Field of the invention

The invention relates to novel processes, novel process steps and novel intermediates useful in the synthesis of valsartan.

Background of the invention

The present invention relates to processes for the preparation of valsartan. Valsartan, i.e. (S)-/V-(1 -carboxy-2-methylprop-1 -yl)-/V-pentanoyl-/V-[2'-(1 H-tetrazol-5-yl)- biphenyl-4- ylmethyl]amine, is an angiotensin II receptor antagonists used e.g. for the treatment of hypertension and that has the following structure:

Valsartan and its synthesis are described in EP-A-0443983 and US 5399578, in particular Examples 16, 37 and 54 thereof.

One of the key structural elements of valsartan is its tetrazole moiety. Various methods of preparing tetrazoles are described in the literature. For example, it is known in the art that tetrazole derivatives can be prepared by reacting a cyano group with an azide reagent, that is a process which involves a [3+2] cycloaddition reaction leading to the formation of 5-substituted tetrazoles. For example, EP 0536400 describes the preparation of a tetrazole compound by reacting a cyano group with hydrazoic acid or a salt thereof, such as metal salts, for example, alkali or earth alkali metal salts, (eg. sodium azide, potassium azide, calcium azide, magnesium azide, aluminium azide or tin azide) and salts with organic bases (eg. tetramethylguanidinium azide). It is also known that tetrazoles can be prepared, for example as described in US 4,874,867, by reacting a cyano group with an organotin azide. Tetrazole forming methods which use organotin azides need special care in production processes because of ecological problems, and require a significant amount of additional process steps to recycle them from the wastewater and remove them from the desired tetrazole product, thereby additionally increasing the production costs. An environmentally friendly alternative to the use of organotin azides is the use trialkylammonium azides or tetraalkylammonium azides, however when using such reagents volatile sublimates may form in the reaction reactors, which have the risk of explosion and are therefore not easy to handle in large scale production.

There is a strong need to develop new tetrazole-forming process variants, that avoid the above-mentioned disadvantages. Organoboron azides and organoaluminium azides have been shown to offer an attractive alternative to organotin azides in

[2+3]cycloadditions with nitrites to form tetrazoles. Said boron and aluminium

compounds, in particular said aluminium compounds, are available in considerably large scales and are inexpensive. In particular, as described in WO 2005/014602, these azides are useful in a process for producing valsartan comprising reacting a compound of formula (IV), or an ester thereof,

wherein a preferred ester of a compound of formula (IV) is, for example a benzyl ester thereof, having the formula (lll-a)

(lll-a).

Thus, one embodiment of the tetrazole-forming methodology described in WO

2005/014602 relates to a one-pot process wherein by the use of a single azide reagent two reaction steps take place: the conversion of an ester moiety into an acid moiety and the conversion of a cyano group into a tetrazole. A one-pot process involves the happening of two or more reaction steps without isolation of the intermediate species. Therefore, they are industrially advantageous synthetic methods because they reduce work-up steps, thus reducing the quantity of solvents required and the time and labor required between consecutive manufacture process steps.

In the above-mentioned one-pot process, it is observed that the conversion of the ester moiety into the acid moiety leads to acyl-azide by-products, which in turn may form isocyanate and/or carbamate by-products. The conversion of an alkyl ester moiety into an acyl-azide in the presence of an organoaluminiumazide reagent is also known to the skilled person from literature references such as Tetrahedron Letters, 1994, 35, 4947. The formation of acyl-azide by-products is undesirable because they are formed at the expense of a decrease yield of the desired product. Thus, the object of the present invention is to provide an alternative process for preparing valsartan that has many of the advantages of the process described in WO 2005/014602 but that avoids the formation of said by-products.

It is found that the present invention meets the objective and thus provides a method to convert an ester of a compound of formula (IV), preferably an ester as described below, into valsartan. Accordingly, the process according to the present invention shows one or more of the following advantages: (1 ) it does not require a process step wherein an organotin azide is used and therefore it is environmentally friendly; (2) it does not require a process step wherein an expensive transition metal catalyst, such as Pd/C, is used for the deprotection of an ester, such as a benzyl ester; (3) it is economically attractive; (4) it may be carried out on a large scale; (5) it may be optionally carried out in a one-pot fashion thus reducing the time and labor required for procedures such as isolation of intermediate products and solvent replacement; (6) it affords enantiomerically pure target products; and (7) it avoids the formation of the above-mentioned side products. Thus, the preparation methods of the present invention are advantageous for the industrial preparation of valsartan.

Summary of the Invention

During an investigation into one-pot processes to prepare valsartan, a novel method for converting the ester group of a compound of formula (III), as defined herein, into the free acid of formula (IV), as described above, was found. Namely, in one aspect, the present invention relates to the conversion of an ester group, such as a benzyl ester, into a free acid by the use of an organoaluminium halide reagent. The use of an organoaluminium halide reagent to effect such a chemical reaction provides many advantages, as explained hereinafter. Typically a benzyl ester is converted into a free acid under hydrogenation conditions (i.e. with hydrogen in the presence of a transition metal catalyst, such a palladium catalyst). By using an organoaluminium halide reagent, the use of flammable hydrogen is avoided, no pressurized reactors are necessary and expensive transition metal catalysts are not needed. Moreover, the use of an

organoaluminium halide reagent is advantageous both in terms of toxicity and costs. In Tetrahedron Letters, 1979, 2793, it is reported that the inorganic compound AICI ₃ can effect the removal of a benzyl ester group to yield the free acid. Therefore, the finding that an organoaluminium halide can effect the conversion of an ester group into a free acid is new and, moreover, fully surprising. In addition, the use of an organoaluminium halide reagent provides means to prepare in-situ an organoaluminium azide reagent, and thus allows the subsequent conversion of a cyano group into a tetrazole group, without having to isolate the free acid intermediate. Therefore, in a further embodiment, the present invention also allows the preparation of valsartan via a one-pot process, wherein the use of an organoaluminium halide reagent effects the conversion of an ester group into an acid group and the use of an azide reagent, such as an organoaluminium azide reagent, preferably prepared in-situ from the organoaluminium halide reagent, effects the conversion of a cyano group into a tetrazole group.

Detailed Description of the Invention

Process for preparing compounds of formula (III), (IV) and (V), as defined herein below, have been described in the literature. For example, the preparation of a compound of formula (IV) has been described in the Chinese Journal of Pharmaceuticals 2001 , 32(9), 385 and in EP1533305A1 . By using standard methods, known to the person skilled in the art, for example as described in Richard C. Larock, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", Second Edition, Wiley- VCH Verlag GmbH, 2000, the compound of formula (III) can be converted into a compound of formula (IV) via an esterification reaction. In particular, the preparation of a compound of formula (IV), wherein R is benzyl, has been described in Organic Process Research & Development 2007 , 1 1 , 892.

A. Use of an organoaluminium halide reagent to convert an ester group into a free acid

In one aspect, the present invention relates to the use of an organoaluminium halide of formula R5R6AIX or R5AIX ₂ wherein R5 and R6 are, independently from one another, d- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci- ₇ alkyl, and X is halogen

to convert an ester group into a free acid.

In particular, the present invention relates to the use of an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C _6- i ₀ aryl, preferably C _1-7 alkyl, and X is halogen

to convert an ester group into a free acid,

in particular, in a process for the manufacture

- of valsartan, or salt thereof; or

- of a compound of formula (IV), or salt thereof,

B. Conversion of an ester group into a free acid with an organoaluminium halide reagent

B. 1 : Conversion of an ester group into a free acid in a cyano-containing compound

In another aspect, the invention relates to a process for the manufacture of a compound of formula (IV) or salt thereof, such as an amine salt thereof,

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; and R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy;

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C _6- i ₀ aryl, preferably C _1-7 alkyl, and X is halogen,

to obtain the compound of formula (IV).

In a preferred embodiment of the above process, the term R for the compound of formula (III) is

wherein R1 is hydrogen, Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci_ ₇ alkoxy, Ci. ₇ alkyl-Ci_ ₇ alkoxy, halo-Ci. ₇ alkyl-Ci_ ₇ alkoxy.

In particular, a process for the manufacture of a compound of formula (IV) or salt thereof,

such as an amine salt thereof,

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen,

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂ wherein R5 and R6 are, independently from one another, d- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci- ₇ alkyl, and X is halogen,

to obtain the compound of formula (IV).

