MXPA99007328A - Process for the preparation of substitute pyridine - Google Patents

Abstract

The present invention concerns a new process for the carbomoylation of substituted pyridines, especially with a process for the preparation of compounds of formula I (See Formula). Where R4 to R5 represents a hydrogen, lower alkoxy or halogen, or optionally salts of

Description

PROCESS FOR THE REPAIR OF SUBSTITUTE PYRIDINE The present invention is concerned with corustus. Novel processes for the carbomoylation of pyridmics, especially with a process for the preparation of compounds of formula I Wherein R 'to R "represent hydrogen, lower alkyl or halogen; Or optionally salts of these.

The process according to the present invention is useful for the preparation of endothelin receptor inhibitors which can be used for the treatment of disorders associated with endothelin receptor activities, especially circulatory disorders such REF .: 30806 - - like hypertension, ischemia, vasospasms and angina.

A radical carbomoylation of basic heteroatoms has been described by F. Minisci et. to the. in Tetrahedron (1985), 41, 4157. The described reaction of this is carried out in the presence of a catalytic amount of iron sulphate (II).

- Surprisingly it has been found that by using the reaction according to the present invention, that is, by carrying out the reaction in the presence of a very high amount of iron (II) salt, a remarkable yield for the specific compounds of formula I can be obtained.

The process according to the present invention is characterized in that a substituted pyridine, preferably a compound of formula II.

Wherein R 4 to R 8 represents hydrogen, lower alkoxy or halogen; Or optionally salts thereof react with formamide and an oxidizing agent in the presence of a high amount of iron (II) salt in an acidic aqueous medium.

The following definitions are stated to illustrate and define the meaning and field of various terms used to describe the invention.

The term "lower" refers to a group consisting of one to seven, preferably one to four carbon atom (s), until otherwise indicated.

The term "lower alkyl" refers to a straight or branched open chain of an alkyl-monovalent radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is also exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, i-butyl, n-butyl, t-butyl and the like.

The term "lower alkoxy" refers to a group -O-R ', wherein R' is a lower alkyl.

The term "halogen" refers to a chlorine, bromine and iodine, with chlorine being preferred.

The term "aryl" refers to an aromatic carbocyclic radical (e.g., phenyl), optionally substituted, independently, with halogen, lower alkyl, lower alkoxy, lower alkylenedioxy, carboxy, trifluoromethyl, and the like.

The term "lower aralkyl" refers to a lower alkyl group substituted by an aryl e.g. phenyl or substituted phenyl, preferably benzyl.

- - The term "heterocyclic" refers to a mono- or bicyclic, heterocycles provided with 5- and 6- members having oxygen, nitrogen or sulfur as the heteroatom such as 2- and 3-furyl, 2-, 4- and 5-membered. -pyrimidinyl, 2-, 3-and 4-pyridyl, 1,2- and 1, -diazinyl, 2- and 3-thienyl, oxazolyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, purinyl, quinolyl, isoquinolyl and quinazolyl, residues which can be replaced, eg by 1 or 2 lower alkyl groups. Preferably, the heterocyclyl is a pyridyl residue or a substituted pyridyl residue.

The term "substituted phenyl" refers to a phenyl group which is mono-, di- or tri-substituted, independently, with halogen, lower alkyl, lower alkoxy, lower alkylenedioxy, carboxy, trifluoromethyl and the like.

The term "substituted pyridyl" refers to a pyridyl group which is mono-, di-, or tri-substituted, independently, with halogen, lower alkyl, lower alkoxy, lower alkylenedioxy, carboxy, trifluoromethyl, and the like.

- - The term "lower alkylenedioxy" refers to a group -O- (CH2) n_0-, wherein n is an integer from two to seven, preferably an integer from two to four.

The term "pharmaceutically acceptable salts" comprises alkali salts such as Na or K salts or alkaline earth metal salts such as Ca or Mg salts or salts with amines such as monoethanolamine as well as salts with organic and inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, which are non-toxic for living organisms.

In a preferred aspect the present invention concerns the preparation of compounds of formula I Where R to R represent hydrogen, lower alkoxy or halogen; characterized in that the process comprises the reaction of a compound of formula II Wherein R 4 to R 8 represents hydrogen, lower alkoxy or halogen; Or optionally salts thereof with formamide and an oxidizing agent in an aqueous acid solution in the presence of 15 to 40% mol of iron (II) salts relative to compounds of formula II. If desired, the compounds of formula I can be obtained as salts.

In another preferred aspect, the reaction is carried out with an iron (II) salt, comprising an anion selected from chloride, bromide, sulfate, phosphate, tetrafluoroborate, or hexafluoroborate. - In still another preferred aspect is the reaction in the presence of 20 to 30 mol% of iron (II) salts concerning compounds of formula (II).

The reaction is carried out at a temperature of 0 ° C to 35 ° C, preferably at a temperature of 0 ° C to 20 ° C, more preferably 0 ° C to 10 ° C.

In another preferred aspect the oxidizing agent is hydrogen peroxide.

