ES2211317B1 - INTERMEDIATE COMPOUNDS FOR OBTAINING ANTIHIPERTENSIVE ACTIVE PRINCIPLES AND CORRESPONDING PROCEDURES. - Google Patents

Abstract

Intermediate compounds for obtaining antihypertensive active ingredients and corresponding procedures. The new compound of general formula (II), where R is methyl, phenyl or 4-methylphenyl, is obtained by reacting the sulfonic acid chloride of formula CI-SO2-R with the corresponding alcohol in an inert solvent. The reaction of the sulfonate group (-OSO2-R) with the ammonium group (-NH3 +) is carried out by reaction of (II) with ammonia. Pharmaceutically acceptable amlodipine sulphonates (e.g. mesylate, besylate, tosylate) can be isolated from the reaction medium without the need to previously isolate amlodipine, which entails significant advantages. If, on the contrary, the reaction medium is basified, amlodipine (I) can be isolated and subsequently transformed into other salts, such as maleate. Amlodipine and its salts have industrial applicability as antihypertensive active ingredients.

Description

Intermediate compounds for obtaining antihypertensive active ingredients and procedures corresponding.

Field of the Invention

The present invention relates to new intermediate compounds for the preparation of active ingredients Pharmacists with antihypertensive activity, as well as procedures for obtaining it and procedures for its utilization.

State of the art

Amlodipine is the international common denomination (DCI) of 2 - [(2-aminoethoxy) -methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl, of formula (I).

2

This compound is known since publication. of European patent application EP 89.167-A, document in which two procedures are also described alternatives for its preparation: one of them comprising the deprotection of an intermediate in which the amino group is find protected; and the other comprising reducing a intermediate in which an azide group is transformed into the amino group. The intermediates are obtained by means of variants of the Hantzsch synthesis to obtain dihydropyridines substituted, reaction well known to those skilled in the art. As illustrated below, they have subsequently been published other procedures for obtaining amlodipine, as well as various industrially applicable intermediates for that purpose

In US Patent 5,723,618 the obtaining amlodipine by reductive amination of an intermediate aldehyde, as well as by reaction of this aldehyde with hydrochloride hydroxylamine and a base to give the oxime, and its subsequent reduction to amine. In application WO 99/25688-A, describes obtaining amlodipine by reaction with hydroxylamine of intermediates that have an acetal in the side chain, to give the oxime, and the subsequent reduction of this to amine; in the application WO 99/25689-A describes obtaining said acetal intermediates through different combinations of the Hantzsch synthesis. In the application WO 00/24714-A intermediate obtaining is described 3-amino-4 - ((2-phthalimido) ethoxy) crotonate of ethyl, already mentioned in the EP application 89.167-A.

Although there are several salts of amlodipine that present commercial interest, the most used until today has been the salt with benzenesulfonic acid, that is, benzenesulfonate or amlodipine besylate. In the EP request 244.944-A describes amlodipine besylate and a  process for its preparation comprising the reaction of amlodipine with a solution of benzenesulfonic acid or its salt Ammonia WO 99/52873-A describes a procedure for obtaining amlodipine besylate by displacement of the anion of other amlodipine salts by reaction with an alkali metal besylate. In the EP request 599.220-A describes a procedure for obtaining of amlodipine besylate consisting of destritilar, in the presence of benzenesulfonic acid, an amlodipine intermediate protected in its amino group with the trityl group. In the EP request 902.016-A describes obtaining besylate of amlodipine by applying the known Reaction of Delpine, namely the reaction of an iodinated intermediate with hexamethylenetetramine and the subsequent reaction of the resulting salt with benzenesulfonic acid. In the WO application 01/02360-A describes obtaining the besylate of amlodipine by reaction of a phthalimidic intermediate of amlodipine with benzenesulfonic acid.

The prior art illustrates the difficulty and the existing interest in finding alternative procedures for obtaining new intermediates that allow amlodipine to be prepared and its pharmaceutically acceptable salts, without interest being limited to amlodipine besylate salt.

