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"A Process For Making Irbesartan"

Abstract: Provided is a novel method of making 2-butyl-3-[[2"(1-trityl-1H-tetrazol-5-yl)biphen-4-yl]methyl]1,3-diazaspiro[4,4]non-1-ene-4-one, which can be converted to irbesartan. Also provided are methods of making irbesartan.

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Patent Information

Application #
Filing Date
12 December 2008
Publication Number
20/2009
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

TEVA PHARMACEUTICAL INDUSTRIES, LTD.
5 BASEL STREET, P.O.BOX 3190, PETAH TIQVA 49131, ISRAEL

Inventors

1. GENNADY NISNEVICH
23 MARGALIT STREET, HAIFA 34464, ISRAEL
2. IGOR RUKHMAN
1/11 JUNIOR STUFF DORMS, TECHNION CITY, HAIFA 32000, ISRAEL
3. BORIS PERTSIKOV
3/4 NATIVE HARIMON, NESHER 36781, ISRAEL
4. JULIA KAFTANOV
84/4 HAALIYA HASHNIYA STR., HAIFA 35471, ISRAEL
5. BEN-ZION DOLITZKY
LOHAME HAGHETTO 32, PETACH TIQVA 49651, ISRAEL

Specification

SYNTHESIS OF 2-BUTYL-3- (2'- (1-TRITYL-1H-TE.TRAZ0L-5-YL) BIPHENYL-4-YL) -1, 3-DIAZASPIROL [4,4]-N0N-ENE-4-0NE RELATED APPLICATIONS The present invention claims the benefit of the filing dates of United States Provisional Patent Applications 60/445,218, filed February 5, 2003, and 60/465,905, filed April 28,2003, the contents of which are incorporated herein. FIELD OF THE INVENTION The present invention relates to methods of making irbesartan and, especially, a precursor therefor. BACKGROUND OF THE INVENTION Irbesartan is a known angiotensin II receptor antagonist (blocker). Angiotensin is an important participant in the renin-angiotensin-aldosterone system (RAAS) and has a strong influence on blood pressure. Irbesartan has the chemical name 2-butyl-3-[[2'-(lH-tetrazole-5-yl)biphenyl-4-yl] methyl]-1,3-diazaspiro[4.4]non-1 -en-4-one. The structure of irbesartan is shown below (I). (Formula Removed) The synthesis of irbesartan is discussed, inter alia, in United States Patents 5,270,317 and 5,559,233; both of which are incorporated herein in their entirety by reference. In the synthesis therein disclosed, the prepenultrmate reaction step (exclusive of work-up and purification) involves the reaction of a cyano group on the biphenyl ring with an azide, for example tributyltin azide. Reaction times as long as 210 hours can be required. See, e.g., '317patent. United States Patent 5,629,331 also discloses a synthesis of irbesartan from a precursor 2-n-butyl-3-[(2,-cyanobiphenyl-4-yl)methyl]-l ,3-diazaspiro[4.4]non-l -ene-4-one with sodium azide using a dipolar aprotic solvent. As acknowledged in the '331 patent, there are safety rides involved in the use of azides (column 4, line 39). Also, dipolar aprotic solvents {e.g. methyl pyrrolidone) are relatively high boiling and can be difficult to remove. There is a need for an improved synthetic route to irbesartan, its derivatives and its precursors. SUMMARY OF THE INVENTION In one aspect, the present invention relates to a process of making a compound of (Formula Removed) including the steps of: reacting, especially at reflux, 1(N'-pentanoylamino)cyclopentanecarboxylic acid amide with 5-(4'-bromomethylbiphenyl-2-yl)-l-trityl-lH-tetrazoIe in the presence of an inorganic base, especially NaOH, KOH, or Na2CO3 (or a mixture of these); a solvent, especially an aliphatic ether having up to 8 carbon atoms or an aromatic hydrocarbon (especially dry toluene); and a phase transfer catalyst, especially tetrabutylanjmonium sulfate; cooling the mixture; adding water to the mixture whereby two phases are obtained; separating the two phases obtained; and recovering the compound of structure H. The compound of structure II can be converted to irbesartan and irbesartan so obtained is another aspect of the present invention. In another embodiment, the present invention relates to a process of making a compound of structure II including the steps of: reacting, for a period of time of about 2 to about 24 hours, a valerimidate derivative, especially ethyl valerimidate or a slat thereof, with a first amine, especially 5'-(4'aminomethylbiphenyl-2-yl)-l-trityI-lH-tetrazole or 1-aminocyclopentane carboxylic acid ethyl ester, in the presence of a first acid, especially HC1, and an organic solvent, especially dry toluene, to form a mixture; cooling the mixture; combining the mixture with a second amine especially 5'-(4'aminometibylbiphenyl-2-yl)-l-trityl-lH-tetrazole or 1-aminocyclopentane carboxylic acid ethyl ester (with the proviso that first and second amines are not the same, and a catalytic amount of a second acid, especially acetic acid; hating the combination at reflux for about 2 to about 24 hours; contacting the combination with a base, especially a base in solution in water whereby two phases are obtained; separating the phases obtained; and recovering the compound of structure II. The compound of structure II so botained can be converted to irbesartan and irbesartan so made is yet another aspect of the present invention. In another aspect, the present invention relates to a method of making a compound of structure II including the steps of: combining a valeramide derivative, estecially ethyl valerimidate, with a base scavenger, especially 2,6-lutidine, and oxalyl