WO2014026657A2 - A process for the preparation of a derivative of 2-methyl-2'-phenylpropionic acid using new intermediates - Google Patents
A process for the preparation of a derivative of 2-methyl-2'-phenylpropionic acid using new intermediates Download PDFInfo
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- WO2014026657A2 WO2014026657A2 PCT/CZ2013/000092 CZ2013000092W WO2014026657A2 WO 2014026657 A2 WO2014026657 A2 WO 2014026657A2 CZ 2013000092 W CZ2013000092 W CZ 2013000092W WO 2014026657 A2 WO2014026657 A2 WO 2014026657A2
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- Prior art keywords
- formula
- base
- compound
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- characteristic peaks
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims description 30
- 239000000543 intermediate Substances 0.000 title description 15
- 239000002585 base Substances 0.000 claims abstract description 22
- ACCMWZWAEFYUGZ-UHFFFAOYSA-N bilastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ACCMWZWAEFYUGZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960004314 bilastine Drugs 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 230000029936 alkylation Effects 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 85
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 29
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 230000005855 radiation Effects 0.000 claims description 12
- BHHYHSUAOQUXJK-UHFFFAOYSA-L zinc fluoride Chemical compound F[Zn]F BHHYHSUAOQUXJK-UHFFFAOYSA-L 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 11
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 10
- 229910016523 CuKa Inorganic materials 0.000 claims description 9
- 150000004985 diamines Chemical class 0.000 claims description 8
- 239000001530 fumaric acid Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- -1 alkali metal alkoxides Chemical class 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 4
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229940125851 compound 27 Drugs 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims 1
- 229940126142 compound 16 Drugs 0.000 claims 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000001387 anti-histamine Effects 0.000 abstract description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000739 antihistaminic agent Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 238000001816 cooling Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000008346 aqueous phase Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 150000001408 amides Chemical class 0.000 description 11
- 239000012458 free base Substances 0.000 description 11
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 10
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000007126 N-alkylation reaction Methods 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 238000010533 azeotropic distillation Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- SRJOCJYGOFTFLH-UHFFFAOYSA-M piperidine-4-carboxylate Chemical compound [O-]C(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-M 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- PDRNJKDODQMLSW-HZVMSULOSA-N N[C@@H](CCCNC(N)=N)C(O)=O.N[C@@H](CCCNC(N)=N)C(O)=O.Nc1nc2[nH]cc(CCc3ccc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)c2c(=O)[nH]1 Chemical compound N[C@@H](CCCNC(N)=N)C(O)=O.N[C@@H](CCCNC(N)=N)C(O)=O.Nc1nc2[nH]cc(CCc3ccc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)c2c(=O)[nH]1 PDRNJKDODQMLSW-HZVMSULOSA-N 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000009435 amidation Effects 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- PMOSJSPFNDUAFY-UHFFFAOYSA-N 2-(4-bromophenyl)ethanol Chemical compound OCCC1=CC=C(Br)C=C1 PMOSJSPFNDUAFY-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 150000001556 benzimidazoles Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001007 flame atomic emission spectroscopy Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 2
- AWUXQUVYMUBJSG-UHFFFAOYSA-N methyl 2-[4-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethyl]phenyl]-2-methylpropanoate Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(=O)OC)C=C1 AWUXQUVYMUBJSG-UHFFFAOYSA-N 0.000 description 2
- RZVWBASHHLFBJF-UHFFFAOYSA-N methyl piperidine-4-carboxylate Chemical compound COC(=O)C1CCNCC1 RZVWBASHHLFBJF-UHFFFAOYSA-N 0.000 description 2
- GXVMJWFIOFNZLW-UHFFFAOYSA-N n-(2-ethoxyethyl)-2-nitroaniline Chemical compound CCOCCNC1=CC=CC=C1[N+]([O-])=O GXVMJWFIOFNZLW-UHFFFAOYSA-N 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- CXWQAPHDSYDHBR-UHFFFAOYSA-N piperidine-4-carboxamide Chemical compound NC(=O)C1CCNCC1.NC(=O)C1CCNCC1 CXWQAPHDSYDHBR-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- HTMYMRSLEMVHNX-UHFFFAOYSA-N 1-bromo-2-phenylethanol Chemical compound OC(Br)CC1=CC=CC=C1 HTMYMRSLEMVHNX-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
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- APZYEQKFJYETHW-UHFFFAOYSA-N 2-[1-[2-(4-bromophenyl)ethyl]piperidin-4-yl]-1-(2-ethoxyethyl)benzimidazole Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(Br)C=C1 APZYEQKFJYETHW-UHFFFAOYSA-N 0.000 description 1
- BPGIOCZAQDIBPI-UHFFFAOYSA-N 2-ethoxyethanamine Chemical compound CCOCCN BPGIOCZAQDIBPI-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- LTVRSJBNXLZFGT-UHFFFAOYSA-N 2-silylethenone Chemical compound [SiH3]C=C=O LTVRSJBNXLZFGT-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BRMNIPUJQIHQIE-UHFFFAOYSA-N ethanol;toluene;hydrate Chemical compound O.CCO.CC1=CC=CC=C1 BRMNIPUJQIHQIE-UHFFFAOYSA-N 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002510 isobutyric acid esters Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
Definitions
- the invention relates to a new process for the preparation of derivatives of 2-methyl-2'- phenylpropionic acid, e.g. the antihistamine Bilastine of formula 9
- LG X, OTs, O s Bilastine
- Synthesis of an intermediate of type 5 is described in a detailed way in the Spanish patent ES 2151442 (priority: January 1 1 , 1999); it starts from alkyl 4-bromophenyl acetate 1, gradual deprotonation with sodium hydride and C-alkylation with methyl iodide 2 leads to the corresponding geminal dimethyl derivative, this step being followed by protection of the ester function by conversion to the oxazoline 3.
- the aryl bromide 3 is converted to the corresponding Grignard reagent and its reaction with the oxirane 4 provides the corresponding phenethyl alcohol and, after, e.g., tosylation, the compound 5.
- a disadvantage of the basic synthesis is repeated use of a suspension of sodium hydride, very toxic alkylation reagents, the pyrophoric Grignard reagent and last, but not least, oxirane.
- an alkyl isobutyrate lithium enolate by an in situ reaction of the corresponding ester with a strong base (e.g. lithium dicyclohexylamide (Cy 2 NLi) or lithium hexamethyldisilazide (LiHDMS)).
- a strong base e.g. lithium dicyclohexylamide (Cy 2 NLi) or lithium hexamethyldisilazide (LiHDMS)
- Sodium hexamethyldisilazide (NaHDMS) has also been successfully used for generation of the corresponding alkyl isobutyrate enolates and their subsequent arylation catalyzed with a palladium complex (Hama, T., Hartwig, J. F. Org. Lett. 2008, 10, 1549-1552).
- the commercially available 4-bromophenethyl alcohol 12 is converted to the corresponding acid ester, which is, after conversion of the hydroxyl group to a leaving group 15, used for N-alkylation of the benzimidazole intermediate 14.
- N-alkylation of the benzimidazole ring 11 is performed at the beginning of the synthesis in this case.
- This invention relates to a new process for the reparation of bilastine of formula 9
- R stands for a C
- R stands for a Ci-C 4 alkyl.
- R is methyl or ethyl.
- auxiliary reagents which are tri(ieri-butyl) phosphine, Pddba 2 (dba - dibenzylideneacetone) and ZnF 2 in an organic solvent such as dimethylformamide (DMF).
- This aikylation can also be successfully carried out with the use of enolates generated in situ by reaction of a strong amide base such as Na or LiHDMS (HDMS hexamethyldisilylamide), LiNCy 2 (lithium dicyclohexylamide) or LDA (lithium diisopropylamide) and esters of isobutyric acid 13b wherein R is as defined above, in an organic solvent (e.g. in toluene), being catalyzed by a palladium complex, e.g. Pddba 2 (dba - dibenzylideneacetone), in the presence of a ligand (e.g. tri(teft-butyl) phosphine).
- a strong amide base such as Na or LiHDMS (HDMS hexamethyldisilylamide), LiNCy 2 (lithium dicyclohexylamide) or LDA (lithium diisopropylamide) and esters of
- Hydrolysis of the intermediate 16 or its salts is then carried out using well-known methods of hydrolysis of carboxylic acid esters such as alkali or acid hydrolysis.
- This invention further relates to a process for the preparation of the intermediate 27, which is prepared by condensation of a compound of formula 24
- is a C i to C 3 alkyl, with the diamine of formula 25
- toluene, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran or their mixtures can be used as non-polar organic solvents.
- Alkali metal alkoxides or hydrides are used as strong organic bases in amounts in the range of 1 -3 equivalents. The best results were achieved when potassium /er/-butoxide (t-BuOK) was used as the base in the range of 2-2.5 equivalents.
- this invention provides the compound of formula 27 in the form of a base or a salt with an organic or inorganic acid, especially its salt with fumaric acid.
- the fumarate of 27 exhibits the following main characteristic peaks ([°2Th.]): 12.24, 17.19, 19.60, 22.59, 3 1.96 °2 ⁇ ⁇ 0.2° 2 ⁇ and further the following characteristic peaks: 6.41 , 10.62, 13.87, 14.95, 15.50, 18.23, 18.79, , 20.89, 21.54, 24.95, 25.29, 26.39, 26.76, 28.08, 29.73, 30.3 1 , 33.25, 37.36 °2 ⁇ ⁇ 0.2° 2 ⁇ .