In a preferred embodiment of the above process, the term R for the compound of formula (III) is

wherein R1 is hydrogen, C _1-7 alkyl, Ci. ₇ alkoxy, C ₃ . ₈ cycloalkyl or C _6- i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen,

Preferably, a process for the manufacture of a compound of formula (IV) or salt thereof,

such as an amine salt thereof,

comprising

reacting a compound of formula (III), or salt thereof,

I) wherein R is

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, Ci. ₇ alkoxy, C ₃ . ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen or Ci_ ₇ alkoxy, most preferably hydrogen,

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci_ ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci- ₇ alkyl, and X is halogen,

to obtain the compound of formula (IV).

Preferably, the group R, for any of the processes above detailed (i.e. section B. 1 ), is benzyl, p-methoxybenzyl, allyl, cinnamyl, prenyl or propargyl, more preferably benzyl, allyl, cinnamyl, prenyl or propargyl, most preferably, benzyl.

In any of the processes above detailed (i.e. section B. 1 ), preferably, the

organoaluminium halide is of formula R5R6AIX, wherein R5, R6 and X are as defined above, and is for example diethylaluminium chloride or dimethylaluminium chloride, most preferably diethylaluminium chloride.

The molar ratio of an organoaluminium halide, as described herein, to a compound of formula (III), as described herein, is for example 6:1 , such as 5:1 , preferably 4:1 or 3:1 .

In any of the processes above detailed, the reaction temperature is preferably in the temperature range of from room temperature to the boiling point of the solvent, for example, a reaction temperature range is of from 20 °C to M0 °C, preferably, of from 60 ^< O to 130°C.

B. 2: Conversion of an ester group into a free acid in a tetrazole-containing compound: synthesis of valsartan

In a further aspect, the invention relates to a process for the manufacture of a compound of formula (I), or salt thereof,

comprising

reacting a compound of formula (V), or salt thereof,

wherein R is C _1-7 alkyl,

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy;

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C _6- i ₀ aryl, preferably C _1-7 alkyl, and X is halogen,

to obtain the compound of formula (I).

In a preferred embodiment of the above process, the term R for the compound of formula (V) is wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci_ ₇ alkyl, Ci_ ₇ alkoxy, C ₃ . ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- d. ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy.

In particular, a process for the manufacture of a compound of formula (I) or salt thereof,

comprising

reacting a compound of formula (V), or salt thereof,

wherein R is C _1-7 alkyl,

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro,

Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen,

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci- ₇ alkyl, and X is halogen,

to obtain the compound of formula (I).

In a preferred embodiment of the above process, the term R for the compound of formula (V) is

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen,

Preferably, a process for the manufacture of a compound of formula (I) or salt thereof,

comprising

reacting a compound of formula (V), or salt thereof,

wherein R is

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen or Ci- ₇ alkoxy, most preferably hydrogen,

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci_ ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci_ ₇ alkyl, and X is halogen,

to obtain the compound of formula (IV).

Preferably, the group R, for any of the processes above detailed (i.e. section B. 2), is benzyl, p-methoxybenzyl, allyl, cinnamyl, prenyl or propargyl, more preferably benzyl, allyl, cinnamyl, prenyl or propargyl, most preferably, benzyl.

In any of the processes above detailed (i.e. section B. 2), preferably, the

organoaluminium halide is of formula R5R6AIX, wherein R5, R6 and X are as defined above, and is for example diethylaluminium chloride or dimethylaluminium chloride, most preferably diethylaluminium chloride.

The molar ratio of an organoaluminium halide, as described herein, to a compound of formula (V), as described herein, is for example 6:1 , such as 5:1 , preferably 4:1 or 3:1 .

In any of the processes above detailed, the reaction temperature is preferably in the temperature range of from room temperature to the boiling point of the solvent, for example, a reaction temperature range is of from 20 °C to 170 °C, preferably, of from 60 ^< O to 130°C.

C. Synthesis of valsatan via conversion of an ester group into a free acid with an organoaluminium halide reagent followed by conversion of a cyano group into a tetrazole.

C.1 : Step-wise synthesis of valsartan Another aspect of the present invention relates to a process for the manufacture of valsartan, wherein the conversion of an ester group into a free acid and the conversion of a cyano group into a tetrazole take place step-wise, i.e. in two separate steps with isolation of the intermediate species.

In another aspect, the invention relates to a step-wise process for the manufacture of a compound of formula (I), or salt thereof,

comprising the steps of

i) reacting a compound of formula (III), or salt thereof,

wherein R is d- ₇ alkyl, wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci_ ₇ alkyl, Ci_ ₇ alkoxy, C ₃ . ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- d. ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci- ₇ alkyl, and X is halogen,

to obtain the compound of formula (IV), or salt thereof,

such as an amine salt thereof,

ii) treating the compound of formula (IV), or salt thereof,

such as an amine salt thereof, with an azide reagent to provide compound of formula (I).

In a preferred embodiment of the above process, the term R for the compound of formula (III) is

wherein R1 is hydrogen, C _1-7 alkyl, Ci. ₇ alkoxy, C ₃ . ₈ cycloalkyl or C _6- i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, C _1-7 alkyl, halo- C _1-7 alkyl, Ci _-7 alkoxy-Ci _-7 alkyl, Ci _-7 alkoxy, halo-Ci _-7 alkoxy, Ci_ ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci _-7 alkyl-Ci- ₇ alkoxy; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci _-7 alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci _-7 alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci _-7 alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy.

In another aspect, the invention relates to a process for the manufacture of a compound of formula (I), or salt thereof,

comprising

i) reacting a compound of formula (III), or salt thereof,

wherein R is d- ₇ alkyl,

wherein R1 is hydrogen, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen, with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci_ ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci_ ₇ alkyl, and X is halogen,

to obtain the compound of formula (IV), or salt thereof,

such as an amine salt thereof,

ii) treating the compound of formula (IV), or salt thereof,

such as an amine salt thereof,

with an azide reagent to provide compound of formula (I).

In a preferred embodiment of the above process, the term R for the compound of formula (III) is

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, Ci. ₇ alkoxy, C ₃ . ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen,

In another aspect, the invention relates to a process for the manufacture of a compound of formula (I), or salt thereof,

comprising

i) reacting a compound of formula (III), or salt thereof,

wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen or Ci- ₇ alkoxy, more preferably hydrogen,

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂ wherein R5 and R6 are, independently from one another, d- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci- ₇ alkyl, and X is halogen,

to obtain the compound of formula (IV), or salt thereof,

such as an amine salt thereof,

ii) treating the compound of formula (IV), or salt thereof,

such as an amine salt thereof,

with an azide reagent to provide compound of formula (I).

Preferred azide reagents are, for example, metal salts of hydrazoic azid, such as alkali or earth alkali metal salts, (eg. lithium azide, sodium azide, potassium azide, calcium azide, magnesium azide, aluminium azide), salts of hydrazoic acid with organic bases (eg. tetramethylguanidinium azide), or an azide of formula R7R8MN ₃ wherein M is boron or aluminium, preferably aluminium, R7 and R8 are, independently from one another, Ci_ ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . ₈ cycloalkyl, C ₃ . ₈ cycloalkyl-Ci. ₇ alkyl or C ₆ _i ₀ aryl-Ci_ ₇ alkyl, preferably C _1-7 alkyl. In particular, the azide reagent is of formula R7R8MN ₃ wherein M is aluminium or boron, preferably aluminium, R7 and R8 are, independently from one another, C _1-7 alkyl, C ₃ -C ₈ alkenyl, C ₃ . ₈ cycloalkyl, C ₃ . ₈ cycloalkyl-Ci_ ₇ alkyl or C ₆ -i ₀ aryl-Ci. ₇ alkyl, preferably C _1-7 alkyl. Preferably, the azide reagent is diethylaluminium azide or dimethylaluminium azide, more preferably diethylaluminium azide.

Preferably, the group R, for any of the processes above detailed (i.e. section C. 1 ), is benzyl, p-methoxybenzyl, allyl, cinnamyl, prenyl or propargyl, more preferably benzyl, allyl, cinnamyl, prenyl or propargyl, most preferably, benzyl. In any of the processes above detailed (i.e. section C. 1 ), preferably, the organoaluminium halide is of formula R5R6AIX, wherein R5, R6 and X are as defined above, and is for example diethylaluminium chloride or dimethylaluminium chloride, most preferably diethylaluminium chloride.

The molar ratio of an organoaluminium halide, as described herein, to a compound of formula (III), as described herein, is for example 6:1 , such as 5:1 , preferably 4:1 or 3:1 ..

In any of the processes above detailed, the reaction temperature of step i) is preferably in the temperature range of from room temperature to the boiling point of the solvent, for example, a reaction temperature range is of from 20 °C to 170 ^, preferably, of from 60 ^< O to 130°C.

In any of the processes above detailed, the reaction temperature of step ii) is preferably in the temperature range of from room temperature to the boiling point of the solvent, for example, a reaction temperature range is of from 20 °C to 170 ^, preferably, of from 60 ^< O to 130°C.

