or protected free, or COOR CH2OH 6 wherein R 6 is H or CpC 6 alkyl; R 3 and R 4 , independently, are selected from H, Ci-Cs alkyl, or together form a 3- to 7-membered ring with the nitrogen to which they are attached; their enantiomers or mixtures thereof, their solvates, hydrates, or salts, comprising: a) reacting a compound of formula (II)
- R "i is C] -C 6 alkyl, Ci-C 6 haloalkyl or alkoxyalkyl of formula
- R 'i, R 2 , R 3 and R 4 have the previously indicated meaning; b) transform R 'i into hydrogen to obtain the compound of formula (F); Y c) if desired, separate the desired (R) or (S) enantiomer, or the mixture of enantiomers, and / or convert the compound of formula (I ') into a salt thereof.
- reaction of the propylenephenylamine of formula (II) with the unsubstituted aromatic hydrocarbon of formula (IH ') constitutes an electro-row substitution reaction of the ortho position of the aromatic ring present in the compound of formula
- said acid is an inorganic acid with the exception of hydrobromic acid for the reasons mentioned previously.
- inorganic acids that may be used include perchloric, sulfuric acids, etc., and mixtures thereof, generally aqueous.
- said acid is an organic acid, advantageously, a strong organic acid.
- organic acids that can be used include sulfonic acids, such as j9-toluenesulfonic acid, methanesulfonic acid, etc., acetic acid, trifluoroacetic acid, etc., or mixtures thereof.
- the reaction medium comprises one or more inorganic acids, with the exception of hydrobromic acid, and one or more organic acids.
- inorganic and organic acids that can be used have already been mentioned previously.
- the reaction medium comprises an inorganic acid selected from the group consisting of perchloric acid, sulfuric acid and mixtures thereof, and an organic acid, such as, for example, acetic acid.
- said acid is a Lewis acid, such as, for example, AlCl 3 , SnCl 4 , ZnCl 2 , BF 3 , etc., or mixtures thereof.
- the aromatic electrophilic substitution reaction can be carried out under different conditions depending on the reactivity of the compound of formula (IH ').
- said aromatic electrophilic substitution reaction can be carried out: - using between 4 and 16 equivalents of the alkoxy derived from formula (IH ') per equivalent of compound of formula (II), in a reaction medium comprising a inorganic acid (except hydrobromic acid), for example, sulfuric, perchloric, etc., generally aqueous acid at a temperature between 80 0 C and the reflux temperature, preferably at the reflux temperature; or using between 4 and 16 equivalents of the alkoxy derivative of formula (IH ') per equivalent of compound of formula (II), which can also act as a solvent, in a reaction medium comprising a Lewis acid, eg, AlCl 3 , SnCl 4 , ZnCl 2 , BF 3 , etc., at a temperature between 2O 0 C and 100 0 C, preferably between 4O 0 C and 6O
- Step b) of transforming R' ⁇ [C] -C 6 alkyl, Ci-C 6 haloalkyl or alkoxyalkyl - (CH 2 ) n -OR 5 ] into hydrogen can be carried out by any method known in the state of The technique; however, in a particular embodiment, said transformation is carried out by a dealkylation reaction by treating the compound with an acid, for example, with aqueous hydrobromic acid optionally together with an organic acid, such as acetic acid. In one embodiment, the desalkylation reaction is carried out by treatment with a mixture of aqueous hydrobromic acid and acetic acid.
- the compound of formula (F) has a chiral carbon and, therefore, exists either in the form of its isolated (R) or (S) enantiomers or in the form of mixtures of said enantiomers.
- the enantiomers (R) and (S) of the compound of formula (F) obtained can be separated by conventional methods of solving mixtures of enantiomers, for example, by fractional crystallization, conventional chromatographic methods, etc.
- the compound of formula (F) obtained by the process provided by this invention is obtained in the form of a mixture of enantiomers, for example, in the form of a racemic mixture.
- the mixture of enantiomers obtained can be resolved in their corresponding enantiomers to obtain the desired enantiomer.
- said enantiomer is the (R) [(R) - (+) - N, N- diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine] enantiomer, or tolterodine, also known as (R) -tolterodine, pharmaceutically useful.
- said enantiomer is the (S) [(S) - (-) - N, N-diisopropyl-3- (2-hydroxy-5- methylphenyl) -3-phenylpropylamine] enantiomer, or (S) - tolterodine, which also has therapeutic applications.