chloride in the presence of an organic solvent, especially dry toluene; cooling the resulting combination; maintaining the combination for between 0.25 and 4 hours, whereby an inidoyl chloride intermediate is presumed to form; further combining an amine, especially 5'-(4,aminomethylbiphenyl-2-yl)-l-trityl-lH-tetrazole or 1-aminocyclopentane carboxylic acid ethyl ester, and an organic solvent with the combination; heating the resulting combination to reflux for about 0.1 to about 1 hours; thereafter contacting the mixture with a base, especially an aqueous solution of anninorganic base whereby two phases are obtained; separating the phases obtained; and recovering the compound of structure II. The compound of structure II so obtained can be converted to irbesartan and irbesartan so made is still yet a further aspect of the present invention. In yet another aspect, the present invention relates to a method of making irbesartan including the step of converting, by removing the trityl group, 2-butyl-3-[[2'-(l-trityl-lH-tetrazol-5-yl)biphen-4-yl]methyI-l,3-diazaspiro[4.4]non-l-ene-4-oneto irbesartan. In still yet a further aspect, the present invention relates to pharmaceutical compositions containing irbesartan made via the novel methods of the present invention. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a one-pot method of making 2-butyl-3-[2'-(l-trityl-Iiy-tetrazol-5-yl)biphenyl-4-ylmethyl]-l ,3-diazaspiro[4.4]non-l-ene-4-one (Structure II, IRB-03, trityl irbesartan) from 1-pentanoylaminocyclopentanecarboxylic acid amide (N-pentanoyl-1-ammo-l-carbamoylcyclopentane, IRB-23) and 5-(4'-bromomethylbiphenyl-2-yl)-l -trityl- lf/-tetrazole (IRB-02) in an at least initially multi-phase system in the presence of a phase transfer catalyst. The multi-phase system can be biphasic (solid-liquid), or it can be triphasic (solid-liquid-liquid). (Formula Removed) In biphasic embodiments of the present invention, IRB-23 is in suspension with an alkali metal hydroxide and an alkali metal carbonate in a first solvent in the presence of a phase transfer catalyst and the desired amount of IRB-02. The preferred alkali metal carbonate is K2CO3. About 1.5 and preferably about 2 equivalents of alkali metal carbonate can be use for each equivalent of IRB-02, The preferred alkali metal hydroxide is NaOH. About 3 and preferably about 3.5 equivalents of alkali metyal hydroxide are used for each equivalent of IRB-02. First solvents are organic compounds, liquid at about 20° C, that dissolve IRB-02, but that are substantially insoluble in water. A liquid organic compound is substantially insoluble in water if it is soluble in water to less than about 5% such that, if equal initial volumes of substantially insoluble organic liquid and water are mixed, a two-phase (liquid-liquid) system results, the total volume of which is approximately equal to the initial volume of water plus the initial volume of the substantially insoluble organic liquid. First solvents useful in the practice of the present invention include linear and cyclic aliphatic ethers having up to 8 carbon atoms, for example methyl t-bnty\ ether and tetrahydrofuran, and aromatic hydrocarbons, for example toluene. The amount of frist solvent is not critical as long as sufficient first solvent is used so that the IRB-02 is in solution. Preferably, between about 3 and about 4 liters of first solvent are used per combined moles of IRB-02 and IRB-23. Phase transfer catalysts are well known to one skilled in the art of organic synthesis. Phase transfer catalysts are of particular utility when at least first and second compounds to be reacted with each other have such different solubihty characteristics that there is no practical common solvent for them and, accordingly, combining a solvent for one of them with a solvent for the other of them results in a two-phase system. Typically, when such compounds are to be reacted, the first reactant is dissolved in a first solvent and the second reactant is dissolved in a second solvent. Because the solvent for the fast reactant is essentially insoluble in the solvent for the second reactant, a two-phase system is formed and reaction occurs at the interface between the two phases. The rate of such an interracial reaction can be greatly increased by use of a phase transfer catalyst (PTC). Several classes of compounds are known to be capable of acting as phase transfer catalysts, for example quaternary ammonium compounds and phosphonium compounds, to mention just two. Tetraburylammonium hydrogensulfate is a preferred PTC for use in the practice of present invention. Approximately 0.1 equivalents of phase tyransfer catalyst per equivalent of IRB-23 to be reacted is usually sufficient, but more or less can be used. IRB-23 can be obtained by Schotten-Baumann reaction between 1-amino-1-carbamoyleyelopentane and valeroyl chloride in THF solvent using triethylamine as acid scavenger. la biphasic embodiments, IRB-02, IRB-23, alkali metal carbonate, alkali metal hydroxide, phase transfer catalyst, and first solvent are combined, in any order, and heated, preferably to a temperature between about 80°C and reflux, most preferably to a temperature of about 90°C. The reaction is