- the fumarate of formula 27 crystallizes very well and it is convenient for isolation and purification of the intermediate 27; the fumarate is prepared by crystallization from common solvents, preferably from acetone or its mixture with ethanol or methanol.
- the ester 24 is prepared by N-alkylation of ethyl or methyl isonipecotate and is preferably isolated, in case where R
- the fumarate further exhibits the following characteristic peaks 12.65, 16.08, 17.07, 18.80, 22.38, 24.94, 25.55, 25.84, 26.72, 28.40, 34.16°2 ⁇ ⁇ 0.2° 2 ⁇ ,
- the fumarate of the compound 24 is prepared by crystallization from common solvents, preferably from ketones in mixtures with alcohols, such as methyisobutylketone in a mixture with ethanol.
- Our new synthesis avoids using toxic alkylation reagents and newly creates the benzimidazole ring using two alternative methods.
- the first method consists in preparation of a new N-alkyl derivative, the ethyl or methyl isonipecotate 23, its reaction with the mesylate or tosylate prepared from 4-bromophenethyl alcohol 12.
- Another starting compound is the well-known diaminobenzene 25 (Iemura et al. J. Med. Chem.
- Reaction conditions a) i) sCI TEA/MIBK, ii) 9/K 2 C0 3 / I/ IBK, (77% in total, fumarate), c) zCOs/D SO, (99%), d) H 2 /Pd-C/EtOH, (95%), e) KOtBu/PhMe-DMF/ 0°C-RT-80°C, (80%)
- the key factors are the amount of the base added and the temperature profile of the reaction; for quick complete transamidation, an excess of the base has to be used (ca. 2 eq) and the first step should be performed at a reduced temperature (-5-5°C) and the reaction temperature maintained until complete conversion to the amide 26. If the reaction mixture is heated up before completion of the amidation, then the side product of the cyclization, potassium or sodium hydroxide, hydrolyzes the unreacted ester 24 to the corresponding potassium or sodium salt of the free acid, which crystallizes out from the reaction mixture, thus reducing the yield of benzimidazole 27.
- the crystalline base of the compound 27 is characterized by the following main peaks in powder X-ray diffraction measured with the use of CuKa radiation: 4.35, 8.62, 20.78, 22. 1 1 , 24.20 °2 ⁇ ⁇ 0.2° 2 ⁇ ; this compound further exhibits the following characteristic peaks in powder X-ray diffraction measured with the use of the radiation: 14.00, 17.59, 18.72, 19.46, 19.91 , 20.50, 21.56, 26.19, 26.53, 26.85, 27.99, 28.24, 30.35, 31.92, 34.45, 37.82 °2 ⁇ ⁇ 0.2° 2 ⁇ .
- the potassium or sodium salt of the acid can be used in the process after acidification to the free acid 26, which is converted to the acyl chloride 29 or activated anhydride 30 and yields the amide 26 by reaction with the diamine 25, which can be conveniently purified by crystallization. Cyclization of the amide to the desired benzimidazole 27 is then performed under reflux in acetic acid.
- the acid 28 can also be prepared by N-alkylation of the sodium salt of isonipecotic acid 33 or also by its reaction with the aldehyde 31 under conditions of reductive amination; Scheme 6.
- the new key intermediate 27 is converted with the use of the above mentioned method to the ester of bilastine 16 by reaction with in situ generated zinc enolate in the presence of zinc difluoride, being catalyzed by a palladium complex, or directly with sodium or lithium enolate generated in situ by reaction of an isobutyric acid ester and a strong base, such as lithium hexamethyldisilylamide (LiHDMS), sodium hexamethyldisilylamide (NaHDMS), lithium dicyclohexylamide (LiNCy 2 ) or lithium diisopropylamide (LDA).
- the product 16 can be used in the crude state or isolated as a crystalline salt with hydrochloric or with fumaric acid.
- the ester 16 or its salt is then converted to biiastine by basic or acid hydrolysis and subsequent pH adjustment; Scheme 7.
- Figure 1 XRPD record of crystalline fumarate of ethyl l -(4-bromophenethyl)piperidine-4- carboxylate
- Figure 3 XRPD record of crystalline -( l -(4-bromophenethyl)piperidin-4-yl)- l -(2- ethoxyethyl)- l H-benzo[d]imidazole 27 in the fumarate form
- Figure 4 XRPD record of crystalline methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)-l H- benzo[d]imidazol-2-yl)piperidin- l -yl)ethyl)phenyl)-2-methylpropanoate 16 in the
- ⁇ and ,J C NMR spectra were measured with a Bruker Avance 250 MHz device in deuterated chloroform with tetramethylsilane (TMS) as the reference standard or in deuterated dimethylsulfoxide.
- IR spectra were measured in a KBr tablet (ca. 1 % concentration) in a Nicolet Nexus FTIR device (64 scans with a resolution of 2 cm '1 ) and compared to the spectra in the patent EP 1 505 066.
- reaction mixture was left to slowly heat up to the room temperature for ca. 2 h.
- reaction suspension was processed by addition of diluted aqueous HC1 (37 ml of 1M HC1 + 100 ml of H20) and intensively stirred for 15 min to achieve mixing of the phases; after stabilization and separation the aqueous phase was removed and the organic phase was still washed with 5% aqueous NaHC0 3 (50 ml), H 2 0 ( 100 ml) and brine (100 ml).
- the crude mesylate solution was then heated up to boil under an argon atmosphere and dried by azeotropic distillation (ca.
- the stirred suspension was heated at 80°C for 17 h under an argon atmosphere, diluted with MIBK ( 100 ml) and after an HPLC check more K 2 C0 3 (5.2 g, 0.25 eq) and KI (2.50 g, 15.07 mmol, 0. 1 eq) were added and the suspension was heated for another 4 h.
- ice water 250 ml was added and the mixture was intensively stirred for 10 min to mix the phases; after stabilization and separation the aqueous phase was removed and the organic phase was washed with brine (50 ml) and water (100 ml).
- the suspension was then cooled to -3°C and maintained at this temperature for 1 h; the product was isolated by filtration, washed with cold MIBK (2 x 50 ml) and dried with passing air on frit and then in a vacuum drier at 50°C/18 kPa (23 h). 53.05 g (77%) of the fumarate salt was obtained, melt, point 162.2- 163.0°C, HPLC 99.28 %. Another fraction of crystals was obtained by concentration of the mother liquors, namely 4.86 g (7%).
- Free base ⁇ -NMR (250 MHz, CDC1 3 ): 7.39 (dt, 2H, 7.5 Hz, 2.5 Hz), 7.07 (dt, 2H, 7.5 Hz, 2.5 Hz), 4.14 (q, 2H, 7.5 Hz), 2.92 (td, 2H, 2.5 and 10.0 Hz), 2.74 (dd, 2H, 5.0 and 10.0 Hz), 2.54 (m, 2H), 2.29 (m, 1 H), 2.08 (dt, 2H, 2.5 and 12.5 Hz), 1.96- 1.69 (m, 4H), 1 .25 (t, 3H, 7.5 Hz).
- N-(2-ethoxyethyl)-2-nitroaniline (20.55 g, 97.74 mmol) was dissolved in ethanol (150 ml) and this solution was cooled under argon to ca. 5- 10°C and 5% Pd-C (1.04 g, 0.5 mol %) was carefully added in portions under stirring.
- Ethyl l -(4-bromophenethyl)piperidine-4-carboxylate fumarate (2.0 g, 4.38 mmol) was converted to a free base by shaking in a mixture of toluene (40ml) and 5% aqueous NaHC0 3 (20 ml), the phases were separated, the aqueous phase was washed with toluene (10 ml). The combined organic phases were washed with brine (10 ml) dried over Na 2 S0 , filtered and evaporated at a reduced pressure. 1.30 g (87%) of the free base was obtained as oil.
- Free base XRPD ([°2Th.](rel. int%)): 4.35 (44.5), 8.62 (100.0), 12.92 (2.2), 14.00 (5.6), 14.39 ( 1.8), 15.12 (1.6), 17.59 (2.7), 18.72 (2,2), 19.46 (1.4), 19.91 (2.0), 20.50 (5.4), 20.78 (20.7), 21.56 (2.3), 22.1 1 (12.4), 24.20 (8.2), 25.67 (1.8), 26.19 (3.5), 26.53 (3.4), 26.85 (3.0), 27.99 (3.2), 28.24 (4.4), 30.35 (1.9), 31.03 (1.4), 31.92 (1.8), 34.45 (1.4), 37.82 (1.4).
- Ethyl l-(4-bromophenethyl)piperidine-4-carboxylate fumarate (8.48 g, 18.57 mmol) was converted to a free base by shaking in a mixture of toluene (100 ml) and water (50 ml) and a 25-30% solution of NH 4 OH (5 ml), the phases were separated, the aqueous phase was washed with toluene (2 x 25 ml). The combined organic phases were washed with brine (25 ml) and a crude purple solution of the amine (ca. 3.72 g, 18.57 mmol in ca.
- Fumarate of the amine 1 (3.66 g) was converted to a free base by stirring in a biphasic system of toluene (70 ml) and 5% aqueous NaHC0 (50 ml); after separation of the phases, the aqueous phase was additionally washed with toluene (30 ml) and the combined organic extracts were washed with brine (20 ml) and dried over sodium sulphate. Filtration and evaporation of the solvent provided the free base as oil (2.53 g, 93%).
