EP1891053A1 - Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci - Google Patents
Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ciInfo
- Publication number
- EP1891053A1 EP1891053A1 EP06763628A EP06763628A EP1891053A1 EP 1891053 A1 EP1891053 A1 EP 1891053A1 EP 06763628 A EP06763628 A EP 06763628A EP 06763628 A EP06763628 A EP 06763628A EP 1891053 A1 EP1891053 A1 EP 1891053A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- ethyl
- methyl
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 46
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title claims description 8
- 239000000543 intermediate Substances 0.000 title abstract description 11
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 2
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims abstract description 15
- 229960000932 candesartan Drugs 0.000 claims abstract description 14
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960004349 candesartan cilexetil Drugs 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 15
- 229950006523 cilexetil Drugs 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- VTDCYOLLYVAJSY-UHFFFAOYSA-N cyclohexyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OC1CCCCC1 VTDCYOLLYVAJSY-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001556 benzimidazoles Chemical class 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- MFOMDTCBCZQHQZ-UHFFFAOYSA-N ethoxymethanetriol Chemical compound CCOC(O)(O)O MFOMDTCBCZQHQZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 230000004224 protection Effects 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical group Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims 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 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- 125000001626 borono group Chemical group [H]OB([*])O[H] 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- HTQMVQVXFRQIKW-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 HTQMVQVXFRQIKW-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- -1 cilexetil ester Chemical class 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- RFKXQGCBYQQWNX-UHFFFAOYSA-N ethyl 2-chloro-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC([N+]([O-])=O)=C1Cl RFKXQGCBYQQWNX-UHFFFAOYSA-N 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- MARUHZGHZWCEQU-UHFFFAOYSA-N 5-phenyl-2h-tetrazole Chemical class C1=CC=CC=C1C1=NNN=N1 MARUHZGHZWCEQU-UHFFFAOYSA-N 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 150000003536 tetrazoles Chemical group 0.000 description 2
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- XRNVSPDQTPVECU-UHFFFAOYSA-N (4-bromophenyl)methanamine Chemical compound NCC1=CC=C(Br)C=C1 XRNVSPDQTPVECU-UHFFFAOYSA-N 0.000 description 1
- ONZWFHWHTYZZLM-UHFFFAOYSA-N 1-chloroethyl cyclohexyl carbonate Chemical compound CC(Cl)OC(=O)OC1CCCCC1 ONZWFHWHTYZZLM-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- JRQDVRIQJJPHEQ-UHFFFAOYSA-N 3970-35-2 Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1Cl JRQDVRIQJJPHEQ-UHFFFAOYSA-N 0.000 description 1
- IRWNVNYVNZBWDD-UHFFFAOYSA-N 5-phenyl-2-(2-phenylpropan-2-yl)tetrazole Chemical compound N1=NC(C=2C=CC=CC=2)=NN1C(C)(C)C1=CC=CC=C1 IRWNVNYVNZBWDD-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- UZMYAXZLWVFGBD-UHFFFAOYSA-N methyl 1h-benzimidazole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1N=CN2 UZMYAXZLWVFGBD-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000007122 ortho-metalation reaction Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- KXJNZVTVRQTOOE-UHFFFAOYSA-M potassium;n,n-dimethylformamide;iodide Chemical compound [K+].[I-].CN(C)C=O KXJNZVTVRQTOOE-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000006478 transmetalation reaction Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the present invention relates to a new method for obtaining benzimidazole derivatives and intermediates thereof .
- Candesartan and candesartan cilexetil are compounds having an intense selective angiotensin II receptor blocking activity which are useful in the treatment of hypertension .
- Candesartan is the international nonproprietary name of 2-ethoxy-l-[ [2 '- (lH-tetrazole-5-yl) [1, 1 ' -biphenyl] -4- yl] methyl] -lH-benzimidazole-7-carboxylic acid of Formula (I) , finding application in medicine and used in the treatment of hypertension.
- European patent EP 459.136 Bl discloses candesartan and candesartan cilexetil for the first time, as well as several methods for preparing benzimidazole derivatives, among which are candesartan and its corresponding cilexetil ester.
- Said methods are characterised in that in the final step of the synthesis the benzimidazole ring is generated, inserted or substituted from the biphenyltetrazolyl group, as shown in the following schema:
- Patent EP 668.272 Bl describes a method for obtaining a number of compounds derived from tetrazole, among which methods are included candesartan and candesartan cilexetil, which method comprises deprotection of an N- tetrazolyl compound protected with a mineral acid in the presence of an alcohol, with a concentration of water of up to 1 mole per mole of the aforesaid protected N- tetrazolyl compound.
- Patent EP 881.212 Bl claims a method for preparing a compound of formula (VII), which is an intermediate useful in the synthesis of candesartan.