allowed to proceed until substantially all of the 1RB-02 has been consumed. The progress of the reaction can be monitored by, for example, thin layer chromatography (TLC) using hexane/ethyl acetate (1:1) eluent. When substantially all of the IRB-02 has been consumed, the reaction mixture is cooled and diluted with water (ca. one to two times the volume of the reaction mixture). The first-solvent phase (organic phase) is separated and, optionally, washed with brine. Preferably, the water content of the first-solvent phase is reduced by, for example, treating it with a solid drying agent. The desired product, ERB-03, can be isolated by concentrating the first-solvent phase to a residue and separating IRB-03 therefrom by column chromatography on a silica gel column using, for example, hexane/ethyl acetate (4:1 to 1:1) eluent The composition of chromatography fractions can be determined by, for example, nuclear magnetic resonance spectroscopy. IRB-03 can be isolated from IRB-03-containing fractions by separating the eluent by, for example, distillation. Triphasic embodiments of the present invention are analogous to the biphasic embodiments and include a second solvent that is essentially water, whereby at least a portion of the alkali metal carbonate, if any, and the alkali metal hydroxide are in solution in the second solvent In these embodiments, the alkali metal carbonate is optional. Thus, in triphasic embodiments, IRB-03, IRB-23, alkali metal hydroxide, optionally alkali metal carbonate, phase transfer catalyst, and first solvent are combined with second solvent The amounts of reactants used in triphasic embodiments are essentially the same as in biphasic embodiments, however an excess, up to about a 100% excess, of IRB-23 is preferred. The volume of second solvent is about one-quarter to one-half of the volume of first solvent. Work-up of the reaction mixture is analogous to that in biphasic embodiments. The first-solvent phase is separated and combined with first-solvent phase obtained by optional extracting of the second-solvent phase with first solvent. The first-solvent phases can the be treated, and the BRB-03 isolated, as in biphasic embodiments. In another embodiment, the present invention provides a novel synthesis of irbesartan, analogues thereof, and, especially, precursors therefor (e.g. trityl ifbesartan) including the step of reacting a reacting a valerimidate derivative with an amine to form ~ an ester intermediate, and further reacting the ester intermediate with an amine to form 2-butyl-3-[[2'-( 1 -trityl-lH-tetrazole-5-yl)biphenyl-4-yl] methyl]-1,3-diazaspiro [4.4]non~ 1 -en-4-one. The step is carried out in the presence of an acid. Preferably the step is carried out in the presence of one equivalent of acid per equivalent of valerimidate derivative. The valerimidate derivative can be any suitable derivative, including but not limited to ethers and esters. Preferred valerimidate derivatives include methyl, ethyl, propyl, butyl, benzyl, pentyl and aryl valerimidate esters (e.g. ester of valeroylimidic acid; R1-C(=NH)-O-R2; R1 = C4H9) ), or, especially, salts thereof. A most preferred ester is the ethyl ester. The reaction is carried out in an organic solvent Examples of preferred organic solvents include, but are not limited to, N,N dimethyl formamide (DMF), dimethyl aoetamide (DMA), toluene, hexane, 1,2-dimethoxyethane (DME), diethoxymethane, tetrahydrofuran (THF), benzene, m-xylene, o-xylene, tetralins, formals, glymes and mixtures thereof. A most preferred organic solvent is dry toluene. Other hydrocarbons useful in the practice of the present invention will be apparent to the skilled artisan. The novel synthesis of irbesartan precursor, irbesartan itself, and analogues thereof, of the present invention includes the step of reacting a valerimidate derivative with an amine to form an N-substituted imido ester-like ester intermediate, and further reacting the ester intermediate with an amine to form 2-butyl-3-[[2'-(l-trityl-lH-tetra2ole-5-yl)biphenyl-4-yl] methyl]-l,3-diazaspiro[4.43non-l-en-4-one. Preferred amines include 5 '-(4' anunomemylbiplienyl-2-yl) aminomethylbiphenyl; Structure HI; IRB-09) and l-aminocyclopentane carboxylic acid ethyl ester (IRB-13). (Formula Removed) A preferred valerimidate derivative is ethyl valeiimidate as its methaaesulfonic acid salt. When the amine is IRB-09, the intermediate has structure IV (2-(l-trityl-lH-te1xazol-5-yl)-4'-(l"-ethoxypetanminyl)biphenyl). When the amine is ethyl 1-amino-1-cyclopentanecaiboxyalte, the intermediate has structure V. The step is carried out in an organic solvent reaction system. To the organic solvent is added an amount of valerimidate derivative and an amount of an acidic material. The acidic material may be any suitable acid, including mineral acids, hydrogen sulfate, trifluoroacetic acid, formic acid, hydrobromic acid, acetic acid and formic acid. A most preferred acid is hydrochloric acid. The ratio of valerimidate derivative to acidic material can be from about 5:1 to about 1:0.5, the most preferred ratio is about 1:1. The resulting mixtwe is agitated at room temperature for a period of from about 6 to about 24 hours. Preferably the reaction mixture