C.2: One-pot synthesis of valsartan

A further aspect of the present invention is related to a process for the manufacture of valsartan, wherein the conversion of an ester group into a free acid and the conversion of a cyano group into a tetrazole take place in a one-pot process.

In another aspect, the invention relates to a one-pot process for the manufacture of a compound of formula (I), or salt thereof,

comprising

i) reacting a compound of formula (III), or salt thereof,

wherein R is d- ₇ alkyl,

wherein R1 is hydrogen, C _1-7 alkyl, Ci. ₇ alkoxy, C ₃ . ₈ cycloalkyl or C _6- i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; and R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro,

Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci-

₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci-

₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy;

with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C _6- i ₀ aryl, preferably C _1-7 alkyl, and X is halogen,

to obtain the compound of formula (IV), or salt thereof,

such as an amine salt thereof,

ii) adding to the resulting reaction mixture of step i) an azide reagent

to obtain the compound of formula (I).

In a preferred embodiment of the above process, the term R for the compound of formula (III) is

wherein R1 is hydrogen, Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each

unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, d- ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci- ₇ alkoxy, Ci- ₇ alkyl-Ci- ₇ alkoxy, halo-Ci- ₇ alkyl-Ci- ₇ alkoxy; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, Ci- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, each unsubstituted or substituted by one or more, e.g. up to three, substituents selected from , halo, nitro, Ci_ ₇ alkyl, halo- Ci- ₇ alkyl, Ci- ₇ alkoxy-Ci- ₇ alkyl, Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy, Ci- ₇ alkoxy-Ci- ₇ alkoxy, halo-Ci- ₇ alkoxy-Ci_ ₇ alkoxy, Ci. ₇ alkyl-Ci_ ₇ alkoxy, halo-Ci. ₇ alkyl-Ci_ ₇ alkoxy.

In another aspect, the invention relates to a one-pot process for the manufacture of a compound of formula (I), or salt thereof,

comprising

i) reacting a compound of formula (III), or salt thereof,

wherein R is Ci_ ₇ alkyl, wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen, with an organoaluminium halide of formula R5R6AIX or R5AIX ₂

wherein R5 and R6 are, independently from one another, Ci_ ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ . scycloalkyl or C ₆ -i ₀ aryl, preferably Ci_ ₇ alkyl, and X is halogen,

to obtain the compound of formula (IV), or salt thereof,

such as an amine salt thereof,

ii) adding to the resulting reaction mixture of step i) an azide reagent

to obtain the compound of formula (I).

In a preferred embodiment of the above process, the term R for the compound of formula (III) is wherein R1 is hydrogen, d- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen; and

R2, R3 and R4 are the same or different form each other and are hydrogen, halo, nitro, Ci- ₇ alkyl, d- ₇ alkoxy, C ₃ - ₈ cycloalkyl or C ₆ -i ₀ aryl, preferably hydrogen,

Preferred azide reagents are, for example, metal salts of hydrazoic azid, such as alkali or earth alkali metal salts, (eg. lithium azide, sodium azide, potassium azide, calcium azide, magnesium azide, aluminium azide), salts of hydrazoic acid with organic bases (eg. tetramethylguanidinium azide), or an azide of formula R7R8MN ₃ wherein M is boron or aluminium, preferably aluminium, R7 and R8 are, independently from one another, Ci_ ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ - ₈ cycloalkyl, C ₃ - ₈ cycloalkyl-Ci- ₇ alkyl or C ₆ -i ₀ aryl-Ci- ₇ alkyl, preferably Ci- ₇ alkyl. In particular, the azide reagent is of formula R7R8MN ₃ wherein M is aluminium or boron, preferably aluminium, R7 and R8 are, independently from one another, Ci- ₇ alkyl, C ₃ -C ₈ alkenyl, C ₃ - ₈ cycloalkyl, C ₃ - ₈ cycloalkyl-Ci- ₇ alkyl or C ₆ -i ₀ aryl-Ci- ₇ alkyl, preferably Ci- ₇ alkyl. Preferably, the azide reagent is diethylaluminium azide or dimethylaluminium azide, more preferably diethylaluminium azide.

In a preferred embodiment, the azide reagent is of formula R7R8MN ₃ , wherein M is aluminium, R7 and R8 are as defined above, and is prepared in-situ by adding a metal salt of hydrazoic azid, for example alkali or earth alkali metal salts, (eg. lithium azide, sodium azide, potassium azide, calcium azide, magnesium azide or aluminium azide) to an organoaluminium halide reagent of formula R5R6MX, as defined herein. Preferably, said in-situ preparation takes place by adding the metal salt of hydrazoic acid to the reaction mixture of step i). In this preferred embodiment, the conversion of the organoaluminium halide reagent to the organoaluminiumazide reagent takes place at room temperature and the subsequent tetrazole formation reaction takes place with heating above room temperature, preferably, of from 60 °C to 130°C, such as of from 90 °C to 130°C. In this embodiment, an excess amount, for example an amount between 1 .2 to 2 equivalents or an amount of 2 or more equivalents, of the azide reagent, preferably an amount of 2 or more equivalents may be used.

Preferably, the group R, for any of the processes above detailed (i.e. section C. 2), is benzyl, p-methoxybenzyl, allyl, cinnamyl, prenyl or propargyl, more preferably benzyl, allyl, cinnamyl, prenyl or propargyl, most preferably, benzyl.

In any of the processes above detailed (i.e. section C. 2), preferably, the

organoaluminium halide is of formula R5R6AIX, wherein R5, R6 and X are as defined above, and is for example diethylaluminium chloride or dimethylaluminium chloride, most preferably diethylaluminium chloride.

The molar ratio of an organoaluminium halide, as described herein, to a compound of formula (III), as described herein, is for example 6:1 , such as 5:1 , preferably 4:1 or 3:1 .

In any of the processes above detailed, the reaction temperature of step i) is preferably in the temperature range of from room temperature to the boiling point of the solvent, for example, a reaction temperature range is of from 20 °C to 170 ^, preferably, of from 60 ^< O to 130°C.

In any of the processes above detailed, the reaction temperature of step ii) is preferably in the temperature range of from room temperature to the boiling point of the solvent, for example, a reaction temperature range is of from 20 °C to 170 ^, preferably, of from 60 °C to 130°C, preferably of from 80 °C to 130 ^< Ό.

D. Novel and inventive compounds

In the processes shown above several novel and inventive compounds are involved. Consequently, further subjects of the present invention are the compounds shown below.

An amine salt of the compound of formula (IV) as defined herein. A compound of formula (III), or salt thereof,

wherein R is benzyl, allyl, cinnamyl, prenyl or propargyl, more preferably, benzyl.

Listed below are definitions of various terms used to describe the novel intermediates and synthesis steps of the present invention. These definitions, either by replacing one, more than one or all general expressions or symbols used in the present disclosure and thus yielding embodiments of the invention, in particular apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.

The term "C C ₂ o-" defines a moiety with up to and including maximally 20, especially up to and including maximally 7, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.

The term alkyl, as a radical or part of a radical, defines a moiety with up to and including maximally 7, C _{1 -7} alkyl, in particular up to and including maximally 4, C _{1 -4} alkyl, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon. In particular, alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; more preferably methyl. halo-CrC ₇ -alkyl may be linear or branched and in particular comprises 1 to 4 C atoms, for example 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

Halo or halogen is fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo, preferably chloro.

Alkenyl, being a radical or part of a radical, is a straight or branched (one or, if desired and possible, more times) carbon chain containing at least one double bond, and is, for example, C ₃ -C ₂ o-alkenyl (such as C ₃ -C ₈ alkenyl). In particular, alkenyl is, for example, allyl, which is unsubstituted or substituted as described herein.

Alkinyl, being a radical or part of a radical, is a straight or branched (one or, if desired and possible, more times) carbon chain containing at least one triple bond, and is, for example, C ₃ -C ₂ o-alkinyl (such as C ₃ -C ₇ -alkinyl). In particular, alkinyl is, for example, propargyl, which is unsubstituted or substituted as described.

The term cycloalkyl, being a radical or part of a radical, is "C ₃ - ₈ cycloalkyl" and defines a cycloalkyl moiety with up to and including maximally 8, in particular up to and including maximally 6, carbon atoms. Said cycloalkyl moiety is for example mono- or bicyclic, in particular monocyclic, which may include one or more double and/or triple bonds.