In another preferred aspect the reaction is carried out in the presence of about 1.5 to 2.5 moles, preferably about 2 moles of oxidizing agent (with respect to the compound of formula II).

The aqueous acid solution can be an organic or inorganic acid solution e.g. a solution of sulfonic acid.

More particularly, the reaction refers to the conversion of 5- (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidine-4,6-diol to 4- [4,6-dihydroxy-5-] -amide. (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carboxylic acid using the reaction conditions as described above.

The compounds of formula I as defined above can be converted to inhibitors of the endothelin receptor of formula VI Wherein: R1 represents a lower alkyl; - - R represents -O- (CRaRb) n-OR; R4 to R8 represent a hydrogen, lower alkoxy or halogen; R9 represents a hydrogen, aryl, lower aralkyl, heterocyclic or a residue -C (0) NHR10; R10 represents a lower alkyl, phenyl, substituted phenyl or pyridyl or substituted pyridyl; Ra and Rb represents a hydrogen or lower alkyl; and n represents 2,3 or 4; Or you get out of these.

These compounds of formula VI are known and have been described, for example, in International Application Patent WO 9619459.

The process for the preparation of compounds of formula VI can comprise the following steps: A compound of formula I as defined above can be converted to a compound of formula III - Wherein: R 4 to R 8 represent a hydrogen, lower alkoxy or halogen; and hai represents a halogen Or optionally salts of these characterized in that the compound of formula I as defined above reacts with a water scavenger and a halogenating agent. Examples of water scavengers and halogenating agents are P0C13, PCI5 or S0C12, preferably POCI3. The reaction is preferably carried out in a solvent such as ethylamine diisopropyl.

The compounds of formula III as defined above can be converted to compounds of formula IV - - Wherein: R1 represents a lower alkyl; R4 to R8 represents a hydrogen, lower alkoxy or halogen; and hai represents a halogen. U optionally salts of these characterized in that the compounds of formula III react with a compound of formula V Where R1 represents a lower alkyl, preferably a methyl or isopropyl.

The type of reaction is known in the field and can be carried out under basic conditions for example in the presence of a coupling agent, e.g. 1,4-diazobicyclo [2.2.2] octane, together with potassium carbonate in acetone.

The compounds of formula IV as defined above can then be converted to compounds of formula VI Wherein: R1 represents a lower alkyl; R3 represents an -O- (CRaRb) n-OR9; R4 to R8 represents a hydrogen, lower alkoxy or halogen; R9 represents a hydrogen, aryl, lower aralguilo, heterocyclic or a residue -C (O) NHR10; R10 represents a lower alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl; Ra and Rb represent a hydrogen or lower alkyl; and n represents 2,3 or 4; 0 salts of this characterized in that the compound of formula IV as defined above reacts with hydrazine hydrate and a nitrite salt, e.g. an alkali nitrite salt such as sodium nitrite, followed by a reaction under basic conditions with a compound of formula H-O-C (RaRb) n-0R9, wherein R9, R10, Ra, Rb and n have the meaning as defined above.

Alternatively, the compound of formula IV as defined above can be reacted under basic conditions with a compound of formula HOC (RaRb) n ~ 0R9, wherein R9, R10, Ra, RB and n have the meaning as defined above, followed by a reaction with hydrazine hydrate and a nitrite salt as defined above. In the above, the term "basic conditions" is intended to be in the presence of a base, preferably in the presence of a hydroxide of a metal, more preferably in the presence of sodium hydroxide.

The reaction is conveniently carried out by heating, e.g. at 40 ° C-100 ° C, in a glycol corresponding to the compound of formula H-O-C (RaRb) n ~ OR 9 - - as a solvent, e.g. in ethylene glycol when n = 2 and Ra and Rb are hydrogen. R3 is preferably -0 (CH2) nOH and n is preferably 2.

Particularly preferred are the above processes wherein R1 is a lower alkyl; R2 is tetrazolyl; R3 is 2-hydroxy-ethoxy; R4 to R7 are hydrogen and R8 is a lower alkoxy. More particularly preferred is the process wherein R1 is a methyl or isopropyl; R2 is tetrazolyl; R3 is 2-hydroxy-ethoxy; R4 to R7 are hydrogen and R8 is a methoxy.

A particularly preferred aspect of the present invention is the process for the preparation of [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) 5-methyl-pyridine-2-sulfonic acid-pyridine-4-yl] -pyrimidin-4-yl] amide or salts thereof using the reaction conditions as described above characterized in that the process comprises a) The reaction of 5- (2-methoxy-phenoxy) -2-pyridine-4-yl-pyrimidine-4,6-dio] to 4- [4,6-dihydroxy-5- (2-methoxy) acid amide -phenoxy) -pyrimidin-2-yl] -pyridine-2-carboxylic acid as described above; b) The reaction of 4- [4,6-dihydroxy-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carboxylic acid amide to 4- [4,6-dichloro-5] - (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile as described above; c) The reaction of 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile to [6-chloro-2- (2-cyano-pyridine 5-Methyl-pyridine-2-sulfonic acid (4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide as described above; d) the reaction of [5-methyl-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of 5-methyl-pyridine- 2-sulfonic acid [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidine-4 -l] 5-methyl-pyridine-2-sulfonic acid amide or salts thereof as described above.