- the method comprises reacting a mixture that contains a monohalogenated compound of formula (VIII) or a dihalogenated compound of formula (VIII') or a salt thereof, with Y being a halogen atom, with a compound of formula (IX) .
- the object of the present invention is a method for obtaining derivatives of benzimidazole and intermediates thereof, in particular for obtaining Candesartan and Candesartan cilexetil.
- the present invention provides a method for obtaining the benzimidazole derivatives of general formula (I) :
- R represents H, methyl, ethyl or cilexetil
- P represents H, cumyl, diphenylmethyl or trityl, and pharmaceutically acceptable salts thereof, which comprises reacting the compound of general formula (H) :
- A represents B (OH) 2 or ZnX; where X represents a halogen group, and
- P represents H, cumyl, diphenylmethyl or trityl; with a compound of general formula (III) :
- R represents H, methyl, ethyl or cilexetil
- Y represents an halogen atom, in the presence of a palladium catalyst, or in an organic solvent .
- the method object of the invention is particularly suitable for obtaining candesartan and candesartan cilexetil, compounds that present an intense selective angiotensin II receptor blocking activity, and which are useful in the treatment of hypertension.
- the coupling reaction is carried out in the presence of palladium catalysts such as trans- dichlorobis (triphenylphosphine) palladium (II) , tetrakis (triphenylphosphine) palladium (0), tetrakis (methyldiphenylphosphine) palladium (0).
- palladium catalysts such as trans- dichlorobis (triphenylphosphine) palladium (II) , tetrakis (triphenylphosphine) palladium (0), tetrakis (methyldiphenylphosphine) palladium (0).
- the catalyst of the coupling reaction can be generated in situ, by carrying out the reaction in the presence of palladium acetate and triphenylphosphine.
- an inert organic solvent preferably aprotic, such as toluene, acetonitrile, THF, dimethoxyethane, N, N-dimethylacetamide and the like can be used as a reaction solvent.
- aprotic such as toluene, acetonitrile, THF, dimethoxyethane, N, N-dimethylacetamide and the like
- the reaction is carried out at a temperature between 30 and 100°C, preferably between 60 and 70°C, for 1-20 hours.
- the benzimidazole derivative of general formula (I) can be converted, if desired, by means of hydrolysis, esterification, protection and/or deprotection to form another compound of formula (I) , by means of methods known in the state of the art.
- the starting compounds of general formula (II) can be synthesised according to methods known in the state of the art, such as those described in patent application DE 4313747, European patent EP 455.423, or application PCT/EP2004/008576 (application date: 30.07.04) and comprising the reaction of the corresponding phenyl tetrazole with BuLi and the subsequent transmetalation reaction.
- the benzimidazole derivatives of general formula (I) obtained in accordance with the first aspect of the invention can be isolated and/or purified from the reaction mixture in accordance with conventional methods, such as recrystallisation and column chromatography, to obtain a crystalline product.
- the present invention provides an intermediate of general formula (III) :
- R is methyl
- Y represents a halogen atom.
- the present invention provides a method for obtaining intermediates of general formula (III) :
- R represents hydrogen, methyl, ethyl or cilexetil
- Y represents a halogen atom; which comprises: a) reacting a compound of general formula (IV)
- R 1 is methyl or ethyl, with a 4-halobenzylamine, in the presence of a base and an organic solvent, to obtain the compound of general formula
- the first step of the reaction is an aromatic nucleophilic substitution of the general compound (IV) by a 4-halobenzylamine in the presence of a base.
- the reaction is carried out in solvents such as toluene, THF, acetonitrile, DMF and the like.
- suitable bases include, but are not limited to, triethylamine, sodium hydride, potassium carbonate and sodium carbonate.
- the second step of the method in accordance with the third aspect of the invention is a reduction reaction of the intermediate of general formula (V) , which can be carried out by using, for example, tin chloride.
- the reaction solvent can be a protic organic solvent such as EtOH.
- the reaction is normally carried out at a temperature between 30 and 100°C, for 1 to 4 hours.
- the third step of the method in accordance with the third aspect of the invention comprises the reaction of the intermediate of general formula (VI) with ethyl orthocarbonate, in the presence of an acid such as acetic acid or p-toluene sulphonic acid.
- an acid such as acetic acid or p-toluene sulphonic acid.
- the reaction solvent halogenated hydrocarbons and ethers can be used, although it is normally more convenient to carry out the reaction without solvent.
- the reaction is normally carried out at a temperature between 30 and 100°c, preferably between 70 and 80°C, for 1 to 3 hours.
- reaction intermediates (V) and (VI) obtained as described above can easily be isolated and/or purified by means of, or in accordance with, conventional methods such as, for example, evaporation of solvents, extraction by means of water or organic solvents, concentration, neutralisation, recrystallisation, distillation and column chromatography .