Embodiments include a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Heterocyclyl is a mono- or polycyclic, preferably a mono-, bi- or tricyclic-, most preferably mono-, unsaturated, partially saturated, saturated or aromatic ring system with preferably 3 to 20 (more preferably 5 to 10) ring atoms and with one or more, preferably one to four, heteroatoms independently selected from nitrogen, oxygen, sulfur, S(=0)- or S-(=0) ₂ . When the heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.

Alkoxy, being a radical or part of a radical, is, for example, Ci-C ₂₀ -alkoxy (-O-C ₁ - C ₂₀ alkyl), preferably Ci-Cy-alkoxy (-0-CrC ₇ alkyl). In particular, alkoxy, is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert- butyloxy, pentyloxy, hexyloxy and heptyloxy radicals.

Alkoxyalkyl may be linear or branched. The alkoxy group for example comprises 1 to 7 and in particular 1 or 4 C atoms, and the alkyl group for example comprises 1 to 7 and in particular 1 or 4 C atoms. Examples are methoxymethyl, 2-methoxyethyl, 3- methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2- ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

Alkanoyl, being a radical or part of a radical, is, for example, In particular, alkanoyl is, for example, acetyl [-C(=0)Me], propionyl, butyryl, isobutyryl or pivaloyl. Aryl being a radical or part of a radical is, for example, C ₆ -i ₀ aryl, being a radical or part of a radical is preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 10 carbon atoms, preferably phenyl, indenyl, indanyl or naphthyl, most preferably phenyl.

The term arylalkyl refers to aryl-Ci-C ₇ -alkyl, wherein aryl is as defined herein and is for example benzyl, which is unsubstituted or substituted as described.

The term carboxyl refers to -C0 ₂ H.

The term "free acid" as used herein refers to the group C0 ₂ H. Typically, a group C0 ₂ H is attached to an organic residue, which is, for example, as defined on page 3 of

WO2005/014602, which is fully incorporated herein by reference.

The term "ester" or "ester group" as used herein refers to a group C0 ₂ R, wherein R is as defined above for a compound of formula (III) or (V); R is preferably benzyl, allyl, cinnamyl, prenyl or propargyl, most preferably, benzyl. Typically, a group C0 ₂ R is attached to an organic residue, which is, for example, as defined on page 3 of

WO2005/014602, which is fully incorporated herein by reference.

Aryloxy refers to a Aryl-O- wherein aryl is as defined above.

Preferred substituents are selected from the group consisting of halo, nitro, CrC ₇ -alkyl, halo-CrC ₇ -alkyl, CrC ₇ -alkoxy, halo-CrC ₇ -alkoxy, CrC ₇ -alkoxy-CrC ₇ -alkyl, C C ₇ -alky- ICrC ₇ -alkoxy and CrC ₇ -alkoxy-Ci-C ₇ -alkoxy.

The term "salt of a compound of formula (IV)" refers, for example, to an amine salt thereof, an alkali salt thereof or an earth alkali metal salt thereof (eg. sodium salt, potassium salt, calcium salt, magnesium salt, etc). In particular, the term "amine" in the expression "amine salt thereof", for example when referring to an amine salt of the compound of formula (IV), means tertiary amine of formula NR9R10R1 1 , secondary amine of formula NHR9R10R or primary amine of formula NH ₂ R9, wherein R9, R10 and R1 1 are, independently from one another, alkyl, aryl, cycloalkyl or heterocyclyl, as defined herein, preferably alkyl or cycloalkyl. The term "amine" is, for example, diphenylamine, diisopropylamine, dimethylamine, triethylamine, diisopropylethylamine, dicyclohexylamine, t-butylamine, n-butylamine or cyclohexylamine, in particular, t- butylamine, n-butylamine or cyclohexylamine, more preferably n-butylamine or cyclohexylamine.

Bonds with the asterisk ( ^* ) denote point of binding to the rest of the molecule.

In formulae above the term " " represents a covalent bond, which comprises an (£) stereoisomer as well as a (Z) stereoisomer of the respective double bond.

The term "one-pot" "or "one-pot process" means that in a series (i.e. in a succession) of reactions, for example two or more successive reactions, each reaction product is provided for the next reaction without isolation and purification. The one-pot processes defined herein encompass not only a series (i.e a succession) of reactions conducted in a single reaction vessel, but also a series (i.e. a succession) of reactions conducted in a plurality of reaction vessels (e.g., by transferring the reaction mixture from one vessel to other) without isolation and and purification. Preferably, the one-pot process is conducted in a single reaction vessel.

The term "step-wise process" means that in a series (i.e a succession) of reactions, each reaction product is provided for the next reaction with isolation and optionally purification.

The term "work-up" means the work of isolation and/or purification which is carried out once the reaction is finished. As used herein, the term "room temperature" or "ambient temperature" means a temperature of from 15 to 30 °C, such as of from 20 to 30 °C, such as of from 20 to 25 °C.

As used herein, the term "in-situ" refers to the capability of forming an azide of formula R7R8MN ₃ , wherein M is aluminium and R7 and R8 are as described herein, with the addition of metal salt of hydrazoic acid to a reagent of formula R5R6AIX, as defined herein.

The term "organoaluminium azide" refers to a reagent is of formula R7R8MN ₃ , wherein M is aluminium and R7 and R8 are as defined herein. Preferably a reagent of formula R7R8MN ₃ is Et ₂ AIN ₃ .

The term "organoalumium halide" refers to a reagent is of formula R5AIX2 or R5R6AIX, as defined herein. Preferably an "organoalumium halide" of formula R5AIX2 is MeAICI ₂ and/or an "organoalumium halide" of formula of formula R5R6AIX is EfeAICI or Me ₂ AICI.

The term "metal salt of hydrazoic acid" refers to alkali or earth alkali metal salts, (eg. sodium azide, potassium azide, calcium azide, magnesium azide) and other metals salts such as aluminium azide or tin azide.

The compounds of the present invention can possess one or more asymmetric centers.

Salts are especially pharmaceutically acceptable salts or generally salts of any of the intermediates mentioned herein, where salts are not excluded for chemical reasons the skilled person will readily understand. They can be formed where salt forming groups, such as basic or acidic groups, are present that can exist in dissociated form at least partially, e.g. in a pH range from 4 to 10 in aqueous solutions, or can be isolated especially in solid, especially crystalline, form.

Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 1 ,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic acid, N- methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines for example triethylamine or tri(2- hydroxyethyl)amine, N-ethyl-piperidine, Ν,Ν'-dimethylpiperazine, t-butylamine, n- butylamine, phenylethylamine, dicyclohexylamine or cyclohexylamine.

When a basic group and an acid group are present in the same molecule, any of the intermediates mentioned herein may also form internal salts.

For isolation or purification purposes of any of the intermediates mentioned herein it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.

In view of the close relationship between the compounds and intermediates in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the compounds or salts thereof, any reference to "compounds", "starting materials" and "intermediates" hereinbefore and hereinafter is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise. Different crystal forms may be obtainable and then are also included. Where the plural form is used for compounds, starting materials, intermediates, salts, pharmaceutical preparations, diseases, disorders and the like, this is intended to mean one (preferred) or more single compound(s), salt(s), pharmaceutical preparation(s), disease(s), disorder(s) or the like, where the singular or the indefinite article ("a", "an") is used, this is not intended to exclude the plural, but only preferably means "one".

The term "Valsartan", if not defined specifically, is to be understood both as the free acid and as a salt thereof, especially a pharmaceutically acceptable salt thereof. Valsartan, or a pharmaceutically acceptable salt thereof, can, e.g., be prepared in a manner known per se, for example as described in WO2004/026847, in WO2005/014602 and in US5,399,578. The term valsartan also refers to /V-(1 -Oxopentyl)-/V-[[2'-(1 /-/-tetrazol-5- yl)[1 ,1 '-biphenyl]-4-yl]methyl]-L-valine; Λ/-[ρ-(ο-1 H-tetrazol-5-ylphenyl)benzyl]-/V-valeryl- L-valine; or (S)-/V-(1 -carboxy-2-methylprop-1 -yl)-/V-pentanoyl-/V-[2'-(1 /-/-tetrazol-5-yl)- biphenyl-4-ylmethyl]amine, as found in Merck Index: an Encyclopedia of Chemicals, Drugs and Biologicals, 13th Ed., Whitehouse Station, NJ, USA: Merck Research

Laboratories, 2001 . ISBN 978-0-91 1910-00-1 .