- Step d) comprises aa) The reaction of [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of 5- methyl-pyridine-2-sulfonic to [6-chloro-2- [2- (hydrazino-imino-methyl) -pyridin-4-yl] -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] - 5-methyl-pyridine-2-sulfonic acid amide by reaction with hydrazine, followed by conversion of the reaction product to [6-chloro-5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo- 5-Methyl-pyridine-2-sulfonic acid 5-yl) -pyridin-4-yl] -pyrimidin-4-yl] -amide or salts thereof by the reaction with an alkali nitrite, eg sodium nitrite; Y bb) The reaction of [6-chloro-5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidin-4-yl] -amide of 5-methyl-pyridine-2-sulfonic acid to [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridine- 5-Methyl-pyridine-2-sulfonic acid 4-yl] -pyrimidin-4-yl] -amide or salts thereof by the reaction with ethylene glycol; - - The sequence of the corresponding reactions of steps aa) and bb) can be optionally exchanged.

Another particularly preferred aspect of the present invention is the process for the preparation of [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (1H-tetrazolo-5-yl) 5-isopropyl-pyridine-2-sulfonic acid-pyridine-4-yl] -pyrimidin-4-yl] amide or salts thereof using the reaction conditions as described above characterized in that the process comprises steps a) and b) as described above followed by c) The reaction of 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile to [6-chloro-2- (2-cyano-pyridine 5-isopropyl-pyridine-2-sulfonic acid (4-yl) -5- (2-methoxy-phenoxy) -pyrimidine-4-yl] -amide as described above; d) the reaction of 5-isopropyl-pyridine-6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide 2-sulfonic acid [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidine-4 -l] 5-isopropyl-pyridine-2-sulfonic acid amide or salts thereof as described above.

Step d) comprises aa) The reaction of [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of 5- isopropyl-pyridine-2-sulfonic acid [6- chloro-2- [2- (hydrazino-imino-methyl) -pyridin-4-yl] -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] - 5-isopropyl-pyridine-2-sulfonic acid amide by reaction with hydrazine, followed by conversion of the reaction product to [6-chloro-5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo- 5-isopropyl-pyridine-2-sulfonic acid 5-yl) -pyridin-4-yl] -pyrimidin-4-yl] -amide or the salts thereof by the reaction with an alkali nitrite, eg sodium nitrite; Y bb) The reaction of [6-chloro-5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidin-4-yl] -amide of 5-isopropyl-pyridine-2-sulfonic acid to [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridine- 5-isopropyl-pyridine-2-sulfonic acid 4-yl] -pyrimidin-4-yl] -amide or salts thereof by the reaction with ethylene glycol; the sequence of the corresponding reactions of steps aa) and bb) can optionally be exchanged.

The compounds of formula I and their salts are novel and are also part of the present invention: Wherein R 4 to R 8 represent a hydrogen, lower alkoxy or halogen; Particularly preferred are the compounds of formula I and salts thereof as defined above, wherein R 4 to R 7 represent a hydrogen and R 8 represents a lower alkoxy. More particularly preferred is the 4- [4,6-dihydroxy-5- (2-methoxy-phenoxy) -pyrimidin-2-yl] -pyridine-2-carboxylic acid amide and salts thereof.

Another aspect of the present invention are compounds of formula III and their salts: Where R to R represent hydrogen, lower alkoxy or halogen; and hai represents halogen; Particularly preferred are the compounds of formula III and salts thereof as defined above wherein R4 to R7 represent a hydrogen, R8 represents lower alkoxy, and hai represents chloro. More particularly preferred is 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidin-2-yl] -pyridine-2-carbonitrile and salts thereof.

In addition, the compounds of formula IV and their salts are novel and also form part of the present invention: Wherein: R1 represents a lower alkyl R4 to R8 represents a hydrogen, lower alkoxy or halogen; and hai represents a halogen; Particularly preferred are the compounds of formula IV and salts thereof as defined above and wherein R 1 represents a methyl or isopropyl, R4 to R7 represents a hydrogen, R8 represents a lower alkoxy and hai represents a chlorine. More particularly preferred are [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of 5-methyl-pyridine- 2-sulfonic acid and salts thereof as well as [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of 5- isopropyl-pyridine-2-sulfonic acid and salts thereof.

The compounds of formula VI as defined above can be converted in a known manner into pharmaceutically acceptable salts. The compounds of formula I to IV as defined above may optionally be obtained as salts, for example as pharmaceutically acceptable salts, or of course as other salts, which do not necessarily have to be pharmaceutically acceptable.

The compounds which are used as starting materials in the present invention are known from WO 9619459 or can be prepared in analogy to the methods described herein. In principle, the preparation of the starting compounds comprises the reaction of 4-amidino-pyridine hydrochloride with the corresponding dimethyl- or diethyl (2-methoxyphenoxy) malonate.