- HPLC determined that the ratio of the product, starting compound and the desbromo derivative was 86:8:6, and therefore more TMS enolate (0.5 eq) was added and the mixture was heated under argon for 6 h, after which HPLC indicated complete consumption of the starting compound. After cooling to the room temperature the mixture was diluted with methyl tert-butyletherMTBE (250 ml) and a 10% aqueous solution of trisodium citrate (100 ml) was added under intensive stirring and the mixture was stirred for 45 min.
- aqueous phase was additionally washed with MTBE (2 x 50 ml), the combined organic phases were washed with water (5 x 10 ml), brine (10 ml) and dried over anhydrous sodium sulphate.
- the drying agent was removed by filtration and a solution of HC1 in diethyl ether (ca. 45 ml, excess of HC1) was added dropwise, the resulting hydrochloride suspension was then cooled to ca. 0-5°C and the hydrochloride was filtered off, washed with cold MTBE and aspirated to dryness.
- Hydrochloride XRPD ([°2Th.](rel ,int%)): 4.83 (100.0), 8.33 (8.8), 9.1 1 (21 .5), 9.58 ( 16.6), 14.37 (86.4), 15.56 (10.6), 16.13 (1 1.7), 17.51 (19.2), 20.48 (3 1.8), 22.41 (16.1 ), 23.21 (21.1), 24.1 1 (12.6), 26.83 (5.2), 27.41 (5.3), 28.76 (5.9), 32.52 (5.7).
- the crude product 16 (ca. 2.98 g, 5.48 mmol) was dissolved when hot (100°C) in methylisobutylketone (30 ml) and a hot solution of fumaric acid (0.63 g , 5.48 mmol, 1.0 eq) in ethanol (10 ml) was added under stirring. The resulting clear solution was slowly cooled down to the room temperature with stirring, the fumarate salt crystallizing quickly. After further cooling to 4°C the crystals were filtered off and washed with cold methylisobutylketone (10 ml) and dried in a vacuum drier (40°CC/18 kPa) for 24 h. 2.53 g of crystals were obtained (78%), HPLC 95.20%.
- Fumarate XRPD ([°2Th.](rel. int%)): 5.76 (100.0), 10.15 (29.3), 10.56 (18.6), 12.17 (22.7), 13.45 (13.6), 14.54 (15.0), 16.71 (25.1 ), 17.48 (37.8), 17.89 (45.5), 19.28 (22.2), 21.24 (52.5), 22.41 (14.7), 22.98 (13.7), 25.14 (13.2), 27.23 (4.3).
- the crude product I was purified by crystallization from isopropanol (0.510 g sample from 40 ml of i-PrOH), 0.466 g (91%) of a crystalline substance with the HPLC purity of 99.80%) was obtained, polymorph 1 in accordance with IR (EP 1 505 066), Form 1 : XRPD ([°2Th.](rel.
- Form 2 XRPD ([°2Th.](rel. int %)): 6.53 (100.0), 9.43 (30.8), 1 1.04 (22.8), 13.39 (6.2), 15.24 (32.2), 15.86 (86.1), 18.07 (29.9), 18.39 (36.2), 18.94 (8.3), 20.19 (16.0), 20.66 (19.0), 21.70 (17.1), 22.17 (15.6), 23.70 (5.7), 26.59 (4.9), 28.03 (3.6), 28.33 (3.6), 29.70 (4.3).
Abstract
The present invention deals with a preparation method of derivatives of methyl-2 '- phenylpropionic acid, e.g. the antihistamine bilastine of formula 9 that uses a new intermediate of formula 27 in the form of a base or salt. The intermediate reacts with a suitable alkylation reagent and with the use of auxiliary reagents, producing the ester of formula 16, wherein R stands for a C 1-C4 alkyl, which is subsequently alkali or acid hydrolyzed to bilastine. Formula 9, 27, 16
Description
A process for the preparation of a derivative of 2-methyl-2'-phenylpropionic acid using new intermediates
Technical Field: The invention relates to a new process for the preparation of derivatives of 2-methyl-2'- phenylpropionic acid, e.g. the antihistamine Bilastine of formula 9
(9)
that uses a new intermediate of formula 27
(27) in the form of a base or salt.
Background Art:
Derivatives of 2-methyl-2'-phenylpropionic acid, e.g. Bilastine 9, exhibit excellent antihistaminic effects and are indicated for treatment of hay fever symptoms. Synthesis of bilastine in accordance with the basic patent EP 0818454 Al to FAES is based on N-alkylation of 4-benzimidazole piperidine 6 with a tosylate 5 in the presence of a base, producing the intermediate 7, which is further alkylated on a nitrogen of the benzimidazole ring in the presence of sodium hydride. Acidic hydrolysis of the protecting group and pH adjustment provided bilastine 9.
Scheme 1 : FAES synthesis
LG = X, OTs, O s Bilastine
Synthesis of an intermediate of type 5 is described in a detailed way in the Spanish patent ES 2151442 (priority: January 1 1 , 1999); it starts from alkyl 4-bromophenyl acetate 1, gradual deprotonation with sodium hydride and C-alkylation with methyl iodide 2 leads to the corresponding geminal dimethyl derivative, this step being followed by protection of the ester function by conversion to the oxazoline 3. The aryl bromide 3 is converted to the corresponding Grignard reagent and its reaction with the oxirane 4 provides the corresponding phenethyl alcohol and, after, e.g., tosylation, the compound 5. A disadvantage of the basic synthesis is repeated use of a suspension of sodium hydride, very toxic alkylation reagents, the pyrophoric Grignard reagent and last, but not least, oxirane.
The method of palladium-catalyzed alkylation of aryl bromides by in situ generated zinc enolate from a reaction of silyl ketene acetate 13 and zinc difluoride known from scientific literature (Hartwig et al J. Am. Chem. Soc. 2003, 125, 1 1 176- 1 1 177) is well used for synthesis of an intermediate for synthesis of bilastine in a patent of the company Yuhan (WO 2009/102155 A2). This alkylation is also described in scientific literature (Hartwig et al J. Am. Chem. Soc. 2002, 124, 12557-12565) with generation of an alkyl isobutyrate lithium enolate by an in situ reaction of the corresponding ester with a strong base (e.g. lithium dicyclohexylamide (Cy2NLi) or lithium hexamethyldisilazide (LiHDMS)). Sodium hexamethyldisilazide (NaHDMS) has also been successfully used for generation of the corresponding alkyl isobutyrate enolates and their subsequent arylation catalyzed with a palladium complex (Hama, T., Hartwig, J. F. Org. Lett. 2008, 10, 1549-1552). Using this method, the commercially available 4-bromophenethyl alcohol 12 is converted to the corresponding acid ester, which is, after conversion of the hydroxyl group to a leaving group
15, used for N-alkylation of the benzimidazole intermediate 14. N-alkylation of the benzimidazole ring 11 is performed at the beginning of the synthesis in this case.
Scheme 2: Yuhan synthesis
Another method of synthesis of bilastine was published in 201 1 (Collier at al Synthetic Communications 2011, 41, 1394-1402), differing from the above mentioned method in preparation of an alcohol precursor of the mesylate 20. The synthesis is based on Stille or Suzuki coupling of the bromide 18 with vinyl tributyl tin or cyclic vinyl boroanhydride 19, being catalyzed by palladium; the product of the reaction - a styrene derivative is then subjected to hydroboration and oxidative processing then provides the above mentioned alcohol.
Scheme 3: Albany Molecular synthesis
This invention relates to a new process for the reparation of bilastine of formula 9
(9)
which consists in reacting 2-( l -(4-bromophenethyl)piperidin-4-yl)- l -(2-ethoxyethyl)- 1 H- benzo[d]imidazole of formula 27
27
in the form of a base or salt with a suitable alkylation reagent, optionally with the
auxiliary reagents, producing an ester of formula 16,
wherein R stands for a C|-C4 alkyl, which is then alkali or acid hydrolyzed to bilastine.
As a suitable alkylation agent a compound of formula 13a
e3SiO /
/ \ Me = methyl
RO x
13a
can be used, where R stands for a Ci-C4 alkyl.
In a preferable embodiment R is methyl or ethyl. The aikylation is preferably performed in the presence of auxiliary reagents, which are tri(ieri-butyl) phosphine, Pddba2 (dba - dibenzylideneacetone) and ZnF2 in an organic solvent such as dimethylformamide (DMF).
This aikylation can also be successfully carried out with the use of enolates generated in situ by reaction of a strong amide base such as Na or LiHDMS (HDMS hexamethyldisilylamide), LiNCy2 (lithium dicyclohexylamide) or LDA (lithium diisopropylamide) and esters of isobutyric acid 13b
wherein R is as defined above, in an organic solvent (e.g. in toluene), being catalyzed by a palladium complex, e.g. Pddba2 (dba - dibenzylideneacetone), in the presence of a ligand (e.g. tri(teft-butyl) phosphine).
Hydrolysis of the intermediate 16 or its salts is then carried out using well-known methods of hydrolysis of carboxylic acid esters such as alkali or acid hydrolysis.
This invention further relates to a process for the preparation of the intermediate 27, which is prepared by condensation of a compound of formula 24
24
25 in a non-polar organic solvent in the presence of a strong organic or inorganic base at a temperature in the range of -5 to +5°C) to the intermediate 26,
26
which is then cyclized at a temperature in the range of 70- 120°C to the compound of formula 27, preferably without isolation of the intermediate of formula 26.
For example, toluene, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran or their mixtures can be used as non-polar organic solvents. Alkali metal alkoxides or hydrides are used as strong organic bases in amounts in the range of 1 -3 equivalents. The best results were achieved when potassium /er/-butoxide (t-BuOK) was used as the base in the range of 2-2.5 equivalents.
