MX2008001565A - Method for isolating 5-substituted tetrazoles - Google Patents

Abstract

The invention relates to a method for isolating 5-substituted tetrazoles of general formula (I) in which R represents a substituted biphenyl radical during which the ring closure, starting from a corresponding nitrile, is carried out in organic solvents while using alkali, alkaline-earth or organotin azides. The organic phases containing the nitrile and the tetrazol are firstly mixed with water while firstly forming three liquid phases, after which the aqueous phase containing the azide and the phase containing the nitrile are separated out, and the middle organic phase containing the tetrazol is subsequently processed. In the case of ester groups to be saponified, this phase is mixed with alkali lye, after which the organic phase is separated out and the aqueous phase is acidified or otherwise, this phase is immediately acidified and purified.

Description

METHOD FOR ISOLATING TETRAZOLES 5-SUBSTITUTE Field of the Invention The invention relates to a method for isolating 5-substituted tetrazoles of the general formula I: I in which R represents a substituted biphenyl radical, during which the ring closure is carried out, starting from a corresponding nitrile, while they are used in organic solvents, alkali metal or alkaline earth metal or organotin azides.

Background of the Invention 5-substituted tetrazoles can be produced by the reaction of cyano compounds or nitriles with azides and in turn, in addition to HN3, with alkali metal or alkaline earth metal or organotin azides, such as trialkyl or triaryltin azides. Here, in conjunction with the production of sartans, EP 443983 A1 shows that reaction with sodium or potassium azide and triethyl, tributyltin or triphenyltin azides is preferred. In particular, the 5-substituted tetrazoles whose substituents represent a biphenyl radical substituted for pharmaceutical products, where, above all, the group of sartans, such as valsartan, losartan, irbesartan, olmesartan, and candesartan, is noteworthy. These 5-substituted tetrazoles are characterized in that in the course of the reaction starting from nitriles or cyanides to tetrazole rings, different substituents are present that act in a hydrophilic or lipophilic manner, where, in the case of valsartan and candesartan, it is required typically a conclusive hydrolysis step, for the production of the desired end product, before the desired product can be obtained as a pure substance or salt. In EP 796852 a particularly detailed description of the preferred reactions can be found. In particular, when organotin compounds are used, it must be taken into consideration that they are highly toxic substances, whose quantitative separation is an essential prerequisite for the applicability of the product obtained. The treatment with azides in organic solvents requires several safety precautions; in particular, the conclusive step of acidification followed by hydrolysis can lead to the formation of highly explosive amounts of hydrazoic acid, where there is also a great risk of explosion in addition to high toxicity.

