WO2011004384A2 - Procédé de préparation d’éprosartan - Google Patents

Procédé de préparation d’éprosartan Download PDF

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Publication number
WO2011004384A2
WO2011004384A2 PCT/IN2010/000374 IN2010000374W WO2011004384A2 WO 2011004384 A2 WO2011004384 A2 WO 2011004384A2 IN 2010000374 W IN2010000374 W IN 2010000374W WO 2011004384 A2 WO2011004384 A2 WO 2011004384A2
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Prior art keywords
formula
compound
iii
alkyl
eprosartan
Prior art date
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Ceased
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PCT/IN2010/000374
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English (en)
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WO2011004384A3 (fr
Inventor
Niranjan Gangadhar Gokhale
Mahinderkar Chandrashekhar
Pothula Srinivasa Rao
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GLOCHEM INDUSTRIES Ltd
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GLOCHEM INDUSTRIES Ltd
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Publication of WO2011004384A3 publication Critical patent/WO2011004384A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel cost effective synthetic process for the preparation of Eprosartan and its pharmaceutically acceptable acid addition salts thereof in high yield and purity.
  • Eprosartan is first described in US 5,185,351 as an angiotensin II receptor antagonist, useful in the treatment of hypertension, congestive heart failure and renal failure. Eprosartan acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding of angiotensin II to AT] receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympathetic norepinephrine production, further reducing blood pressure.
  • Eprosartan chemically known as 4-( ⁇ 2-butyl-5-[2-carboxy-2-(thiophen-2-ylmethyl) eth-l-en-l-yl]-lH-imidazol- 1-yl ⁇ methyl) benzoic acid is represented by formula ( I ).
  • Eprosartan is prepared by a process, which comprises treating methyl-3-acetoxy-3-[2-n-butyl-l- ⁇ (4- carbomethoxyphenyl) methyl ⁇ -lH-imidazol-5-yl]-2-(2-thienyl) methyl propanoate with 1, 8-diazabicylo [5.4.0]undec-7-ene, followed by ester hydrolysis.
  • the efficiency of this process and the quality and yield of the imidazole product are particularly important, when preparing said product on a large scale for therapeutic use.
  • Eprosartan is prepared by reacting 4-[[2-butyl-5- formyl-1 H-imidazol-l-yl]methylbenzoic acid or the bisulfite addition compound of 4- [[2-butyl-5-formyl-lH-imidazol-l-yl]methyl]benzoic acid with (2-thienylmethyl)- propanedioic acid, mono-ethyl ester in a solvent (and/or solvent systems) selected from the group consisting of toluene, cyclohexane, cyclohexanerdichloroethane, cyclohexane: pyridine, and cyclohexane:ethyl acetate:pyridine, in the presence of piperidine as catalyst at reflux temperature at reduced pressure followed by hydrolysis of the intermediate ethyl ester.
  • the yield of Eprosartan obtained is very low. Moreover, it is difficult to maintain the reaction at reflux under
  • WO 2008/078330 describes a process for preparing Eprosartan comprising reacting methyl 4-[[2-butyl-5-formyl-lH-imidazol-l-yl] methyl] benzoate with ethyl 2-carboxy-3- (2-thienyl) propionate, in the presence of a base, in a solvent selected from cyclohexane and n-hexane to give diester intermediate, and further hydrolyzing the above compound with sodium or potassium hydroxide to obtain pure Eprosartan and optionally pharmaceutically acceptable acid addition salts thereof.
  • the object of the present invention is to provide an improved, cost effective and process for preparing Eprosartan with improved yield and purity by ameliorating the drawbacks of existing prior art processes. Summary of the invention:
  • the present invention discloses an improved novel synthetic process for the preparation of Eprosartan, which comprises treating 2-n-butyl-4-formylimidazole with N-protecting group (P) selected from the group Of Ci-C 4 alkyl ester derivative of methacrylic acid, preferably ethyl methacrylate Ci-C 4 alkyl ester derivative of crotonic acid, preferably ethyl crotonate; in the presence of anion resin or DBU and optionally in presence of solvent to get N-protected (P) compound of formula III in Stage-I.
  • N-protecting group selected from the group Of Ci-C 4 alkyl ester derivative of methacrylic acid, preferably ethyl methacrylate Ci-C 4 alkyl ester derivative of crotonic acid, preferably ethyl crotonate