Summary of the invention

According to one aspect of the present invention, provide new compounds of general formula (II)

3

where R is a selected radical of the group formed by (C 1 -C 4) - alkyl, phenyl and mono- or disubstituted phenyl radicals (C 1 -C 4) -alkyl. The Compounds (III) are useful as intermediates for obtaining amlodipine and its pharmaceutically acceptable salts. Result preferred compounds (II) in which R is selected from the group formed by methyl, phenyl and 4-methylphenyl.

Another aspect of the invention relates to a method of obtaining the compound (III) comprising making reacting the alcohol of formula (IIIb) with a chloride of sulfonic acid of formula Cl-SO2 -R in a solvent inert, as represented in the following scheme:

4

Inert solvents can be, for example, chlorinated solvents such as methylene chloride, chloroform, carbon tetrachloride or perchlorethylene; or hydrocarbons aromatics such as benzene, toluene or xylene (i.e. mixtures of o-, m- and p-xylene). Preferably the reaction it is performed in the presence of an acid pickup compound, such as a tertiary amine (eg triethylamine or pyridine), and at a temperature between 0 ° C and the reflux temperature of solvent used

Alcohol (III_ {b}) is known and can be obtained as described in Example 1 of the ES patent 550,965, by reduction with diborane of a precursor carboxylic, although this procedure is cumbersome and little appropriate from the industrial point of view. Preferably the Alcohol (III_b) can be obtained by Hantzsch synthesis, according to any of the alternatives reflected in the following scheme:

5

         \ vskip1.000000 \ baselineskip
      

In scheme X it represents a halogen, preferably chlorine or bromine, and R2 represents a protective group (GP) of hydroxyl and, in the case of intermediates (IV), (VI) and (VII), may also represent hydrogen. Hydroxyl protecting groups are well known to those skilled in the art, for example from the monograph of TW Greene & PGM Wuts ("Protective Groups in Organic Synthesis", Third edition, 1999, pp 17-246, John Wiley & Sons) As the hydroxyl protecting group, tetrahydropyranyl ether is preferred, the formation and rupture of which is described in great detail on p. 49-54 of the cited book, although the person skilled in the art will appreciate any equivalent substitution thereof among the other known hydroxyl protecting groups. In a first alternative indicated in the scheme, one starts from the ethyl 4-chloroacetoacetate and monoprotected ethylene glycol, and passes through intermediates (VII) and (IV), following a method analogous to that described to prepare bioisteroster compounds of the amlodipine containing two chlorine atoms in the benzene ring (cf. S. Yiu et al., Arch. Pharm. Med. Chem. 1999, vol. 332, pp. 363-367). In a second alternative indicated in the scheme, the ketoester (VII) is transformed into the enamine (VI), by reaction with ammonium acetate, and said enamine (VI) is reacted with the compound (V) obtained by the conventional reaction of 2-Chlorobenzaldehyde and methyl acetoacetate. Once the intermediate (VII) is obtained, the hydroxyl group can be deprotected and the next steps can be continued or, if desired, protection can be maintained throughout the different stages, even until the compound (III_ {a }) which is a precursor of alcohol (IIIb) protected with the protective group R2 = GP.

A third aspect of the present invention is refers to a method of using the compounds (II) which comprises reacting them in a suitable medium with ammonia, to carry out the replacement of the sulfonate group (-OSO2 -R) by the ammonium group (-NH_3 +). In one case, the reaction is carried out with a dissolution of ammonia in water or in mixtures of water and a aliphatic monoalcohol- (C 1 -C 6). In other case, the reaction is carried out with ammonia gas under pressure in a non-aqueous solvent, solvents being preferred selected from the group consisting of a monoalcohol aliphatic- (C 1 -C 6), benzene, toluene, xylene, an aliphatic ether- (C 4 -C 6) and its mixtures

A particular embodiment of the procedure of Use of the present invention relates to insulation, directly from the reaction medium, from the amlodipine salt corresponding to sulfonic acid HO-SO_ {2} -R, without the need for basify to form and / or previously isolate amlodipine. When R = phenyl, this embodiment carries the advantage of simplicity and efficacy with respect to the procedures known in the art for obtaining amlodipine besylate. In addition, it has the advantage additionally can be used for other amlodipine sulphonates, such as mesylate (R = methyl) or tosylate (R = 4-methylphenyl).