- the resolution of the mixture of enantiomers can be carried out by any conventional method, for example, using chiral chromatographic columns or by fractional crystallization of salts of the corresponding enantiomers with the appropriate optically active (chiral) acids.
- the separation of the enantiomer (R) from the compound of formula (F) is performed by optical resolution by treating the mixture of enantiomers with L-tartaric acid.
- the salt (R) -tolterodine L-tartrate or any other corresponding salt with an appropriate chiral acid can be recrystallized as many times as necessary until the enantiomer (R) of the compound of formula (F) is obtained with the desired purity.
- the enantiomer obtained can be transformed into a pharmaceutically acceptable salt thereof by conventional procedures known to those skilled in the art.
- the compound of formula (F) is an amine and can form addition salts with organic or inorganic acids when it reacts with the appropriate acids.
- Such salts include both pharmaceutically acceptable salts and salts that are not Pharmaceutically acceptable, which, on occasion, may be useful in the synthesis, isolation or purification of the compound of formula (V) desired or of the pharmaceutically desired salt.
- Illustrative, non-limiting examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate, although not limited thereto.
- Said salts can be obtained by conventional methods by reacting the free amine with the acid in question.
- said salt is a pharmaceutically acceptable salt, for example, hydrobromide or tartrate.
- Said salt can be obtained either by reacting the free amine with hydrobromic acid or as a result of carrying out the addition reaction by treatment with hydrobromic acid in the presence of acetic acid, or by reaction with tartaric acid.
- said addition salt can be transformed into the corresponding free amine by conventional methods, for example, by varying the pH of a solution comprising said salt until the free amine is obtained.
- the compound of formula (T) can be obtained as a free base or salt.
- said process provides the compound N 5 N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpro ⁇ ylamine, its enantiomers, or salts thereof.
- this process provides the compound (R) - (+) - N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine or a salt thereof, such as the hydrobromide or tartrate.
- the compound of formula (II), the starting product of the process of the invention or of the compound of formula (V) can be obtained by a process comprising reacting a compound of formula (IV)
- R 3 and R 4 independently, are selected from hydrogen and linear or branched C 1 -C 8 alkyl or together form a 3- to 7-membered ring with the nitrogen to which they are attached.
- This reaction consists of a nucleophilic substitution of the leaving group Y by an amine of formula (V), which is in a proportion that varies between 1 and 8 equivalents, preferably between 2 and 6 equivalents, per equivalent of compound of formula (IV).
- Y is a halogen, a tosylate or a mesylate, preferably, Y is Br or Cl, and, for economic reasons , it is preferred that Y is Cl.
- the reaction is carried out in a solvent.
- solvents alcohols, toluene, xylene, acetonitrile, acetone, dimethylformamide (DMF), 1,2-dichloroethane, etc., preferably alcohols, toluene or xylene, more preferably even alcohols of five or less carbon atoms, for example, can be used.
- ethanol or isopropanol preferably ethanol.
- the reaction is carried out at a temperature between room temperature (typically between 18 ° C and 22 ° C) and reflux temperature, preferably between 30 0 C and 78 0 C, even more preferably between 4O 0 C and 7O 0 C.
- the reaction is carried out at a temperature between 0 ° C and the boiling temperature of the solvent.
- solvents toluene or xylene the reaction is carried out at a temperature between 80 0 C and the boiling temperature of the solvent.
- this process allows to obtain compounds of formula (II) where R 3 and R 4 are both isopropyl.
- the compound of formula (II) is an amine and can form addition salts with organic or inorganic acids when it reacts with the appropriate acids.
- Illustrative, non-limiting examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate, although not limited thereto.
- Said salts can be obtained by conventional methods by reacting the free amine with the acid in question.
- said addition salt can be transformed into the corresponding free amine by conventional methods, for example, by varying the pH of a solution comprising said salt until the free amine is obtained.
- the invention relates to an acid addition salt of a compound of formula (II) comprising said compound of formula (II) and an acid.
- Said acid may be an organic or inorganic acid.
- the anion of said acid may be hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate, etc.
- R 3 and R 4 are both isopropyl.
- said salt is the hydrochloride or hydrobromide of the compound of formula (II), preferably N, N-diisopropyl-3-phenyl-2-propenamine hydrochloride or N, N-diisopropyl-3- hydrobromide. phenyl-2-propenamine.
