SI22585A - Procedure for preparation of telmisartan - Google Patents
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Abstract
Description
POSTOPEK ZA PRIPRAVO TELMISARTANAPROCEDURE FOR THE PREPARATION OF TELMISARTAN
Področje izumaFIELD OF THE INVENTION
Predloženi izum se nanaša na postopke za pripravo intermediata telmisartan nitrila, (4'-[[(2-n-propil-4-metil-6-(l-metil-benzimidazol-2-il)-benzimidazol-l-il)-metil]bifenil-2-nitrila), in nadalje za njegovo pretvorbo v telmisartan in/ali njegove soli, ki so stroškovno in časovno učinkoviti in dajejo telmisartan v visokem dobitku in kvaliteti.The present invention relates to processes for the preparation of an telmisartan nitrile intermediate, (4 '- [[(2-n-propyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) - methyl] biphenyl-2-nitrile), and further for its conversion to telmisartan and / or its salts, which are cost effective and time efficient and give telmisartan in high yield and quality.
Ozadje izumaBACKGROUND OF THE INVENTION
Telmisartan, s svojim kemijskim imenom 4'-[(2-n-propil-4-metil-6-(l-metilbenzimidazol-2-il)-benzimidazol-l-il)-metil]-bifenil-2-karboksilna kislina in formulo 1,Telmisartan, with its chemical name 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid and formula 1,
je nepeptidni antagonist angiotenzin II receptorja tipa ATb ki se uporablja za zdravljenje hipertenzije. Uporablja se lahko samega ali v kombinaciji z aktivno spojino, npr. hidroklorotiazidom.is a nonpeptide antagonist of the angiotensin II receptor type AT b used for the treatment of hypertension. It can be used alone or in combination with an active compound, e.g. hydrochlorothiazide.
Opisan je v EP 502314, kot tudi v J. Med. Chem. 36 (25), 4040-4051 (1993). Njegovi polimorfi so znani iz EP 1144386 in J. Pharm. Sci, 89 (11), 1465-1479 (2000).It is described in EP 502314, as well as in J. Med. Chem. 36 (25), 4040-4051 (1993). Its polymorphs are known from EP 1144386 and J. Pharm. Sci, 89 (11), 1465-1479 (2000).
EP 502314A in J. Med. Chem., 36 (25), 4040^1051 (1993) opisujeta postopek priprave telmisartana z uporabo terc.-butil substituiranega intermediata (shema 1). Končni produkt tega postopka je bilo težko filtrirati, sprati in izolirati. Te lastnosti so ovira za proizvodnjo v velikem merilu.EP 502314A and J. Med. Chem., 36 (25), 4040 ^ 1051 (1993) describe a process for the preparation of telmisartan using a tert-butyl substituted intermediate (Scheme 1). The end product of this process was difficult to filter, wash and isolate. These qualities are a barrier to large-scale production.
Sinteza telmisartana iz spojine s formulo 3 in kemijskim imenom 4'-[[(2-n-propil-4metil-6-(l-metil-benzimidazol-2-il)-benzimidazol-l-il)-metil]-bifenil-2-nitril (nadalje imenovana kot telmisartan nitril)Synthesis of telmisartan from a compound of formula 3 and the chemical name 4 '- [[(2-n-propyl-4methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl- 2-nitrile (hereinafter referred to as telmisartan nitrile)
je opisana v EP 502314A, WO 2004087676, CN 1412183 in US 2006/264491.is described in EP 502314A, WO 2004087676, CN 1412183 and US 2006/264491.
V WO 2004087676 in CN 1412183 je telmisartan pripravljen s hidrolizo spojine s formulo 3 (shema 2).In WO 2004087676 and CN 1412183, telmisartan is prepared by hydrolysis of a compound of formula 3 (Scheme 2).
Shema 2:Scheme 2:
Opisan postopek lahko uporabimo v proizvodnji telmisartana v velikem merilu, ki daje zlahka očiščeno substanco.The process described can be used in the production of telmisartan on a large scale, giving an easily purified substance.
Obstaja potreba po izboljšani sintezni poti v telmisartan nitril.There is a need for an improved synthesis pathway to telmisartan nitrile.
Torej je predmet predloženega izuma zagotoviti nove postopke za proizvodnjo telmisartan nitrila, ki bo primeren za industrijsko merilo, bo stroškovno, časovno in ekonomsko učinkovit in ki bi ga lahko pretvorili v telmisartan in/ali njegove soli visoke kvalitete in v visokem dobitku.Therefore, it is an object of the present invention to provide novel processes for the production of telmisartan nitrile that are suitable for an industrial scale, will be cost-effective, time-efficient and cost-effective and can be converted to high-quality telmisartan and / or its salts and in high yield.
Povzetek izumaSummary of the Invention
V enem vidiku predloženi izum zagotavlja tri različne postopke za pripravo ključnega intermediata v sintezi telmisartana, namreč telmisartan nitrila.In one aspect, the present invention provides three different processes for the preparation of a key intermediate in the synthesis of telmisartan, namely telmisartan nitrile.
V še enem vidiku predloženi izum zagotavlja nove intermediate v sintezi telmisartan nitrila, po izbiri v izolirani in/ali očiščeni obliki in na njihovo uporabo kot intermediati v pripravi telmisartana in/ali njegovih soli.In another aspect, the present invention provides novel intermediates in the synthesis of telmisartan nitrile, optionally in isolated and / or purified form, and for use as intermediates in the preparation of telmisartan and / or its salts.
V še enem vidiku predloženi izum zagotavlja farmacevtski sestavek za dajanje učinkovite količine telmisartana ali njegovih soli, pripravljenega s postopki po predloženem izumu, v enotski dozirni obliki, samega ali v kombinaciji z drugo aktivno sestavino.In another aspect, the present invention provides a pharmaceutical composition for administering an effective amount of telmisartan or its salts prepared by the methods of the present invention, in unit dosage form, alone or in combination with another active ingredient.
Podroben opis izumaDETAILED DESCRIPTION OF THE INVENTION
Predmet predloženega izuma je zagotoviti postopek za pripravo telmisartan nitrila, ki obsega:It is an object of the present invention to provide a process for the preparation of telmisartan nitrile comprising:
a) acilacijo alkil substituiranega diamino benzena z izhodno spojino 8, da tvorimo spojino 7,a) acylation of alkyl substituted diamino benzene with starting compound 8 to form compound 7,
b) kondenzacijo, da tvorimo spojino 6,b) condensation to form compound 6,
c) redukcijo do spojine 5,c) reduction to compound 5,
d) alkilacijo do spojine 4,d) alkylation to compound 4,
e) kondenzacijo, da pripravimo 3e) condensation to prepare 3
kjer je:where:
Ri Ci-C6 alkil,R 1 -C 1 -C 6 alkyl,
R2 CrC6 alkil,R 2 C r C 6 alkyl,
R3 CrC6 alkil,R 3 C r C 6 alkyl,
Z skupina, ki jo lahko pretvorimo v tetrazoilno ali karboksilno skupino,With a group that can be converted into a tetrazoyl or carboxyl group,
X Cl, Br, J.X Cl, Br, J.
Bolj podrobno je predmet predloženega izuma zagotoviti postopek za pripravo telmisartan nitrila (shema 3), ki obsega:More specifically, it is an object of the present invention to provide a process for the preparation of telmisartan nitrile (Scheme 3) comprising:
a) acilacijo 7V-metilbenzen-l,2-diamina s spojino 8, 4-(butiramido)-3-metil-5nitrobenzojsko kislino, da tvorimo spojino 7, 7Vr-(2-aminofenil)-4-(butiramido)M3-dimetil-5-nitrobenzamid;a) acylation of 7V-methylbenzene-1,2-diamine with compound 8, 4- (butyramido) -3-methyl-5nitrobenzoic acid to form compound 7, 7V r - (2-aminophenyl) -4- (butyramido) M3- dimethyl-5-nitrobenzamide;
b) kondenzacijo spojine 7, A-(2-aminofenil)-4-(butiramido-/7,3-dimetil-5nitrobenzamida, da tvorimo spojino 6, /V-(2-metil-4-(l -metil-1/7benzo[d]imidazol-2-il)-6-nitrofenil)butiramid;b) condensation of compound 7, A- (2-aminophenyl) -4- (butyramido- / 7,3-dimethyl-5nitrobenzamide, to form compound 6, N- (2-methyl-4- (1-methyl-1 / 7benzo [d] imidazol-2-yl) -6-nitrophenyl) butyramide;
c) redukcijo spojine 6, Az-(2-metil-4-(l-metil- 177-benzo[dJimidazol-2-il)-6nitrofenil)butiramida, v spojino 5, 7V-(2-amino-6-metil-4-(l -metil- ΪΗbenzo[d]imidazol-2-il)fenil)butiramid;c) reduction of compound 6, A by - (2-methyl-4- (1-methyl-1 H -benzo [dimidazol-2-yl) -6nitrophenyl) butyramide, to compound 5,7V- (2-amino-6-methyl -4- (1-Methyl-benzo [d] imidazol-2-yl) phenyl) butyramide;
d) alkilacijo spojine 5, /V-(2-amino-6-metil-4-(l-metil- 177-benzo[d]imidazol-2il)fenil)butiramida s 4'-(bromometil)bifenil-2-nitrilom, da tvorimo spojino 4, N((2-nitril-bifenil-4'-metil)amino-6-metil-4-( 1 -metil-17/-benzo[d]imidazol-2il)fenil)butiramid;d) alkylation of compound N, N- (2-amino-6-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2yl) phenyl) butyramide with 4 '- (bromomethyl) biphenyl-2-nitrile to form compound 4, N ((2-nitrile-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2yl) phenyl) butyramide;
e) kondenzacijo spojine 4, 7vr-((2-nitril-bifenil-4'-metil)amino-6-metil-4-(l-metil-1/7benzo[d]imidazol-2-il)fenil)butiramida, da pripravimo spojino 3, 4'-[(2-n-propil4-metil-6-( 1 -metilbenzimidazol-2-il)-benzimidazol-1 -il)-metil]-bifenil-2-nitril.e) condensation of compound 4, 7v r - ((2-nitrile-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) phenyl) butyramide to prepare compound 3, 4 '- [(2-n-propyl4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile.