- - The following examples illustrate the preferred aspects of the present invention but it is not intended to limit the scope of the invention.

EXAMPLES EXAMPLE 1 1360 ml of formamide are added to 136 g (437 mmol) of 5- (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidine-4,6-diol. Then at a temperature of 0 ° C, 11.7 ml (219 mmol) of concentrated sulfuric acid and then 36.5 g (130 mmol) of iron (II) sulfate heptahydrate are added to the suspension. Then 89 ml (874 mmol) of 30% hydrogen peroxide is added as drops in 1 hr at a temperature of 0 ° C to 5 ° C. The viscous yellow-brown suspension is stirred at 0 ° C for 1.5 hrs. Subsequently, a solution of 88g (437 mmol) of sodium pyrosulfite e? 680 ml of deionized water is added dropwise to the reaction mixture in 3D min from 0 ° C to 5 ° C and the reaction mixture is stirred at a temperature of 0 ° C to 5 ° C for 30 min. The suspension is then filtered under reduced pressure. The filtrate is first washed with 1750 ml of deionized water and then with 700 ml of ethanol. Then the solid is dried at 80 ° C, 2000 Pa for 16 hrs. Obtaining 132.4 g (91% theory) of 4- [4,6-dihydroxy-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carboxylic acid amide with an HPLC purity of 91.4 % (p / p).

PREPARATION OF STARTING MATERIAL: ~ a) 53.1 g of 4-cyano-pyridine (98%) is added immediately to a solution of 1.15 g of sodium in 200 ml of pure MeOH. After 6 hr 29.5 g of NHC1 are added and vigorously stirred for a while. The mixture is stirred at room temperature overnight. 600 ml of ether are added thereto, after which the precipitate is filtered under suction and then dried at 50 ° C under reduced pressure. In this way, 4-amidino-pyridine hydrochloride (decomposition point of 245-247 ° C) is obtained. b) 112.9 g of diethyl (2-methoxyphenoxy) malonate are added in the form of drops for 30 min. to a solution of 27.60 g of sodium in 400 ml of MeOH. Then 74.86 g of the amidine hydrochloride is obtained in a) everything is added instantly. The mixture is stirred at room temperature overnight and evaporated at 50 ° C under reduced pressure. The residue is treated with 500 ml of ether and filtered under suction. The filtered layer is dissolved in 1000 ml of H20 and treated slowly with 50 ml of CH3COOH. The precipitate is filtered under suction, washed with 400 ml of H20 and dried at 80 ° C under reduced pressure. In this manner, 5- (2-methoxy-phenoxy) -2- (pyridin-4-yl) -pyrimidine-4,6-diol (or tautomer) is obtained, with a melting point above 250 ° C.

EXAMPLE 2 In 20 min. 61 ml (633 mmol) of P0C13 are added dropwise to 34 ml (200 mmol) of diisopropyl ethylamine at a temperature of 5 ° C to 10 ° C followed by stirring at a temperature of 5 ° C to 10 ° C. C for 15 min. Then 23.5 g (66 mmol) of 4- [4,6-dihydroxy-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carboxylic acid amide are added in four portions under cooling followed by stirring at 90 ° C for 25 hr. The reaction mixture is cooled to below 20 ° C and transferred to a new flask together with 50 ml of dichloromethane. The volatile compositions (i.e. excess of POCI3) are removed by evaporation at a temperature of 20 ° C to 70 ° C followed by a redistillation with 100 ml of toluene. Then 250 ml of dichloromethane is added to the residue (88 g of a black oil), the solution is heated to a temperature of 36 ° C to 40 ° C and 80 ml of deionized water are added in the form of drops in 30 min. whereby the pH is kept constant due to the subsequent addition of 28% of a NaOH solution (60 ml) for a time of 5 to 6 hr. The mixture is stirred at a temperature of 35 ° C to 40 ° C for 30 min. Followed by the elimination of dichloromethane by distillation. The resulting suspension is allowed to cool to below 20 ° C and is stirred for an additional 2 hr. The solid is filtered under suction, washed with 500 ml of water and dried at 70 ° C, 2000 Pa for 16 hr. Obtaining 21.3 g (86% theory) of 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile with an HPLC purity of 94.3% (p. / p).

EXAMPLE 3 12. 5 g (33.5 mmol) of 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile and 6.06 g (35-myolol) of 5-methyl- pyridine-2-sulfonamide are added to 130 ml of acetone. 15 g of potassium carbonate and 190 mg (1.6 mmol) of 1,4-diazobicyclo [2,2,2] octane are added and the suspension is stirred at 40 ° C for 5 h and at 20 ° C for 15 hr.