- the invention relates to a process, hereinafter the method of the invention [21, for obtaining a 3,3-diphenylpropylamine of formula (I):
- Ri is Ci-C 6 alkyl, Ci-C6 haloalkyl or alkoxyalkyl of formula - (CH 2) -O-Rs I1, where n is an integer between 1 and 3 and
- R 5 is Ci-C 6 alkyl
- R 2 is Ci-C 6 alkyl, Cj-C 6 alkoxy, halogen, NO 2 , CN, free or protected CHO, CH 2 OH or COOR 6 , where R 6 is H or a Ci-C 6 alkyl group; R 3 and R 4 , independently, are selected from H and Ci-Cg alkyl or together form a 3- to 7-membered ring with the nitrogen to which they are attached; their enantiomers or mixtures thereof, their solvates, hydrates, or salts, comprising: a) reacting a compound of formula (IV)
- Step a) of the process of the invention [2] corresponds to the stage previously described in relation to the process for obtaining the compound of formula (II), while steps b) and c) correspond to stages a) and b) of procedure of the invention [1] and have been previously described.
- the compounds of formula (I) that can be obtained by the process of the invention [2], as well as their enantiomers or mixtures thereof, their solvates, hydrates, or salts, correspond to those previously described in relation to the process of invention [1], whose content is considered reproduced.
- the solid obtained constitutes N, N-diisopropyl-3- (2-hydroxy-5-methylfenü) -3-phenylpropylamine (tolterodine) in the form of crude hydrobromide, which can be recrystallized from ethanol, methanol or isopropanol to give N, N- Purified diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpi.
- reaction can be carried out using 70% HClO 4 in water or aqueous sulfuric acid and heating to 100-11O 0 C.
- the volatiles are distilled off under reduced pressure and the reaction mixture is distributed between 100 ml of water and 100 ml of toluene, the suspension formed is brought to pH 9-10 and the organic phase is separated. , The solvent is distilled under reduced pressure and the reaction mass obtained is purified by column chromatography, obtaining the title product as an oil. 2 g of purified N, N-diisopropyl-3- (2- hydroxy-5-methylphenyl) -3-phenylpropylamine were obtained.
- High-performance liquid chromatography shows the majority presence of N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropylamine together with N, N-diisopropyl-3- (2- hydroxy-5-methylphenyl) ⁇ 3- phenylpropylamine as the main impurity.
- the reaction mixture is treated by adding 60 ml of water and extracting with 100 ml of dichloromethane. To the organic extract, another 100 ml of water is added and neutralized to pH 9-10, the phases are separated and the organic phase is stored. The solvent is removed under reduced pressure and the residue obtained consisting of excess anisole and the title product (mainly) are passed through a chromatographic column, the title product being isolated as an oil.
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06807906.0A EP1927585B1 (en) | 2005-08-05 | 2006-08-03 | Method of obtaining 3,3-diphenylpropylamines |
BRPI0614387-3A BRPI0614387A2 (pt) | 2005-08-05 | 2006-08-03 | método de obtenção de 3,3-difenilpropilaminas |
US11/989,962 US8039672B2 (en) | 2005-08-05 | 2006-08-03 | Method of obtaining 3,3-diphenylpropylamines |
ES06807906.0T ES2592885T3 (es) | 2005-08-05 | 2006-08-03 | Procedimiento para la obtención de 3,3-difenilpropilaminas |
AU2006277906A AU2006277906A1 (en) | 2005-08-05 | 2006-08-03 | Method of obtaining 3,3-diphenylpropylamines |
CA002618446A CA2618446A1 (en) | 2005-08-05 | 2006-08-03 | Method of obtaining 3,3-diphenylpropylamines |
JP2008524533A JP2009503035A (ja) | 2005-08-05 | 2006-08-03 | 3,3−ジフェニルプロピルアミンを得る方法 |
NO20081037A NO20081037L (no) | 2005-08-05 | 2008-02-27 | Fremgangsmate for oppnaelse av 3,3-difenylpropylaminer |