Preferred salts forms include acid addition salts. The compounds having at least one acid group (e.g., COOH or 5-tetrazolyl) can also form salts with bases. Suitable salts with bases are, e.g., metal salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, calcium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri- lower alkylamine, e.g., ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, e.g., mono-, di- or tri-ethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, e.g., for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included. Even more preferred salts are, e.g., selected from the mono-sodium salt in amorphous form; di-sodium salt of Valsartan in amorphous or crystalline form, especially in hydrate form, thereof. Mono-potassium salt of Valsartan in amorphous form; di- potassium salt of Valsartan in amorphous or crystalline form, especially in hydrate form, thereof. Calcium salt of Valsartan in crystalline form, especially in hydrate form, primarily the tetrahydrate thereof; magnesium salt of Valsartan in crystalline form, especially in hydrate form, primarily the hexahydrate thereof; calcium/magnesium mixed salt of Valsartan in crystalline form, especially in hydrate form; 6/s-diethylammonium salt of Valsartan in crystalline form, especially in hydrate form; £>/s-dipropylammonium salt of Valsartan in crystalline form, especially in hydrate form; 6/s-dibutylammonium salt of Valsartan in crystalline form, especially in hydrate form, primarily the hemihydrate thereof; mono-L-arginine salt of Valsartan in amorphous form; £>/s-L-arginine salt of Valsartan in amorphous form; mono-L-lysine salt of Valsartan in amorphous form; bis-L- lysine salt of Valsartan in amorphous form. Most preferably, Valsartan is used as the free acid.

Abbreviations:

AB AB system

AB-gem AB geminal system ar. aromatic

arom. aromatic

arom-H aromatic-H

ar-H aromatic-H

ar-CH aromatic-CH al-CH aliphatic-CH ali. aliphatic

ali.-CH liphatic-CH

δ chemical shift

Bn benzyl

Boc tert-butoxycarbonyl

BOC ₂ 0 di-tert-butyl carbonate brm broad multiplet br. sign. broad signal br. s. broad signal br. m. broad multiplet br. mult. broad multiplet cat. catalytic amount compl. m complex multiplet compl. mult. ; copl. m. complex multiplet cpl. m. complex multiplet

Cbz benzyl carbamate

Cbz-CI enzyl chloroformate d doublet

dd doublet of doublet

DCM dichloromethane de diastereomeric excess

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

Et ethyl EtOAc ethyl acetate

EtOH ethanol

FeCI ₃ iron (III) chloride

FTIR fourier transform infrared spectroscopy h hour(s)

HCI hydrochloric acid

HNMR proton nuclear magnetic resonance

HPLC high performance liquid chromatography i-Pr isopropyl

IR infrared

L litre

LCMS liquid chromatography-mass spectrometry

LRMS low resolution mass spectroscopy

M molarity

m/e mass-to-charge ratio

Me methyl

mg milligram

MgS0 ₄ magnesium sulfate

m multiplet

min minute(s)

ml_ millilitre

mmol(s) millimole(s)

mol(s) mole(s)

monosub. monosubstituted

m.p. melting point

MS mass spectrometry

mult, d multiplet of doublets

NaOH sodium hydroxide

NaOCI sodium hypochlorite

nm nanometre

NMR nuclear magnetic resonance

oct. octet

Pd/C palladium on carbon

Ph phenyl ppm parts per million

psi pounds per square inch

RT room temperature

RuCI ₃ ruthenium (III) chloride

s singlet

S1O2 silica gel

sev. brm several broad multiplets

sev. dd several doublets of doublets

t triplet

temp. temperature

TBME tertbutylmethylether

TEMPO 2,2,6,6-tetramethyl-1 -piperidinyloxy

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Tos- tosyl

t _R retention time

vol. volume

wt. weight

Experimental:

The following terms are used herein below.

"Methylester-nitrile" = (S)-2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-met hyl- butyric acid methyl ester

"Benzylester-nitrile" = (S)-2-[(2'-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-met hyl- butyric acid benzyl ester (described in Organic Process Research & Development 2007 , 1 1 , 892)

"Acid-nitrile" = (S)-2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-met hyl-butyric acid (described in Chinese Journal of Pharmaceuticals 2001 , 32(9), 385 and in

EP1533305A1 ) "Valsartan" =

A/-(1 -Oxopentyl)-/V-[[2'-(1 H-tetrazol-5-yl)[1 ,1 '-biphenyl]-4-yl]methyl]-L-valine; or

Λ/-[ρ-(ο-1 H-tetrazol-5-ylphenyl)benzyl]-/V-valeryl-L-valine; or

(S)-/V-(1 -carboxy-2-methylprop-1 -yl)-/V-pentanoyl-/V-[2'-(1 /-/-tetrazol-5-yl)-biphenyl-4- ylmethyl]amine.

Reference Example I: Preparation of "acid-nitrile" via hydrogenation of "benzylester- nitrile" with Pd/C

"Benzylester-Nitrile" "Acid-Nitril

40 g (84 mmol) of "benzylester-nitrile" are dissolved in 400 ml of dry ethanol and are hydrogenated by addition of Pd/C 10 wt. % (Engelhard 4505) at 0.1 bar and 20-25 ° C in a shaking apparatus. After 1 hour the theoretical hydrogen up take is complete. For work up the catalyst is filtered and washed with additional 100 ml ethanol. The filtrate is evaporated in vacuum and dried in high vacuum to give a colourless oil.

¹ H-NMR: (400 MHz, CDCI3); δ _Η (ppm):

0.67-0.70 (6H, 2 dd, 2x -CH ₃ ), 0.78 (3H, d, -CH ₃ ), 1 .06-1 .18 (2H, m, -CH ₂ -),

1 .40-1 .48 (2H, m, -CH ₂ -), 2.18-2.33 (2H, m, -CH ₂ -C=0), 2.50-2.58 (1 H, m, -CH-),

3.37-3.50 (1 H, d, -N-CH-COOH), 4.21 (1 H, d, N-CH ₂ -Ph-), 4.63 (1 H, d, N-H ₂ -Ph), 7.09 (2H, d, ar.-H), 7.24 (1 H, t, ar.-H), 7.28 (1 H, d, ar.-H), 7.34 (2H, d, ar.-H), 7.42 (1 H, t, ar.-H), 7.53 (1 H, d, ar.-H) MS: [M+H] ⁺ = 393

IR: FTIR microscope in transmission [cm ¹ ]

broad -COOH, 3600-2400, 3064, 3030 (CH, ar-H), 2962,2932,2873 (ali.-CH), 2224(CN), 1735 (C=0), 1650 (C=0 amide), 1650,1613 (ar.), 1478, 1469, 1446(ar), 1410, 1390, 1373, 1354, 1271 , 1203, 1 169, 1 131 , 1 106, 1047, 1026, 1005, 967, 941 , 850, 823 (CH- para), 765 (CH-ortho), 692

Example II: Preparation of "acid-nitrile" via cleavage of the benzylester of "benzyl-nitrile" with diethylaluminium chloride

To solution of 2.41 g (5 mmol) of "Benzylester-Nitrile" in 10 ml of dry toluene is added via a syringe a 1 .8 molar solution of diethylaluminium chloride (12.5 ml, 22.5 mmol) in toluene at room temperature under nitrogen and stirring. The addition is exotherm. After complete addition of the Et^AICI solution the reaction mixture is warmed up to 50 °C.

After 2 hours, the reaction mixture is cooled to 0 °C and is then quenched by slow addition of 20 ml of 2 molar hydrochloric acid. The quench reaction is quite exotherm and gas evolution is observed. The phases are separated and the organic phase is washed with 3 x 20 ml of water. The organic phase is evaporated in vacuum to give an oil. Spectroscopic data are the same as in Example I.

Reference Example III: Preparation of valsartan via a one-pot process with

Diethylaluminium Azide Preparation of the Diethylaluminium azide reagent:

A dry 250ml flask under Argon is charged with 6.82 g (105 mmol) dry sodium azide. To the solid is added via a syringe under stirring a 2.7 molar solution (38.9 ml), 105 mmol of diethyl aluminium azide in xylene (isomeric mixture) during 1 hour. The white suspension is stirred at room temperature overnight. After this time, the suspension, containing solid NaCI and diethylaluminium azide, is then ready for use.