- the compounds (I) and (III) obtained in the above- mentioned way can be in the form of solvates or salts (including addition salts) from pharmaceutically or physiologically acceptable acids or bases.
- the following examples illustrate the invention but must not be considered as limiting the scope thereof.
- Tin (II) chloride dihydrate 14.87 g is added to a solution of ethyl 2- (4-bromobenzylamine) -3-nitrobenzoate (5.0 g) in ethyl alcohol (25 ml) .
- the mixture is heated at reflux for 2 hours, following which the solvent is distilled at reduced pressure to dryness.
- the concentration residue is cooled with an ice bath and sodium hydroxide 2 N (265 ml) is added dropwise.
- the aqueous phase is extracted with ethyl acetate (2 x 150 ml) .
- the organic phases are combined, washed with water, dried over anhydrous sodium sulphate and filtered.
- the solvent is concentrated at reduced pressure to a final volume of 100 ml, and a current of HCl gas (at least 1 equivalent) is passed over said solution, to obtain the ethyl 3-amino-2- (4-bromobenzylamine) benzoate hydrochloride .
- Acetic acid (1 g) is added to a solution of ethyl 3- amino-2- (4-bromobenzylamine) benzoate (5.0 g) in ethyl orthocarbonate (25 ml) and is heated at 80°C for 1 hour. The reaction is concentrated and the residue is dissolved in ethyl acetate. The so obtained solution is washed with a sodium bicarbonate solution in water and afterwards with water. The organic phase is dried over anhydrous magnesium sulphate and is concentrated, to obtain a residue which is recrystallised in ethyl acetate and heptane (1:5). A yellow solid (4.33 g, 75%) is obtained in the form of needles .
- Tin (II) chloride dihydrate (244.1 g) in a mixture of 35% hydrochloric acid (307.5 g) and water (93 ml) is added to a suspension of methyl 2- (4-bromobenzylamine) -3- nitrobenzoate (123.0 g) in toluene/THF (3:2 v/v) (615 ml).
- the mixture is heated at 55 0 C for 2 hours, following which the mixture is cooled to room temperature and the phases are separated.
- the organic phase is washed with water and to the resulting organic phases, sodium hydroxide 30% (175 ml) is added dropwise. Once the addition is finished, water is added (900 ml) and phases are separated.
- the aqueous phase is extracted with toluene (2 x 300 ml) .
- the organic phases are combined, washed with water, dried over anhydrous sodium sulphate and filtered.
- the solvent is concentrated at reduced pressure to yield 144 g of an orange oily mixture of methyl 3-amino-2- (4- bromobenzylamine) benzoate (113 g) and toluene (31 g) .
- reaction mixture is heated between 60 and 75°C and stirred for approximately 18 hours at that temperature.
- reaction is completed, the mixture is washed with 100 ml of water and the organic phase is dried with
- the so obtained oil is suspended in water and washed with ethyl acetate.
- the phases are separated and the aqueous phase is acidified with concentrated HCl to pH 4-4.5.
- a solid is precipitated and filtered, washed with water and dried in a vacuum oven at 40°C, obtaining 0.58 g (60%) of a white solid.
- Methane sulphonic acid (62 mg) is added to a solution of cilexetil 2-ethoxy-l- [2 '- (trityl) -2H-tetrazole-5- yl) [ 1, 1 ' -biphenyl] -4-yl] methyl] - lH-benzimidazole-7- carboxylate (0.42 g) , which can be obtained from candesartan according to the method described in examples 7 and 8 of European patent EP 459.136 Bl, in methylene chloride, keeping the temperature between -5 and 0°C. Once the acid has been added, the ice bath is removed and the mixture is stirred for 2 hours at room temperature.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un procédé permettant d'obtenir des dérivés de benzimidazole et des intermédiaires de ceux-ci, de préférence un procédé permettant d'obtenir candesartan et candesartan cilexetil. ce procéder permet d'obtenir ces dérivés benzimidazole avec de meilleurs rendements.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200501480A ES2264641B1 (es) | 2005-06-17 | 2005-06-17 | Procedimiento para la obtencion de derivados de bencimidazol y sus intermedios. |