In another embodiment, the means of reaction to form amlodipine (I). Preferably, (I) is separates from the reaction medium and then reacts with the appropriate amount of a pharmaceutically acceptable acid to get the desired salt. Regarding the procedures of obtaining amlodipine besylate known in the art, this procedure has the advantage that other ones can be prepared pharmaceutically acceptable salts of amlodipine, including types other than sulphonates. Thus, e.g., hydrochloride can be prepared, hydrobromide, sulfate, phosphates, acetate, maleate (1: 1), hemimaleate, fumarate, lactate, tartrate, citrate, gluconate, tosylate, mesylate and succinate. Especially preferred is the obtaining amlodipine maleate (1: 1) by reaction with acid maleic, described in detail in the attached examples.

In summary, from an industrial point of view the The present invention provides simple, clean and effective in obtaining amlodipine base and / or several of its salts pharmaceutically acceptable (besylate, maleate and many more), what which is feasible thanks to the preparation of the new intermediates of formula (II), with high yields and high purity, and through relatively economic transformations.

The invention is illustrated below by several detailed examples, which should not be considered limiting of the scope of protection, indicated in the claims attached. From the information provided and knowledge common and general, the subject matter expert will find it evident how to execute the invention in all its scope. Along the description and claims, the word "understand" and its variations are used in the sense of not pretending to exclude others elements, components or stages.

Examples Example 1 Preparation of 1,4-dihydro-2 - [(2-benzenesulfonyloxyethoxy) methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl (II with R = phenyl)

\hbox{193 ml}

de una disolución de bicarbonato sódico al 2%, y posteriormente una vez con 363 ml de agua. Se concentró la fase orgánica por destilación a presión reducida hasta un sexto de su volumen inicial. Se enfrió la solución y se recuperó el producto cristalizado por filtración, obteniéndose 100,3 g (76 %) del compuesto del título, caracterizado por los siguientes datos analíticos:48.7 g of triethylamine were added to a dispersion of 98.5 g of 1,4-dihydro-2 - [(2-hydroxyethoxy) methyl-6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl (IIIb) in 200 ml of xylene. It was heated to 30 ° C and 63.7 g of benzenesulfonyl chloride were added. After 8 h it was diluted with 1 liter of xylene and treated at 50 ° C with a solution of 121 g of 5% hydrochloric acid. The organic phase was washed at the same temperature, once with

 \ hbox {193 ml} 

of a 2% sodium bicarbonate solution, and then once with 363 ml of water. The organic phase was concentrated by distillation under reduced pressure to one sixth of its initial volume. The solution was cooled and the crystallized product was recovered by filtration, obtaining 100.3 g (76%) of the title compound, characterized by the following analytical data:

Mp .: 102-4 ° C.

IR (KBr, cm -1): 3401, 2986, 2359, 2342, 1699, 1684, 1644, 1600, 1478, 1355, 1284, 1187, 1101, 1031, 924, 758, 687, 601.

1 H-NMR (CDCl 3, 250 Hz, ppm): 6.90-7.95 (m, 10H, ArH, NH); 5.38 (s, 1 H, CH); 4.70 (q, 2H, CH2); 4.29 (m, 2H, CH2); 4.00 (q, 2H, CH2); 3.73 (m, 2H, CH2); 3.60 (s, 3H, CH3); 2.32 (s, 3H, CH3); 1.14 (t, 3H, CH3).

13 C-NMR (CDCl 3, 60 Hz, ppm): 167.7; 166.9 (carbonyls); 145.5; 144.5; 144.1; 135.9; 133.7; 132.0; 131.2; 129.1 (double intensity, 2 C); 128.9; 127.5 (double intensity, 2 C); 127.1; 126.6; 103.6; 101.2 (aromatic carbons and RCH = CHR '); 68.5; 68.4; 67.8; 59.5; 50.5; 36.9; 18.9; 14.0 (carbons aliphatic).