- Then 50 ml of deionized water followed by a dropwise addition of 50 ml of 3 N hydrochloric acid (pH of the solution = 1). The acetone removed by evaporation and the suspension is stirred for 1 hr. The solid is filtered and washed with 100 ml of water. The residue is heated (reflux) in 100 ml of methanol for 1 hr followed by cooling to 20 ° C. The solid is filtered and dried at 80 ° C, 2000 Pa for 16 hr. Obtaining 16. Og (93% theory) of [6-chloro-2- (2-cians-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of the acid 5-methyl-pyridine-2-sulfonic acid with a HPLC purity of 90.3% (w / w).

EXAMPLE 4 8. 95 g (24 mmol) of 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidin-2-yl] -pyridine-2-carbonitrile are suspended in 100 ml of acetone at a temperature of 20 ml. ° C, 5.04 g (25 mmol) of 5-isopropyl-pyridine-2-sulfonamide, 1 ml of deionized water, 10.6 g (77 mmol) of potassium carbonate and 135 mg (1.2 mmol) of 1,4-diazobicyclo [ 2,2,2] octane are added. The reaction mixture is stirred for 24 hr at 40 ° C followed by cooling to 20 ° C. Then 50 ml of deionized water and 45 ml of 3N aqueous hydrochloric acid are slowly added until pH = 1. The acetone is removed by distillation and the resulting suspension is stirred at 20 ° C for 1.5 hr. The solid is filtered under suction, washed first with 100 ml of deionized water and then with 50 ml of t-butylmethylether. Then the solid is dried at 70 ° C, 2000 Pa for 20 hr. 13.2 g (102% theory) of [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) pyrimidin-4-yl] -amide of the acid is obtained. -isopropyl-pyridine-2-sulfonic acid with a purity of 87.8% (w / w).

EXAMPLE 5 g (39 mmol) of [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) pyrimidin-4-yl] -amide of 5-methyl-pyridine 2-Sulfonic acid are suspended in 100 ml of N, -dimethyl formamide and 7.6 ml (156 mmol) of hydrazine hydrate are added in 15 min. The reaction mixture is allowed to warm slowly to 20 ° C. After 17.5 hrs, at a temperature of 15 ° C, 250 ml of deionized water is added followed by the slow addition of 10.5 ml of acetic acid (up to pH = 5.4). The resulting suspension is stirred 2 hrs at 20 ° C and then for 2 additional hrs at 0 ° C. The solid is filtered under suction, first washed with - - 200 ml of deionized water and then with 100 ml of t-butylmethylether. The residue is dried at 40 ° C 2000 Pa per lhrs. Obtaining 21.7 g (102% theory) of [6-chloro-2- [2- (hydrazino-imino-methyl) -pyridin-4-yl] -5- (2-methoxy-phenoxy) -pyrimidine-4-yl ] -amide 5-methyl-pyridine-2-sulfonic acid with a HPLC purity of 81.4% (w / w).

EXAMPLE 6 122 g (233 mmol) of [6-chloro-2- [2- (cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of 5-isopropyl acid -pyridine-2-sulfonic acid are suspended in 450 ml of N, N-dimethyl formamide and the mixture is cooled to below 15 ° C. At this temperature, 35 ml of hydrazine hydrate are added as drops in 1 hr. The resulting solution is stirred at a temperature of 15 ° C to 20 ° C for 16 hr and then diluted with 600 ml of deionized water. Then 50 ml of glacial acetic acid is added in the form of drops at a temperature of 0 ° C to 5 ° C until a pH = 5.5. 600 g of ice are added and the suspension is stirred for 1 hr. The solid is filtered under suction, washed with 3000 ml of water and dried at 40 ° C, 2000 Pa per 24 hr. Obtaining 126 g (97% theory) of [6-chloro-2- [2- (hydrazino-imino-methyl) -pyridin-4-yl] -5- (2-methoxy-phenoxy) -pyrimidine-4-yl ] -amide of 5-isopropyl-pyridine-2-sulfonic acid with a HPLC purity of 91.8% (w / w).

EXAMPLE 7 g (37 mmol) of [6-chloro-2- [2- (hydrazino-imino-methyl) -pyridin-4-yl] -5- (2-methoxy-phenoxy) -pyrimidine-4-yl] -amide of 5-methyl-pyridine-2-sulfonic acid are added to 160 ml of N, N-dimethyl formamide. To this solution it is added in the form of drops 23 ml of 6 N hydrochloric acid at a temperature of 15 ° C. Then a solution containing 5.1 g (71 mmol) of sodium nitrate in 20 ml of deionized water is added slowly. The reaction mixture is allowed to warm above 20 ° C and is stirred for 1.5 hrs. Then 160 ml of deionized water is added and the suspension is stirred for 1 hr. The solid is filtered under suction at 50 ° C, washed with 100 ml of deionized water and dried at 50 ° C, 2000 Pa for 17 hr. Obtaining in this way 18.9 g (92% theory) of [6-chloro-5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] - 5-methyl-pyridine-2-sulfonic acid pyrimidin-4-yl] -amide with an HPLC purity of 89.6% (w / w).