Shema 3:Scheme 3:
Stopnja a) vključuje acilacijo N-metilbenzen-l,2-diamina s spojino 8 v prisotnosti ustreznega topila in katalizatorja, da tvorimo spojino 7, N-(2-aminofenil)-4(butiramido)-N,3-dimetil-5-nitrobenzamid.Step a) involves the acylation of N-methylbenzene-1,2-diamine with compound 8 in the presence of a suitable solvent and catalyst to form compound 7, N- (2-aminophenyl) -4 (butyramido) -N, 3-dimethyl-5- nitrobenzamide.
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, piridin, trietilamin in podobne.Suitable catalysts that may be used include, but are not limited to, pyridine, triethylamine and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, dioksan, diklorometan, kloroform, toluen, dimetilformamid in podobne; in njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, dimethylformamide and the like; and mixtures thereof.
Temperatura za vodenje acilacije lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 60 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The temperature for guiding the acylation may range from about 0 to about 100 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.
Stopnja b) vključuje kondenzacijo spojine 7 v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 6, N-(2-metil-4-(l-metil-lH-benzo[d]imidazol-2-il)6-nitrofenil)butiramid.Step b) involves condensation of compound 7 in the presence of a suitable solvent and catalyst to form compound 6, N- (2-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) 6-nitrophenyl) butyramide .
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, piridin, p-toluen sulfonsko kislino, ocetno kislino in podobne.Suitable catalysts that may be used include, but are not limited to, pyridine, p-toluene sulfonic acid, acetic acid and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, dioksan, piridin, ocetno kislino, toluen in podobne in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and the like, and any mixtures thereof.
Temperatura za vodenje kondenzacije lahko sega od okoli 0 do okoli 130 °C, zlasti od okoli 20 do okoli 60 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The temperature for conducting the condensation may range from about 0 to about 130 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.
Stopnja c) vključuje redukcijo N-(2-metil-4-(l-metil-lH-benzo[d]imidazol-2-il)-6nitrofenil)butiramida s formulo 6 s hidrogeniranjem v prisotnosti primernega topila in katalizatorja, da dobimo N-(2-amino-6-metil-4-(l-metil-lH-benzo[d]imidazol-2il)fenil)butiramid s formulo 5.Step c) involves the reduction of N- (2-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) -6nitrophenyl) butyramide of formula 6 by hydrogenation in the presence of a suitable solvent and catalyst to give N - (2-Amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2yl) phenyl) butyramide of formula 5.
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, paladij na oglju, Raney-Ni in podobne.Suitable catalysts that can be used include, but are not limited to, palladium on charcoal, Raney-Ni and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, metanol, etanol, propanol in podobne; vodo; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, methanol, ethanol, propanol and the like; water; and any mixtures thereof.
Temperatura za vodenje redukcije lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 50 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The temperature to guide the reduction can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.
Stopnja d) vključuje alkilacijo spojine 5 s 4'-(bromometil)bifenil-2-nitrilom v prisotnosti primernega topila in katalizatorja, da tvorimo N-((2-nitril-bifenil-4'metil)amino-6-metil-4-(l-metil-lH-benzo[d]imidazol-2-il)fenil)butiramid s formulo 4.Step d) involves the alkylation of compound 5 with 4 '- (bromomethyl) biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form N - ((2-nitrile-biphenyl-4'methyl) amino-6-methyl-4- (1-Methyl-1H-benzo [d] imidazol-2-yl) phenyl) butyramide of formula 4.
Primerni katalizatorji, so lahko anorganski bazični katalizatorji, ki vključujejo, toda nanje niso omejeni, hidrokside alkalijskih kovin, kot so litijev hidroksid, natrijev hidroksid, kalijev hidroksid in podobni; karbonate alkalijskih kovin, kot so npr. natrijev karbonat, kalijev karbonat in podobni; in bikarbonate alkalijskih kovin, kot so npr. natrijev bikarbonat, kalijev bikarbonat in podobni.Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as e.g. sodium carbonate, potassium carbonate and the like; and alkali metal bicarbonates such as e.g. sodium bicarbonate, potassium bicarbonate and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, acenitril, toluen, Ν,Ν-dimetilformamid in podobne; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, acenitrile, toluene, Ν, Ν-dimethylformamide and the like; and any mixtures thereof.
Temperatura za izvedbo alkilacije lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 50 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The temperature for performing the alkylation may range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.
Stopnja e) vključuje kondenzacijo spojine 4 v prisotnosti primernega topila in katalizatorja, da tvorimo 4'-[(2-n-propil-4-metil-6-(l-metilbenzimidazol-2-il)benzimidazol-l-il)-metil]-bifenil-2-nitril s formulo 3.Step e) involves condensation of compound 4 in the presence of a suitable solvent and catalyst to form 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-yl) -methyl ] -biphenyl-2-nitrile of formula 3.
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, piridin, p-toluen sulfonsko kislino, ocetno kislino in podobne.Suitable catalysts that may be used include, but are not limited to, pyridine, p-toluene sulfonic acid, acetic acid and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, dioksan, piridin, ocetno kislino, toluen in podobne; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and the like; and any mixtures thereof.
Temperatura za vodenje kondenzacije lahko sega od okoli 0 do okoli 130 °C, zlasti od okoli 20 do okoli 60 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The temperature for conducting the condensation may range from about 0 to about 130 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.
Izhodno spojino 8, 4-(butiramido)-3-metil-5-nitrobenzojsko kislino, lahko pripravimo, kot je opisano v J. Med. Chem. 36, 4040 (1993), ali z acilacijo 4-amino-5-metil-3nitrobenzojske kisline, kije opisana v US 3691166, US 7220862, WO 2005065779 in WO 2007056155. Uporabimo lahko acilacijske postopke, kot so znani v stroki za acilacijo amino skupine, kot je aktivacija s kloridi, mešanimi anhidridi in pripojitvenimi reagenti.The starting compound 8, 4- (butyramido) -3-methyl-5-nitrobenzoic acid can be prepared as described in J. Med. Chem. 36, 4040 (1993), or by acylation of 4-amino-5-methyl-3-nitrobenzoic acid described in U.S. Pat. No. 3691166, U.S. Pat. , such as activation with chlorides, mixed anhydrides and coupling reagents.
Še en predmet predloženega izuma je zagotoviti postopek za pripravo telmisartan nitrila, ki obsega:It is another object of the present invention to provide a process for the preparation of telmisartan nitrile comprising:
a) esterifikacijo izhodne spojine 12, da tvorimo spojino 11a) esterifying the starting compound 12 to form compound 11
b) alkilacijo, da tvorimo spojino 10b) alkylation to form compound 10
d) kondenzacijo, da tvorimo spojino 3d) condensation to form compound 3
Rje CrC6 alkil,R is C r C 6 alkyl,
R2 je CrC6 alkil,R 2 is a C r C 6 alkyl,
R3 je Ci-C6 alkil,R 3 is C 1 -C 6 alkyl,
R4 je CrC6 alkil,R 4 is C r C 6 alkyl,
Z je skupina, ki jo lahko pretvorimo v tetrazoilno ali karboksilno skupino,Z is a group which can be converted into a tetrazoyl or carboxyl group,
XjeCl, Br, J.X is Cl, Br, J.
Bolj podrobno je predmet predloženega izuma zagotoviti postopek za pripravo telmisartan nitrila (shema 4), ki obsega:More specifically, it is an object of the present invention to provide a process for the preparation of telmisartan nitrile (Scheme 4) comprising:
a) esterifikacijo karboksilne skupine spojine 12, 7-metil-2-propil-3Hbenzo[d]imidazol-5-karboksilne kisline, da tvorimo spojino 11, metil 7-metil-2propil-3H-benzo[d]imidazol-5-karboksilno kislino;a) esterification of the carboxylic group of compound 12, 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid to form compound 11, methyl 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid;
b) alkilacijo spojine 11, metil 7-metil-2-propil-3H-benzo[d]imidazol-5-karboksilne kisline s 4'-(bromometil)bifenil-2-nitrilom, da tvorimo spojino 10, ((7-metil-2propil-3H-benzo[d]imidazol-5-metoksikarbonil-3-il)-metil)-bifenil-2-nitril;b) alkylation of compound 11, methyl 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid with 4 '- (bromomethyl) biphenyl-2-nitrile to form compound 10, ((7-methyl -2propyl-3H-benzo [d] imidazol-5-methoxycarbonyl-3-yl) -methyl) -biphenyl-2-nitrile;
c) hidrolizo spojine 10, ((7-metil-2-propil-3H-benzo[d]imidazol-5-metoksikarbonil3-il)-metil)-bifenil-2-nitrila, da tvorimo spojino 9, ((7-metil-2-propil-3Hbenzo[d]imidazol-5-karboksil-3-il)-metil)-bifenil-2-nitril;c) hydrolysis of compound 10, ((7-methyl-2-propyl-3H-benzo [d] imidazol-5-methoxycarbonyl3-yl) -methyl) -biphenyl-2-nitrile to form compound 9, ((7-methyl -2-propyl-3H-benzo [d] imidazole-5-carboxyl-3-yl) -methyl) -biphenyl-2-nitrile;
d) kondenzacijo spojine 9, ((7-metil-2-propil-3H-benzo[d]imidazol-5-karboksil-3il)-metil)-bifenil-2-nitrila, z N-metilbenzen-l,2-diaminom, da tvorimo spojino 3,d) condensation of compound 9, ((7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxyl-3yl) -methyl) -biphenyl-2-nitrile, with N-methylbenzene-1,2-diamine to form compound 3,
4'-[[(2-n-propil-4-metil-6-( 1 -metilbenzimidazol-2-il)-benzimidazol-1 -il)-metil]bifenil-2-nitril.4 '- [[(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] biphenyl-2-nitrile.