MS (chemical ionization): 550 (M + H); 552 (M + H + 2); fragmentation: 518, 504, 392.

Example 2 Preparation of 1,4-dihydro-2 - [(2-p-toluenesulfonyloxyethoxy) methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl (II with R = p-tolyl)

15.4 g of triethylamine was added to a 25 g dispersion of 1 , 4-dihydro-2 - [(2-hydroxyethoxy) methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate  of 3-ethyl and 5-methyl (IIIb) in 77 ml of xylene. It was heated to 30 ° C and 17.5 g of p-toluenesulfonyl chloride. After 7 h it diluted the reaction with 100 ml of xylene and treated at 50 ° C with a 38.3 g solution of 5% hydrochloric acid. The organic phase is washed once with 49 ml of a solution of sodium bicarbonate at 2%, and then once with 36 ml of water. He concentrated until approximately one third of its initial volume by distillation at reduced pressure The solution was cooled and the product recovered. crystallized by filtration, obtaining 25.5 g (74%) of title compound, characterized by the following data analytical:

Mp .: 103-5 ° C.

IR (KBr, cm -1): 3338, 2975, 2946, 1702, 1684, 1650, 1606, 1489, 1334, 1284, 1204, 1190, 1177, 1100, 1038, 913, 754, 689, 571, 553.

1 H-NMR (CDCl 3, 250 Hz, ppm): 7.80-6.90 (m, 9H, ArH, NH); 5.39 (s, 1 H, CH); 4.70 (q 2H, CH2); 4.26 (m, 2H, CH2); 4.02 (m, 2H, CH2); 3.72 (m, 2H, CH2); 3.60 (s, 3H, CH3); 2.44 (s, 3H, CH3); 2.34 (s, 3H, CH3); 1.17 (t, 3H, CH3).

MS (chemical ionization): 564 (M + H); 566 (M + H + 2); fragmentation: 532, 452, 392, 360, 190.

Example 3 Preparation of 1,4-dihydro-2 - [(2-methanesulfonyloxyethoxylmethyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl (II with R = methyl)

92.5 g of triethylamine was added to a 150 g dispersion of 1,4-dihydro-2 - [(2-hydroxyethoxy) methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate  of 3-ethyl and 5-methyl (IIIb) in 1.2 l of toluene. It was heated to 30 ° C and 52.4 g of methanesulfonyl chloride. After 3 h it was treated at 60 ° C with 300 g of a 5% hydrochloric acid solution. The organic phase is washed once with 142 g of a sodium bicarbonate solution at 2%, and then once with 105 ml of water. It cooled solution and the crystallized product was recovered by filtration, obtaining 160 g (90%) of the title compound, characterized for the following analytical data:

Mp .: 122.5-123.5 ° C.

IR (KBr, cm -1): 3336, 3020, 2988, 2938, 1687, 1642, 1603, 1483, 1430, 1370, 1344, 1333, 1311, 1283, 1174, 1150, 1099, 1041, 1015, 979, 914, 838, 802, 754, 732, 550.

Example 4 Preparation of amlodipine (I) with aqueous solution of ammonia

103.5 g of dissolved 1,4-dihydro-2 - [(2-methanesulfonyloxyethoxy) methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl in 14.7 I of isopropanol and 3.3 l of a 25% aqueous solution of ammonia. Be left at room temperature for 15 days. The Isopropanol by azeotropic distillation under reduced pressure. Subsequently 1306 ml of water and 959.5 g of one were added. 1% sodium hydroxide solution, and the product was extracted with xylene (2x535 ml). The combined organic phases were washed two times with water (2x535 ml). The organic phase was concentrated by distillation under reduced pressure up to one third of its volume initial. The solution was cooled and the product recovered. crystallized by filtration, obtaining 60.8 g (70%) of amlodipine, identified by comparison with analytical data published.