Description of the Invention The objective of the invention under consideration is to design this conclusive step essential in the synthesis of 5-substituted tetrazoles, mentioned above, in a way that provides greater security and guarantees quantitative separation of the starting product and reagents in the conclusive step of purification and in particular, before acidification. To achieve this objective, the method according to the invention consists essentially of first mixing the organic phases containing the nitrile and the tetrazole with water, forming three liquid phases, after which the aqueous phase containing the azide and the upper phase containing the nitrile are separated, and the intermediate organic phase containing the tetrazole is subsequently treated. In the case of the ester groups to be saponified, this phase is mixed with alkaline liquor, after which the organic phase is separated and the aqueous phase is acidified, or otherwise, this phase is acidified immediately and it is purified. If the 5-substituted tetrazoles meet certain conditions with respect to the hydrophilic and lipophilic substituents, and in particular, if the substituted biphenyl radicals are 5-substituted tetrazoles, immediate hydrolysis is not necessary, for example, after the reaction of the azide with the nitrile in the presence of amine salts, such as triethylamine hydrochloride, but rather water is first added to form three liquid phases. While the reaction also initially takes place in three phases constituting a solid-liquid-liquid system, it is also possible to dissolve the solid phase after the end of the reaction by the addition of water. It has been shown surprisingly that one of the two liquid phases present already expands clearly. In principle, the organic liquid phases consist of the solvent, in particular an aromatic solvent, especially toluene, xylene, or mesitylene; this solvent, of course, contains the non-reactive starting product, specifically, the corresponding nitrile, and the impurities, if soluble in this solvent. The water-soluble components of the reaction mixture, and in particular, the originally solid phase, are found in the aqueous phase, which now contains unreacted sodium azide and triethylamine hydrochloride, by way of example. An intermediate phase expandable with the organic solvent containing the desired product, specifically, the 5-substituted tetrazole in a high concentration, is then formed between these two phases. This step, which is in the subsequent stage of the subsequent purification, or if necessary, the hydrolysis step, in which the mixture is mixed with water, thus allows the realization of a high degree of preliminary purification in a particularly simple; in particular, the unreacted azides can be discharged with the aqueous phase. In a single step, therefore, the highly concentrated 5-substituted tetrazole can be released from the unreacted intermediate / product and some impurities present in small amounts, where the separation of the salts is essential, not least due in the case from a non-separation during acidification, large amounts of hydrazoic acid are released and in this way, in addition to the high toxicity, there will also be a high risk of explosion. As proposed in accordance with this invention, the intermediate organic phase can be subsequently mixed with alkali liquor, so that, depending on the type of substituents, saponification or hydrolysis can be carried out in the case where the compound present in the intermediate organic phase it is not the final product. As already mentioned above, the 5-substituted tetrazoles are preferably compounds of the general formula I, in which R represents a substituted biphenyl radical. According to the invention, the specifically defined compounds valsartan, losartan, irbesartan, candesartan, and olmesartan are particularly preferred. In the case of valsartan, the nitrile is methyl ester of N-valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valin, which of course must be saponified subsequently to obtain the final product, specifically, (S) -N- (l-carboxy-2-methylprop-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl ] amine. In the case of valsartan, it should be noted that in the reaction of the methyl ester of N-valeryl-N- [2'-cyanobiphenyl-4-yl) methyl] - (L) -valin with alkaline azides, the metal salt is formed alkaline of (S) -N- (l-methoxycarboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] amine, which , due to its special characteristics (lipophilic substituents with the simultaneous presence of an ionic group), it does not dissolve either in water or in toluene, if not rather it is deposited at the interface in a highly concentrated form and as a third phase. In a subsequent reaction to achieve the final purified product, the intermediate organic phase containing the highly concentrated and still esterified product is subjected to hydrolysis or saponification with aqueous or ethanolic potassium hydroxide or sodium hydroxide, after which a organic and aqueous phase. The lower phase, which is aqueous for most, is subsequently treated and then contains the saponified or hydrolyzed product, while discarding the upper phase containing selected solvent, for example, toluene, xylene or mesitylene.

In the additional treatment, the separated aqueous phase is preferably mixed and subsequently acidified with an organic solvent, preferably an alkyl ester of lower acetic acid such as methyl acetate, ethyl acetate, or butyl acetate . Here, it is essential that this aqueous phase does not include any azide, after which, as long as it is heated, branched or cyclic hydrocarbons and / or ethers are added, in particular methylcyclohexane and / or diisopropyl ether. A quantitative ratio 1-2 of the acetic acid ester to the subsequently added cyclic branched hydrocarbon or diisopropyl ether has proven to be good here. Subsequently, the organic phase is further treated, and the water is completely separated by means of a water separator. The complete separation of water is a prerequisite to obtain a filterable, partially crystalline product in the following crystallization process. Even small amounts of water will lead to a two-phase system, in which the product separates as a second liquid phase and can not be filtered. After cooling in crystallization of the product, the product can be separated by filtration in a simple manner, and dried. The invention is explained in more detail below with the help of examples.

Example 1: Valsartan production Reaction scheme MW = 358 87 MW = 406 53 MW = 449 56 MW = 435 53 C20H22N2O2 C25H30N2O3 C25H31 N503 C24H29N503 N-methyl esters of N- (S) -N- (l-methox? Carbox? -2- (S) -N- (l-carboxy? -2- [(2'-c? Anob? Fem) -4- valenl-N- (2'-met? Lprop-1-? L) -N-met? Lprop-1-? L) -N-yl l methyl] - () -valina c? Anob? Fen? l-4-pentane? lN-2 '- (1H-pentane? lN-2' - (1H-ylmethyl] - () -valine te razol-5-? l) bifeml-y-tetrazole-5? l) b? phen? l-4-methylmethyl amine methyl] amine A + = Cation (NA + or Net3H +) First, K2C03 (110 g) is dissolved in water (250 mL), then toluene (800 mL) is added and N- [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine methyl ester (100 g), followed by vigorous stirring at room temperature until all solids have dissolved (approximately 30 minutes). Valeroyl chloride (44 mL) is added dropwise at T <20 ° C. Subsequently, stirring is carried out for 1.5-2.0 h at 20-25 ° C. The precipitating salts are filtered off. The reaction The aqueous phase is separated, the organic phase is washed with a mixture of 100 mL of brine and 100 mL of water; the washing phase is separated and discarded.

