WO2007029267A1 - Process for industrially viable preparation of imidapril hydrochloride - Google Patents
Process for industrially viable preparation of imidapril hydrochloride Download PDFInfo
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- WO2007029267A1 WO2007029267A1 PCT/IN2006/000183 IN2006000183W WO2007029267A1 WO 2007029267 A1 WO2007029267 A1 WO 2007029267A1 IN 2006000183 W IN2006000183 W IN 2006000183W WO 2007029267 A1 WO2007029267 A1 WO 2007029267A1
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- WIPO (PCT)
- Prior art keywords
- formula
- product
- acid
- hydrochloride
- methyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 229960003409 imidapril hydrochloride Drugs 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 title claims abstract description 8
- 230000008569 process Effects 0.000 title claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- GFZFELCFSBCPDB-AAEUAGOBSA-N ethyl (2s)-2-[(4s)-4-methyl-2,5-dioxo-1,3-oxazolidin-3-yl]-4-phenylbutanoate Chemical compound C([C@@H](C(=O)OCC)N1C(OC(=O)[C@@H]1C)=O)CC1=CC=CC=C1 GFZFELCFSBCPDB-AAEUAGOBSA-N 0.000 claims abstract description 3
- 230000001476 alcoholic effect Effects 0.000 claims abstract 4
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- -1 inorganic acid salts Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 239000002585 base Substances 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 238000006264 debenzylation reaction Methods 0.000 claims 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 239000011976 maleic acid Substances 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000006408 oxalic acid Nutrition 0.000 claims 1
- 238000005897 peptide coupling reaction Methods 0.000 claims 1
- 230000001376 precipitating effect Effects 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 claims 1
- 235000002906 tartaric acid Nutrition 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- LSLQGMMMRMDXHN-GEUPQXMHSA-N Imidapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 LSLQGMMMRMDXHN-GEUPQXMHSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 229960001195 imidapril Drugs 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 3
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- WFLQXECQLHZKMV-NSHDSACASA-N ethyl (2s)-2-amino-4-phenylbutanoate Chemical compound CCOC(=O)[C@@H](N)CCC1=CC=CC=C1 WFLQXECQLHZKMV-NSHDSACASA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QXYOROBKCZWFKK-UHFFFAOYSA-N 2-(4-methylphenyl)sulfonyloxypropanoic acid Chemical compound OC(=O)C(C)OS(=O)(=O)C1=CC=C(C)C=C1 QXYOROBKCZWFKK-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- LJPCNSSTRWGCMZ-UHFFFAOYSA-N 3-methyloxolane Chemical compound CC1CCOC1 LJPCNSSTRWGCMZ-UHFFFAOYSA-N 0.000 description 1
- AGEUQNZXCIVHPB-UHFFFAOYSA-N 4-(hydroxyamino)-4-oxobutanoic acid Chemical compound ONC(=O)CCC(O)=O AGEUQNZXCIVHPB-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- LPHRTQQOKYRTQS-UHFFFAOYSA-N NC(=O)C([SiH3])[SiH3] Chemical compound NC(=O)C([SiH3])[SiH3] LPHRTQQOKYRTQS-UHFFFAOYSA-N 0.000 description 1
- 229910018954 NaNH2 Inorganic materials 0.000 description 1
- WWISPHBAYBECQZ-UHFFFAOYSA-N Pyrazine, 3,6-dihydro-3,6-dimethyl-2,5-dihydroxy- Chemical compound CC1NC(=O)C(C)NC1=O WWISPHBAYBECQZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- AGWNCRTUZAZYKJ-HDHUNYPFSA-N tert-butyl (4s)-3-[(2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-1-methyl-2-oxoimidazolidine-4-carboxylate;hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(=O)OC(C)(C)C)=O)CC1=CC=CC=C1 AGWNCRTUZAZYKJ-HDHUNYPFSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
Definitions
- the invention relates to a novel method for the preparation of imidapril hydrochloride of formula I
- the chemical entity (4S)-3-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3- phenylpropyl]amino]-1-oxopropyl]-1-methyl-2-oxo-4-imidazolidinecarboxylic acid hydrochloride of formula I belongs to a group of medicines called ACE inhibitors, which block the action of a chemical in the body called angiotensin converting enzyme (ACE). Normally ACE produces another chemical, angiotensin II. Thus imidapril reduces the amount of angiotensin Il in the blood. Angiotensin Il has two actions.