US13/227,067 US20110319666A1 (en) | 2005-08-05 | 2011-09-07 | Method of obtaining 3,3-diphenylpropylamines |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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ESP200501990 | 2005-08-05 | ||
ES200501990A ES2268987B1 (es) | 2005-08-05 | 2005-08-05 | Procedimiento para la obtencion de 3,3-difenilpropilaminas. |
Related Child Applications (1)
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US13/227,067 Division US20110319666A1 (en) | 2005-08-05 | 2011-09-07 | Method of obtaining 3,3-diphenylpropylamines |
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WO2007017544A2 true WO2007017544A2 (es) | 2007-02-15 |
WO2007017544A3 WO2007017544A3 (es) | 2007-04-19 |
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PCT/ES2006/000458 WO2007017544A2 (es) | 2005-08-05 | 2006-08-03 | Procedimiento para la obtención de 3,3-difenilpropilaminas |
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US (2) | US8039672B2 (es) |
EP (1) | EP1927585B1 (es) |
JP (1) | JP2009503035A (es) |
KR (1) | KR20080043811A (es) |
CN (1) | CN101277926A (es) |
AU (1) | AU2006277906A1 (es) |
BR (1) | BRPI0614387A2 (es) |
CA (1) | CA2618446A1 (es) |
ES (2) | ES2268987B1 (es) |
NO (1) | NO20081037L (es) |
WO (1) | WO2007017544A2 (es) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007147547A1 (en) * | 2006-06-20 | 2007-12-27 | Lek Pharmaceuticals D.D. | Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-n-alkyl-3-phenylpropylamines |
WO2011012584A1 (en) | 2009-07-27 | 2011-02-03 | Ragactives, S.L.U. | Process for obtaining 3,3-diphenylpropylamines |
EP1693361B1 (en) * | 2005-02-18 | 2011-04-20 | Dipharma Francis S.r.l. | A process for the preparation of tolterodine |
EP2364966A1 (en) | 2010-03-09 | 2011-09-14 | LEK Pharmaceuticals d.d. | Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-3-phenylpropylamines, intermediates for making hydroxytolterodine |
WO2014012832A1 (en) | 2012-07-16 | 2014-01-23 | Cambrex Profarmaco Milano S.R.L. | Process for the preparation of 2-(3-n,n-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol and its derivatives |
CN111470971A (zh) * | 2020-05-09 | 2020-07-31 | 浙江大学衢州研究院 | 防止二异丙基乙胺生产中催化剂ZnCl2结块的方法 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1396373B1 (it) * | 2009-10-29 | 2012-11-19 | Dipharma Francis Srl | Procedimento per la preparazione di fesoterodina. |
IT1397521B1 (it) | 2009-12-21 | 2013-01-16 | Dipharma Francis Srl | Procedimento per la preparazione di fesoterodina con un basso contenuto di impurezze. |
IT1403094B1 (it) | 2010-12-09 | 2013-10-04 | Dipharma Francis Srl | Procedimento per la preparazione di fesoterodina o un suo sale |
CN103044273B (zh) * | 2012-11-29 | 2014-12-24 | 珠海保税区丽珠合成制药有限公司 | 一种酒石酸托特罗定的合成方法 |
CN103044274B (zh) * | 2012-11-29 | 2014-10-22 | 珠海保税区丽珠合成制药有限公司 | 一种无溶剂合成酒石酸托特罗定的方法 |
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US5382600A (en) | 1988-01-22 | 1995-01-17 | Pharmacia Aktiebolag | 3,3-diphenylpropylamines and pharmaceutical compositions thereof |
WO1998003067A1 (en) | 1996-07-19 | 1998-01-29 | Gunnar Aberg | S(-)-tolterodine in the treatment of urinary and gastrointestinal disorders |
US5922914A (en) | 1996-12-31 | 1999-07-13 | Pharmacia & Upjohn Company | Process to prepare tolterodine |
US6310248B2 (en) | 1999-12-30 | 2001-10-30 | Pharmacia Ab | Process and intermediates |
WO2003014060A1 (en) | 2001-08-03 | 2003-02-20 | Ranbaxy Laboratories Limited | Process for the preparation of tolterodine |
US6538035B2 (en) | 2000-10-24 | 2003-03-25 | Pharmacia & Upjohn Company | Use of tolterodine to treat asthma |
ES2235648A1 (es) | 2003-12-22 | 2005-07-01 | Ragactives, S.L. | Procedimiento para la obtencion de tolterodina. |
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-
2005
- 2005-08-05 ES ES200501990A patent/ES2268987B1/es not_active Expired - Fee Related
-
2006