EXAMPLE 8 g (35 mmol) of [6-chloro-2- [2- (hydrazino-imino-methyl) -pyridin-4-yl] -5- (2-methoxy-phenoxy) -pyrimidine-4-yl] -amide of 5-isopropyl-pyridine-2-sulfonic acid are added to 160 ml of N, N-dimethyl formamide. The solution is maintained at a temperature of 15 ° C to 20 ° C and 23 ml of aqueous 6 N hydrochloric acid is added, followed by the addition of a solution containing 4.8 g (7 mmol) of sodium nitrite in 20 ml of deionized water in 10 min. The mixture is stirred at 20 ° C for 1 hr, then 140 ml of deionized water is added and the suspension is stirred at 0 ° C for 1 hr. The solid is filtered, first washed with 80 ml of deionized water and then with 80 ml of t-butylmethylether. Then the solid is dried at 70 ° C and 2000 Pa for 16 hrs. The crude product (23.4 g) is taken with 117 ml of tetrahydrofuran for 1 hr. After filtration at 0 ° C the catalyzed product is washed with 25 ml of t-butylmethylether and then dried at 70 ° C, 2000 Pa for 16 hrs. Obtaining 17.3 g (84% theory) of [6-chloro-5- (2-methoxy-ethoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidine-4 -yl] -amide of 5-isopropyl-pyridine-2-sulfonic acid with a HPLC purity of 91.1% (w / w).

- - EXAMPLE 9 g (27 mmol) of [6-chloro-5- (2-methoxy-ethoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidin-4-yl] 5-Methyl-pyridine-2-sulfonic acid amide is suspended in 75 ml of ethylene glycol and 6.5 g (163 mmol) of sodium hydroxide are added. The reaction mixture is heated to 85 ° C and stirred for 5 hr. Then 55 ml of deionized water and then 55 ml of 3 N aqueous hydrochloric acid are added in the form of drops. The suspension is stirred at 20 ° C for 1 hr. The solid is filtered under suction, washed with 150 ml of deionized water and dried at 70 ° C, 2000 Pa for 17 hrs. The crude product (16.4 g) is dissolved in 50 ml of N, N-dimethyl formamide and 40 ml of dioxane at 70 ° C. Gas monoxide is introduced into this solution until pH = 9. The resulting suspension is allowed to warm slowly. The suspension is stirred at 0 ° C. The solid is filtered under suction, first washed with 25 ml of dioxane and then with 25 ml of ethanol. Then the solid is dried at 50 ° C 2000 Pa for 23 hrs. The resulting ammonium salt (10.4 g, 17.5 mmol) is suspended in 50 ml of methanol and then 6.3 ml (35 mmol) of a 5.4 N sodium methylate solution are added. The solution is heated (refluxed) for 3 hrs, - - it cools slowly below 20 ° C and then at 0 ° C. The solid is recovered by filtration, washed with 10 ml of cold methanol as ice and dried at 70 ° C, 2000 Pa for 17 hrs. Obtaining in this way 6.9 g (41% theory) of sodium salt [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl 5-methyl-pyridine-2-sulfonic acid (1: 2) -pyridin-4-yl] -pyrimid-4-yl] -amide with an HPLC purity of 98.2% (w / w).

EXAMPLE 10 6. 2 g of sodium hydroxide are added to 15 g (26 mmol) of [6-chloro-5- (2-methoxy-ethoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridine-4- yl] -pyrimidin-4-yl] -amide of 5-isopropyl-pyridine-2-sulfonic acid and 75 ml of ethylene glycol. The mixture is heated to 85 ° C for 5 hrs. Then 55 ml of deionized water are added and then 55 ml of 3N hydrochloric acid are added in the form of drops. The mixture is allowed to cool below 20 ° C and is stirred for 1 hr. The solid is filtered and dried at 70 ° C, 2000 Pa for 18 hrs. Obtaining 16.2 g (103%) of [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] 5-isopropyl-pyridine-2-sulfonic acid-pyrimidine-4-yl] -amide with an HPLC purity of 92% (w / w) • 80 ml of dioxane and 80 ml of ethanol are added to this solid. At a temperature of 60 ° C, gaseous ammonia is introduced into the liquid until a pH = 9 to 10. The resulting suspension is allowed to cool below 20 ° C and is stirred at 20 ° C for 20 hrs and then at 0 ° C for 2.5 hrs. Then the solid is filtered and dried at 70 ° C, 2000 Pa for 18 hrs. Obtaining 14.2 g of a mono ammonium salt with an HPLC purity of 96.2% (w / w). The solid is heated (refluxed) in 70 ml of methanol, cooled slowly below 20 ° C and stirred at 20 ° C for 19 hrs and then at 0 ° C for 2 hrs. Then the solid is filtered and dried at 70 ° C, 2000 Pa for 19 hrs. Obtaining in this way 11.5 g (66% theory) of the sodium salt [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5- 5-isopropyl-pyridine-2-sulfonic acid (1: 2) yl) -pyridin-4-yl] -pyrimid-4-yl] -amide with an HPLC purity of 98.6% (w / w).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (23)

- - CLAIMS

1. A compound for the preparation of compounds of formula I in which R to Rh represent hydrogen, lower alkoxy or halogen; or optionally salts thereof and also characterized in that the process comprises the reaction of a compound of formula II wherein R a R represents hydrogen, lower alkoxy or halogen; - Or optionally salts thereof with formamide in an acidic aqueous solution in the presence of 15 to 40 mol% of iron (II) salts concerning compounds of formula II and an oxidizing agent if desired.