Shema 4:Scheme 4:
Stopnja a) vključuje esterifikacijo karboksilne skupine spojine 12 v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 11, metil 7-metil-2-propil-3Hbenzo[d]imidazol-5-karboksilno kislino.Step a) involves the esterification of the carboxylic group of compound 12 in the presence of a suitable solvent and catalyst to form compound 11, methyl 7-methyl-2-propyl-3Hbenzo [d] imidazole-5-carboxylic acid.
Primerni katalizatorji so lahko anorganski kislinski katalizatorji, ki vključujejo, toda nanje niso omejeni, klorovodikovo kislino, žveplovo kislino in podobne.Suitable catalysts may be inorganic acid catalysts including, but not limited to, hydrochloric acid, sulfuric acid and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, metanol, tetrahidrofuran, acenitril, toluen in podobne; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, methanol, tetrahydrofuran, acenitrile, toluene and the like; and any mixtures thereof.
Temperatura za esterifikacijo lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 50 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The esterification temperature can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.
Stopnja b) vključuje alkilacijo metil 7-metil-2-propil-3H-benzo[d]imidazol-5karboksilne kisline s 4'-(bromometil)bifenil-2-nitrilom v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 10, ((7-metil-2-propil-3H-benzo[d]imidazol-5metoksikarbonil-3-il)-metil)-bifenil-2-nitril.Step b) involves the alkylation of methyl 7-methyl-2-propyl-3H-benzo [d] imidazole-5carboxylic acid with 4 '- (bromomethyl) biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form compound 10, (( 7-methyl-2-propyl-3H-benzo [d] imidazole-5methoxycarbonyl-3-yl) -methyl) -biphenyl-2-nitrile.
Primerni katalizatorji so lahko anorganski bazični katalizatorji, ki vključujejo, toda nanje niso omejeni, hidrokside alkalijskih kovin, kot so na primer litijev hidroksid, natrijev hidroksid, kalijev hidroksid in podobni; karbonate alkalijskih kovin, kot so na primer natrijev karbonat, kalijev karbonat in podobni; in bikarbonate alkalijskih kovin, kot so na primer natrijev bikarbonat, kalijev bikarbonat in podobni.Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, acenitril, toluen, Ν,Ν-dimetilformamid in podobne; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, acenitrile, toluene, Ν, Ν-dimethylformamide and the like; and any mixtures thereof.
Temperatura za alkilacijo lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 50 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The alkylation temperature can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.
Stopnja c) vključuje hidrolizo ((7-metil-2-propil-3H-benzo[d]imidazol-5metoksikarbonil-3-il)-metil)-bifenil-2-nitrila v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 9, ((7-metil-2-propil-3H-benzo[d]imidazol-5karboksil-3-il)-metil-bifenil-2-nitril.Step c) involves hydrolysis of ((7-methyl-2-propyl-3H-benzo [d] imidazole-5methoxycarbonyl-3-yl) -methyl) -biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form compound 9, ((7-Methyl-2-propyl-3H-benzo [d] imidazole-5carboxyl-3-yl) -methyl-biphenyl-2-nitrile.
Primerni katalizatorji so lahko anorganski bazični katalizatorji, ki vključujejo, toda nanje niso omejeni, hidrokside alkalijskih kovin, kot so na primer litijev hidroksid, natrijev hidroksid, kalijev hidroksid in podobni; karbonate alkalijskih kovin, kot so na primer natrijev karbonat, kalijev karbonat in podobni.Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, metanol, etanol, propanol in podobne, in vodo; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, methanol, ethanol, propanol and the like, and water; and any mixtures thereof.
Temperatura za vodenje hidrolize lahko sega od okoli 0 do okoli 80 °C, zlasti od okoli 20 do okoli 50 °C, še posebno je pri temperaturi refluksa uporabljenih topil.The hydrolysis guidance temperature may range from about 0 to about 80 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvents used.
Stopnja d) vključuje kondenzacijo ((7-metil-2-propil-3H-benzo[d]imidazol5-karboksil-3-il)-metil)-bifenil-2-nitrila s formulo 9 z N-metilbenzen-l,2-diaminom v prisotnosti katalizatorja in primernega topila, da tvorimo spojino 3, 4'-[(2-n-propil-4metil-6-(l-metilbenzimidazol-2-il)-benzimidazol-l-il)-metil]-bifenil-2-nitril.Step d) involves the condensation of ((7-methyl-2-propyl-3H-benzo [d] imidazole5-carboxyl-3-yl) -methyl) -biphenyl-2-nitrile of formula 9 with N-methylbenzene-1,2- diamine in the presence of a catalyst and a suitable solvent to form compound 3, 4 '- [(2-n-propyl-4methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl- 2-nitrile.
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, SOC12 in podobne.Suitable catalysts that can be used include, but are not limited to, SOC1 2 and the like.
Primerna topila, kijih lahko uporabimo, vključujejo, toda nanje niso omejena, piridin, toluen in podobne; in njihove zmesi.Suitable solvents which may be used include, but are not limited to, pyridine, toluene and the like; and mixtures thereof.
Temperatura za vodenje kondenzacije lahko sega od okoli 0 do okoli 130 °C, zlasti od okoli 20 do okoli 100 °C, še zlasti je pri temperaturi refluksa uporabljenih topil.The temperature for conducting the condensation can range from about 0 to about 130 ° C, in particular from about 20 to about 100 ° C, especially at the reflux temperature of the solvents used.
Izhodno spojino 12, 7-metil-2-propil-3H-benzo[d]imidazol-5-karboksilno kislino, lahko pripravimo po kateremkoli postopku znanem iz stanja tehnike, kot je na primer opisan v Journal of Medicinal Chemistry (1993), 36 (25), 4040-51, WO 9719911, CN 1623992, Youji Huaxue (2006), 26 (3), 318-323, WO 2006044754.The starting compound 12, 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid can be prepared by any method known in the art, such as described in Journal of Medicinal Chemistry (1993), 36 (25), 4040-51, WO 9719911, CN 1623992, Youji Huaxue (2006), 26 (3), 318-323, WO 2006044754.
Še en predmet predloženega izuma je zagotoviti postopek za pripravo telmisartan nitrila, ki obsega:It is another object of the present invention to provide a process for the preparation of telmisartan nitrile comprising:
a) acilacijo alkildiaminobenzena spojine 12, da tvorimo spojino 15,a) acylation of the alkyldiaminobenzene of compound 12 to form compound 15,
b) alkilacijo, da tvorimo spojino 14,b) alkylation to form compound 14,
d) kondenzacijo, da tvorimo spojino 3,d) condensation to form compound 3,
Rije Ci-C6 alkil,Ri is Ci-C 6 alkyl,
R2 je CrC6 alkil,R 2 is a C r C 6 alkyl,
R3 je CrC6 alkil,R 3 is C r C 6 alkyl,
Z je skupina, ki jo lahko pretvorimo v tetrazoilno ali karboksilno skupino, XjeCl, Br, J.Z is a group which can be converted to a tetrazoyl or carboxyl group, X is Cl, Br, J.
Bolj podrobno (Še posebno) je predmet predloženega izuma zagotoviti postopek za pripravo telmisartan nitrila (shema 5), ki obsega:More specifically (In particular), it is an object of the present invention to provide a process for the preparation of telmisartan nitrile (Scheme 5) comprising:
a) acilacijo N-metil-2-nitrobenzenamina s spojino 12, 7-metil-2-propil-3Hbenzo[d]imidazol-5-karboksilno kislino, da tvorimo spojino 15, N,7-dimetil-N(2-nitrofenil)-2-propil-3H-benzo[d]imidazol-5-karboksamid,a) acylation of N-methyl-2-nitrobenzenamine with compound 12, 7-methyl-2-propyl-3Hbenzo [d] imidazole-5-carboxylic acid to form compound 15, N, 7-dimethyl-N (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide,
b) alkilacijo spojine 15, benzo[d]imidazol-5-karboksamida, tvorimo spojino 14,b) alkylation of compound 15, benzo [d] imidazole-5-carboxamide, forms compound 14,
N,7-dimetil-N-(2-nitrofenil)-2-propil-3Hs 4'-(bromometil)bifenil-2-nitrilom, da ((N,7-dimetil-Ar-(2-nitrofenil)-2-propil-3Hbenzo[d]imidazol-5-karboksamid-3-il)-metil)-bifenil-2-nitril,N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3Hs 4 '- (bromomethyl) biphenyl-2-nitrile to ((N, 7-dimethyl-N r - (2-nitrophenyl) -2 -propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile,
c) redukcijo spojine 14, ((N,7-dimetil-/V-(2-nitrofenil)-2-propil-3Hbenzo[d]imidazol-5-karboksamid-3-il)-metil)-bifenil-2-nitrila, da tvorimo spojino 13, ((N,7-dimetil-7V-(2-aminofenil)-2-propil-3H-benzo[d]imidazol-5karboksamid-3-il)-metil)-bifenil-2-nitril,c) reduction of compound 14, ((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile to form compound 13, (((N, 7-dimethyl-7V- (2-aminophenyl) -2-propyl-3H-benzo [d] imidazole-5carboxamid-3-yl) -methyl) -biphenyl-2-nitrile,
d) kondenzacijo spojine 13, ((N,7-dimetil-7V-(2-aminofenil)-2-propil-3Hbenzo[d]imidazol-5-karboksamid-3-il)-metil)-bifenil-2-nitrila, da tvorimo spojino 3, 4'-[[(2-n-propil-4-metil-6-( 1 -metilbenzimidazol-2-il)-benzimidazol-1 il)-metil]-bifenil-2-nitril.d) condensation of compound 13, ((N, 7-dimethyl-N- (2-aminophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile, to form compound 3, 4 '- [[(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile.