PCT/EP2006/063062 WO2006134078A1 (fr) | 2005-06-17 | 2006-06-09 | Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1891053A1 true EP1891053A1 (fr) | 2008-02-27 |
Family
ID=36808692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06763628A Withdrawn EP1891053A1 (fr) | 2005-06-17 | 2006-06-09 | Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1891053A1 (fr) |
ES (1) | ES2264641B1 (fr) |
WO (1) | WO2006134078A1 (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101781286B (zh) * | 2010-01-28 | 2013-07-10 | 青岛黄海制药有限责任公司 | 一种制备坎地沙坦酯的方法 |
CN101880241B (zh) * | 2010-07-14 | 2013-04-17 | 浙江美诺华药物化学有限公司 | 一锅法制备2-(取代苯基)甲氨基-3-硝基苯甲酸甲酯的方法 |
BR102016024814A2 (pt) * | 2016-10-24 | 2018-05-08 | Aché Laboratórios Farmacêuticos S.A. | composto, processo de obtenção do composto, composição farmacêutica, uso do composto e método de tratamento de desordens psiquiátricas e/ou distúrbios do sono |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0525129A4 (en) * | 1990-04-13 | 1993-03-24 | Smith-Kline Beecham Corporation | Substituted benzimidazoles |
US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
US5039814A (en) * | 1990-05-02 | 1991-08-13 | Merck & Co., Inc. | Ortho-lithiation process for the synthesis of 2-substituted 1-(tetrazol-5-yl)benzenes |
CN1207287C (zh) * | 2002-12-23 | 2005-06-22 | 重庆圣华曦药业有限公司 | 苯并咪唑的酯类化合物及其制备方法和在制备药用化合物坎地沙坦酯中的应用 |
CN100540541C (zh) * | 2003-08-08 | 2009-09-16 | 迪法玛有限公司 | 制备苯基四唑衍生物的方法 |
DE102004060699A1 (de) * | 2004-12-16 | 2006-06-22 | Ratiopharm Gmbh | Verfahren zur Herstellung von Candesartan |
-
2005
- 2005-06-17 ES ES200501480A patent/ES2264641B1/es not_active Expired - Fee Related
-
2006
- 2006-06-09 EP EP06763628A patent/EP1891053A1/fr not_active Withdrawn
- 2006-06-09 WO PCT/EP2006/063062 patent/WO2006134078A1/fr not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO2006134078A1 * |
Also Published As
Publication number | Publication date |
---|---|
ES2264641A1 (es) | 2007-01-01 |
WO2006134078A1 (fr) | 2006-12-21 |
ES2264641B1 (es) | 2008-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8592474B2 (en) | Process for the preparation or purification of olmesartan medoxomil | |
US7227026B2 (en) | Synthesis of irbesartan | |
CA2980965C (fr) | Procede de preparation d'antagonistes des recepteurs androgeniques et de leurs intermediaires | |
KR20110015703A (ko) | 발사르탄의 제조 방법 | |
WO2014036823A1 (fr) | Nouveau procédé de préparation d'un médicament antithrombotique | |
JPH08500323A (ja) | A▲ii▼受容体アンタゴニストの合成のためのテトラゾリルフェニルボロン酸中間体 | |
JP2007112800A (ja) | アンジオテンシンii拮抗化合物の製造方法 | |
EP1853591B1 (fr) | Procede pour l'obtention d'un compose pharmaceutiquement actif (irbesartan) et son intermediaire de synthese | |
US20080076932A1 (en) | A process for the preparation of phenyltetrazole compounds | |
EP1891053A1 (fr) | Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci | |
JP2803905B2 (ja) | A▲ii▼受容体アンタゴニストの合成のための中間体化合物の製法 | |
US7041832B2 (en) | Processes for preparing losartan and losartan potassium | |
WO2007049293A1 (fr) | Meilleur procédé pour la préparation d'irbésartan | |
EP1984356B1 (fr) | Procédé amélioré pour la préparation de candésartan cilexetil | |
WO2007049813A1 (fr) | Derive de benzo[b]thiophene et procede permettant de produire ce derive | |
KR100809159B1 (ko) | 로사탄의 개선된 제조방법 | |
JP2001507711A (ja) | テトラゾリルベンゾピランの製法 | |
JP2007501770A (ja) | フェニルテトラゾール誘導体の製造方法 | |
WO2008148599A2 (fr) | Procédé de fabrication d'un sel de valsartan servant à obtenir du valsartan | |
EP1899328A1 (fr) | Procede de fabrication de derives du losartan par chloration et reduction des 1h-imidazole-5-carbaldehydes respectifs | |
KR20100110438A (ko) | 올메살탄의 신규한 에스테르 화합물, 이의 중간체, 이의 제조방법 및 이를 포함하는 조성물 | |
EP2022790A1 (fr) | Procédé pour la préparation ou la purification d'olmésartan médoxomil | |
JP2019196359A (ja) | ピリミジン誘導体およびそれらの中間体を調製する化学的方法 | |
EP1548009A2 (fr) | Procede pour la preparation des derives de benzimidazole et de losartan | |
EP1634880A2 (fr) | Procédé pour la fabrication de losartan et losartan sous forme de sel de potasse |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20071210 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20080416 |
|
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20090728 |