In a further aspect this invention provides the compound of formula 27 in the form of a base or a salt with an organic or inorganic acid, especially its salt with fumaric acid.
The fumarate of 27 exhibits the following main characteristic peaks ([°2Th.]): 12.24, 17.19, 19.60, 22.59, 3 1.96 °2Θ ± 0.2° 2Θ and further the following characteristic peaks: 6.41 , 10.62, 13.87, 14.95, 15.50, 18.23, 18.79, , 20.89, 21.54, 24.95, 25.29, 26.39, 26.76, 28.08, 29.73, 30.3 1 , 33.25, 37.36 °2Θ ± 0.2° 2Θ. The fumarate of formula 27 crystallizes very well and it is convenient for isolation and purification of the intermediate 27; the fumarate is prepared by crystallization from common solvents, preferably from acetone or its mixture with ethanol or methanol.
The ester 24 is prepared by N-alkylation of ethyl or methyl isonipecotate and is preferably isolated, in case where R| is ethyl, as crystalline fumarate, which exhibits the following main characteristic peaks ([°2Th.]): 9.70, 14.65, 21.82, 24.60, 28.94 °2Θ ± 0.2° 2Θ. The fumarate further exhibits the following characteristic peaks 12.65, 16.08, 17.07, 18.80, 22.38, 24.94, 25.55, 25.84, 26.72, 28.40, 34.16°2Θ ± 0.2° 2Θ,
and is convenient for isolation and purification of the intermediate 24. The fumarate of the compound 24 is prepared by crystallization from common solvents, preferably from ketones in mixtures with alcohols, such as methyisobutylketone in a mixture with ethanol.
Our new synthesis avoids using toxic alkylation reagents and newly creates the benzimidazole ring using two alternative methods. The first method consists in preparation of a new N-alkyl derivative, the ethyl or methyl isonipecotate 23, its reaction with the mesylate or tosylate prepared from 4-bromophenethyl alcohol 12. Another starting compound is the well-known diaminobenzene 25 (Iemura et al. J. Med. Chem. 1986, 29, 1 178- 1 183); its reaction with ethyl isonipecotate in refluxing 6N HC1 provided the corresponding benzimidazole in a very low yield of 5% (ibid). We have used, for the preparation of the diamine 25, a modified and more convenient procedure in two steps from the 2-halonitrobenzene 21, where the first step is nucleophilic aromatic substitution in a polar aprotic solvent (DMF, DMSO) in the presence of potash and, after processing, the nitro derivative is reduced by hydrogenation on Pd-C in an alcohol to the desired amine 25. The amine 25 can be purified by vacuum distillation or it can be conveniently used crude for the next reaction. Initial attempts at condensing the ester and diamine by heating at 170°C without a solvent in 6N HC1 or in polyphosphoric acid, i.e. in accordance with preparation methods of similar benzimidazole derivatives described in literature, have not been successful.
It was first by more detailed investigation of the reaction conditions that we have found out that the desired transformation can surprisingly be carried out in the presence of a strong base (alkali metal hydrides (e.g. sodium hydride) and metal alkoxides (preferably potassium /- butoxide)); in a mixed organic solvent there is first formed the corresponding amide, which then smoothly cyclizes to the new benzimidazole derivative upon heating. Under the mixed solvent one should understand a mixture of a non-polar aprotic solvent selected from the group of toluene, 2-methyltetrahydrofuran, tetrahydrofuran and a polar aprotic solvent (e.g. DMF, DMSO).
Scheme 4: Zentiva I synthesis:
Reaction conditions: a) i) sCI TEA/MIBK, ii) 9/K2C03/ I/ IBK, (77% in total, fumarate), c) zCOs/D SO, (99%), d) H2/Pd-C/EtOH, (95%), e) KOtBu/PhMe-DMF/ 0°C-RT-80°C, (80%)
The key factors are the amount of the base added and the temperature profile of the reaction; for quick complete transamidation, an excess of the base has to be used (ca. 2 eq) and the first step should be performed at a reduced temperature (-5-5°C) and the reaction temperature maintained until complete conversion to the amide 26. If the reaction mixture is heated up before completion of the amidation, then the side product of the cyclization, potassium or sodium hydroxide, hydrolyzes the unreacted ester 24 to the corresponding potassium or sodium salt of the free acid, which crystallizes out from the reaction mixture, thus reducing the yield of benzimidazole 27.
After complete conversion to the amide, the cyclization runs quickly at an increased temperature (50- 120°C); after cooling and processing of the reaction mixture the desired benzimidazole 27 is obtained in a very good total yield and purity (80%, HPLC 99.32%). An advantage of this new intermediate is that it is crystalline and can be easily purified by crystallization from higher alcohols (e.g. isopropanol) or from heptane.
The crystalline base of the compound 27 is characterized by the following main peaks in powder X-ray diffraction measured with the use of CuKa radiation: 4.35, 8.62, 20.78, 22. 1 1 , 24.20 °2Θ ± 0.2° 2Θ; this compound further exhibits the following characteristic peaks in powder X-ray diffraction measured with the use of the radiation: 14.00, 17.59, 18.72, 19.46,
19.91 , 20.50, 21.56, 26.19, 26.53, 26.85, 27.99, 28.24, 30.35, 31.92, 34.45, 37.82 °2Θ ± 0.2° 2Θ.
Scheme 5 : Zentiva II synthesis - regeneration:
Reaction conditions: a) (COCI)2/DCM, b) -BuOCOCI/2- e-THF/NH , b) 2-Me-THF, (92% crude, 62% from IPA, c) AcOH/Δ, (93%, crude)
The potassium or sodium salt of the acid can be used in the process after acidification to the free acid 26, which is converted to the acyl chloride 29 or activated anhydride 30 and yields the amide 26 by reaction with the diamine 25, which can be conveniently purified by crystallization. Cyclization of the amide to the desired benzimidazole 27 is then performed under reflux in acetic acid. The acid 28 can also be prepared by N-alkylation of the sodium salt of isonipecotic acid 33 or also by its reaction with the aldehyde 31 under conditions of reductive amination; Scheme 6.
Scheme 6:
Then, the new key intermediate 27 is converted with the use of the above mentioned method to the ester of bilastine 16 by reaction with in situ generated zinc enolate in the presence of zinc
difluoride, being catalyzed by a palladium complex, or directly with sodium or lithium enolate generated in situ by reaction of an isobutyric acid ester and a strong base, such as lithium hexamethyldisilylamide (LiHDMS), sodium hexamethyldisilylamide (NaHDMS), lithium dicyclohexylamide (LiNCy2) or lithium diisopropylamide (LDA). The product 16 can be used in the crude state or isolated as a crystalline salt with hydrochloric or with fumaric acid. The ester 16 or its salt is then converted to biiastine by basic or acid hydrolysis and subsequent pH adjustment; Scheme 7.
Scheme 7: Zentiva III synthesis
Reaction conditions: a) Pddba2/Bu3P/ZnF2/DMF, b) Pddba2/Bu3P/PhMe/RT-100°C, NaoH/ eOH/H20, adjustment of pH or HCI/HjO, adjustment of pH
Brief Description of Drawings:
Figure 1: XRPD record of crystalline fumarate of ethyl l -(4-bromophenethyl)piperidine-4- carboxylate
Figure 2: XRPD record of crystalline -(l -(4-bromophenethyl)piperidin-4-yl)- l -(2- ethoxyethyl)- l H-benzo[d]imidazole 27
Figure 3: XRPD record of crystalline -( l -(4-bromophenethyl)piperidin-4-yl)- l -(2- ethoxyethyl)- l H-benzo[d]imidazole 27 in the fumarate form
Figure 4: XRPD record of crystalline methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)-l H- benzo[d]imidazol-2-yl)piperidin- l -yl)ethyl)phenyl)-2-methylpropanoate 16 in the
hydrochloride form
Figure 5: XRPD record of crystalline methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin- l -yl)ethyl)phenyl)-2-methylpropanoate 16 in the fumarate form
Figure 6: IR (KBr) record of crystalline bilastine, polymorph 1 :
Figure 7: XRPD record of crystalline bilastine, polymorph 1
Figure 8: IR (KBr) record of crystalline bilastine, polymorph 2:
Figure 9: XRPD record of crystalline bilastine, polymorph 2
Examples:
Analytic methods used:
The Ή and ,JC NMR spectra were measured with a Bruker Avance 250 MHz device in deuterated chloroform with tetramethylsilane (TMS) as the reference standard or in deuterated dimethylsulfoxide.
HPLC method: A 5μιη C8 Luna 250 x 4.6mm column, CH3CN : H20 (+0.1 % vol. Et3N) 70:30, l ml/min, detection 215 nm.
The XRPD diffraction patterns were measured in an X'PERT PRO MPD device equipped with a graphite monochromator with the use of CuKa (λ = 1.542 A) radiation.
IR spectra were measured in a KBr tablet (ca. 1 % concentration) in a Nicolet Nexus FTIR device (64 scans with a resolution of 2 cm'1) and compared to the spectra in the patent EP 1 505 066.
MS spectra were measured using a Finigan LTQ XL Orbitrap device from Thermo.
Example 1 : Preparation of ethyl l -(4-bromophenethyl)piperidine-4-carboxylate
24
A solution of methane sulfonyl chloride (12.8 ml, 165.8 mmol, 1.1 eq) in methylisobutylketone (MIBK) (40 ml) was added dropwise to a cooled (5-10°C) solution of bromophenethyl alcohol 12 (30.3 g, 150.7 mmol) and triethylamine (23.1 ml, 165.8 mmol, 1.1 eq) in MIBK (300 ml) an argon atmosphere within ca. 1 hour.