Shema 5:Scheme 5:
Stopnja a) vključuje obdelavo spojine 12 s tionil kloridom ali oksalil kloridom in naknadno acilacijo N-metil-2-nitrobenzenamina v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 15, N,7-dimetil-N-(2-nitrofenil)-2-propil-3Hbenzo[d]imidazol-5-karboksamid.Step a) involves treating compound 12 with thionyl chloride or oxalyl chloride and subsequent acylation of N-methyl-2-nitrobenzenamine in the presence of a suitable solvent and catalyst to form compound 15, N, 7-dimethyl-N- (2-nitrophenyl) -2 -propyl-3Hbenzo [d] imidazole-5-carboxamide.
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, piridin, trietilamin in podobne.Suitable catalysts that may be used include, but are not limited to, pyridine, triethylamine and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, dioksan, diklorometan, kloroform, toluen, dimetilformamid in podobne; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, dimethylformamide and the like; and any mixtures thereof.
Temperatura za vodenje acilacije lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 60 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The temperature for guiding the acylation may range from about 0 to about 100 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvent used.
Stopnja b) vključuje alkilacijo N,7-dimetil-7V-(2-nitrofenil)-2-propil-3Hbenzo[d]imidazol-5-karboksamida s 4'-(bromometil)bifenil-2-nitrilom v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 14, ((N,7-dimetil-N-(2nitrofenil)-2-propil-3H-benzo[d]imidazol-5-karboksamid-3-il)-metil)-bifenil-2-nitril.Step b) involves the alkylation of N, 7-dimethyl-7V- (2-nitrophenyl) -2-propyl-3Hbenzo [d] imidazole-5-carboxamide with 4 '- (bromomethyl) biphenyl-2-nitrile in the presence of a suitable solvent and catalyst to form compound 14, ((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile.
Primerni katalizatorji so lahko anorganski bazični katalizatorji, ki vključujejo, toda nanje niso omejeni, hidrokside alkalijskih kovin, kot so na primer litijev hidroksid, natrijev hidroksid, kalijev hidroksid in podobni; karbonate alkalijskih kovin, kot so na primer natrijev karbonat, kalijev karbonat in podobni; in bikarbonate alkalijskih kovin, kot so na primer natrijev bikarbonat, kalijev bikarbonat in podobne.Suitable catalysts may be inorganic basic catalysts including, but not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, acetonitril, toluen, Ν,Ν-dimetilformamid in podobne; in katerekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, acetonitrile, toluene, Ν, Ν-dimethylformamide and the like; and any mixtures thereof.
Temperatura za vodenje alkilacije lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 50 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The alkylation guide temperature may range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.
Stopnja c) vključuje redukcijo ((N,7-dimetil-N-(2-nitrofenil)-2-propil-3Hbenzo[d]imidazol-5-karboksamid-3-il)-metil)-bifenil-2-nitrila v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 13, ((N,7-dimetil-N-(2aminofenil)-2-propil-3H-benzo[d]imidazol-5-karboksamid-3-il)-metil-bifenil-2-nitril.Step c) involves the reduction of ((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile in the presence of suitable solvent and catalyst to form compound 13, (((N, 7-dimethyl-N- (2aminophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamid-3-yl) -methyl-biphenyl-2 -nitrile.
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, paladij na oglju, Raney-Ni in podobne.Suitable catalysts that can be used include, but are not limited to, palladium on charcoal, Raney-Ni and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, metanol, etanol, propanol in podobne; vodo in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, methanol, ethanol, propanol and the like; water and any mixtures thereof.
Temperatura za vodenje redukcije lahko sega od okoli 0 do okoli 100 °C, zlasti od okoli 20 do okoli 50 °C, še zlasti je pri temperaturi refluksa uporabljenega topila.The temperature to guide the reduction can range from about 0 to about 100 ° C, in particular from about 20 to about 50 ° C, especially at the reflux temperature of the solvent used.
Stopnja d) vključuje kondenzacijo ((N,7-dimetil-N-(2-aminofenil)-2-propil-3Hbenzo[d]imidazol-5-karboksamid-3-il)-metil)-bifenil-2-nitrila v prisotnosti primernega topila in katalizatorja, da tvorimo spojino 3, 4'-[(2-n-propil-4-metil-6-(lmetilbenzimidazol-2-il)-benzimidazol-l-il)-metil]-bifenil-2-nitril.Step d) involves the condensation of ((N, 7-dimethyl-N- (2-aminophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl) -methyl) -biphenyl-2-nitrile in the presence of suitable solvent and catalyst to form compound 3, 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-nitrile .
Primerni katalizatorji, ki jih lahko uporabimo, vključujejo, toda nanje niso omejeni, piridin, p-toluen sulfonsko kislino, ocetno kislino in podobne.Suitable catalysts that may be used include, but are not limited to, pyridine, p-toluene sulfonic acid, acetic acid and the like.
Primerna topila, ki jih lahko uporabimo, vključujejo, toda nanje niso omejena, tetrahidrofuran, dioksan, piridin, ocetno kislino, toluen in podobne; in kakršnekoli njihove zmesi.Suitable solvents that may be used include, but are not limited to, tetrahydrofuran, dioxane, pyridine, acetic acid, toluene and the like; and any mixtures thereof.
Temperatura za vodenje kondenzacije lahko sega od okoli 0 do okoli 130 °C, zlasti od okoli 20 do okoli 60 °C, še zlasti je pri temperaturi refluksa uporabljenih topil.The temperature for conducting the condensation can range from about 0 to about 130 ° C, in particular from about 20 to about 60 ° C, especially at the reflux temperature of the solvents used.
Izhodno spojino 12, 7-metil-2-propil-3//-benzo[d]imidazol-5-karboksilno kislino, lahko pripravimo po kateremkoli postopku, ki je znan iz stanja tehnike, kot je na primer opisan v Journal of Medicinal Chemistry (1993), 36 (25), 4040-51, WO 9719911, CN 1623992, Youji Huaxue (2006), 26 (3), 318-323, WO 2006044754.The starting compound 12, 7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxylic acid can be prepared by any method known in the art, such as described in the Journal of Medicinal Chemistry (1993), 36 (25), 4040-51, WO 9719911, CN 1623992, Youji Huaxue (2006), 26 (3), 318-323, WO 2006044754.
Telmisartan nitril s formulo 3 in kemijskim imenom 4'-[(2-n-propil-4-metil-6-(l-metil benzimidazol-2-il)-benzimidazol-l-il)-metil]-bifenil-2-nitril, pripravljen po postopkih v smislu predloženega izuma, se pretvori v telmisartan v postopku hidrolize (shema 6) po postopkih, ki so znani iz stanja tehnike, kot so opisani na primer v EP 502314, CN 1412183, WO 2004087676 in prijavi, ki je istočasno v postopku, PCT/EP2007/056251.Telmisartan nitrile of formula 3 and the chemical name 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-benzimidazol-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2- nitrile prepared according to the methods of the present invention is converted to telmisartan by the hydrolysis process (Scheme 6) according to methods known in the art, such as those described, for example, in EP 502314, CN 1412183, WO 2004087676 and the application which is at the same time in the proceedings, PCT / EP2007 / 056251.
Shema 6Scheme 6
Dobljeni telmisartan prednostno pretvorimo v farmacevtsko sprejemljivo sol, kot je natrijeva, kalijeva, megluminska, erbuminska ali katerakoli druga sol, znana iz stanja tehnike, kot na primer iz prijave, ki je istočasno v postopku, PCT/EP2007/056251.The resulting telmisartan is preferably converted to a pharmaceutically acceptable salt, such as sodium, potassium, meglumine, erbumine or any other salt known in the art, such as, for example, from a concurrent application PCT / EP2007 / 056251.