is agitated for a period of about 12 hours. The time of the reaction can be conveniently monitored using thin layer chromatography. Following completion of me reaction, the reaction mixture is cooled and precipitated byproducts removed. Preferably the reaction mixture is cooled to a temperature of from about -15°C to about 15°C. Most preferably the reaction mixture is cooled to a temperature of about 0°C. To the reaction mixture is added an amount of a suitable amine such as DRB-09 and IRB-13, and a catalytic amount of an acid material added. Preferred acid materials include mineral acids, hydrogen sulfate, trifluoroacetic acid, formic acid, hydrobromie acid, acetic acid and formic acid. A most preferred acid is acetic acid. The reaction mixture is heated under reflux for a period of from 2 hours to about 10 hours. Preferably the reaction mixture is agitated for a period of from about 3 hours to about 5 hours. The time of the reaction can be conveniently monitored using thin layer chromatography. Following completion of the reaction, the reaction mixture is contacted with a base, preferably an inorganic base, more preferably a solution of an inorganic base in water, especially aqueous NaHCO3, whereby essentially all of the acid in the reaction mixture is preferably neutralized. When aqueous base is used a two-phase (liquid-liquid) system results. If solid base is used, a two-phase (solid-liquid) system may result- m either instance, the resulting two-phase reaction system is separated. The organic phase is preferably washed and dried, and the reaction product, 2-butyl~3-[[2'-(l~ trityl-1 H-tetrazole-5-yl)biphenyl-4-yl] methyl] -1,3 -diazaspiro [4.4]non-1 -en-4-one, (IRB-03), separated out. The separation may be carried out by any known method, but is typically carried out by filtration and evaporation under reduced pressure. Without "wishing to be bound by theory, it is believed that the reaction proceeds via the production of imidate esters such as an N-valerimidate 5'-(4'arninomethylbiphenyl-2-yl)-l-trrty2-lH-tetra2ole (IRB-20) in the reaction of 5'-(4'aminomethylbiphenyl-2-yl)-l-trityl-IH-tetrazole (IRB-09) and ethyl vaJerimidate methanesulfonic acid salt, or an N- valerimidate - 1-aminocyclopentane carboxylic acid ethyl ester (IRB-26) in the reaction of 1-anunocyciopentane carboxylic acid ethyl ester (IRB-09) and ethyl valerimidate methanesulfonic acid salt. In another aspect, the novel synthesis of irbesartan, and analogues thereof, of the present invention, includes the step of reacting an amide with a base scavenger, preferably 2,6-lutidine, and oxalyl chloride, followed by the addition of an amine to form 2-btityi-3-[(2'-(I-trityl-lH-tetra2oIe-5-yl)biphenyJ-4-yl3methyl]-l,3-diazaspiro[4.4Jnon-l-en-4-one. The novel synfliesis of irbesartan, and analogies tiiereof, of the present invention, mclades the step of reacting a valerimidate derivative with 2,6-lutidine and oxalyl chloride to fcam a reaction mixture, and further adding an amine to fonn 2-butyI-3-[[2'-(l-tiityHH-tetra2ole-5>yl)biphenyl-4-yl3methyl]-l,3-diazaspiro[4.4]non-l>ett-4-one (IRB-03). Piefared vderimidate derivatives include cyclopentyl valeramide 0RBr23) and5-(4'jnethylvale33tnide-biphenyl-2-yl)-l-trityl-lH-tetraz:ole (ERB-IO). Preferred amines include 2'-(l-trityl-IH-terazoI-5-yi)biphenyI-4-ylmethyianiine (IRB-09) and 1-amino cyclopeaatane cai1>ox>4ic acid ethyl ester (IRB-13). The step is carried out in an organic solvent reaction system. To the organic solvent is added an amourrt of valeramide derivative and an amount of 2,6-lutidine. The reaction mixture is cooled to a teat^rature of from about -15°C to about 15°C, and oxjdyl chloride added. Most preferably the reaction mixture is cooled to a tempwature of about 0°C. The ratio of 2,6-lutidine to oxaiyi chloride can be from about 10:1 to about 1:5, the most prefeixed ratio is atwut 2:1. The resulting mixture is agitated for a period of from about 0.25 to about 4 hours, Prefccably the neaction mixture is agitated for a period of about 1 hour. To the reaction mixture is adcted a solution of a suitable amine such as IRB-09 and IRB-13 in a suitable organic solvent, and the reaction mixture agitated for a period of about 0.1 to about 1 hour at ^3out 0°C, then agitated for a period of about 0.1 to about 1 hoiu' at about room tempeiratere. The time of the reaction can be convetuently monitored wsing thin layer chromatography. Follovmg completion of tiie reaction, the reaction maxture is neutr^ized vsith a molar excess of base, preferably aqueous NaBCO}, and tb& resulting two-phase reaction system is separated. The organic phase is washed and dried, and the reaction product, 2-hut^'3-[i2'-(l -trityl- !H-tetrazoIe-5-yI)biphenyl-4-ylj m^yl3-l,3-dia2^piK>[4.43non-l-ea-4-one, (IRB-03), separated out. The separation may be carried out by any known method, but is typically carried out by filtration and evapcsation under reduced pressure. Without wishing to be bound by theory, it is believed that the reactioa proceeds via the producticMi of imidoyl chloride intermediates. To obtsdn iib^artan, the compound of structure 11 obtained by any embodiment of the present invaetiau can be dissolved in a suitable solvent, for example acet