Then, the reaction mixture was left to slowly heat up to the room temperature for ca. 2 h. After a check of the reaction by means of HPLC the reaction suspension was processed by addition of diluted aqueous HC1 (37 ml of 1M HC1 + 100 ml of H20) and intensively stirred for 15 min to achieve mixing of the phases; after stabilization and separation the aqueous phase was removed and the organic phase was still washed with 5% aqueous NaHC03 (50 ml), H20 ( 100 ml) and brine (100 ml). The crude mesylate solution was then heated up to boil under an argon atmosphere and dried by azeotropic distillation (ca. 50 ml of the H 0-MIBK mixture removed by distillation). After cooling to 20°C, K2C03 (26.04 g, 188.0 mmol, 1.25 eq) and KI (2.50 g, 15.07 mmol, 0.1 eq) were added to the solution and the suspension was stirred for 10 min, which was followed by addition of a solution of ethyl isonipecotate 23 (23.69 g, 150 mmol, 1.0 eq) in methylisobutylketone (MIBK) (50 ml) during 20 min. The stirred suspension was heated at 80°C for 17 h under an argon atmosphere, diluted with MIBK ( 100 ml) and after an HPLC check more K2C03 (5.2 g, 0.25 eq) and KI (2.50 g, 15.07 mmol, 0. 1 eq) were added and the suspension was heated for another 4 h. After cooling to the room temperature, ice water (250 ml) was added and the mixture was intensively stirred for 10 min to mix the phases; after stabilization and separation the aqueous phase was removed and the organic phase was washed with brine (50 ml) and water (100 ml). Then, the crude solution of the product was heated up to boil under argon and dried with azeotropic distillation (ca. 35 ml of the H20-MIBK mixture removed by distillation). After cooling of the solution to 100°C a hot solution of fumaric acid (17.41 g, 1.0 eq) in ethanol (175 ml) was added under stirring and the resulting yellow solution was cooled to 20°C under stirring and then seeded with crystals of the product fumarate (5 mg) - the crystallization then went on quickly. The suspension was then cooled to -3°C and maintained at this temperature for 1 h; the product was isolated by filtration, washed with cold MIBK (2 x 50 ml) and dried with passing air on frit and then in a
vacuum drier at 50°C/18 kPa (23 h). 53.05 g (77%) of the fumarate salt was obtained, melt, point 162.2- 163.0°C, HPLC 99.28 %. Another fraction of crystals was obtained by concentration of the mother liquors, namely 4.86 g (7%).
Fumarate, XRPD ([°2Th.](rel. int%)): 7.41 (4.8), 8.61 (5.2), 9.70 ( 12.2), 12.65 (21.5), 14.65 (99.0), 16.08 (28.5), 17.07 (44.8), 18.80 (17.0), 20.25 (12.9), 21.82 (55.5), 22.38 (5 1.9), 24.60 (100.0), 24.94 (35.6), 25.55 (19.8), 25.84 (14.7), 26.72 (14.2), 27.96 (12.1 ), 28.40 (16.1), 28.94 (28.9), 30.15 (9.6), 31.91 (5.6), 32.68 (6.2), 34.16 (16.4), 35.44 (5.7)
Ή-NMR (250 MHz, dDMSO): 7.47 (d, 10 Hz, 2H), 7.21 (d, 10 Hz, 2H), 6.60 (d, 2H, 2,5Hz), 4.07 (q, 7.5Hz, 2H), 2.93 (m, 2H), 2.72 (m, 2H), 2.60 (m, 2H), 2.39-2.10 (m, 3H), 1.87-1 .82 (m, 2H), 1.63 (m, 2H), 1.17 (t, 7.5Hz, 3H).
I 3C-NMR (62.89 MHz, dDMSO): 163.7, 159.8, 156.2, 133.2, 133.1 , 131.2, 131.0, 130.4, 129.9, 126.5, 125.3, 121.0, 120.9, 1 14.8, 1 14.4, 95.5, 71.6, 71.5, 67.7, 58.7, 51.5, 50.4, 24.5, 24.4.
Free base: Ή-NMR (250 MHz, CDC13): 7.39 (dt, 2H, 7.5 Hz, 2.5 Hz), 7.07 (dt, 2H, 7.5 Hz, 2.5 Hz), 4.14 (q, 2H, 7.5 Hz), 2.92 (td, 2H, 2.5 and 10.0 Hz), 2.74 (dd, 2H, 5.0 and 10.0 Hz), 2.54 (m, 2H), 2.29 (m, 1 H), 2.08 (dt, 2H, 2.5 and 12.5 Hz), 1.96- 1.69 (m, 4H), 1 .25 (t, 3H, 7.5 Hz).
I 3C-NMR (62.89 MHz, CDCI3): 175.0, 139.5, 131.4, 130.4, 1 19.8, 60.4, 60.3, 53.0, 41.2, 33.1 , 28.3, 14.2. [M-H]+ C|6H23 79BrN02 theory: 340.0912, found: 340.0905
A solution of 2-ethoxyethylamine (22.52 g, 0.253 mol, 1.15 eq) in 2-methyltetrahydrofuran (60 ml) was added dropwise to a mechanically stirred suspension of potassium carbonate (53.22 g, 0.384 mol, 1.75 eq) in a solution of 2-fluoronitrobenzene (31.0 g, 0.220 mol, 1 .0 eq) in dry DMSO (124 ml) under argon at ca. 10°C during 30 min. The reaction mixture was left
to heat up to the room temperature (ca. 4 h) and then heated at 45°C for 19 h. Then the mixture was cooled to ca. 10°C and diluted with water (350 ml) and toluene (250 ml); the biphasic mixture was then intensively stirred to mix the phases for 20 min. The phases were separated, the aqueous phase was washed with toluene (2x 50 ml) and the combined organic extracts were washed with a solution of HCl (35 ml of 1 M HCl and 35 ml of H20), water (2 x 25 ml), 5% aqueous NaHC03 (50 ml), water (2 x 25 ml) and finally brine (50 ml). After drying over sodium sulphate, filtration and evaporation of the solvents in a rotary vacuum evaporator (bath temperature 50°C, 2 h) a crude product was obtained as bright orange oil (45.77 g, 99%). GC 99.33%, 'HNMR corresponds to the structure.
25
N-(2-ethoxyethyl)-2-nitroaniline (20.55 g, 97.74 mmol) was dissolved in ethanol (150 ml) and this solution was cooled under argon to ca. 5- 10°C and 5% Pd-C (1.04 g, 0.5 mol %) was carefully added in portions under stirring. The reaction vessel having been rinsed with nitrogen (3 x 0.203 MPa) the reaction mixture was hydrogenated in a Parr shaking hydrogenator at the hydrogen pressure of 300-400 kPa for 3 h (the reaction was monitored with TLC). After inertization with nitrogen the reaction mixture was filtered through a cellulose filter, the catalyst washed with ethanol (3 x 10 ml) and the filtrate was evaporated until dry in a rotary vacuum evaporator. The crude product (18.07 g, oil of wine colour) was purified by vacuum distillation in a Kugelrohr apparatus (ca. 150-160°C, 4 kPa). The product was obtained as thick yellow oil (16.72 g, 95%), HPLC 99.85%, GC 99.37% and was stored under a nitrogen atmosphere at the temperature of -15°C. Ή-NMR, GC-MS corresponds to the structure.
Example 4:
Preparation of 2-( 1 -(4-bromophenethy l)piperidin-4-y 1)- 1 -(2-ethoxyethyl)- 1 H- benzo[d]imidazole - use of sodium hydride
27
Ethyl l -(4-bromophenethyl)piperidine-4-carboxylate fumarate (2.0 g, 4.38 mmol) was converted to a free base by shaking in a mixture of toluene (40ml) and 5% aqueous NaHC03 (20 ml), the phases were separated, the aqueous phase was washed with toluene (10 ml). The combined organic phases were washed with brine (10 ml) dried over Na2S0 , filtered and evaporated at a reduced pressure. 1.30 g (87%) of the free base was obtained as oil. Then, 60% NaH in oil (0.152 g, 3.79 mmol) was charged in a dry flask under argon and dry- toluene (5 ml) and DMF (2 ml) were added under stirring and then a solution of diamine (0.68 g, 3.79 mmol) in toluene (10 ml) was added dropwise and the mixture was stirred under argon at 35°C for 20 minutes. Then, a solution of the base prepared above in toluene (10 ml) was added dropwise and the mixture was slowly heated up to reflux under Ar ( 14 h), cooled to RT, the separated precipitate was removed by filtration and washed with toluene ( 10 ml) and air- dried; 0.54 g (43%) of the sodium salt of carboxylic acid (NMR) was obtained. The filtrate was diluted with water (50 ml) and brine (50 ml) and washed with toluene (100 ml); after separation of the phases the aqueous phase was additionally washed with toluene (50 ml). The combined organic fractions were washed with water (3 x 10 ml), brine ( 10 ml) and dried over Na2SC>4. After filtration and evaporation of toluene at a reduced pressure dark oil was obtained (1.2 g), which was dissolved in acetone (50 ml), and when hot, a hot solution of fumaric acid (0.508 g, 1.0 eq) in ethanol ( 10 ml) was added and the resulting solution was cooling down to the room temperature under slow stirring and then it was seeded with crystals of the product. The resulting suspension was cooled to - 10°C and the fumarate salt crystals were removed by filtration and washed with acetone and dried with passing air. 0.57 g (26%) of the fumarate was obtained, melt, point 216.1 -217.8°C, HPLC 99.74%.