V še enem vidiku predloženi izum zagotavlja nove intermediate v sintezi telmisartan nitrila, po izbiri v izolirani in/ali očiščeni obliki, izbrane iz skupine, katero sestavljajo:In another aspect, the present invention provides novel intermediates in the synthesis of telmisartan nitrile, optionally in isolated and / or purified form, selected from the group consisting of:
spojina 4 s kemijskim imenom jV-((2-ciano-bifenil-4'-metil)amino-6-metil-4-( 1 -metil- l/7-benzo[d]imidazol-2-compound 4 with the chemical name N - ((2-cyano-biphenyl-4'-methyl) amino-6-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2-
spojina 5 s kemijskim imenom yV-(2-amino-6-metil-4-( 1 -metil- l#-benzo[d] imidazol-2-il)fenil-butiramidcompound 5 with the chemical name N- (2-amino-6-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) phenyl-butyramide
spojina 6 s kemijskim imenomcompound 6 with the chemical name
A-(2-metil-4-(l-metil-l//-benzo[d]imidazol-2-il)-6-nitrofenil)butiramidN- (2-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2-yl) -6-nitrophenyl) butyramide
spojina 7 s kemijskim imenomcompound 7 with a chemical name
7V-(2-aminofenil)-4-(butiramido)-/V.3-dimetil-5-nitrobenzamidN- (2-aminophenyl) -4- (butyramido) - N-dimethyl-5-nitrobenzamide
spojina 8 s kemijskim imenomcompound 8 with the chemical name
4-(butiramido)-3-metil-5-nitrobenzojska kislina4- (Butyramido) -3-methyl-5-nitrobenzoic acid
spojina 9 s kemijskim imenom ((7-metil-2-propil-3/f-benzo[d] imidazol- 5 -karboksil-3 -il)-metil)-bifenil-2-nitrilcompound 9 with the chemical name ((7-methyl-2-propyl-3 / t-benzo [d] imidazole-5-carboxyl-3-yl) -methyl) -biphenyl-2-nitrile
spojina 10 s kemijskim imenom ((7-metil-2-propil-3 H-benzo- [djimidazol- 5 -metoksikarbonil-3-il)-metil)-bifenil-2-compound 10 with the chemical name ((7-methyl-2-propyl-3H-benzo- [dimidazol-5-methoxycarbonyl-3-yl) -methyl) -biphenyl-2-
spojina 13 s kemijskim imenom ((/V,7-dimetil-7V-(2-aminofenil)-2-propil-37/-benzo[d]imidazol-5-karboksamid-3-il)compound 13 with the chemical name ((N, 7-dimethyl-N- (2-aminophenyl) -2-propyl-3H-benzo [d] imidazole-5-carboxamide-3-yl)
spojina 14 s kemijskim imenom ((N,7-dimetil-JV-(2-nitrofenil)-2-propil-3J7-benzo[d]imidazol-5-karboksamid-3-il)-compound 14 with the chemical name ((N, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-3 H -benzo [d] imidazole-5-carboxamide-3-yl) -
spojina 15 s kemijskim imenom /V,7-dimetil-/V-(2-nitrofenil)2-propil-37/-benzo[d]imidazol-5-karboksamidcompound 15 with the chemical name N, 7-dimethyl- N- (2-nitrophenyl) 2-propyl-3H-benzo [d] imidazole-5-carboxamide
MeMe
—Pr-n—Pr-n
OOh
NO2 NO 2
V še enem vidiku predloženi izum zagotavlja uporabo novih intermediatov v pripravi telmisartana in/ali njegovih soli.In another aspect, the present invention provides the use of novel intermediates in the preparation of telmisartan and / or its salts.
Postopek v smislu predloženega izuma se izogne ključnemu intermediatu v znanih sintezah telmisartana s kemijskim imenom l,7'-dimetil-2’-propil-lH,3'H-2,5'bibenzo[d]imidazol, katerega je težko pripraviti (postopki opisani v stanju tehnike uporabljajo polifosfomo kislino pri temperaturi 150 °C 20 ur).The process of the present invention avoids a key intermediate in known syntheses of telmisartan by the chemical name l, 7'-dimethyl-2'-propyl-1H, 3'H-2,5'bibenzo [d] imidazole, which is difficult to prepare (processes described in the prior art use polyphosphomic acid at 150 ° C for 20 hours).
Se en vidik predloženega izuma je farmacevtski sestavek za dajanje učinkovite količine telmisartana in/ali njegove soli, pripravljenega po predloženem izumu v enotski dozirni obliki, samega ali v kombinaciji s še eno aktivno sestavino, kot je hidroklorotiazid, in farmacevtsko prenesljivimi nosilci, ki obsegajo neaktivne sestavine, kot so polnila (razredčila), veziva, dezintegranti, drsljivci, maziva in drugi ekscipienti. Uporabimo lahko kakršenkoli postopek izdelave za trdno oralno dozirno obliko, vključno s postopkom mokrega granuliranja (z vodo ali kakršnimkoli primernim in farmacevtsko sprejemljivim organskim topilom), postopek suhega granuliranja in postopek direktnega stiskanja, ali kakršenkoli drug postopek, znan v stroki. Takšne farmacevtske sestavke lahko dajemo bolniku v kakršnikoli dozirni obliki, kot na primer tableti, piluli, pastili, sesalni tableti, kapsuli, prašku, tekočini, svečki, vrečki, eliksirju, raztopini, sirupu, suspenziji itd.. Dozirne oblike so lahko prilagojene za dajanje bolniku na primer po peroralni, bukalni, parenteralni, oftalmični, rektalni in transdermalni poti.Another aspect of the present invention is a pharmaceutical composition for administering an effective amount of telmisartan and / or its salt prepared according to the present invention in a unit dosage form, alone or in combination with another active ingredient such as hydrochlorothiazide, and pharmaceutically acceptable carriers comprising inactive ingredients such as fillers (diluents), binders, disintegrants, gliders, lubricants and other excipients. Any manufacturing process for the solid oral dosage form may be used, including the wet granulation process (with water or any suitable and pharmaceutically acceptable organic solvent), the dry granulation process and the direct compression process, or any other method known in the art. Such pharmaceutical compositions may be administered to the patient in any dosage form, such as tablets, pills, lozenges, suction tablets, capsules, powder, liquids, suppositories, bags, elixirs, solutions, syrups, suspensions, etc. The dosage forms may be adapted for administration. for example, the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes.
Telmisartanovo sol, pripravljeno po predloženem izumu, lahko vključimo v farmacevtski sestavek ali pa jo lahko tvorimo in-situ med pripravo farmacevtskega sestavka. V zadnjem primeru damo telmisartan v topilo skupaj z ustreznim bazičnim sredstvom in pomešamo skupaj. Dobimo telmisartan v obliki raztopljene soli. Telmisartanovo sol lahko uporabimo neposredno bodisi v postopku sušenja z razprševanjem ali v postopku z zvrtinčenim slojem.The telmisartan salt prepared according to the present invention may be incorporated into the pharmaceutical composition or may be formed in situ during the preparation of the pharmaceutical composition. In the latter case, telmisartan is added to the solvent together with the appropriate basic agent and mixed together. Telmisartan is obtained in the form of dissolved salt. Telmisartan salt can be used directly either in the spray drying process or in the fluidized bed process.
Končno predloženi izum zagotavlja postopek zdravljenja bolezenskega stanja, preprečenega, izboljšanega ali odstranjenega z dajanjem telmisartana in/ali njegovih soli, pripravljenega po predloženem izumu, bolniku, ki potrebuje takšno zdravljenje.Finally, the present invention provides a method of treating a disease condition prevented, improved or eliminated by administering telmisartan and / or its salts prepared according to the present invention to a patient in need of such treatment.
Naslednji primeri so podani za bolj podrobno ponazoritev določenih vidikov izuma in jih ne gre razlagati, kot da na kakršenkoli način omejujejo izum.The following examples are given to illustrate certain aspects of the invention in more detail and should not be construed as limiting the invention in any way.
Primer 1Example 1
Priprava 7V-(2-aminofenil)-4-(butiramido)-yV,3-dimetil-5-nitrobenzamida 7:Preparation of N- (2-aminophenyl) -4- (butyramido) -N, 3-dimethyl-5-nitrobenzamide 7:
K zmesti 3,9 g (20 mmol) 2V-metilbenzen-l,2-diamin dihidroklorida in 10 ml CH2C12, dodamo 1,6 ml piridina (20 mmol), mešamo pri sobni temperaturi, da dobimo raztopino prostega /V-metilbenzen-l,2-diamina. Nastalo raztopino dodamo k zmesi 2,66 g (10 mmol) 8, 3,24 g (20 mmol) CDI in 60 ml THF, mešamo 3 ure in odfiltriramo. Mokro pogačo posušimo v peči, da dobimo 2,26 g trdne snovi 7 (dobitek 61 %).To a mixture of 3.9 g (20 mmol) of 2V-methylbenzene-1,2-diamine dihydrochloride and 10 ml of CH 2 Cl 2 , 1.6 ml of pyridine (20 mmol) was added, stirred at room temperature to obtain a free / V solution. -methylbenzene-1,2-diamine. The resulting solution was added to a mixture of 2.66 g (10 mmol) of 8, 3.24 g (20 mmol) of CDI and 60 ml of THF, stirred for 3 hours and filtered. The wet cake was dried in an oven to give 2.26 g of solid 7 (61% yield).
‘HNMR (300 MHz, DMSO-dg): δ 8,33 (s, IH), 8,19 (s, IH), 7,11 (d, 2H, J=6,9 Hz), 6,63 (d, 2H, J=7,8 Hz), 2,70 (s, 3H), 2,30-2,36 (m, 5H), 1,60 (m, 2H), 0,93 (t, 3H, J=7,5 Hz);1H NMR (300 MHz, DMSO-dg): δ 8.33 (s, 1H), 8.19 (s, 1H), 7.11 (d, 2H, J = 6.9 Hz), 6.63 ( d, 2H, J = 7.8 Hz), 2.70 (s, 3H), 2.30-2.36 (m, 5H), 1.60 (m, 2H), 0.93 (t, 3H) , J = 7.5 Hz);
ESI-MS: 369 [M-l]'.ESI-MS: 369 [M-1] '.
Primer 2Example 2
Priprava /V-(2-metil-4-(l-metil-l H-benzo [d] imidazol-2-il)-6nitrofenil)butiramida 6:Preparation of N- (2-methyl-4- (1-methyl-1H-benzo [d] imidazol-2-yl) -6nitrophenyl) butyramide 6:
Zmes 370 mg (1 mmol) 7 in 5 ml piridina segrevamo do refluksa in mešamo 5 ur. Zmes razredčimo z etil acetatom, speremo z vodo, posušimo nad Na2SO4, filtriramo in topilo odstranimo pod vakuumom, da dobimo 0,3 g spojine 6 (dobitek 85 %).A mixture of 370 mg (1 mmol) of 7 and 5 ml of pyridine was heated to reflux and stirred for 5 hours. The mixture was diluted with ethyl acetate, washed with water, dried over Na 2 SO 4 , filtered and the solvent removed in vacuo to give 0.3 g of compound 6 (85% yield).