2. The process according to claim 1, characterized in that said reaction is carried out with an iron (II) salt, comprising an anion selected from chloride, bromide, sulfate, phosphate, tetrafluoroborate, or hexafluoroborate.

3. The process according to any of claims 1 to 2, characterized in that the reaction is carried out at a temperature of 0 ° C to 35 ° C.

4. The process according to any of claims 1 to 3, characterized in that the reaction is carried out in the presence of 20 to 30 mol% of iron (II) salts relative to compounds of formula (II).

5. The process according to any of claims 1 to 4, characterized in that the oxidizing agent is hydrogen peroxide. - -

6. The process according to any of claims 1 or 5, characterized in that it is followed by the transformation of the compound of formula I as defined above in claim I into a compound of formula III Qn wherein R4 to R8 represent a hydrogen, lower alkoxy or halogen; and hai represents a halogen or optionally salts of these characterized in that the compound of formula I reacts with a water scavenger and a halogenating agent.

7. The process according to claim 6, characterized in that the scavenging water and the halogenated agent is P0C13. -

8. The process according to any of claims 6 or 7, followed by the transformation of a compound of formula III as defined above in claim 6 to a compound of formula IV. wherein: R "represents a lower alkyl, R a Re represents a hydrogen, lower alkoxy or halogen, and hal represents a halogen. or optionally salts of these characterized in that the compounds of formula III react with a compound of formula V -. t J5n where R1 represents a lower alkyl;

9. The process according to claim, followed by the transformation of a compound of formula IV as defined above in claim 8, to a compound of formula VI Characterized in that: R1 represents a lower alkyl; and R3 represents -O- (CRaRb) n-OR9; R4 to R8 represent a hydrogen, lower alkoxy or halogen; R9 represents a hydrogen, aryl, lower aralkyl, heterocyclic or a residue -C (0) NHR10; - R10 represents a lower alkyl, phenyl, substituted phenyl, pyridyl or substituted pyridyl Ra and Rb represents a hydrogen or lower alkyl; and n represents 2,3 or 4; Or salts thereof characterized in that the compound of formula IV as defined above reacts with hydrazine hydrate and a nitrite salt, followed by a reaction under basic conditions with a compound of formula HOC (RaRb) n-OR9, wherein R9 , R10, Ra, Rb and n have the meaning as defined above.

10. The compound according to claim 9, characterized in that, the compound of formula IV can react with a compound of formula HOC (RaRb) n-OR9, wherein R9, R10, Ra, RB and n have the meaning as defined above, followed by a reaction with hydrazine hydrate and a nitrite salt.

11. The process according to any of claims 1 to 10, characterized in that wherein R1 is methyl; R2 is tetrazolyl; R3 is 2-hydroxy-ethoxy; R4 to R7 are hydrogen and R8 is methoxy.

12. The process according to any of claims 1 to 10, characterized in that wherein R "is isopropyl, R2 is tetrazolyl, R3 is 2-hydroxy-ethoxy, R" to R 'are hydrogen and R8 is methoxy.

13. A process for the preparation of 4- [4,6-dihydroxy-5- (2-methoxy-phenoxy) -pyrimidin-2-yl] -pyridine-2-carboxylic acid amide characterized in that the process comprises the reaction of (2-methoxy-phenoxy) -2-pyridin-4-yl-pyrimidine-4,6-diol according to any of claims 1-5.

14. A process for the preparation of [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidine 4-yl] 5-methyl-pyridine-2-sulfonic acid amide or salts thereof characterized in that the process comprises a) The reaction of • 5- (2-methoxy-phenoxy) -2-pyridine-4-pyrimidine-4,6-diol to 4- [4,6-dihydroxy-5- (2- methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carboxylic acid according to any of claims 1 to 5; - - b) the reaction of 4- [4,6-dihydroxy-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carboxylic acid amide to 4- [4,6-dichloro] -5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile according to any of claims 6 to 7; c) the reaction of 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile to [6-chloro-2- (2-cyano-pyridine 5-methyl-pyridine-2-sulfonic acid (4-yl) -5- (2-methoxy-phenoxy) -pyrimidine-4-yl] -amide according to claim 8; d) the reaction of [5-methyl-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -amide of 5-methyl-pyridine- 2-sulfonic acid [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidine-4 -l] 5-methyl-pyridine-2-sulfonic acid amide or salts thereof according to any of claims 9 to 10;