Fumarate
XRPD Q°2Th.](rel. int%)): 6.41 ( 1 1.5), 10.62 (9.7), 12.24 (41.8), 13.87 (29.0), 14.95 (8.7), 15.50 (8.7), 17.19 (70.8), 1 8.23 (30.9), 18.79 (21.5), 19.60 (93.2), 20.89 (78.0), 21 .54 ( 19.3), 22.59 ( 100.0), 24.95 (27.6), 25.29 (33.5), 26.39 (25. 1 ), 26.76 (22.5), 28.08 (13.9), 29.73 (9.6), 30.31 (9.2), 3 1 .96 (43.6), 33.25 (9.6), 37.36 (6.4)
Ή-NMR (250 MHz, dDMSO): 7.58-7.48 (m, 2H), 7.50 (d, 10.0 Hz, 2H), 7.25 (d, 10.0 Hz, 2H), 7.21 -7.14 (m, 2H), 6.60 (d, 2.5 Hz, 2H), 4.41 (t, 5.0Hz, 2H), 3.66 (t, 5.0Hz, 2H), 3.35 (q, 7.5Hz, 2H), 3.31 -3.28 (m, 2H), 3.15 (m, 1H), 2.92 (bs, 3H), 2.62 (m, 2H), 2.05- 1 .98 (m, 3H), 1.00 (t, 7.5Hz, 3H). l3C-NMR (62.89 MHz, dDMSO): 167.0, 158.3, 142.7, 138.3, 135.2, 134.8, 131 .7, 13 1.5, 122.0, 121.8, 1 19.8, 1 18.9, 1 10.7, 68.9, 66.2, 58.5, 52.6, 43.6, 32.6, 30.1 , 15.4.
Example 5:
Preparation of 2-( 1 -(4-bromophenethyl)piperidin-4-y 1)- 1 -(2-ethoxyethy 1)- 1 H- benzo[d]imidazole 27 - use of potassium f-butoxide.
A 25-30% solution of NH4OH (6.4 ml, 2.2 eq) was added to a stirred suspension of ethyl l -(4- bromofenethyl)piperidine-4-carboxylate fumarate (17.54 g, 38.45 mmol) in a mixture of toluene (100 ml) and water (50 ml), it was stirred intensively at RT for 30 min, the phases were separated, the aqueous phase was washed with toluene (2 x 35 ml). The combined organic phases were washed with water (25 ml) and dried by azeotropic distillation at the atmospheric pressure (ca. 82 ml of the toluene-water mixture removed by distillation). The solution of thus prepared free base was cooled to the room temperature and then a solution of N I -(2-ethoxyethy l)benzene-l ,2-diamine (6.93 g, 38.45 mmol, 1.0 eq) in dry toluene (60 ml) was added under argon and the solution was cooled under Ar to the temperature of -2 to 0°C and subsequently a solution of fresh t-BuOK (8.63 g, 76.87 mmol, 2.0 eq) in dry DMF (40 ml) was added dropwise at this temperature during 30 min (the solution changes its colour from yellow to orange and gradually to wine, the progress of amidation is monitored by HPLC). After stirring under cooling for two hours, the cooling bath was removed and the mixture was left to slowly heat up to the room temperature. After another 1.5 hours' stirring (t ca. 16°C) HPLC analysis confirmed consumption of both starting compounds thus prepared solution of
crude amide was heated at 55 to 60°C for 21 h; HPLC analysis indicated a benzimidazole : amide ratio of 95.4 : 4.6, the temperature was gradually increased to 100°C during 4 h, and a 96.5 : 3.5 ratio was achieved. After cooling to RT and then to 10°C brine (100 ml) was added and the mixture was intensively stirred for ca. 10 min (its colour changing from wine to orange), the. phases were separated, the aqueous phase washed with toluene (4 x 50 ml). The combined organic fractions were washed with water (5 x 10 ml), brine (50 ml) and dried (Na2S04 or azeotropic distillation). Toluene was evaporated at a reduced pressure and, after drying in vacuum (ca. 2.5 kPa), a crude crystalline product was obtained ( 16.47 g, 94%), which was purified by crystallization from isopropanol (165 ml), boiling - room temperature - -20°C. The crystals were filtered off, washed with cooled (ca. -20°C) isopropanol (/-PrOH) and dried with passing air on frit and subsequently in a vacuum drier at 55°C/18 kPa for 7 hours. 14.14 g (80 %) of a beige crystalline substance in the free base form was obtained. HPLC 99.32%, melt, point 1 12.9- 1 13.7°C (/-PrOH).
Free base: XRPD ([°2Th.](rel. int%)): 4.35 (44.5), 8.62 (100.0), 12.92 (2.2), 14.00 (5.6), 14.39 ( 1.8), 15.12 (1.6), 17.59 (2.7), 18.72 (2,2), 19.46 (1.4), 19.91 (2.0), 20.50 (5.4), 20.78 (20.7), 21.56 (2.3), 22.1 1 (12.4), 24.20 (8.2), 25.67 (1.8), 26.19 (3.5), 26.53 (3.4), 26.85 (3.0), 27.99 (3.2), 28.24 (4.4), 30.35 (1.9), 31.03 (1.4), 31.92 (1.8), 34.45 (1.4), 37.82 (1.4).
Ή-NMR (250 MHz, CDC13): 7.74 (m, 1H), 7.40 (d, 2H, 7.5 Hz), 7.33-7. 18 (m, 3H), 7.10 (d, 2H, 7.5 Hz), 4.30 (t, 2H, 7.5 Hz), 3.71 (t, 2H, 5.0 Hz), 3.39 (q, 2H, 5.0 Hz), 3.1 1 (m, 2H), 2.98 (m, 1 H), 2.80-2.70 (m, 2H), 2.63-2.57 (m, 2H), 2.16 (m, 4H), 1.94 (m, 2H), 1.10 (t, 3H, 7.5 Hz).
I 3C-NMR (62.89 MHz, CDC13): 158.4, 142.7, 139.7, 134.8, 131.2, 130.5, 121 .9, 121.7, 1 19.6, 1 19.4, 109.1 , 68.6, 66.8, 60.1 , 53.7, 43.6, 34.4, 33.1 , 3 1.1 , 14.9. [M-H]+ C24H3i79BrN30 theory: 456.1651 found: 456.1645.
Example 6: Preparation of 2-(l-(4-bromophenethyl)piperidin-4-yl)-l-(2-ethoxyethyl)-l H- benzo[d]imidazole, use of crude diamine:
27
Ethyl l-(4-bromophenethyl)piperidine-4-carboxylate fumarate (8.48 g, 18.57 mmol) was converted to a free base by shaking in a mixture of toluene (100 ml) and water (50 ml) and a 25-30% solution of NH4OH (5 ml), the phases were separated, the aqueous phase was washed with toluene (2 x 25 ml). The combined organic phases were washed with brine (25 ml) and a crude purple solution of the amine (ca. 3.72 g, 18.57 mmol in ca. 40 ml of ethanol - obtained by hydrogenation of the corresponding nitro derivative and filtration of the catalyst) was added to the organic phase and the mixture was subjected to azeotropic distillation at the atmospheric pressure (ca. 130 ml of the toluene-ethanol-water mixture removed by distillation, up to the boiling point of 108°C). The solution of thus prepared free base and diamine in toluene was cooled to the room temperature and further to -2 to 0 °C and, at this temperature, a solution of fresh t-BuO (4.17 g, 37.17 mmol, 2.0 eq) in dry DMF (20 ml) was added dropwise during 30 minutes (the progress of amidation was monitored by HPLC). After stirring under cooling for two hours the cooling bath was removed and the mixture was left to slowly heat up to the room temperature overnight. HPLC analysis confirmed consumption of both starting compounds and thus prepared solution of the crude amide was heated at 100°C during 5 h; HPLC analysis indicated the benzimidazole : amide ratio of ca. 95 : 4, the heating continued for another 4.5 h and a ca. 97 : 3 ratio was achieved. After cooling down to the room temperature and then to 10°C, brine (55 ml) was added and the mixture was intensively stirred for 10 min, the phases were separated, the aqueous phase was washed with toluene (3 x 25 ml). The combined organic fractions were washed with water (5 x 10 ml), brine (25 ml) and shortly stirred with active carbon (0.7 g) and dried (Na2S04). Toluene was evaporated at a reduced pressure and, after drying in vacuum (ca. 2.5kPa), a crude brown crystalline product was obtained (7.45 g, 88%), which was purified by crystallization from isopropanol (75 ml), boiling - room temperature - -20°C. The crystals were filtered off, washed with cooled (ca. -20°C) isopropanol and dried with passing air on frit and then at 55°C/18 kPa in a vacuum
drier (2h); 5.59 g (66%) of a beige crystalline substance was obtained. HPLC 99.06%, melt, point 1 12.5- 1 14.7°C ( -PrOH).
28
Fumarate of the amine 1 (3.66 g) was converted to a free base by stirring in a biphasic system of toluene (70 ml) and 5% aqueous NaHC0 (50 ml); after separation of the phases, the aqueous phase was additionally washed with toluene (30 ml) and the combined organic extracts were washed with brine (20 ml) and dried over sodium sulphate. Filtration and evaporation of the solvent provided the free base as oil (2.53 g, 93%). A 1M solution of NaOH (0.744 g of NaOH, 2.5 eq + 19 ml of H20) was added to a stirred solution of the base in methanol (30 ml) at the room temperature and the resulting white suspension was stirred at the room temperature overnight. During stirring, pH was adjusted to ca. 6 by addition of a 2M solution of HC1; pH was further adjusted to 7 by careful additions of 5% aqueous NaHC03; the product crystallized from the mixture. After continuing stirring at 0-5°C (3 h) the free acid was isolated by filtration and washed with cold water (10 ml) and dried with passing air on frit and further in a vacuum drier (45°C/18 kPa, 24 h). 2.0 g (86 %) of the product was obtained, HPLC 99.81 %, melt, point 221.5-223.6°C.