Cleavage of benzylester-nitrile to "Acid-Nitrile" and cvcloaddition with Diethylaluminium azide

"Benzylester-Nitrile" Intermediate "Acid-Nitrile" Valsartan

The above-prepared diethylaluminium azide suspension is warmed up in the same flask to 80 °C under stirring and under nitrogen. At this temperature, it is added slowly (45 min) via a dropping funnel a solution of 14.48 g (30 mmol) of "benzylester-nitrile" in 50 ml of xylene (isomeric mixture). After complete addition, HPLC analysis shows full conversion of the starting material to the "acid-nitrile". The internal temperature is then increased to 100 °C. After stirring for 3.5 hours at this temperature, the internal temperature is further increased to 1 10 °C. The reaction mixture is stirred for additional 4 hours at 1 10 °C and then heating is stopped and stirring is continued overnight at room temperature. Next, the suspension is cooled to 0 °C. To the suspension is then slowly added (1 hour) a mixture of an aqueous solution of sodium hydroxide (9 g, 225 mmol ) in 50 ml of water and 15.52 g (225 mmol) of sodium nitrite. During the quenching the internal temperature is kept at 0 °C. Additional 2 molar aqueous sodium hydroxide solution (40 ml) and isopropyl acetate (50 ml) is added, to give a 3-phasic clear solution. The phases are separated, and the organic phase is extracted with water. The combined aqueous phases are neutralized with concentrated HCI and finally the pH is adjusted to 1 .8. The product is extracted with ethyl acetate. The combined organic phases of the extractions are combined and evaporated in vacuum to give a slightly yellowish oil. The oily residue is crystallized from cyclohexane to give after filtration, and drying in a vacuum oven, valsartan. Spectroscopic data are the same as in Example IV.

Example IV: Preparation of Valsartan: via "one-pot process" with Diethylaluminium Chloride (for ester cleavage) and Diethylaluminium Azide (for the cycloaddition reaction) which is generated in-situ by reacting with Diethylaluminium Chloride and Sodium azide.

"Benzylester-Nitrile" Intermediate "Acid-Nitrile" Valsartan

60 g of a solution of (S)-2-[(2'-Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-met hyl- butyric acid benzyl ester ("Benzylester-Nitrile") in xylenes (67.1 mmol) is mixed at 0 °C with 33 g diethylaluminiumchloride (265.5 mmol) and stirred for 1 h, allowing the mixture to warm up to max. 50 °C by intermittent cooling. 8.82 g of sodium azide (1 34.3 mmol) are added and the mixture is heated to 1 10 °C. After 4 h, the reaction mixture is carefully transferred to a flask containing 201 .6 g of 1 2 (w/w) % aqueous NaOH, while the temperature of the mixture is allowed to rise to 50 °C. The upper organic phase is discarded, and the aqueous phase is washed with 60 g of xylenes.

An oily phase containing the product is separated and used for further work-up. It is dissolved in 1 20 g of water and 0.94 g of sodium nitrite (13.6 mmol) are added. Then, 41 .5 g of 32% hydrochloric acid are added under cooling to 5 °C. The resulting suspension is filtered on a Buchner funnel and washed with 100 ml of a 0.5%

hydrochloric acid. The filter cake is dried in vacuum at 40-50 °C to provide (S)-3-Methyl- 2-{pentanoyl-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid.

H-NMR (CDCI ₃ , 400 MHz, ppm): mixture of rotamers δ = 0.90-1 .01 (9 H, m), 1 .40 (2 H, m), 1 .67 (2 H, m), 2.52 (2 H, m), 2.61 (1 H, m), 3.65 (1 H, d _bra a _d ), 4.05 and 4.29 (1 H, 2 d, ³ J = 15.6 Hz), 4.89 and 5.16 (1 H, 2 d, ³ J = 15.5 Hz), 7.12-7.14 (4 H, m), 7.41 -7.60 (3 H, m), 7.87-7.94 (1 H, m) ppm.

Example V: Esterification of intermediate "acid-nitrile" with 3-methyl-1 -(p-tolyl)-triazene

9.8 g (65.56 mmol) of 3-methyl-1 -(p-tolyl)-triazene are dissolved in 100 ml of

dichloromethane. To this solution is added via a dropping funnel a solution of 24.4 g (59.6 mmol) of "acid-nitrile" dissolved in 200 ml of dichloromethane at room temperature during 45 minutes under stirring. After 2 hours, the reaction mixture is treated with 100 ml of 1 molar hydrochloric acid. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuum to give a slightly yellow oil, which is pure according to HPLC and H-NMR analysis.

¹ H-NMR: (400 MHz, CDCI3); δ _Η (ppm), rotamer mixture (6 : 4) at room temperature. 0.82-0.95 (5H, m, -CH ₃ , 60 %), 0.95-1 .03 (4H, m, -CH ₃ , 40%), 1 .25-1 .37 (1 H, m,-CH-, 40%), 1 .40-1 .49 (1 H, m, -CH-,60%), 1 .60-1 .70 (1 H, m, -CH-, 60%), 1 .70-1 .82 (1 H, m, - CH-, 40%), 2.22-2.65 (3H, br, copl. m, -CH- and -CH ₂ -). 3.37 (s, -OCH ₃ , 40%), 3.45 (s, - OCH ₃ , 60%), 4.07 (0.5 1-1,40%, d, N-CH-C0 ₂ Me), 4.27 (0.5 H, 40%, d, N-CH ₂ -Ph-Ph), 4.69 (2H, 60%, ab, dd, -N-CH ₂ -Ph-Ph), 4.98 (1 H, 60%, d, N-CH-C0 ₂ Me), 5.08 (0.5H, 40%, -N-CH ₂ -Ph-Ph), 7.25-7.34 (3H, m, ar.-H), 7.40-7.58 (4H, m, ar.-H), 7.60-7.69 (1 H, m, ar.-H), 7.72-7.80 (1 H, m, ar.-H).

MS: [M+H] ⁺ = 407, [M+NH ₄ ] ⁺ = 424

IR: FTIR microscope in transmission [cm ¹ ]

3064, 3029 (CH, ar-H), 2980,2933,2873 (ali.-CH), 2224(CN), 1739 (C=0), 1652 (C=0 amide), 1597,1561 , 519,1504,1478,1464,1435 (ar), 1408, 1372, 1265, 1204 (C-O-ester) 1 169, 1 133, 1 106, 1007, 974, 946, 888, 824 (CH-para), 765 (CH-ortho).

Example VI: Preparation of Valsartan: via "one-pot process" with Diethylaluminium Chloride (for ester cleavage) and Diethylaluminium Azide (for the cycloaddition reaction) which is generated in-situ by reacting the excess of Diethylaluminium Chloride with Sodium azide.

"Methylester-Nitrile" Intermediate "Acid-Nitrile" Valsartan

In an argon filled three necked flask, 2.4 g (3.00 mmol) of a solution of (S)-2-[(2'-cyano- biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester in xylenes (3.00 mmol) is diluted with 5 ml of dry xylene (40 mmol). The mixture is heated to 1 10°C and 1 .94 ml of diethylaluminium chloride (15 mmol) are added. The mixture is stirred at 1 10 ^. After 60 minutes, 0.59 g of sodium azide are added as a solid in one portion. The mixture is stirred at 1 10^. After 44h, the reaction mixture is allowed to cool to room temperature and transferred into a three necked flask containing 20 eq of 10% (w/w) aqueous sodium hydroxide (24.0 g, 60 mmol) while the temperature is maintained below 30 °C. The resulting biphasic mixture is transferred into a separation funnel and the upper xylenic phase is discarded. The aqueous phase is washed with 6.8 ml of xylenes (55 mmol). Sodium nitrite (0.45 g, 6.6 mmol) is dissolved in the basic aqueous solution. The mixture is added carefully to an emulsion of 7.99 g of 37% aqueous hydrochloric acid (81 mmol) and 10 ml ethyl acetate (102 mmol) while the temperature is maintained below 5 °C in an ice-bath. The phases are separated and the aqueous phase is extracted with 10 ml ethyl acetate (102 mmol). The combined organic phases are washed with 10 ml H ₂ 0 (555 mmol). The solvent is removed under vacuum and 20 ml of xylenes (160 mmol) are added and the mixture is again concentrated to dryness. The crude oily product is dissolved in 15 ml EtOAc (153 mmol), concentrated to approx. 5 ml and 2 ml cyclohexanes (21 mmol) are added dropwise until a white precipitate does just re- dissolve at 60 °C. The mixture is placed in a fridge at 8 °C. After 16 h, an off-white precipitate is collected by filtration. The product is washed with cold ethyl acetate /cyclohexane 1 :1 and dried under vacuum to give (S)-3-Methyl-2-{pentanoyl-[2'-(1 H- tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid (Valsartan). 1 H-NMR (CDCI3, 400 MHz, ppm): main rotamer δ = 0.94-1 .05 (9 H, m), 1 .40-1 .48 (2 H, m), 1 .72-1 .79 (2 H, m), 2.61 -2.65 (2 H, m), 2.69-2.78 (1 H, m), 3.36 (1 H, d, JH,H = 1 1 .1 Hz), 4.21 (1 H, d, JH,H = 14.8 Hz), 5.00 (1 H, d, JH,H = 14.8 Hz), 7.19-7.25 (4 H, m), 7.47-7.50 (1 H, m), 7.52-7.56 (1 H, m), 7.59-7.63 (1 H, m), 8.07-8.09 (1 H, m).