- EP 95163/US4508727 discloses synthesis of imidapril hydrochloride of formula employing several stages. This is shown in the following schemes IA and IB
- ECPP alanine of formula-Ilia is activated with N- hyroxysuccinicimide using dicyclohexylcarbodiimide and the activated ester is coupled with t-butyl imidaozlinone-4-carboxylate of formula-ll a in the presence of potassium tert. butoxide to give a dipeptide of formula-V, which is converted to the product of formula-l by treatment with dioxane-HCI
- the scheme I B describes a methodology, which is similar to the one described in scheme IA, except the fact that benzyl imidazolidinone-4-carboxylate of formula-l I b is used instead of the t-butyl ester Ha.
- the coupled product of formula-VI is debenzylated using Pd/C - H 2 and treated with dioxane-HCI to get the product of formula-l.
- the present invention provides a novel process for the preparation of imidapril of formula I by reacting esters of 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate of formula-ll with (S)-ethyl-2-[(S)-4-methyl-2,5-dioxooxazolidin-3-yl]-4-phenylbutanoate of formula-Ill in presence of a base like sodium hydride/sodium methoxide, potassium tert. butoxide etc. After the coupling, the protecting group was removed by means of catalytic hydrogenation or hydrolysis to get the required compound
- the reaction of the product of formula-Ill with imidazolidinone-4-carboxylicacid of formula-ll was tried using different bases viz., NaH, NaOBu', KOBu 1 , NaNH 2 etc. It was preferable to use NaH, Na/KOBu 1 . It was more preferable to use Na/KOBu 1 .
- the reaction was studied in different solvents like dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran, 2 or 3 methyl tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, sulfolane etc.
- esters of 4(S)-1-methyl-2-oxoimidazolidine-4- carboxylate of formula-ll with (S)-ethyl-2-[(S)-4-methyl-2,5-dioxooxazolidin ⁇ 3-yl]-4- phenylbutanoate of formula-Ill can be prepared conventionally by well known methods.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a novel method for the preparation of imidapril hydrochloride of formula-l by reacting esters of 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate of formula-ll with (S)-ethyl-2-[(S)-4-methyl-2,5-dioxooxazolidin-3-yl]-4-phenylbutanoate of formula-Ill and hydrolyzing the coupled product with an alcoholic hydrochloride.
Description
TITLE:
PROCESS FOR INDUSTRIALLY VIABLE PREPARATION OF IMIDAPRIL HYDROCHLORIDE
FILED OF THE INVENTION:
The invention relates to a novel method for the preparation of imidapril hydrochloride of formula I
Formula-I by reacting the compound of formula Il with a compound for formula-Ill followed by reduction/hydrolysis and salting
BACKGROUND OF THE INVENTION AND RELEVANT PRIOR ART:
As known in the art, the chemical entity (4S)-3-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3- phenylpropyl]amino]-1-oxopropyl]-1-methyl-2-oxo-4-imidazolidinecarboxylic acid hydrochloride of formula I, known generically as imidapril hydrochloride, belongs to a group of medicines called ACE inhibitors, which block the action of a chemical in the body called angiotensin converting enzyme (ACE). Normally ACE produces another chemical, angiotensin II. Thus imidapril reduces the amount of angiotensin Il in the blood.
Angiotensin Il has two actions. Firstly it acts on blood vessels to make them narrow and secondly it acts on the kidney to produce less urine. As imidapril stops the production of angiotensin II, these actions are reversed. Therefore more urine is produced by the kidneys, which results in less fluid in the blood vessels. The blood vessels also widen. The overall effect of this is a drop in blood pressure and a decrease in the workload of the heart.
The preparation of a compound of formula I can be achieved by any of the well know methods described in a few patents and publications viz., EP 95163,/US4508727 and JMC 32,289 (1989).