Ή-NMR (250 MHz, dDMSO): 7.45 (d, 7.5Hz, 2H), 7.20 (d, 7.5Hz, 2H), 2.87-2.83 (m, 2H), 2.73 (m, 2H), 2.48 (m, 2H), 2.17 (m, 1 H), 2.01 (m, 2H), 1.81- 1 .76 (m, 2H), 1.55-1.43 (m, 2H).
13C-NMR (62,89 MHz, dDMSO): 176.1 , 140.0, 131.0, 130.9, 1 18.8, 59.5, 52.4, 32.0, 28.1.
[M-H]+ Ci4Hi979BrN02 theory: 312.0599 found: 3 12.0594.
Example 8: Preparation of l-(4-bromophenethyl)-N-(2-((2- ethoxyethyl)amino)phenyl)piperidine-4-carboxamide
26
A suspension of the acid (3.63 g, 1 1.63 mmol) in dry 2-methylTHF (50 ml) was cooled to ca. 0-5°C under argon, N-methylpyrrolidone (2.35 g, 23.25 mmol, 2.0 eq) was added, followed by slow addition of a solution of isobutyl chloroformate (1.83 g, 13.37 mmol, 1.15 eq) in dry 2- methylTHF (5 ml) during 20 minutes (the dripping funnel was then washed with 5 ml of 2- methylTHF). The suspension was stirred at this temperature for another hour and then addition of a solution of Nl -(2-ethoxyethyl)benzene-l ,2-diamine (2.1 g, 1 1.63 mmol, 1.0 eq) in 2-methylTHF (10 ml) was started, and it was completed in ca. 10 min. The reaction mixture was heated at the room temperature and stirred for ca. 21 hours. After addition of water (40 ml) the suspension was stirred intensively for 10 min, the phases were then separated, the aqueous phase was washed with 2-methylTHF (2 x 10 ml). The combined organic fractions were washed with 5% NaHC03 (30 ml), brine (30 ml) and dried over sodium sulphate. Filtration and evaporation of the solvent at a reduced pressure provided the crude product as a solid substance (5.32 g, 96%). Re-crystallization from isopropanol (37 ml) provided white crystals, which were filtered and dried with air passing through frit. 2.94 g (53%) of the product with the purity of 99.87% (HPLC) was obtained. Melt, point 161.5- 163.2°C ( -PrOH).
Ή-NMR (250 MHz, CDC13): 7.44 (m, 1 H), 7.40 (d, 2H, 7.5 Hz), 7.14-7.07 (m, 1 H), 7.09 (d, 2H, 7.5 Hz), 6.81 (m, 2H), 3.97 (bs, 1 H), 3.64 (t, 2H, 5.0 Hz), 3.54 (q, 2H, 7.5 Hz), 3.25 (m, 2H), 3.06 (bd, 2H, 12.5 Hz), 2.80-2.73 (m, 2H), 2.61 -2.55 (m, 2H), 2.32 (m, 1 H), 2.14-1.79 (m, 6H), 1.22 (t, 3H, 7.5Hz).
13C-NMR (62.89 MHz, CDC13): 173.59, 141.59, 139.43, 131.39, 130.43, 126.72, 125.26, 124.92, 1 19.76, 1 19.12, 1 14.34, 68.79, 66.37, 60.25, 53.12, 44.39, 43.88, 33.1 1 , 29.14, 15.18. [M-H C24H3279BrN302 theory: 474.1751 found: 474.1757.
Example 9: Preparation of 2-(l-(4-bromophenethyl)piperidin-4-yl)- l -(2-ethoxyethyl)- l H- benzo[d]imidazole by cyclization of the amide:
27 l-(4-bromophenethyl)-N-(2-((2-ethoxyethyl)amino)phenyl)piperidine-4-carboxamide ( 1.38 g, 2.91 mmol) was dissolved in acetic acid and then heated in a bath under an argon atmosphere with stirring at 125 °C for 18 h. After cooling to the room temperature acetic acid was evaporated at a reduced pressure and the evaporation residue was dissolved in toluene (50 ml), shortly boiled with active carbon and the solution was filtered. After cooling to the room temperature it was diluted with toluene (100 ml) ,washed with a 5% aqueous solution of NaHC03 (100 ml) and cone. NH4OH (5 ml). The aqueous phase was additionally washed with ethyl acetate (50 ml) and the combined organic extracts were washed with water (30 ml) and brine (30 ml). After drying over Na2S04, filtration and evaporation at a reduced pressure 1.33 g of brown oil was obtained. Re-crystallization from isopropanol (13 ml) provided the white crystalline product (0.89 g, 67%).
Example 10: Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-l H-benzo[d]imidazol-2- yl)piperidin- 1 -yl)ethyl)phenyl)-2-methylpropanoate 16 (hydrochloride)
16 The derivative 27 (10 g, 21.91 mmol) was dissolved in dry DMF (80 ml) under argon with stirring and mild heating (40-50°C); after cooling to the room temperature /-Bu P (239 μΐ,
0.986 mmol, 4.5 mol%), Pddba2 (0.189 g, 0.328mmol, 1 .5 mol%) and ZnF2 (2.28 g, 21.91 mmol, 1.0 eq) were added and the mixture was stirred under Ar at the room temperature for 40 minutes. Then, TMS enolate (7.4 ml, 32.86 mmol, 1.5 eq) was added dropwise and the reaction mixture was heated in a bath at 90°C for 16 h. HPLC determined that the ratio of the product, starting compound and the desbromo derivative was 86:8:6, and therefore more TMS enolate (0.5 eq) was added and the mixture was heated under argon for 6 h, after which HPLC indicated complete consumption of the starting compound. After cooling to the room temperature the mixture was diluted with methyl tert-butyletherMTBE (250 ml) and a 10% aqueous solution of trisodium citrate (100 ml) was added under intensive stirring and the mixture was stirred for 45 min. After separation of the phases the aqueous phase was additionally washed with MTBE (2 x 50 ml), the combined organic phases were washed with water (5 x 10 ml), brine (10 ml) and dried over anhydrous sodium sulphate. The drying agent was removed by filtration and a solution of HC1 in diethyl ether (ca. 45 ml, excess of HC1) was added dropwise, the resulting hydrochloride suspension was then cooled to ca. 0-5°C and the hydrochloride was filtered off, washed with cold MTBE and aspirated to dryness. The filtration cake was then dried in a vacuum drier at 55°C/18 kPa for 19 h; 8.95 g of the hydrochloride as a yellowish crystalline substance (79%) was obtained. HPLC: 92.40% (desBr: 2.80%), melt point 152.2-159.5°C.
Hydrochloride XRPD ([°2Th.](rel ,int%)): 4.83 (100.0), 8.33 (8.8), 9.1 1 (21 .5), 9.58 ( 16.6), 14.37 (86.4), 15.56 (10.6), 16.13 (1 1.7), 17.51 (19.2), 20.48 (3 1.8), 22.41 (16.1 ), 23.21 (21.1), 24.1 1 (12.6), 26.83 (5.2), 27.41 (5.3), 28.76 (5.9), 32.52 (5.7).
Free base:
Ή-NMR (250 MHz, CDC13): 7.75 (m, 1H), 7.33-7.15 (m, 7h), 4.32 (t, 2H, 5.0 Hz), 3.72 (t, 2H, 5.0 Hz), 3.66 (s, 3H), 3.39 (q, 2H, 7.5 Hz), 3.15 (bd, 2H, 7.5Hz), 2.98 (m, 1H), 2.81 (dd, 2H, 5.0 and 10.0 Hz), 2.64 (t, 2H, 7.5Hz), 2.18 (m, 4H), 1.93 (m, 2H), 1.57 (s, 6H), 1.1 1 (t, 2H, 7.5Hz).
I 3C-NMR (62.89 MHz, CDCI3): 177.37, 158.48, 142.85, 142.30, 139.89, 128.03, 125.58, 121.95, 121.78, 1 19.53, 109.15, 68.68, 66.92, 60.46, 53.78, 52.16, 46.24, 43.69, 34.63, 33.19, 31.15, 25.25, 15.02. [M-H]+ C29H40N3O3 theory: 478.3070 found: 478.3073.
Example 11: Preparation of methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)-lH-benzo[d]imidazol-2- yl)piperidin-l -yl)ethyl)phenyl)-2-methylpropanoate 16 (fumarate)
The crude product 16 (ca. 2.98 g, 5.48 mmol) was dissolved when hot (100°C) in methylisobutylketone (30 ml) and a hot solution of fumaric acid (0.63 g , 5.48 mmol, 1.0 eq) in ethanol (10 ml) was added under stirring. The resulting clear solution was slowly cooled down to the room temperature with stirring, the fumarate salt crystallizing quickly. After further cooling to 4°C the crystals were filtered off and washed with cold methylisobutylketone (10 ml) and dried in a vacuum drier (40°CC/18 kPa) for 24 h. 2.53 g of crystals were obtained (78%), HPLC 95.20%.