Reference Example VII: Cleavage of Phthalic acid bisallylester with Me2AI-CI

246 mg (1 mmol) of diallyl phthalate are dissolved in 10 ml of dry toluene under nitrogen. The solution is heated to reflux (1 10 °C) and 2.1 ml of a 1 molar solution of dimethyl aluminium chloride (2.1 equiv.) are added via a syringe under nitrogen. The reaction mixture is stirred over night at 1 10 °C. The reaction mixture is cooled to room

temperature, quenched with 15 ml of 2 molar HCI and extracted with 7 x 15 ml of ethyl acetate. The combined organic phases are extracted with 2 x 12 ml of saturated sodium bicarbonate solution. The combined basic, aqueous phase is adjusted to pH 1 with 10 ml of diluted (2 Molar) sulfuric acid. The acidic aqueous phase is again extracted with 7 x 15 ml of ethyl acetate and the combined organic phase are washed with brine, dried over sodium sulfate, filtered and evaporated in vacuum to phthalic acid. H-NMR and LC-MS confirm the structure of phthalic acid (identical to a commercial sample from Fluka).

Reference Example VIII : Cleavage of benzoic acid benzylester with MeAICl2

212 mg (1 mmol) of benzoic acid benzyl ester are dissolved in 10 ml of dry toluene under nitrogen atmosphere. The reaction mixture is heated up to reflux and 1 .05 ml (1 .05 equv.) of methyl aluminium dichloride in hexane solution (1 molar) is added in 1 portion. Heating is continued over night. The reaction mixture is cooled to room temperature and quenched onto 15 ml of 2 M hydrochloric acid. The reaction mixture is extracted with 4 x 15 ml of dichloromethane. The combined organic phases are extracted with 2 x 12 ml of saturated sodium bicarbonate solution. The combined aqueous basic phases are then adjusted to pH 1 with 2 ml of cone, sulfuric acid. The acidic aqueous phase is extracted with 4 x 15 ml of dichloromethane and the combined dichloromethane extracts are then washed with brine, dried over sodium sulfate, filtered and evaporated in vacuum to give benzoic acid. ¹ H-NMR and LC-MS confirm the structure of benzoic acid (comparison with reference material).

Example IX: Preparation of Valsartan: via "one-pot process" with Diethyl-aluminium Chloride (for ester cleavage) and Diethylaluminium Azide (for the cycloaddition reaction)

Preparation of the diethyl-AI-azide reagent:

A 250 ml flask is charged under argon with 3.9 g (65 mmol) of NaN3 and 1 0 ml of dry xylene is added. To this suspension is added, at room temperature under stirring, 33 ml of a 2 molar solution (66 mmol) of diethylaluminium chloride during 15 min. The suspension is then stirred for further 5 hours at room temperature and it is then ready for use. The diethyl aluminium azide is in solution but the solid NaCI is in a suspension.

Cleavage of benzylester-Nitrile to "Acid-Nitrile" and cvcloaddition with Diethylaluminium azide

A separate 1 00 ml flask is charged with 9.64 g (20 mmol) of (benzylester-nitrile) which is then dissolved at room temperature under argon and stirring with 20 ml of dry xylene. To the solution is added at room temperature under stirring 33 ml of a 2 molar solution of diethylaluminium chloride. After stirring at room temperature over night additional 17 ml of 2 M diethylaluminium chloride is added. After stirring for additional 3 hours at room temperature, the solution is then added via a dropping funnel to the 250 ml flask containing the above diethylaluminium solution at room temperature.

The reaction mixture is then heated to reflux (external temp. 150 °C). After 14 hours, the reaction mixture is cooled to room temperature and worked up by quenching the reaction mixture to a solution of sodium nitrite (4.14 g) in 25 ml of water and 6.7 g of a sodium hydroxide aqueous solution (30 % wt) under vigorous stirring under argon and external cooling. The reaction flask is rinsed with 1 0 ml of water and 20 ml of xylene. The resulting suspension is then adjusted to pH 2-3 by slow addition of 25 ml of a 5 M hydrochloric acid under stirring. By further addition of 60 ml of 5 M HCI, until pH 0 is reached, a slightly turbid yellowish solution is obtained. The phases are separated and the organic phase is washed with 4 x 25 ml of water. The organic phase is evaporated in vacuum to give a yellow foam. The yellow residue is dissolved in 50 ml of EtOAc. The product is extracted to the aqueous phase by 50 ml and 20 ml of sodium bicarbonate aqueous solution (8% wt). The aqueous phase contains the desired product. The product containing basic aqueous phase is adjusted to pH 0-1 by addition of 25 ml of 5 molar hydrochloric acid and extracted to 50 ml of EtOAc. The organic phase is washed with water (2 x 25 ml), evaporated in vacuum to give a yellowish foam. The foam is dissolved for crystallization in 30 ml of ethyl acetate and treated with additional 5 ml of heptane. Crystallization in the fridge at 7 °C occurs overnight. The crystal suspension is further diluted at 0 °C by addition of 100 ml of heptane. Filtration, washing and drying at

40 ° C in vacuum gives valsartan (as confirmed by ¹ H-NMR analysis). Example X: Preparation of "Propargylester-Nitrile" from "Acid-Nitrile"

7.85 g (20 mmol) of "Acid-Nitrile" are dissolved in 100 ml of dry DMF. To this solution is added 3.36 (40 mmol) of solid sodium bicarbonate under stirring to give a slightly yellow suspension. To this suspension is added 8.9 ml (100 mmol) of propargyl bromide, dissolved in 100 ml of dry DMF. The reaction mixture is stirred at room temperature overnight. Additional 1 ml (1 1 .3 mmol) of propargyl bromide and 0.4 g (1 1 .9 mmol) of sodium bicarbonate are added. After further stirring at room temperature for 4 hours, the reaction mixture is diluted with 200 ml of ethylacetate, followed by extraction of the organic phase with 3 x 250 ml of water and finally with 200 ml of brine. The organic phase is dried over MgS04, filtered and evaporated and dried under high vacuum to give crude propargylic ester, which is pure enough for further reactions.

¹ H-NMR: (400 MHz, d6-DMSO); δ _Η (ppm), the product is a mixture of rotamers at room temperature:

0.75-0.87 (5H, br.m, -CH ₃ ), 0.90-1 .00 (4H, m, -CH ₃ ), 1 .15-1 .27 (2H, br. m), 1 .31 -1 .54 (2H, br.m), 2.15-2.25 (1 H, br.m), 2.28-2.40 (3H, br.m), 2.52-2.65 (1 H, br.m), 3.03 (1 H, s, acetylen-H), 4.30-4.60 (4H, compl. m), 4.68-4.82 (2H, m), 7.24-7.98 (8H, sev. mpl., rotamer mix).

MS: [M+H] ⁺ = 431 .2, (M+NH4) ⁺ = 448.2 IR: FTIR microscope in transmission [cm ¹ ]

3288, 3064, 3030 (CH, ar-H), 2962, 2933, 2873 (ali.-CH), 2224(CN), 2128 (CC-triple b.) 1745 (C=0, ester), 1652 (C=0, amide), 1597, 1478, 1469, 1445, 1408, 1389, 1374, 1354, 1267, 1234, 1 193, 1 167, 1 129, 1024, 997, 973, 942, 824, 766.

Example XI: Preparation of "Cinnamylester-Nitrile" from "Acid-Nitrile'

3.93 g (10 mmol) of "Acid-Nitrile" is dissolved in 50 ml of dry DMF. To this solution is added 1 .68 (20 mmol) of solid sodium bicarbonate under stirring to give a slightly yellow suspension. To the suspension is added 5.85 g (50 mmol) of 3-bromo-1 -phenyl- I propene, dissolved in 50 ml of dry DMF. The reaction mixture is stirred at room temperature overnight. After 16 hours, the reaction mixture is diluted with 100 ml of ethylacetate, followed by extraction of the organic phase with 3 x 130 ml of water and finally with 100 ml of brine. The organic phase is dried over MgS04, filtered, evaporated and dried under vacuum to give crude "cinnamylester-nitrile". The crude product was purified by column chromatography on silica gel (400 g) first with cyclohexane and then with cyclohexane/ethylacetate (8 : 1 ). The product containing fractions were again chromatographed by a second Si0 ₂ -column (360 g) with cylohexane/ethylacetate (5 : 1 ) to give the product as a colourless oil.