ESI-MS: 353 [M+l]+.ESI-MS: 353 [M + 1] + .
Primer 3Example 3
Priprava A-(2-amino-6-metiI-4-(l-metil-l//-benzo[d]imidazol-2il)fenil)butiramida 5:Preparation of A- (2-amino-6-methyl-4- (1-methyl-1 H -benzo [d] imidazol-2yl) phenyl) butyramide 5:
Zmes 0,21 g (0,6 mmol) 6 in 8 ml metanola, 3,5 mg (0,06 mmol) Raney-Ni mešamo 2 uri pod H2 pri sobni temperaturi. Tvori se bela trdna snov, dodamo metanol, da raztopimo belo trdno snov. Nastalo zmes filtriramo, filtrat uparimo pod vakuumom, da dobimo trdno snov, 0,183 g (dobitek 94,8 %).A mixture of 0.21 g (0.6 mmol) of 6 and 8 ml of methanol, 3.5 mg (0.06 mmol) of Raney-Ni was stirred for 2 hours under H 2 at room temperature. A white solid is formed, methanol is added to dissolve the white solid. The resulting mixture was filtered, the filtrate was evaporated in vacuo to give a solid, 0.183 g (94.8% yield).
*H NMR (300 MHz, DMSO-cU): δ 7,61 (d, IH, >4,5 Hz), 7,57 (d, IH, >7,2 Hz), 7,24 (m, 2H), 7,05 (s, IH), 6,90 (s, IH), 3,86 (s, 3H), 2,34 (t, 2H, >7,2 Hz), 1,65 (m, 2H), 0,97 (t, 3H, >4,5 Hz); ESI-MS: 323 [M+l]+ 1 H NMR (300 MHz, DMSO-cU): δ 7.61 (d, 1H,> 4.5 Hz), 7.57 (d, 1H,> 7.2 Hz), 7.24 (m, 2H ), 7.05 (s, 1H), 6.90 (s, 1H), 3.86 (s, 3H), 2.34 (t, 2H,> 7.2 Hz), 1.65 (m, 2H), 0.97 (t, 3H,> 4.5 Hz); ESI-MS: 323 [M + 1] +
Primer 4Example 4
Priprava 7V-((2-nitril-bifenil-4’-metil)ammo-6-metil-4-(l-metil-17ybenzo [d] imidazol-2-iI)feniI)butiramida 4:Preparation of 7V - ((2-Nitrile-biphenyl-4′-methyl) amino-6-methyl-4- (1-methyl-17ybenzo [d] imidazol-2-yl) phenyl) butyramide 4:
K zmesi 0,13 g (0,4 mmol) 5, 0,11 g K2CO3 (0,8 mmol) in 5 ml DMF, dodamo 0,115 g (0,42 mmol) 4'-bromometil-bifenil-2-karbonitrila, mešamo 22 ur pri sobni temperaturi. Zmes razredčimo z etil acetatom, speremo z vodo in nasičeno slanico, posušimo nad Na2SO4, filtriramo in topilo odstranimo pod znižanim tlakom, da dobimo trdno snov. Za spiranje trdne snovi uporabimo metanol, da dobimo 81 mg 4 (dobitek 40 %).To a mixture of 0.13 g (0.4 mmol) 5, 0.11 g K 2 CO 3 (0.8 mmol) and 5 ml DMF, 0.115 g (0.42 mmol) of 4'-bromomethyl-biphenyl-2 is added -carbonitrile, stirred for 22 hours at room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure to give a solid. Methanol was used to wash the solid to give 81 mg 4 (40% yield).
NMR (300 MHz, DMSO-d6): δ 7,93 (d, IH, >8,1 Hz), 7,79 (m, IH), 7,45-7,62 (m, 8H, >7,2 Hz), 7,21 (m, 2H), 6,90 (s, IH), 6,62 (s, IH), 4,52 (s, 2H), 3,49 (s, 3H), 2,42 (t, 2H, >7,2 Hz), 1,69 (m, 2H), 0,96 (t, 3H, >4,5 Hz); ESI-MS: 514 [M+l]+ NMR (300 MHz, DMSO-d 6 ): δ 7.93 (d, 1H,> 8.1 Hz), 7.79 (m, 1H), 7.45-7.62 (m, 8H,> 7 , 2 Hz), 7.21 (m, 2H), 6.90 (s, 1H), 6.62 (s, 1H), 4.52 (s, 2H), 3.49 (s, 3H). 2.42 (t, 2H,> 7.2 Hz), 1.69 (m, 2H), 0.96 (t, 3H,> 4.5 Hz); ESI-MS: 514 [M + 1] +
Primer 5Example 5
Priprava 4’-[(2-n-propil-4-metil-6(l-metilbenzimidazol-2-il)-benzimidazol-liI)metil]-bifenil-2-nitrila 3 iz 4:Preparation of 4 '- [(2-n-propyl-4-methyl-6 (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) methyl] -biphenyl-2-nitrile 3 from 4:
K zmesi 45 mg (0,08 mmol) 4 in 5 ml toluena dodamo 15 mg (0,42 mmol) /?-TsOH, segreto do refluksa mešamo 5 ur. Zmes razredčimo z etil acetatom, speremo z vodo in nasičeno slanico, posušimo nad Na2SO4, filtriramo in topilo odstranimo pod vakuumom, da dobimo 37 mg spojine 3 (dobitek 86 %).To a mixture of 45 mg (0.08 mmol) 4 and 5 ml of toluene was added 15 mg (0.42 mmol) /? - TsOH, stirring to reflux for 5 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over Na 2 SO 4 , filtered and the solvent removed in vacuo to give 37 mg of compound 3 (86% yield).
‘HNMR (300 MHz, CDC13): δ 7,75 (m, 2H), 7,62 (m, IH), 7,16-7,51 (m, 11H), 5,48 (s, 2H), 3,80 (s, 3H), 2,94 (t, 2H, J=7,2 Hz), 2,77 (s, 3H), 1,85 (m, 2H), 1,06 (t, 3H, J=4,5 Hz);1 H NMR (300 MHz, CDCl 3 ): δ 7.75 (m, 2H), 7.62 (m, 1H), 7.16-7.51 (m, 11H), 5.48 (s, 2H) , 3.80 (s, 3H), 2.94 (t, 2H, J = 7.2 Hz), 2.77 (s, 3H), 1.85 (m, 2H), 1.06 (t. 3H, J = 4.5 Hz);
EI-MS: 495 [M]+ EI-MS: 495 [M] < + & gt ; .
Primer 6Example 6
Priprava metil 7-metil-2-propil-3JT-benzold]imidazol-5-karboksilne kisline 11:Preparation of methyl 7-methyl-2-propyl-3 H -benzold] imidazole-5-carboxylic acid 11:
g (23 mmol) 7-metil-2-propil-3//-benzo[d]imidazol-5-karboksilne kisline dodamo k 100 ml metanola, mešamo, dodamo 3 ml koncentrirane klorovodikove kisline (37 %), segrevamo na 70 °C 20 ur. Dodamo še 3 ml koncentrirane klorovodikove kisline, segrevamo do refluksa 4 ure. Dodamo 4 ml koncentrirane klorovodikove kisline, segrevamo do refluksa 3 ure. Topilo odstranimo pod vakuumom, da dobimo 6,6 g surovega 11.g (23 mmol) of 7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxylic acid was added to 100 ml of methanol, stirred, 3 ml of concentrated hydrochloric acid (37%) was added, heated to 70 ° C 20 hrs. 3 ml of concentrated hydrochloric acid were added, heated to reflux for 4 hours. Add 4 ml of concentrated hydrochloric acid, reflux for 3 hours. The solvent was removed in vacuo to give 6.6 g of crude 11.
Primer 7Example 7
Priprava ((7-metil-2-propil-3//-benzo[d]imidazol-5-metoksikarbonil-3-il)-metil)bifenil-2-nitrila 10:Preparation of ((7-methyl-2-propyl-3 H -benzo [d] imidazol-5-methoxycarbonyl-3-yl) -methyl) biphenyl-2-nitrile 10:
6,6 g surovega 11 in 5,48 g (20 mmol) 4'-bromometil-bifenil-2-karbonitrila raztopimo v 100 ml DMF, dodamo 13,8 g (100 mmol) K2CO3, mešamo 18 ur pri sobni temperaturi. K zmesi dodamo 150 ml vode, tvori se bela trdna snov, ki jo filtriramo, da dobimo pogačo, katero posušimo, da dobimo 8 g surovega 10, dobitek 82,5 % v dveh žetvah.6.6 g of crude 11 and 5.48 g (20 mmol) of 4'-bromomethyl-biphenyl-2-carbonitrile were dissolved in 100 ml of DMF, 13.8 g (100 mmol) of K 2 CO 3 was added , stirred for 18 hours at room temperature. temperature. 150 ml of water was added to the mixture to form a white solid which was filtered to give a cake which was dried to give 8 g of crude 10, a yield of 82.5% in two harvests.