EP 95163/US4508727 discloses synthesis of imidapril hydrochloride of formula employing several stages. This is shown in the following schemes IA and IB
Scheme-I A
As per the scheme IA, ECPP alanine of formula-Ilia is activated with N- hyroxysuccinicimide using dicyclohexylcarbodiimide and the activated ester is coupled with t-butyl imidaozlinone-4-carboxylate of formula-ll a in the presence of potassium tert.
butoxide to give a dipeptide of formula-V, which is converted to the product of formula-l by treatment with dioxane-HCI
The scheme I B describes a methodology, which is similar to the one described in scheme IA, except the fact that benzyl imidazolidinone-4-carboxylate of formula-l I b is used instead of the t-butyl ester Ha. The coupled product of formula-VI is debenzylated using Pd/C - H2 and treated with dioxane-HCI to get the product of formula-l. These data are published in JMC 32, 289 (1989).
Vl
Scheme-I B
The methodology adopted in US patent 5013845 is depicted in scheme Il A and Il B. As per the scheme HA 2-(tosyloxy)-propionic acid of formula VII is activated by reacting with N-hyroxysuccinicimide to get a product of formula-VIII, which is coupled with benzyl imidazolidinone-4-carboxylate of formula-ll b to give a product of formula-IX. This is reacted with ethyl-(S)-2-amino-4-phenyl butyrate to get a product of formula-VI a. The product of formula-VI a is debenzylated to get imidapril hydrochloride.
Scheme-IIA
A similar sequence of reactions is followed in scheme HB, where t-butyl imidazolidinone- 4-carboxylate of formula-ll a is used. Here the tosyloxy derivative of formula IX a is coupled with ethyl-(S)-2-amino-4-phenyl butyrate of formula to get a protected dipeptide of formula V a , which on treatment with dioxane-HCI give imidapril hydrochloride of formula-l
VII
Scheme-IIB
Analyzing the sequence of reactions described in US patent 4508727 (scheme IA and IB) and the results, it can be observed that there are three draw backs viz., a) the activation of ECPP alanine using N-hyroxysuccinicimide in presence of dicyclohexylcarbodiimide is tedious process b) final yields are moderate and c) moderate yields and use of expensive reagents makes the process uneconomical
Coming to the methodology used as per US patent 5013845 (schemes MA and HB), this involves preparation of tosyloxy derivative (VIl), followed by activation using N- hyroxysuccinicimide using dicyclohexylcarbodiimide, further coupling and deprotection. Finally a column purification is also involved. This makes the process very tedious and uneconomical.
SUMMARY OF THE INVENTION:
The present invention provides a novel process for the preparation of imidapril of formula I by reacting esters of 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate of formula-ll with (S)-ethyl-2-[(S)-4-methyl-2,5-dioxooxazolidin-3-yl]-4-phenylbutanoate of formula-Ill in presence of a base like sodium hydride/sodium methoxide, potassium tert. butoxide etc. After the coupling, the protecting group was removed by means of catalytic hydrogenation or hydrolysis to get the required compound
The above description briefly outlines the preferred embodiments of the present invention, which enables those skilled in the art to understand the detailed description that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed concept and specific embodiment as a basis for preparation of similar derivatives. Those skilled in the art should realize such equivalent concept do not depart from the spirit and scope of the invention in its broadest sense.
OBJECTIVES AND ADVANTAGES OF THE INVENTION:
Considering the short comings of the processes described in the prior art, there is every need to develop a method for the synthesis of imidapril by a novel process, which is economical and eco-friendly.
The following are the advantages gained by this invention
a) avoiding costly reagents like dicyclohexylcarbodiimide, N-hydroxysuccinicimide etc., b) improving yield to get high quality product.
By achieving these objects, a new economical process giving rise to a quality product will result.