- 2006-08-03 JP JP2008524533A patent/JP2009503035A/ja active Pending
- 2006-08-03 CA CA002618446A patent/CA2618446A1/en not_active Abandoned
- 2006-08-03 WO PCT/ES2006/000458 patent/WO2007017544A2/es active Application Filing
- 2006-08-03 ES ES06807906.0T patent/ES2592885T3/es active Active
- 2006-08-03 EP EP06807906.0A patent/EP1927585B1/en not_active Not-in-force
- 2006-08-03 KR KR1020087005419A patent/KR20080043811A/ko not_active Application Discontinuation
- 2006-08-03 US US11/989,962 patent/US8039672B2/en not_active Expired - Fee Related
- 2006-08-03 CN CNA2006800368322A patent/CN101277926A/zh active Pending
- 2006-08-03 BR BRPI0614387-3A patent/BRPI0614387A2/pt not_active Application Discontinuation
- 2006-08-03 AU AU2006277906A patent/AU2006277906A1/en not_active Abandoned
-
2008
- 2008-02-27 NO NO20081037A patent/NO20081037L/no not_active Application Discontinuation
-
2011
- 2011-09-07 US US13/227,067 patent/US20110319666A1/en not_active Abandoned
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US5382600A (en) | 1988-01-22 | 1995-01-17 | Pharmacia Aktiebolag | 3,3-diphenylpropylamines and pharmaceutical compositions thereof |
WO1998003067A1 (en) | 1996-07-19 | 1998-01-29 | Gunnar Aberg | S(-)-tolterodine in the treatment of urinary and gastrointestinal disorders |
US5922914A (en) | 1996-12-31 | 1999-07-13 | Pharmacia & Upjohn Company | Process to prepare tolterodine |
US6310248B2 (en) | 1999-12-30 | 2001-10-30 | Pharmacia Ab | Process and intermediates |
US6538035B2 (en) | 2000-10-24 | 2003-03-25 | Pharmacia & Upjohn Company | Use of tolterodine to treat asthma |
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1693361B1 (en) * | 2005-02-18 | 2011-04-20 | Dipharma Francis S.r.l. | A process for the preparation of tolterodine |
WO2007147547A1 (en) * | 2006-06-20 | 2007-12-27 | Lek Pharmaceuticals D.D. | Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-n-alkyl-3-phenylpropylamines |
US8193391B2 (en) | 2006-06-20 | 2012-06-05 | Lek Pharmaceuticals, D.D. | Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-N-alkyl-3-phenylpropylamines |
WO2011012584A1 (en) | 2009-07-27 | 2011-02-03 | Ragactives, S.L.U. | Process for obtaining 3,3-diphenylpropylamines |
EP2281801A1 (en) | 2009-07-27 | 2011-02-09 | Ragactives, S.L.U. | Process for obtaining 3,3-diphenylpropylamines |
US8722920B2 (en) | 2009-07-27 | 2014-05-13 | Crystal Pharma S.A.U. | Process for obtaining 3, 3-diphenylpropylamines |
EP2364966A1 (en) | 2010-03-09 | 2011-09-14 | LEK Pharmaceuticals d.d. | Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-3-phenylpropylamines, intermediates for making hydroxytolterodine |
WO2011110556A1 (en) | 2010-03-09 | 2011-09-15 | Lek Pharmaceuticals D.D. | Short synthesis of tolterodine, intermediates and metabolites |
WO2014012832A1 (en) | 2012-07-16 | 2014-01-23 | Cambrex Profarmaco Milano S.R.L. | Process for the preparation of 2-(3-n,n-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol and its derivatives |
CN111470971A (zh) * | 2020-05-09 | 2020-07-31 | 浙江大学衢州研究院 | 防止二异丙基乙胺生产中催化剂ZnCl2结块的方法 |
CN111470971B (zh) * | 2020-05-09 | 2023-06-16 | 浙江大学衢州研究院 | 防止二异丙基乙胺生产中催化剂ZnCl2结块的方法 |
Also Published As
Publication number | Publication date |
---|---|
AU2006277906A1 (en) | 2007-02-15 |
EP1927585A4 (en) | 2010-08-18 |
ES2592885T3 (es) | 2016-12-02 |
EP1927585B1 (en) | 2016-07-27 |
KR20080043811A (ko) | 2008-05-19 |
US20100286446A1 (en) | 2010-11-11 |
EP1927585A2 (en) | 2008-06-04 |
JP2009503035A (ja) | 2009-01-29 |
ES2268987A1 (es) | 2007-03-16 |
CA2618446A1 (en) | 2007-02-15 |
BRPI0614387A2 (pt) | 2011-03-22 |
CN101277926A (zh) | 2008-10-01 |
US20110319666A1 (en) | 2011-12-29 |
ES2268987B1 (es) | 2008-02-01 |
WO2007017544A3 (es) | 2007-04-19 |
US8039672B2 (en) | 2011-10-18 |
NO20081037L (no) | 2008-04-23 |
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