Fumarate XRPD ([°2Th.](rel. int%)): 5.76 (100.0), 10.15 (29.3), 10.56 (18.6), 12.17 (22.7), 13.45 (13.6), 14.54 (15.0), 16.71 (25.1 ), 17.48 (37.8), 17.89 (45.5), 19.28 (22.2), 21.24 (52.5), 22.41 (14.7), 22.98 (13.7), 25.14 (13.2), 27.23 (4.3).
Example 12: Preparation of 2-(4-(2-(4-(l -(2-ethoxyethyl)-l H-benzo[d]imidazol-2- yl)piperidin- 1 -yl)ethyl)pheny l)-2-methylpropanoic acid (bilastine)
9 bilastine methyl ester hydrochloride (8.69 g, 16.92 mmol) was dissolved in methanol (86 ml) and then a solution of potassium hydroxide (4.75 g, 84.62 mmol, 5.0 eq) in water (86 ml) was added under stirring and the reaction mixture was heated at 100°C under nitrogen for 16 h. Then, the bath temperature was increased to 120°C and methanol was removed by distillation at patm (ca. 1 18 ml of the distillate was removed, up to the boiling point of 98°C). After cooling to RT the mixture was washed with MTBE (3 x 50 ml) and the aqueous phase was then acidified to pH 7 by addition of 1 M HC1 (ca. 40 ml) under stirring; ethyl acetate (100 ml) was added to the precipitate of the product in the aqueous phase and the mixture was intensively stirred for 20 min. Then, the precipitate was filtered off, washed with water (10 ml) and ethyl
acetate (10 ml) and dried in vacuum (55°C/18 kPa, 2h) -4.58 g of a white crystalline substance was obtained (58%, melt, point 199.9-203.8°C, lit. 58%, 199-201 °C, HPLC 99.61 %). Ή and 13C NMR spectra in dDMSO are in conformity with the literature (EP 0 818 454 Al). The aqueous phase was additionally washed with ethyl acetate (2 x 100 ml) and the combined organic extracts were dried over Na2S0 and evaporated after filtration of the drying agent; 0.55 g of the product was obtained (HPLC 91.1 %). The crude product I was purified by crystallization from isopropanol (0.510 g sample from 40 ml of i-PrOH), 0.466 g (91%) of a crystalline substance with the HPLC purity of 99.80%) was obtained, polymorph 1 in accordance with IR (EP 1 505 066), Form 1 : XRPD ([°2Th.](rel. int%)): 3.64 (4.4), 10.57 (23.3), 1 1.27 (78.1), 12.47 (38.8), 14.08 (26.9), 15.07 (38.4), 15.50 (16.5), 16.27 (43.6), 17.16 (100.0), 18.89 (71.8), 19.73 (74.0), 21.13 (33.9), 22.17 (18.1), 22.71 (26.9), 23.34 (10.3), 24.88 ( 18.6), 25.82 (9.2), 26.58 ( 1 1.5), 28.43 (9.7), 29.16 (8.8), 30.92 (4.6), 34.38 (9.5), 37.01 (5.4).
Crystallization of the API from n-pentanol (0.375 g from 3.75 ml) provided the yield of 0.125 g (33%), HPLC purity improved from 95.60% to 97.90%, form 2 in accordance with IR was provided (EP 1 505 066).
Form 2: XRPD ([°2Th.](rel. int %)): 6.53 (100.0), 9.43 (30.8), 1 1.04 (22.8), 13.39 (6.2), 15.24 (32.2), 15.86 (86.1), 18.07 (29.9), 18.39 (36.2), 18.94 (8.3), 20.19 (16.0), 20.66 (19.0), 21.70 (17.1), 22.17 (15.6), 23.70 (5.7), 26.59 (4.9), 28.03 (3.6), 28.33 (3.6), 29.70 (4.3).
Claims
1. A process for the preparation of 2-(4-(2-(4-(l -(2-emoxyethyl)-l H-benzo[d]imidazol- 2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoic acid (bilastine) of formula 9,
9
characterized in that 2-(l-(4-bromofenethyl)piperidin-4-yl)-l -(2-ethoxyethyl)- l H- benzo[d]imidazole of formula 27
in the form of a base or salt is reacted with a suitable alkylation reagent and with the use of suitable auxiliary reagents, producing the ester of formula 16,
wherein R stands for a C 1-C4 alkyl,
which is subsequently alkali or acid hydrolyzed to bilastine.
13a
wherein R stands for a C1-C4 alkyl and Me means methyl, is used as the suitable alkylation reagent.
3. The process according to claim 2, characterized in that R means methyl or ethyl.
The process according to claims 2 or 3, characterized in that the alkylation is carried out in the presence of auxiliary reagents, which are tri(/ert-butyl) phosphine, Pd(dibenzylideneacetone)2 and ZnF2.
is used as the suitable alkylation reagent, which is converted to the corresponding sodium or lithium enolate in the presence of a strong base.
6. The process according to claim 5, characterized in that R means methyl or ethyl and the strong base is selected from Na or lithium hexamethyldisilylamide, lithium dicyclohexylamide and lithium diisopropylamide.
7. The process according to claim 1 , wherein the compound 16 is isolated in the form of a crystalline salt with hydrochloric or fumaric acid.
8. The crystalline hydrochloride as obtained by the process of claim 7, exhibiting the following main characteristic peaks in powder X-ray diffraction, measured with the use of CuKa radiation: 4.83, 9.1 1 , 14.37, 20.48, 23,21 °2Θ ± 0.2° 2Θ.
9. The crystalline hydrochloride according to claim 8, exhibiting the following other characteristic peaks in powder X-ray diffraction measured with the use of CuKa radiation: 8.33, 9.58, 15.56, 16.13, 17.51 , 22.41 , 24.1 1 , 26.83, 27.41 , 28.76, 32.52 °2Θ ± 0.2° 2Θ.
10. The crystalline fumarate as obtained by the process of claim 7, exhibiting the
following main characteristic peaks in powder X-ray diffraction, measured with the use of CuKa radiation: 5.76, 10.15, 16.71, 17.48, 17.89, 22.98 °2Θ ± 0.2° 2Θ.
1 1. The crystalline fumarate according to claim 10, exhibiting the following other
. characteristic peaks in powder X-ray diffraction measured with the use of CuKa radiation: 10.56, 12.17, 13.45, 14.54, 19.28, 21.24, 22.41 , 25.14, 27.23 °2Θ ± 0.2° 20.
12. A process for the preparation of the intermediate of formula 27, characterized in that a compound of formula 24,
wherein R| is a Ci to C3 alkyl, is condensed with the diamine of formula 25
in a non-polar organic solvent in the presence of a strong organic or inorganic base at a temperature in the range of -5 to +5°C to the intermediate 26,
26
which is then cyclized at a temperature in the range of 70-120°C to the compound 27, preferably without isolation of the intermediate of formula 26.
13. The process according to claim 12, characterized in that said non-polar organic solvent is selected from toluene, dimethylformamide, tetrahydrofuran, 2- methyltetrahydrofuran and their mixtures.
14. The process according to claim 12, characterized in that said strong organic base is selected from of alkali metal alkoxides or hydrides.
15. The process to claim 12, characterized in that said strong organic base is used in an amount of 1 -3 equivalents.
16. The process according to claim 12, characterized in that potassium ½r/-butoxide in the range of 2-2.5 equivalents is used as the strong organic base.
17. The compound of formula
27
in the form of a base or salt with an organic or inorganic acid.
18. The compound according to claim 17 in the form of a base, exhibiting the following main characteristic peaks in powder X-ray diffraction measured with the use of CuK.cc radiation: 4.35, 8.62, 20.78, 22.1 1 , 24.20 °2Θ ± 0.2° 2Θ.
19. The compound according to claim 18 in the form of a base, exhibiting the following other characteristic peaks in powder X-ray diffraction measured with the use of CuKct radiation: 14.00, 17.59, 18.72, 19.46, 19.91 , 20.50, 21.56, 26.19, 26.53, 26.85, 27.99, 28.24, 30.35, 31.92, 34.45, 37.82 °2Θ ± 0.2° 2Θ.
20. The compound according to claim 17 in the form of a salt with fumaric acid, exhibiting the following main characteristic peaks in powder X-ray diffraction, measured with the use of CuKa radiation: 12.24, 17.19, 19.60, 22.59, 31.96 °20 ± 0.2° 2Θ.
21. The compound according to claim 20, exhibiting the following other characteristic peaks in powder X-ray diffraction measured with the use of CuKa radiation: 6.41 , 10.62, 13.87, 14.95, 15.50, 18.23, 18.79, , 20.89, 21 .54, 24.95, 25.29, 26.39, 26.76, 28.08, 29.73, 30.31, 33.25, 37.36 °2Θ ± 0.2° 2Θ.
24
wherein Ri stands for ethyl, in the form of a base or salt with an inorganic or organic acid.
23. The compound according to claim 22 in the form of a salt with fumaric acid, exhibiting the following main characteristic peaks in powder X-ray diffraction, measured with the use of CuKa radiation: 9.70, 14.65, 21.82, 24.60, 28.94 °2Θ ± 0.2° 2Θ.
24. The compound according to claim 23, exhibiting the following other characteristic peaks: 12.65, 16.08, 17.07, 18.80, 22.38, 24.94,
25.55, 25.84,
26.72, 28.40, 34. 16°2Θ ± 0.2° 2Θ.
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Also Published As
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CZ307500B6 (en) | 2018-10-24 |
WO2014026657A3 (en) | 2014-04-10 |
CZ2012551A3 (en) | 2014-02-26 |
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