DETAILED DESCRIPTION OF THE INVENTION:
The initial studies for the synthesis involved coupling of ECPP alninoyl chloride hydrochloride with imidazolidinone-4-carboxylate ester using silylated reagent like HMDS and bis silyl acetamide. The reaction was also tried using an organic base. Eventhough product was formed, yields were moderate and impurities were formed. Later attempts were made to synthesise imidapril using the ECPP alanine anhydride viz., (S)-ethyl-2-[(S)-4-methyI-2,5-dioxooxazolidin-3-yl]-4-phenylbutanoate of formula-Ill
The reaction of the product of formula-Ill with imidazolidinone-4-carboxylicacid of formula-ll was tried using different bases viz., NaH, NaOBu', KOBu1, NaNH2 etc. It was preferable to use NaH, Na/KOBu1. It was more preferable to use Na/KOBu1. The reaction was studied in different solvents like dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran, 2 or 3 methyl tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, sulfolane etc. It was preferable to use solvents like THF, DMF, DMAc, DMSO or sulfolane. It was preferable to conduct the reaction at -1000C to +10 0C. It was more preferable to conduct the reaction at -800C to 00C. It was still more preferable to conduct the reaction at -650C to -10 0C. The progress of the reaction was monitored by TLC and on completion was isolated in the form of maleate or hydrochloride salt. The salt, thus obtained, was neutralized and deprotected to get imidapril hydrochloride of formula-l
The yields at coupling stage and further are very good (overall yield: 82 %) and the product of formula-l is obtained in excellent purity (>99.8%)
Thus the objectives of synthesizing imidapril hydrochloride of formula-l of high purity by an economical process has been achieved by the above deserted process
The starting material viz, esters of 4(S)-1-methyl-2-oxoimidazolidine-4- carboxylate of formula-ll with (S)-ethyl-2-[(S)-4-methyl-2,5-dioxooxazolidin~3-yl]-4- phenylbutanoate of formula-Ill can be prepared conventionally by well known methods.
The following scheme was described the invention
EXAMPLE
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, this does not limit the scope of the present invention in any way.
I - Preparation of t-butyl-(4S)-3-r(2SV2-fr(1S)-1-(Ethoxycarbonvn-3- phenylpropynaminoi-i-oxopropyn-i-methyl^-oxo^-imidazolidinecarboxylate hydrochloride
150gms of t-butyl 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate charged into 450ml of tetrahydrofuran and cooled a temperature of -45 to -5O0C. 235gms of (S)-ethyl~2-[(S)- 4-methyl-2,5-dioxooxazolidin-3-yl]-4-phenylbutanoate was dissolved in 550ml of tetrahydrofuran and added to above reaction mixture at -45 to -5O0C. The reaction mass was stirred for 90min at -45 to -5O0C and quenched into another flask which contains 1.2lts of ethyl acetate and 600ml of water. The organic layer, after separation, was washed with saturated sodium chloride and dried over anhydrous sodiumsulphate. 350ml of 10% isopropanolic hydrochloride added to the organic layer and concentrated under reduced pressure. After complete removal of the solvent, 600ml of diisopropylether was added. The precipitated crystals were filtered and dried. The product obtained was 338gms with a specific rotation of -57.4°. (The product was characterized by 1H NMR)
1.28 (3H, -CH3); 1.30 (3H, -CH3); 1.40 (9H, 3 x -CH3); 2.70 ( 3H;-CH3); 2.09(2H, -CH2) ; 2.55 (2H, -CH2);3.64 (2H1 -CH2); 4.12 (2H, -CH2); 3.45 (1 H1-CH); 3.74 (1 H1-CH); 5.05 (1H, -CH); 7.08-7.21 (5H, aromatic CH);2.00 (1H, NH)
Il - Preparation of imidapril hydrochloride
300gms of t-butyl-(4S)-3-[(2S)-2-[[(1 S)-1 -(Ethoxycarbonyl)-3-phenylpropyl]amino]-1 - oxopropyl]-1-methyl-2-oxo-4-imidazolidinecarboxylate hydrochloride was charged into a flask which contains 1.5lts of dichloromethane and 2.0lts of demineralised water. Reaction mixture pH was adjusted to 10 using aqueous potassium carbonate solution and organic layer was separated. The organic layer washed twice with 500ml each brine solution and dried over sodium sulphate. After complete removal of the solvent under reduced pressure, 750ml of 15% isopropanolic HCI was added and stirred for 6 hours at 25-3O0C. 900ml of diisopropylether was added after cooling the reaction mass to 10-15 0C. The precipitated crystals were filtered and dried. The product obtained was 244 gms with a specific rotation of -64.2°, melting point 215-2170C and purity by HPLC was 99.82%. (The product was characterized by 1H NMR)