Ή NMR (300 MHz, DMSO-de): δ 7,97(m, 2H), 7,74 (t, IH, J=6,3 Hz), 7,53-7,67 (m, 5H), 7,19 (d, 2H, J=8,l Hz), 5,68 (s, 2H), 3,83 (s, 3H), 2,88 (t, 2H, J=7,2 Hz), 2,58 (s, 3H), 1,76 (m, 2H), 0,94 (t, 3H, J=4,5 Hz).Ή NMR (300 MHz, DMSO-de): δ 7.97 (m, 2H), 7.74 (t, 1H, J = 6.3 Hz), 7.53-7.67 (m, 5H). 7.19 (d, 2H, J = 8, 1 Hz), 5.68 (s, 2H), 3.83 (s, 3H), 2.88 (t, 2H, J = 7.2 Hz). 2.58 (s, 3H), 1.76 (m, 2H), 0.94 (t, 3H, J = 4.5 Hz).
Primer 8Example 8
Priprava ((7-metil-2-propiI-3//-benzo[d]imidazol-5-karboksil-3-il)-metiI)-bifeniI2-nitrila 9:Preparation of ((7-methyl-2-propyl-3 H -benzo [d] imidazole-5-carboxyl-3-yl) -methyl) -biphenyl 2-nitrile 9:
K zmesi 7,2 g 10 in 180 ml metanola dodamo 30 ml 10 %-nega NaOH, segrevamo do refluksa 5 ur. Topilo pod vakuumom odstranimo, k zmesi dodamo 50 ml vode in uporabimo 1 M HC1, da naravnamo vrednost pH na 5~6. Zmes filtriramo, da dobimo mokro pogačo, jo speremo z vodo, posušimo, da dobimo 4,5 g 9, dobitek 65 %.To the mixture of 7.2 g of 10 and 180 ml of methanol was added 30 ml of 10% NaOH, heated to reflux for 5 hours. The solvent was removed in vacuo, 50 ml of water was added to the mixture and 1 M HCl was used to adjust the pH to 5 ~ 6. The mixture was filtered to give a wet cake, washed with water, dried to give 4.5 g of 9, yield 65%.
’H NMR (300 MHz, DMSO-d6); δ 7,94 (m, 2H), 7,75 (t, IH, J=6,3 Hz), 7,54-7,65 (m, 5H), 7,20 (d, 2H, J=8,l Hz), 5,68 (s, 2H), 2,88 (t, 2H, J=7,5 Hz), 2,58 (s, 3H), 1,77 (m, 2H), 0,96 (t, 3H, J=4,5 Hz).1 H NMR (300 MHz, DMSO-d 6 ); δ 7.94 (m, 2H), 7.75 (t, 1H, J = 6.3 Hz), 7.54-7.65 (m, 5H), 7.20 (d, 2H, J = 8) , 1 Hz), 5.68 (s, 2H), 2.88 (t, 2H, J = 7.5 Hz), 2.58 (s, 3H), 1.77 (m, 2H), 0. 96 (t, 3H, J = 4.5 Hz).
Primer 9Example 9
Priprava 4’-[(2-n-propil-4-metil-6-(l-metilbenzimidazol-2-il)-benzimidazol-l-iI)metil]-bifenil-2-nitrila 3 iz 9:Preparation of 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) methyl] -biphenyl-2-nitrile 3 from 9:
200 mg 9 dodamo v 1 ml SOC12. Zmes segrevamo do refluksa. Po 2 urah uparimo SOC12 pri 45 °C pod znižanim tlakom, da dobimo svetlo rumen penast ostanek. Ostanek raztopimo v 2 ml suhega piridina in dodamo 100 mg /V-metilbenzen-1,2diamina. Zmes segrevamo do refluksa 24 ur.200 mg 9 was added to 1 ml of SOCl 2 . The mixture was heated to reflux. After 2 hours, evaporate SOC1 2 at 45 ° C under reduced pressure to give a light yellow foam residue. The residue was dissolved in 2 ml of dry pyridine and 100 mg / V-methylbenzene-1,2diamine was added. The mixture was heated to reflux for 24 hours.
Piridin uparimo v vakuumu. Ostanek ekstrahiramo z etil acetatom, speremo z vodnim NaHCO3 in slanico, posušimo nad brezvodnim Na2SO4. Nato filtriramo in koncentriramo, da dobimo 188 mg (78 % dobitek) surovega 3.The pyridine was evaporated in vacuo. The residue was extracted with ethyl acetate, washed with aqueous NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 . It was then filtered and concentrated to give 188 mg (78% yield) of crude 3.
EI-MS: 496[M+1]+.EI-MS: 496 [M + 1] < + >.
Primer 10Example 10
Priprava A,7-dimetil-/V-(2-nitrofenil)-2-propil-37T-benzo [d] imidazol-5karboksamida 15:Preparation of A, 7-dimethyl-N- (2-nitrophenyl) -2-propyl-37T-benzo [d] imidazole-5carboxamide 15:
K zmesi 1,09 g (5 mmol) 2-propil-3//-benzo[d]imidazol-5-karboksilne kisline in 50 ml CH2C12, dodamo 7,26 ml (100 mmol) SOC12. Zmes mešamo 18 ur. Zmes uparimo pod znižanim tlakom.To a mixture of 1.09 g (5 mmol) of 2-propyl-3 H -benzo [d] imidazole-5-carboxylic acid and 50 ml of CH 2 Cl 2 , 7.26 ml (100 mmol) of SOCl 2 was added . The mixture was stirred for 18 hours. The mixture was evaporated under reduced pressure.
Ostanek raztopimo v 30 ml DMF in dodamo 1,6 g (10,5 mmol) 7V-metil-2-nitroanilina. Zmes mešamo pri sobni temperaturi 48 ur. Dodamo nasičen NaHCO3, da naravnamo vrednost pH na 8. Nastalo zmes dvakrat ekstrahiramo z etil acetatom. Združeno organsko plast speremo z vodo in slanico, posušimo nad brezvodnim Na2SO4. Nato jo filtriramo in koncentriramo, da dobimo ostanek, ostanek očistimo na silikagelni kromatografiji, da dobimo 0,69 g (39 %-ni dobitek) 15.The residue was dissolved in 30 ml of DMF and 1.6 g (10.5 mmol) of N-methyl-2-nitroaniline was added. The mixture was stirred at room temperature for 48 hours. Saturated NaHCO 3 was added to adjust the pH to 8. The resulting mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 . It was then filtered and concentrated to give a residue, the residue was purified by silica gel chromatography to give 0.69 g (39% yield) 15.
NMR (300 MHz, DMSO-dg): δ 7,70-7,83 (m, 3H), 7,44 (m, IH), 6,84-7,07 (m, 2H), 3,47 (s, 3H), 3,37 (s, 3H), 2,29 (m, 2H), 1,775 (m, 2H), 0,93 (t, 3H, J=4,5 Hz);NMR (300 MHz, DMSO-dg): δ 7.70-7.83 (m, 3H), 7.44 (m, 1H), 6.84-7.07 (m, 2H), 3.47 ( s, 3H), 3.37 (s, 3H), 2.29 (m, 2H), 1.775 (m, 2H), 0.93 (t, 3H, J = 4.5 Hz);
ESI-MS: 353 [M+l]+; 351 [M-l]’.ESI-MS: 353 [M + 1] + ; 351 [Ml] '.
Primer 11Example 11
Priprava ((/V,7-dimetil-/V-(2-nitrofenil)-2-propil-3H-benzo [d] imidazol-5karboksamid-3-il)-metil)-bifenil-2-nitrila 14:Preparation of ((N, 7-Dimethyl-N- (2-nitrophenyl) -2-propyl-3H-benzo [d] imidazole-5carboxamide-3-yl) -methyl) -biphenyl-2-nitrile 14:
0,7 g 15 (2 mmol) in 0,82 g (3 mmol) 4'-bromometil-bifenil-2-karbonitrila raztopimo v 30 ml acetonitrila, dodamo 0,55 g (4 mmol) K2CO3, mešamo 22 ur pri sobni temperaturi. Dodamo metanol, da razredčimo reakcijsko zmes, jo filtriramo in filtrat koncentriramo pod vakuumom, da dobimo ostanek. Da raztopimo ostanek uporabimo etilen acetat, speremo ga z vodo, posušimo nad brezvodnim Na2SO4, filtriramo in koncentriramo, da dobimo ostanek 0,84 g surovega 14, dobitek 77 %.0.7 g of 15 (2 mmol) and 0.82 g (3 mmol) of 4'-bromomethyl-biphenyl-2-carbonitrile were dissolved in 30 ml of acetonitrile, 0.55 g (4 mmol) of K 2 CO 3 was added and stirred 22 hours at room temperature. Methanol was added to dilute the reaction mixture, filtered, and the filtrate was concentrated in vacuo to give a residue. Ethylene acetate was used to dissolve the residue, washed with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue of 0.84 g of crude 14, yield 77%.
Ή NMR (300 MHz, DMSO-d6): δ 7,95 (d, IH, >4,8 Hz), 7,52-7,81 (m, 8H), 7,32 (m, IH), 6,88-6,99 (m, 4H), 5,38 (s, 3H), 3,37 (s, 3H), 2,71 (m, 2H), 2,39 (s, 3H), 1,66 (m, 2H), 0,91 (t, 3H, >4,5 Hz); EI-MS: 543 [M]+.Ή NMR (300 MHz, DMSO-d 6 ): δ 7.95 (d, 1H,> 4.8 Hz), 7.52-7.81 (m, 8H), 7.32 (m, 1H). 6.88-6.99 (m, 4H), 5.38 (s, 3H), 3.37 (s, 3H), 2.71 (m, 2H), 2.39 (s, 3H), 1 , 66 (m, 2H), 0.91 (t, 3H,> 4.5 Hz); EI-MS: 543 [M] < + >.