Sodium azide (54 g) and triethylamine hydrochloride (115 g, each 3.0 Eq) are added; Subsequently, stirring is carried out for 20-24 h, at 90 ± 3 ° C. Prior to the subsequent addition of water, a three-phase system (solid-liquid-liquid) is presented. The two liquid phases correspond to the upper and intermediate phases with the subsequent addition of water, which apparently increases the volume of the intermediate phase. Water (250 mL) is added followed by vigorous stirring, until all the solids have dissolved. 3 phases The lower phase is discarded; the two upper phases are washed with 200 mL of water; and the washing phase and the upper phase are discarded; and the intermediate phase is used for additional treatment. The uppermost phase (toluene) contains N- [(2'-cyanobiphenyl-4-yl) methyl] - (L) - unreacted valine methyl ester and N-valeryl-N- [(2'-cyanobiphenyl) methyl ester -4-yl) methyl] - (L) -valine and impurities; It has a light appearance; and it is light brownish-yellow; The intermediate phase (toluene and a small amount of water) contains highly concentrated solution of (S) -N- (l-methoxycarboxy-2-methylprop-l-yl) -N-pentanoyl-N- [2 '- (1H- tetrazol-5-yl) biphenyl-4-ylmethyl] amine and is of brown appearance. The lower (aqueous) phase contains salts (unreacted sodium azide and treithieramine hydrochloride) and is light brown-yellow in appearance. Through this three-phase system, it is possible in one step to liberate (S) -N- (l-methoxycarboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl- 4- ilmethyl] amine, both of salts as well as of the unreacted intermediate / product and some impurities present in small amounts. The separation of the salts is essential, because in the case of a non-separation during the final acidification, large quantities of hydrazoic acid (HN3) will be released (high toxicity and risk of explosion). The addition of 14% potassium hydroxide (2.5 N) (400 mL) to the isolated intermediate phase is carried out, after which stirring is carried out for 3.0 h at 40 ± 3 ° C 2 phases are formed. A lower phase, which is aqueous for the most part, is ((S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5 -yl) biphenyl-4-ylmethyl] amine) with a small volume of an upper phase of toluene. The upper phase is separated and discarded. 5 g of activated carbon and 5 g of celite are added to the lower phase and the stirring is carried out for 1 hour at 40-50 ° C, after which the filtration is carried out. Then, 720 mL of ethyl acetate are added and acidification is carried out at pH 2.0 ± 0.5 with 6N HCL. The lower aqueous phase is separated, the upper organic phase is washed with 200 mL of water, and the aqueous phases are discarded. Subsequently, the heating is carried out at 50 ° C and 480 mL of methylcyclohexane are added dropwise. The water is completely separated with a water separator. Complete separation of water is essential (the prerequisite for crystallization in the next step). The presence of even small amounts of water leads to a two-phase system, where the product can be separated as a second liquid phase and can not be filtered. Cooling is carried out slowly at 5 ± 5 ° C, followed by stirring for 1 hour, filtration and washing with ethyl acetate-methylcyclohexane 3/2, after which the drying is carried out at 40 ° C in a vacuum. Performance: approximately 65% with respect to all stages. In general, for the Sartans mentioned in the following, it is accepted that liquid systems of three phases can be expected in the treatment. In the case of candesartan, a methyl ester group is present, just as with valsartan, which is divided to free acid by hydrolysis.

What is valid in principle is that if a carboxylic acid ester is converted to a free acid, one can correctly speak of a synthesis, whereas in other cases where this division of ester is not required in the last step, One can refer only to a purification, strictly speaking. The conclusive step of the hydrolysis with subsequent acidification is, however, in any case carried out as a purification step as well, so that the nomenclature selected from pure preparation makes no difference here between purification and synthesis. In another exemplary embodiment of the pure propagation of valsartan by hydrolysis by aqueous KOH, it was possible to increase the yield, during the last step, to about 75% of the theoretical yield.