Node Shift Base Comment
CH 5.09 1.50 methine
CH2 3.78;3.53 1.37 methylene
OH 11.0 11.00 carboxylic acid
CH3 2.70 0.86 methyl
CH 3.74 1.50 methine
CH3 1.28 0.86 methyl
NH 2.0 2.00 amine
CH 3.45 1.50 methine
CH2 2.09 1.37 methylene
CH2 2.55 1.37 methylene
CH 7.12 7.26 1 -benzene
CH 7.21 7.26 1 -benzene
CH 7.08 7.26 1 -benzene
CH 7.12 7.26 1 -benzene
CH 7.21 7.26 1 -benzene
CH2 4.12 1.37 methylene
CH3 1.30 0.86 methyl
270
Claims
CLAIMS:
01. An industrially viable process for the preparation of imidapril hydrochloride by a) reacting esters of 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate of formula-ll with (S)-ethyl-2-[(S)-4-methyl-2,5-dioxooxazolidin-3-yl]-4- phenylbutanoate of formula-Ill, b) precipitating the coupled (peptide coupling) product as salt of formula-IV, c) hydrolyzing with an alcoholic solvent by in-situ conversion of the product of formula IV to the hydrochloride salt of formula I or de-benzylating using a catalyst and hydrogen and converting to the hydrochloride salt of formula-l
02. A claim, as claimed in claim 1a, wherein the reaction of the product of formula-ll with the product of formula-ll is carried out using a base.
03. A claim, as claimed in claim 2, wherein the base used to activate the ester is of alkali earth oxide such as potassium tertiary butoxide, sodium methoxide / ethoxide
04. A claim, as claimed in claim 1b, wherein the product is isolated as salt of an organic acid or inorganic acid
05. A claim, as claimed in claim 4, wherein, the organic salts are of oxalic acid, maleic acid, fumaric acid, tartaric acid and inorganic acid salts are of hydrochloric acid, hydrobromic acid and sulpuric acid .
06. A claim, as claimed in claim 1c, wherein the hydrolysis of the product of formula- IV carried out using alcoholic hydrochloride
07. A claim, as claimed in claim 1c, wherein debenzylation is carried out using Pd/C and hydrogen and the product obtained is converted to the product of formula I by treatment with alcoholic hydrogen chloride
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| IN1247/CHE/2005 | 2005-09-06 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119424A (en) * | 2014-07-01 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Method for preparing (4S)-3-[(2S)-2[(1S)-1-ethoxycarbonyl-3-phenylpropyl] amino-propionyl]-1-methyl-2-oxo-imidazole-4-carboxylic acid |
| CN111253315A (en) * | 2020-03-10 | 2020-06-09 | 北京阳光诺和药物研究有限公司 | Imidapril hydrochloride organic impurities and preparation method thereof |
| CN113024632A (en) * | 2021-03-28 | 2021-06-25 | 山东中健康桥制药有限公司 | Preparation method of imidapril hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6541635B1 (en) * | 2002-03-29 | 2003-04-01 | Everlight Usa, Inc. | Method for producing angiotensin converting enzyme inhibitor |
-
2006
- 2006-05-29 WO PCT/IN2006/000183 patent/WO2007029267A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6541635B1 (en) * | 2002-03-29 | 2003-04-01 | Everlight Usa, Inc. | Method for producing angiotensin converting enzyme inhibitor |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119424A (en) * | 2014-07-01 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Method for preparing (4S)-3-[(2S)-2[(1S)-1-ethoxycarbonyl-3-phenylpropyl] amino-propionyl]-1-methyl-2-oxo-imidazole-4-carboxylic acid |
| CN104119424B (en) * | 2014-07-01 | 2018-12-18 | 上海天慈生物谷生物工程有限公司 | The preparation method of (4S) -3- [(2S) -2 [(1S) -1- ethoxycarbonyl-3-phenylpropyl] aminopropionyl] -1- methyl -2- oxoimidazolinium -4- carboxylic acid |
| CN111253315A (en) * | 2020-03-10 | 2020-06-09 | 北京阳光诺和药物研究有限公司 | Imidapril hydrochloride organic impurities and preparation method thereof |
| CN113024632A (en) * | 2021-03-28 | 2021-06-25 | 山东中健康桥制药有限公司 | Preparation method of imidapril hydrochloride |
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