  • N-protecting group(P)selected from the group of CpC 4 alkyl ester derivative of methacrylic acid, preferably ethyl methacrylate or Ci-C 4 alkyl ester derivative of crotonic acid, preferably ethyl crotonate in the presence 1,8-Diazabicyclo [5,4.0] undec-7-ene ( DBU ) to get N-protected compound of formula ( III) in stage-I.
  • Stage-I I comprises reacting N-protected compound of formula (III) with 2-(2-thienyl methyl) propanedioic acid monoethyl ester to get the compound of formula (V),
  • Stage III comprises bromo condensation of compound of formula (V) with methyl-4- bromo methyl) benzoate of formula to get compound of formula VII,
  • the present invention provides a synthetic method for the preparation of Eprosartan, comprising the following stages:
  • Stage-I comprises reacting 2-n-butyl-4-formylimidazole of formula (II)
  • N-protecting reagent "P" selected from the group consisting Of Ci-C 4 alkyl ester derivative of methacrylic acid or crotonic acid, preferably ethyl methacrylate, ethyl acrylate or ethyl crotonate, in the presence of anion resin and optionally in presence of solvent to obtain the compound of formula III, i.e., formula (HI-A), ( IH-B ) or (HI-C) respectively.
  • R is a C1-C4 alkyl; R' is H or C1-C4 alkyl and R" is H or C1-C4 alkyl; preferably when R' is H, R" is C1-C4 alkyl and when R" is H, R' is C1-C4 alkyl.
  • 2-n-butyl-4-formylimidazole of formula ( II ) with a N-protecting reagent selected from the group of Ci-C 4 alkyl ester derivative of methacrylic acid or crotonic acid, preferably ethyl methacrylate, or ethyl crotonate, in the presence of 1,8- Diazabicyclo [5,4.0] undec-7-ene ( DBU ), optionally in presence of solvent to obtain the compound of formula (HI-A) or (HI-C) respectively.
  • a N-protecting reagent selected from the group of Ci-C 4 alkyl ester derivative of methacrylic acid or crotonic acid, preferably ethyl methacrylate, or ethyl crotonate
  • N-protecting reagent selected from the group of Ci-C 4 alkyl ester derivative of methacrylic acid or crotonic acid, preferably ethyl methacrylate, or ethyl crotonate, in the presence of anion resin or DBU, optionally in presence of solvent.
  • the solvent can be selected from the group consisting of ethyl acetate, 1,4 dioxane and dimethylformamide.
  • the compound of formula III wherein the protecting group "P” is ethyl methacrylate
  • This stage comprises reacting N-protected compound of formula III with 2-(2-thienyl methyl) propanedioic acid monoethyl ester of formula (IV)
  • the rection is carried out in presence of piperidine and toluene at a temperature of about 40-60 0 C under vaccum.
  • the compound of formula V wherein the protecting group "P” is ethyl methacrylate
  • R is as defined above
  • R is as defined above
  • the compound of formula (V) wherein the protecting group "P” is ethyl crotonate
  • R is as defined above.
  • This stage comprises reaction of compound of formula V with methyl-4-(bromo methyl) benzoate of formula (VI)
  • Stage-IV comprises simultaneous hydrolysis of ester groups and removal of N-protecting group of the quaternary salt of Formula VII to get Eprosartan of Formula (I).
  • Stage-V comprises formation of mesylate salt of Eprosartan by reacting Eprosartan with methane sulphonic acid.
  • P Nitrogen protecting group selected from; C 1 -C 4 alkyl ester derivative of acrylic acid, C1 -C4 alkyl ester derivative of methacrylic acid or Ci-C 4 alkyl ester derivative of crotonic acid.
  • One preferred compound of ester derivative of methacrylic acid is ethyl methacrylate or ester derivative of acrylic acid which is ethyl acrylate and one preferred compound of ester derivative of crotonic acid is ethyl crotonate.
  • Example 1 Preparation of compound of Formula fill) with ethyl methacryiate as protecting group (in presence of anion resin and in absence of solvent):
  • NMR of Formula V wherein the protecting group is ethyl methaerylate 1 H NMR ⁇ (ppm): BRUKER - 400 MHz, CDCl 3 7.6 ( s, 1 H ), 7.0 ( t, 2 H ), 6.9 ( d,l H ), 6.8 ( m, 1 H ), 4.4 ( s, 2 H ), 4.1 ( m, 4 H ), 3.0 ( q, 2 H ), 2.8 ( m, 1 H ), 2.6 ( t, 2 H ),1.8(p,2H), 1.5(m,2H), 1.3(t,3H), 1.2(t,6H), 0.9(t,3H).
  • Eprosartan ( 50.0 gm) obtained from Stage-IV was charged in a 500 ml three-neck round bottom flask at 25-35 0 C, followed by addition of isopropyl alcohol ( 200.0 ml ) and water (25.0ml). Reaction mass was heated to 35-40 0 C, followed by slow addition of methanesulphonic acid ( 30.0 ml ) for 30 minutes. Temperature was maintained between 35-45 0 C for 30 minutes. Reaction mass was cooled to 10-15 0 C and maintained for 2.0 hours. The precipitated product was filtered and washed with isopropyl alcohol. Product was dried at 55-60 0 C