Example 2: Synthesis of valsartan (hydrolysis by means of aqueous KOH) Steps 2b and 2c in the above reaction scheme. N-Valeryl-N - [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valin methyl ester (110 g, 270 mmol) is reacted in an aromatic hydrocarbon, preferably toluene, xylolene or mesitylene (typically 500-1000 mL), with alkali metal azides and other reagent (ammonium halide derivatives, typically, triethylamine hydrochloride, or organotin halides, typically, trimethyltin chloride or tributyltin chloride), while heated, to form (S) -N- (l-methoxycarboxy-2-methylprop-l-yl) -N-pentanoyl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] amine . The initial two-phase solid-liquid system is converted, as the reaction progresses, into a three-phase system (solid-liquid-liquid). After the end of the reaction, the reaction solution is stirred with water or a saline solution (250 mL), after which the solids are dissolved and a three-phase liquid system is formed. The lower phase separates; the two upper phases are washed with water or a saline solution (200 mL). The intermediate phase is isolated and vigorously stirred with aqueous potassium hydroxide (2.5N, 400 mL) for 3 hours at 40 ° C. A two-phase system is formed with an aqueous lower phase containing the product and an organic upper phase. The aqueous phase is isolated, stir with 5 g of activated carbon and 5 g of celite for 1 hour at 40 ° C, and then filter. Ethyl acetate (720 mL) is added to the filtrate and acidification is carried out with hydrochloric acid (5-6N) at pH 2.0, with vigorous stirring and cooling with ice. The organic phase is washed with 300 mL of water and after separation of the washing phase, an aliphatic hydrocarbon or a mixture of aliphatic hydrocarbons (480 mL), preferably methylcyclohexane or isooctane, is added dropwise. The residual water present in the system is separated by means of a water separator. Cooling is carried out slowly at 5 ° C, at which point the crystallization begins. The solids are filtered, washed with a mixture of ethyl acetate and hydrocarbon and dried at 40 ° C in a vacuum. Performance with respect to both stages: approximately 75% of the theoretical.

Example 3: Candesartan synthesis (hydrolysis by ethanolic KOH) MW = 411 46 MW = 45449 MW = 44047 C25H21N303 C25H22N603 C24H20N6O3 Compound I, l- (2'-c? Anob? Phen? L-4-? L) methyl) -2-ethoxy? Benz? M? Dazole-7-carboxylic acid methyl ester (111 g, 270 mmol) is reacted in an aromatic hydrocarbon, preferably toluene, xylolene or mesitylene (typically, 500-1000 mL), with alkali metal azides and another reagent (ammonium halide derivatives, typically, triethylamine hydrochloride or organotin, typically, tetramethyltin chloride or tetrabutyltin chloride), while heating, to form compound II, 2-ethoxy-1 - ((2'- (1H-tetrazol-5-yl) biphenyl) methyl ester -4-yl) methyl) benzimidazole-7-carboxylic acid. After the end of the reaction, the reaction solution is stirred with water or a saline solution (250 mL), after which the solids are dissolved and a three-phase liquid system is formed. If only two phases are present, petroleum alcohol 80/110 is added until there are three phases that can be separated well. The lower phase separates; the two upper phases are washed with water or a saline solution (200 mL). The intermediate phase is isolated and stirred with potassium hydroxide in ethanol (2.5 N, 400 mL) for 2 hours at 40 ° C. Water (400 mL) is added, and 500 mL of liquid is distilled under reduced pressure. With the addition of 5 g of activated carbon and 5 g of celite, stirring is carried out for 1 hour at 40 ° C, followed by filtration. Ethyl acetate (720 mL) is added to the filtrate and acidification is carried out with hydrochloric acid (5-6N) to pH 2.0, while stirring vigorously and cooling with ice. The organic phase is washed with 300 mL of water, and after the separation of the washing phase, an aliphatic hydrocarbon or a mixture of aliphatic hydrocarbons (480 mL), preferably methylcyclohexane or petroleum alcohol, is added dropwise. 80/110. The residual water present in the system is separated by means of a water separator. Cooling is done slowly at 5 ° C, at which point the crystallization begins. The solids are completely filtered, washed with a mixture of ethyl acetate and hydrocarbon, and dried at 40 ° C in a vacuum. Performance with respect to the two stages: approximately 70% of the theoretical Example 4: Synthesis of valsartan (hydrolysis by means of tetraalkylammonium hydroxide bases) Steps 2b and 2c in the above reaction scheme. N-Valeryl-N - [(2'-cyclobiphenyl-4-yl) methyl] - (L) -valine methyl ester (110 g, 270 mol) is reacted in an aromatic hydrocarbon, preferably toluene, xylolene or mesitylene (typically, 500-1000 mL), with alkali metal azides, and other reagents (ammonium halide derivatives, typically, triethylamine hydrochloride or organotin halides, typically, trimethyltin chloride or tributyltin chloride), while warm, to form (S) -N- (l-methoxycarboxy-2-methylprop-l-yl) -N-pentanoyl-N-2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl) amine . The initial two-phase solid-liquid system is converted, as the reaction progresses, into a three-phase system (solid-liquid-liquid). After the end of the reaction, the reaction solution is stirred with water or a saline solution (250 ml), after which the solids dissolve and a three-phase liquid system is formed. The lower phase separates; the two upper phases are washed with water or a saline solution (200 mL). The intermediate phase is isolated and stirred with 40% tetrabutylammonium hydroxide in methanol (260 mL, 400 mmol) for 3 hours at 40 ° C. Water (400 mL) is added, and 400 mL of liquid is distilled first under normal pressure. , and towards the end, under reduced pressure. With the addition of 5 g of activated carbon and 5 g of celite, stirring is carried out for 1 hour at 40 ° C followed by filtration. Ethyl acetate (720 mL) is added to the filtrate, followed by acidification with hydrochloric acid (5-6N) to PH 2.0, while stirring vigorously and cooling with ice. The organic phase is washed twice with 300 ml of water and after the separation of the washing phase at about 50 ° C, aliphatic hydrocarbon or a mixture of predominantly aliphatic hydrocarbons (480 ml) is added dropwise, preferably , methylcyclohexane or petroleum alcohol 80/110. The residual water present in the system is separated by means of a water separator. Cooling is carried out slowly at 5 ° C, at which point the crystallization begins. The solids are filtered, washed with a mixture of ethyl acetate and hydrocarbon and dried at 40 ° C in a vacuum. Performance with respect to the two stages, each according to the synthesis protocol of II: 70% of the theoretical.