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# Name Date
1 10324-delnp-2008-gpa.pdf 2011-08-21
1 10324-DELNP-2008_EXAMREPORT.pdf 2016-06-30
2 10324-delnp-2008-abstract.pdf 2011-08-21
2 10324-delnp-2008-form-5.pdf 2011-08-21
3 10324-delnp-2008-form-3.pdf 2011-08-21
3 10324-delnp-2008-claims.pdf 2011-08-21
4 10324-delnp-2008-form-2.pdf 2011-08-21
4 10324-delnp-2008-correspondence-others.pdf 2011-08-21
5 10324-delnp-2008-description (complete).pdf 2011-08-21
5 10324-delnp-2008-form-18.pdf 2011-08-21
6 10324-delnp-2008-form-1.pdf 2011-08-21
7 10324-delnp-2008-description (complete).pdf 2011-08-21
7 10324-delnp-2008-form-18.pdf 2011-08-21
8 10324-delnp-2008-correspondence-others.pdf 2011-08-21
8 10324-delnp-2008-form-2.pdf 2011-08-21
9 10324-delnp-2008-claims.pdf 2011-08-21
9 10324-delnp-2008-form-3.pdf 2011-08-21
10 10324-delnp-2008-form-5.pdf 2011-08-21
10 10324-delnp-2008-abstract.pdf 2011-08-21
11 10324-DELNP-2008_EXAMREPORT.pdf 2016-06-30
11 10324-delnp-2008-gpa.pdf 2011-08-21