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L’invention concerne un nouveau procédé de synthèse d’éprosartan, comprenant le traitement du 2-n-butyl-4-formylimidazole de formule II avec un groupe protecteur d’azote choisi parmi un dérivé d’ester d’alkyle en C1 à C4 de l’acide méthacrylique; un dérivé d’ester d’alkyle en C1 à C4 de l’acide crotonique; ou un dérivé d’ester d’alkyle en C1 à C4 de l’acide acrylique, en présence d’une base choisie parmi une résine échangeuse d’anions ou le DBU et, éventuellement, en présence d’un solvant, pour obtenir un composé (III) N-protégé dans l’étape I. L’étape II comprend la réaction du composé (III) N-protégé avec l’ester de monoéthyle de l’acide 2-(2-thiényl méthyl) propanedioïque pour obtenir un composé (V). L’étape III comprend la réaction du composé (V) obtenu dans l’étape II avec le benzoate de méthyl-4-(bromométhyle) pour obtenir un composé (VII). En outre, une hydrolyse des groupes esters et l’élimination du groupe protecteur d’azote sont effectuées simultanément au moyen d’une solution de soude caustique, pour obtenir l’éprosartan de formule (I) dans l’étape IV. Finalement, un sel d’éprosartan pharmaceutiquement acceptable est préparé dans l’étape V.
PCT/IN2010/000374 2009-06-05 2010-06-07 Procédé de préparation d’éprosartan Ceased WO2011004384A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1331/CHE/2009 2009-06-05
IN1331CH2009 2009-06-05

Publications (2)

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WO2011004384A2 true WO2011004384A2 (fr) 2011-01-13
WO2011004384A3 WO2011004384A3 (fr) 2011-04-21

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403159A2 (fr) 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazoalcénoiques
WO1992010189A1 (fr) 1990-12-14 1992-06-25 Smithkline Beecham Corporation Acides imidazolyl-alcenoiques
US5185351A (en) 1989-06-14 1993-02-09 Smithkline Beecham Corporation Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists
WO1998035962A1 (fr) 1997-02-14 1998-08-20 Smithkline Beecham Corporation Procede de preparation de l'eprosartan
US6172237B1 (en) 1997-02-14 2001-01-09 Smithkline Beecham Corporation Process for preparing eprosartan
WO2008078330A1 (fr) 2006-12-27 2008-07-03 Hetero Drugs Limited Procédé amélioré pour la préparation d'éprosartan

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403159A2 (fr) 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazoalcénoiques
US5185351A (en) 1989-06-14 1993-02-09 Smithkline Beecham Corporation Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists
WO1992010189A1 (fr) 1990-12-14 1992-06-25 Smithkline Beecham Corporation Acides imidazolyl-alcenoiques
WO1998035962A1 (fr) 1997-02-14 1998-08-20 Smithkline Beecham Corporation Procede de preparation de l'eprosartan
US6172237B1 (en) 1997-02-14 2001-01-09 Smithkline Beecham Corporation Process for preparing eprosartan
WO2008078330A1 (fr) 2006-12-27 2008-07-03 Hetero Drugs Limited Procédé amélioré pour la préparation d'éprosartan

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHILCRAT, S.C. ET AL., J. ORG. CHEM, vol. 62, no. 24, 28 November 1997 (1997-11-28), pages 8449 - 8454

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