Primer 12Example 12
Priprava ((yV,7-dimetiI-/V-(2-aminofenil)-2-propiI-3ZZ-benzo[d]imidazol-5karboksamid-3-il)-metil)-bifenil-2-nitriIa 13:Preparation of ((N, 7-dimethyl-N- (2-aminophenyl) -2-propyl-3ZZ-benzo [d] imidazole-5carboxamid-3-yl) -methyl) -biphenyl-2-nitrile 13:
Zmes 100 mg (0,2 mmol) 14 raztopimo v 35 ml metanola, dodamo 40 mg Pd/C (10 %), mešamo 2 uri pod H2 pri sobni temperaturi. Reakcijsko zmes filtriramo, da odstranimo Pd/C, filtrat uparimo pod vakuumom, da dobimo belo trdno snov 13, 63 mg (dobitek 67 %).A mixture of 100 mg (0.2 mmol) 14 was dissolved in 35 ml of methanol, 40 mg Pd / C (10%) was added, stirred for 2 hours under H 2 at room temperature. The reaction mixture was filtered to remove Pd / C, the filtrate was evaporated under vacuum to give a white solid 13.63 mg (67% yield).
ESI-MS spekter je: ESI-MS: 514 [M+l]+.The ESI-MS spectrum is: ESI-MS: 514 [M + 1] + .
Primer 13Example 13
Priprava 4'-[(2-n-propil-4-metil-6-(l-metilbenzimidazol-2-il)-benzimidazol-l-il)metil]-bifenil-2-nitrila 3 iz 13:Preparation of 4 '- [(2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) methyl] -biphenyl-2-nitrile 3 from 13:
Zmes 100 mg (0,2 mmol) 13 in 5 ml piridina segrevamo do refluksa 22 ur (TLC spremljanje reakcije), ohladimo do sobne temperature, dodamo etil acetat, da razredčimo reakcijsko zmes. Organsko fazo speremo zaporedoma z vodo, nasičeno raztopino NH4C1 in slanico, posušimo nad Na2SO4, filtriramo, koncentriramo, da dobimo 74 mg ostanka. Ostanek očistimo na silikagelni kromatografiji, da dobimo 45 mg spojine 3, dobitek 47 %.A mixture of 100 mg (0.2 mmol) of 13 and 5 ml of pyridine was heated to reflux for 22 hours (TLC reaction monitoring), cooled to room temperature, ethyl acetate was added to dilute the reaction mixture. The organic phase was washed successively with water, saturated NH 4 Cl solution and brine, dried over Na 2 SO 4, filtered, concentrated to give 74 mg of residue. The residue was purified by silica gel chromatography to give 45 mg of compound 3, yield 47%.
*H NMR (300 MHz, CDCI3): δ 7,77 (m, 2H), 7,59 (m, IH), 7,51-7,26 (m, 9H), 5,47 (s, 3H), 3,78 (s, 3H), 2,94 (t, 2H, J=7,8 Hz), 2,77 (s, 3H), 1,88 (m, 2H), 1,06 (t, 3H, J=4,5 Hz);1 H NMR (300 MHz, CDCl 3): δ 7.77 (m, 2H), 7.59 (m, 1H), 7.51-7.26 (m, 9H), 5.47 (s, 3H) , 3.78 (s, 3H), 2.94 (t, 2H, J = 7.8 Hz), 2.77 (s, 3H), 1.88 (m, 2H), 1.06 (t. 3H, J = 4.5 Hz);
EI-MS: 495 [M]+ EI-MS: 495 [M] < + & gt ; .
Primer 14Example 14
Priprava 4’-[(2-«-propil-4-metil-6-(l-metiIbenzimidazol-2-il)-benzimidazol-l-il)metiIj-bifenil-2-karboksilne kisline 1:Preparation of 4 '- [(2 -? - propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl) methylbiphenyl-2-carboxylic acid 1:
Zmes 2,5 g 3 (5 mmol), 1,0 g natrijevega hidroksida (25 mmol), 0,18 g vode (10 mmol) in 30 ml etilenglikola refluktiramo 8 ur. Reakcija se konča. Reakcijsko zmes ohladimo na sobno temperaturo, dodamo H2O (250 ml). Potem, ko pH vrednosti raztopine naravnamo na 4 z HOAc (12 ml), produkt nato oborimo in trikrat estrahiramo s CH2C12, združene organske plasti speremo s slanico, posušimo nad NaSO4, filtriramo, filtrat koncentriramo, da dobimo surov 1 2,55 g, dobitek 98 %.A mixture of 2.5 g 3 (5 mmol), 1.0 g sodium hydroxide (25 mmol), 0.18 g water (10 mmol) and 30 ml ethylene glycol was refluxed for 8 hours. The reaction ends. The reaction mixture was cooled to room temperature, H 2 O (250 ml) was added. After adjusting the pH of the solution to 4 with HOAc (12 ml), the product was then precipitated and extracted three times with CH 2 Cl 2 , the combined organic layers were washed with brine, dried over NaSO 4 , filtered, the filtrate was concentrated to give crude 1 2 , 55 g, 98% yield.
Primer 15Example 15
Priprava telmisartana in/ali njegovih farmacevtsko sprejemljivih soliPreparation of telmisartan and / or its pharmaceutically acceptable salts
Zmes 1,0 g (2,0 mmol) 4'-((l,7'-dimetil-2'-propil-lH,3'H-2,5'-bibenzo[d]imidazol-3'il)metil)bifenil-2-karbonitrila, 5 ml izopropanola, 5 ml vode in 1,03 g (18,4 mmol) KOH segrevamo na 120 °C približno 48 ur. Nato raztopino ohladimo do sobne temperature in dodamo 10 ml vode. Zmes nevtraliziramo z dodatkom 3M HC1 do pH okoli 7. Produkt telmisartan filtriramo, speremo in posušimo.Mixture of 1.0 g (2.0 mmol) 4 '- ((1,7'-dimethyl-2'-propyl-1H, 3'H-2,5'-bibenzo [d] imidazol-3'yl) methyl ) of biphenyl-2-carbonitrile, 5 ml of isopropanol, 5 ml of water and 1.03 g (18.4 mmol) of KOH was heated to 120 ° C for approximately 48 hours. The solution was then cooled to room temperature and 10 ml of water were added. The mixture was neutralized by adding 3M HCl to a pH of about 7. The telmisartan product was filtered, washed and dried.
Dobljeni telmisartan pretvorimo v njegove soli z dodatkom ustrezne kisline ali baze in z izolacijo.The resulting telmisartan is converted into its salts by the addition of a suitable acid or base and by isolation.
Primer 16Example 16
Farmacevtske formulacije, ki vključujejo telmisartan ali njegove soli, pripravljen s postopki po predloženem izumuPharmaceutical formulations comprising telmisartan or its salts prepared by the methods of the present invention
Zgoraj omenjene sestavke, ki vsebujejo telmisartan, lahko pripravimo z različnimi postopki. Dva izmed primernih postopkov sta sušenje z razprševanjem in granuliranje v zvrtinčenem sloju. V kolikor telmisartan pripravimo s postopkom sušenja z razprševanjem, telmisartan raztopimo skupaj z bazičnim sredstvom in po izbiri s sredstvom za upočasnitev kristalizacije v ustreznem topilu (vodi ali organskem topilu) in posušimo z razprševanjem. Granulat, posušen z razprševanjem, nadalje zmešamo z drugimi ekscipienti, da tvorimo končni sestavek, pripravljen za tabletiranje. V primeru granulacije v zvrtinčenem sloju, telmisartan raztopimo skupaj z bazičnim sredstvom in po izbiri s sredstvom za upočasnitev kristalizacije, v ustreznem topilu (vodi ali organskem topilu), da tvorimo granulacijsko tekočino. Ostale ekscipiente damo v stroj za granuliranje v zvrtinčenem sloju in napršimo z granulacijsko tekočino. Ko je granuliranje končano, granulat posušimo in po izbiri zmešamo z dodatnimi ekscipienti, kot s sredstvom za nadzorovanje tekočnosti in/ali mazivom, da tvorimo končni sestavek pripravljen za tabletiranje.The above-mentioned compositions containing telmisartan can be prepared by various procedures. Two of the suitable methods are spray drying and whirling granulation. If telmisartan is prepared by spray drying, telmisartan is dissolved together with a basic agent and optionally a crystallization retarder in a suitable solvent (water or organic solvent) and spray dried. The spray dried granulate is further mixed with other excipients to form the final composition ready for tableting. In the case of granulation in the vortex layer, telmisartan is dissolved together with the basic agent and optionally with the crystallization retardant, in a suitable solvent (water or organic solvent) to form a granulation fluid. The other excipients are placed in a pelletizing machine in a fluidized bed and sprayed with the granulation fluid. When the granulation is complete, the granulate is dried and optionally mixed with additional excipients, such as a liquid control agent and / or lubricant, to form the final composition ready for tabletting.
Claims (15)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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SI200700161A SI22585A (en) | 2007-07-03 | 2007-07-03 | Procedure for preparation of telmisartan |
CN200880022887.7A CN101743228B (en) | 2007-07-03 | 2008-07-03 | Process for preparing telmisartan |
PCT/EP2008/058616 WO2009004064A1 (en) | 2007-07-03 | 2008-07-03 | Process for preparing telmisartan |
EA200901619A EA200901619A1 (en) | 2007-07-03 | 2008-07-03 | METHOD OF OBTAINING TELMISARTANA |
EP20080774728 EP2170835A1 (en) | 2007-07-03 | 2008-07-03 | Process for preparing telmisartan |
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SI200700161A SI22585A (en) | 2007-07-03 | 2007-07-03 | Procedure for preparation of telmisartan |
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SI200700161A SI22585A (en) | 2007-07-03 | 2007-07-03 | Procedure for preparation of telmisartan |
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