¹ H-NMR: (400 MHz, CDCI3); δ _Η (ppm), the product is a ca. 2 : 1 -mixture of rotamers at room temperature:

0.84-1 .02 (6H, compl. m., 2x -CH ₃ ), 1 .05 (3H, d, -CH ₃ ), 1 .40-1 .50 (1 H, m), 1 .40-1 .48 (2H, m, -CH ₂ -), 2.18-2.33 (2H, m, -CH ₂ -C=0), 2.50-2.58 (1 H, m, -CH-), 3.37-3.50 (1 H, d, -N-CH-COOH), 4.20 (1 H, d, N-CH ₂ -Ph-), 4.63 (1 H, d, N-H ₂ -Ph), 7.20-7.39 (5H, compl. m., ar.-H), 7.40-7.51 (4H, br.m., ar.-H), 7.60-7.67 (1 H, m, ar.-H), 7.78 (1 H, t, ar.-H)

MS: [M+H] ⁺ = 509.3, (M+NH4) ⁺ = 526.3, 527.3

IR: FTIR microscope in transmission [cm ¹ ]

3061 , 3028 (CH, ar-H), 2961 , 2933, 2873 (ali.-CH), 2224(CN), 1737 (C=0, ester), 1653 (C=0, amide), 1495, 1478, 1466, 1447, 1408, 1388, 1356, 1299, 1264, 1 195, 1 168, 1 130, 1 109, 1027, 1004, 970, 944, 823, 765, 746, 693.

Example XII : Preparation of "Allyleste r-Nitrile'

Compound "Allylester-Nitrile" is prepared according to analogous method to that described in the example above for the "Cinnamylester-Nitrile". Spectroscopic data of "Allylester-Nitrile'

¹ H-NMR: (400 MHz, d6-DMSO); δ _Η (ppm), the product is a ca. 2 : 1 -mixture of rotamers at room temperature:

0.75-0.85 (5H, br. m., -CH ₃ ), 0.88-0.98 (4H, br. m., -CH ₃ ), 1 .15-1 .25 (2H, br. m.,) 1 .30- 1 .38 (1 H, br. m.), 1 .40-1 .52 (2H, br. m), 1 .53-1 .66 (1 H, br. m), 2.13-2.22 (1 H, m), 2.28- 2.40 (2H, m), 2.50-2.63 (1 H, br. m), 4.16-4.40 (3H, br. m), 4.60 (1 H, d), 4.68 (1 H, d), 4.85 (1 H, dd, AB), 5.20 (1 H, q, olef.-H), 5.25 (1 H, d, olef.-H), 5.68-5.83 (1 H, br. m., olef.- H), 7.23 (rota, mix, d, ar.-H), 7.38 (rota.mix, d, ar.-H), 7.48 (rota.mix, d, ar.-H), 7.52-7.62 (3H, br. m, ar.-H), 7.78 (1 H, q, ar.-H), 7.93(1 H, t, ar.-H).

MS: [M+H] ⁺ =433.2.3, (M+NH4) ⁺ = 450.3

IR: FTIR microscope in transmission [cm ¹ ]

3065, 3029 (CH, ar-H), 2961 , 2933, 2873 (ali.-CH), 2224 (CN), 1738 (C=0, ester), 1653 (C=0, amide), 1597, 1562, 1518, 1479, 1468, 1445, 1408, 1388, 1372, 1267, 1 197, 1 170, 1 131 , 1 107, 1005, 991 , 937, 822, 765.

Example XIII : Preparation of "Prenylester-Nitrile'

Compound "Allylester-Nitrile" is prepared according to analogous method to that described in the example above for the "Cinnamylester-Nitrile".

Spectroscopic data of "Prenylester-Nitrile' ^{; 1} H-NMR: (400 MHz, CDCI ₃ ); δ _Η (ppm), the product is a mixture of rotamers at 27° C. 0.85-1 .05 (9H, compl. m, 3x -CH ₃ ), 1 .25-1 .30 (2H, m, -CH-), 1 .55-1 .70 (2H, m, and 3H, s, -CH ₃ ), 1 .70-1 .83 (1 H, m, & 3H, s,-CH ₃ ), 2.20-2.68 (3H, br.m), 4.05-4.22 (1 H, compl. m), 4.30-4.55 (3H, compl. m), 4.68 (1 H, d, AB), 4.8 (1 H, d, AB), 4.88-4.98 (2H, m), 5.20- 5.32 (2H, m), 7.32-7.38 (2H, m, ar.-H), 7.40-7.58 (5H, br.m., ar.-H), 7.62-7.71 (1 H, br.m., ar.-H), 7.74-7.82 (1 H, br.m., ar.-H).

MS: [M+H] ⁺ =461 , (M+NH4) ⁺ = 478

IR: FTIR microscope in transmission [cm ¹ ]

3064, 3029 (CH, ar-H), 2962, 2933, 2873 (ali.-CH), 2224(CN), 1734 (C=0, ester), 1654 (C=0, amide), 1597, 1561 , 1518, 1478, 1445, 1408, 1384, 1356, 1267, 1 196, 1 168, 1 130, 1 108, 1047, 975, 942, 823, 765.

Example XIV: Cleavage of "Prenylester-Nitrile" with methylaluminium dichloride

A 25 ml flask, dried with a heating gun under a flow of nitrogen, is charged with 460 mg (1 mmol) of "prenylester-nitrile" and 8 ml of dry toluene to get a yellow solution. To this solution is added dropwise a 1 molar n-hexane solution (3.5 ml , 3.5 mmol) of methylaluminium dichloride at room temperature to get a red suspension. The reaction mixture is heated to reflux over night (16 hours). The reaction mixture is cooled to room temperature and then quenched on 20 ml of 1 molar HCI. To the biphasic reaction mixture is added 20 ml of ethylacetate. The organic phase is separated and washed 3- times with 20 ml of water and with 20 ml of brine. The organic phase is dried with sodium sulfate, filtered and evaporated under vacuum to give the crude "acid-nitrile" as a brown oil. The crude product is purified by column chromatograhy over 20 g of Si02 with a solvent mix of cyclohexane : ethylacetate : acetic acid (60 : 40 : 2). The product containing fractions are combined to give the "acid-nitrile" as a brown oil. The

spectroscopic data of this material are identical with the data of "acid-nitrile" obtained in example above.

Propargylester-Nitrile, Cinnamylester-nitrile and Allylester-nitrile are cleaved by this method using different alkylaluminium halides, as defined above, to give the desired product "acid-nitrile" in different yields.

Example XV: Formation of the n-Butylamine salt of "acid-nitrile"

1 .0 g (2.55 mmol) of "acid nitrile" is dissolved in 10 ml of ethyl acetate. To the solution of the acid is added a solution of 330 mg (4.5 mmol) of n-butylamine in 2 ml of ethyl acetate under stirring. Precipitation of a white solid is observed. The white suspension is kept overnight at 0 - 5 °C and is then filtered, washed with a mixture of 10 ml heptane/ethyl acetate (1 : 1 ) and dried at 40 °C in vacuum to give a white crystalline solid.

MS: [M+H] ⁺ = 393

IR: FTIR microscope in transmission [cm ¹ ]

3600-2400, broad, -COOH & -NH ⁺ , 3029 (CH, ar-H), 2961 ,2934,2871 ,2758 (ali.-CH), 2507, 2423, 2226(CN), 1637 (C=0 -amide), 1595 (ar.), 1560 (COO ), 1477, 1467, 1456(ar), 1407, 1385, 1313, 1301 , 1264, 1248, 1210, 1 173, 1 103, 1026, 1005, 974, 941 , 901 , 858, 830 (CH-para), 765 (CH-ortho), 737. Example XVI : Formation of the dicyclohexylamine salt of "acid-nitrile"

1 .0 g (2.55 mmol) of "acid nitrile" is dissolved in 10 ml of ethyl acetate. To the solution of the acid is added a solution of 462 mg (2.55 mmol) of dicyclohexylamine in 2 ml of ethyl acetate under stirring. After addition of 7.5 ml of n-heptane, under stirring, the formation of a white solid is observed after 10 minutes. The suspension is stored overnight at 0 - 5 °C, is then filtered, washed with 10 ml of a mixture of heptane/ethyl acetate (1 : 1 ) and finally dried in vacuum at 40 °C to give a white solid.

MS: [M+H] ⁺ = 393

IR: FTIR microscope in transmission [cm ¹ ]

3600-2400, broad, -COOH & -NH ⁺ , 3030 (CH, ar-H), 2933,2860 (ali.-CH), 2227(CN), 1633 (C=0-amide), 1650 (C=0 amide), 1597 (ar.), 1558 (COO ), 1452(ar), 141 1 , 1387 (COO ), 1314, 1304, 1249, 1230, 1212, 1 178, 1 107, 1063, 1033, 1005, 972, 939, 896, 832, 810,765 (ar-CH), 759 (CH-ortho), 722.