15. A process according to claim characterized in that aa) the reaction of [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] - 5-Methyl-pyridine-2-sulphonic acid amide to [6-chloro-2- [2- (hydrazino-imino-methyl) -pyridin-4-yl] -5- (2-methoxy-phenoxy) -pyrimidine- 4-yl] -amide of 5-methyl-pyridine-2-sulfonic acid by reaction with hydrazine, followed by conversion of the reaction product to [6-chloro-5- (2-methoxy-phenoxy) -2- [2- 5-Methyl-pyridine-2-sulfonic acid (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidin-4-yl] -amide or salts thereof by the reaction with an alkali nitrite, eg sodium nitrite; Y bb) the reaction of [6-chloro-5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidin-4-yl] -amide of 5-methyl-pyridine-2-sulfonic acid to [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridine- 5-Methyl-pyridine-2-sulfonic acid 4-yl] -pyrimidin-4-yl] -amide or salts thereof by the reaction with ethylene glycol; where the sequence of the corresponding reactions of steps aa) and bb) can optionally be exchanged.

16. A process for the preparation of [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidine 5-isopropyl-pyridine-2-sulfonic acid amide or salts thereof using the reaction conditions as described above characterized in that the process comprises a) the reaction of 5- (2-methoxy-phenoxy) -2-pyridine-4-yl-pyrimidine-4,6-diol to 4- [4,6-dihydroxy-5- (2-methoxy) acid amide phenoxy) -pyrimidin-2-yl] -pyridine-2-carboxylic acid according to any of claims 1 to 5; b) the reaction of 4- [4,6-dihydroxy-5- (2-methoxy-phenoxy) -pyrimidin-2-yl] -pyridine-2-carboxylic acid amide to 4- [4,6-dichloro-5] - (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile according to any of claims 6 to 7; c) the reaction of 4- [4,6-dichloro-5- (2-methoxy-phenoxy) -pyrimidine-2-yl] -pyridine-2-carbonitrile to [6-chloro-2- (2-cyano-pyridine 5-isopropyl-pyridine-2-sulfonic acid (4-yl) -5- (2-methoxy-phenoxy) -pyrimidine-4-yl] -amide according to claim 8; d) the reaction of 5-isopropyl-pyridine [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -? irimidin-4-yl] -amide -2-sulphonic to [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidine- 5-isopropyl-pyridine-2-sulfonic acid 4-yl] amide or salts thereof according to any of claims 9 to 10;

17. A process according to claim characterized in that - aa) the reaction of [6-chloro-2- (2-cyano-pyridin-4-yl) -5- (2-methoxy-phenoxy) -pyrimidine-4-yl) ] - 5-methyl-pyridine-2-sulfonic acid a [6- chloro-2- [2- (hydrazino-imino-methyl) -pyridine-4-yl] -5- (2-methoxy-phenoxy) - pyrimidin-4-yl] -amide of 5-methyl-pyridine-2-sulfonic acid by reaction with hydrazine, followed by conversion of the reaction product to [6-chloro-5- (2-methoxy-phenoxy) -2- [ 5-Methyl-pyridine-2-sulfonic acid 2- (1H-tetrazolo-5-yl) -pyridin-4-yl] -10-pyrimidin-4-yl] -amide or salts thereof by the reaction with an alkali nitrite , eg sodium nitrite; Y 15 bb) the reaction of [6-chloro-5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -pyridin-4-yl] -pyrimidin-4-yl] - 5-Methyl-pyridine-2-sulfonic acid amide a [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) -20 5-methyl-pyridine-2-sulfonic acid pyridin-4-yl] -pyrimidin-4-yl] -amide or salts thereof by the reaction with ethylene glycol; - - where the sequence of the corresponding reactions of steps aa) and bb) can optionally be exchanged.

18. The use of the process according to any of claims 1 to 17 for the production of compounds of formula VI characterized in that: R "represents a lower alkyl, R" represents -O- (CR3Rb) r-OR °; R "to R" represent a hydrogen, lower alkoxy or halogen; R01 represents a hydrogen, aryl, lower aralkyl, heterocyclic or a residue -C (0) NHR? p; R1 represents a lower alkyl, phenyl, substituted phenyl or pyridyl or substituted pyridyl; - 9 - Ra and Rb represents a hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof.

19. The use according to claim 18 characterized in that it is for the production of [6 (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) - 5-methyl-pyridine-2-sulfonic acid pyridin-4-yl] -pyrimidin-4-yl] -amide and the pharmaceutically acceptable salts thereof.

20. The use according to claim 18 characterized in that it is for the production of [6 (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- [2- (lH-tetrazolo-5-yl) - 5-isopropyl-pyridine-2-sulfonic acid pyridin-4-yl] -pyrimidin-4-yl] -amide and the pharmaceutically acceptable salts thereof.

21 A compound of formula I characterized in that: R4 to R8 represent hydrogen, lower alkyl or halogen.

22. A compound of formula ttt_ characterized in that: R4 to RB represent hydrogen, lower alkoxy or halogen; Hal represents halogen

23. A compound of formula IV Characterized in that: R1 represents a lower alkyl; R4 to R8 represents a hydrogen, lower alkoxy or halogen; and hal represents a halogen.