Example 5: Synthesis of (S) -N- (l-carboxy-2-methylprop-1-yl) -N- [2 '(lH-tetrazol-5-yl) biphenyl-4-ylmethyl] amine hydrochloride (co Methyl ester of N- [2'-cyanobiphenyl-4-yl) methyl- (L) -valine N- [(2'-cyanobiphenyl-4-yl) methyl] - (L) -valine methyl ester is reacted 96.9 g, 270 mmol) in an aromatic hydrocarbon, preferably toluene, xylolene or mesitylene (typically, 500-1000 mL), with alkali metal azides and other reagents (ammonium halide derivatives, typically, triethylamine hydrochloride, or organotin halides, typically, trimethyltin chloride or tributyltin chloride), while heated, to form (S) -N- (1-methoxycarboxy-2-methylprop-1-yl) -N-pentanoyl-N- [ 2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] amine. The initial two-phase solid-liquid system is converted, as the reaction progresses, into a three-phase system (solid-liquid-liquid). After the end of the reaction, add water (200 mL). The solids dissolve in this way. Subsequently, the pH is adjusted to 6-7, after which a three-phase liquid system is formed. The lower phase separates; the two upper phases are washed with water (200 mL). The intermediate phase is isolated, mixed with ethyl acetate (500 mL), washed with water (200 mL), dried over sodium sulfate and filtered. The solvent evaporates in a rotoevaporator; The product is dried at 60 ° C in a vacuum. Performance, 58-60%.

Claims (8)

1. CLAIMS 1. Method for isolating 5-substituted tetrazoles of general formula I:
2. I in which R represents a substituted biphenyl radical, during which ring closure is carried out, starting from a corresponding nitrile, in organic solvents while using alkali metal or alkaline earth metal azides or organotin azides, characterized in that the organic phases containing the nitrile and the tetrazole are first mixed with water while three liquid phases are formed, after which the aqueous phase containing the azide and the nitrile-containing phase are separated, and the intermediate organic phase containing tetrazole is subsequently processed, wherein in the case of ester groups to be saponified, this phase is mixed with alkaline liquor, after which the organic phase is separated and the aqueous phase acidified, or otherwise Thus, this phase is acidified and purified immediately. Method according to claim 1, characterized in that the compound of the general formula I is valsartan
3. 3. Method according to claim 1, characterized in that the compound of the general formula I is losartano
4. 4. Method according to claim 1, characterized in that the compound of the general formula I is irbesartan
5. 5. Method according to claim 1, characterized in that the compound of the general formula I is candesartan
6. 6. Method according to claim 1, characterized in that the compound of the general formula I is olmesartan
7. 7. Method according to one of claims 1 to 6, characterized in that the reaction of the nitrile of the general formula R-CDN with a metal azide of the general formula M (N3) n, wherein M is an alkaline or alkaline earth metal, and n is 1 or 2, in the presence of an amine salt in an aromatic solvent, in particular, toluene, xylene or mesitylene, and the hydrolysis or saponification is carried out with aqueous or ethanolic KOH or NaOH, after which forms an organic and aqueous phase. Method according to one of claims 1 to 7, characterized in that the aqueous phase mixed with acid is extracted with ethyl acetate and the organic phase is mixed with a cyclic branched hydrocarbon and / or ether, in particular methylcyclohexane and / or diisopropyl ether, and the water is separated, after which during cooling, the crystallized product is isolated by filtration and dried.