Example 5 Preparation of amlodipine (I) with gas ammonia

1.1 g of mixed were mixed in a mini-key 1,4-dihydro-2 - [(2-methanesulfonyloxyethoxy) methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl in 33 ml of isopropanol It was brought to 60 ° C and pressurized with ammonia (g) to 2.5 bar pressure. It was held for 12 h at 60 ° C. The isopropanol, initially by vacuum distillation and, after adding 22.5 ml of water, by azeotropic distillation. Subsequently added 4 ml of water and 0.5 g of a solution of sodium hydroxide at 20%, and the product was extracted with xylene (2x6 ml). Phases The combined organics were washed twice with water (2x6 ml). Be concentrated the organic phase by distillation under reduced pressure until one third of its initial volume. The solution was cooled and recovered. the product crystallized by filtration, obtaining 0.46 g (50%) of amlodipine.

Example 6 Preparation of amlodipine mesylate

To a solution of 9.5 g of amlodipine in 38 ml of ethanol, heated to 40 ° C, 2.24 g of acid was added methanesulfonic acid The resulting solution was concentrated under pressure. reduced to a third of its initial volume. It cooled solution and the crystallized product was recovered by filtration, obtaining 7.75 g (66%) of amlodipine mesylate, characterized for the following analytical data:

Mp .: 183 ° C.

IR (KBr, cm -1): 3341, 2973, 1687, 1646, 1606, 1572, 1534, 1486, 1430, 1387, 1366, 1348, 1279, 1209, 1103, 1043, 1014, 837, 784, 756, 704, 684, 620, 530, 556.

Example 7 Preparation of amlodipine maleate

To a solution of 1 g of amlodipine in 10 ml of ethanol, heated to 40 ° C, 0.29 g of maleic acid and It was heated to 78 ° C. The solution was cooled and the product recovered. crystallized by filtration, obtaining 1.18 g (92%) of maleate of amlodipine (1: 1), characterized by the following data analytical:

Mp .: 166.7-168.5 ° C.

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IR (KBr, cm -1): 3369, 2989, 2948, 1690, 1578, 1485, 1386, 1368, 1347, 1311, 1288, 1204, 1104, 1040, 1013, 874, 835, 763, 740, 702, 655, 615, 560.

Example 8 Preparation of amlodipine hydrochloride

To a solution of 1 g of amlodipine in 2 ml of ethanol, heated to 40 ° C, 0.25 g of acid was added 36% hydrochloric. The solvent was removed under reduced pressure. He The resulting solid was dissolved in 1.1 ml of ethanol. It cooled solution and the crystallized product was recovered by filtration, obtaining 0.37 g (34%) of amlodipine hydrochloride, characterized by the following analytical data:

IR (KBr, cm -1): 3366, 2974, 2649, 1690, 1604, 1483, 1432, 1380, 1367, 1348, 1289, 1210, 1103, 1041, 1019, 838, 757, 734, 704, 685, 613, 571.

Example 9 Preparation of amlodipine tosylate

To a solution of 30 ml of isopropanol / water 5: 1 saturated with ammonia gas, a solution of 0.34 g of 1,4-dihydro-2 - [(2-p-toluenesulfonyloxyethoxy) methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl in 5 ml of isopropanol It was heated at 40 ° C for 15 h, and at 60 ° C for 6 h plus. After completion of the reaction, the solvent was evaporated to reduced pressure and 0.36 g of a yellow solid was obtained, whose recrystallization in 5 ml of absolute ethanol yielded 0.13 g (37%) of a white solid of m.p. 175-7 ° C, whose NMR data were consistent with those described for tosylate of amlodipine

Example 10 Preparation of amlodipine besylate

6.7 g of dissolved 1,4-dihydro-2 - [(2-benzenesulfonyloxyethoxy-methyl] -6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl in 958 ml of isopropanol and 192 ml of a 25% aqueous solution of ammonia. Be kept at room temperature for 6 days. He concentrated to reduced pressure and 7.49 g of a colored solid were obtained yellow, whose recrystallization from 37.5 ml of absolute ethanol allowed to obtain 5.09 g (73%) of amlodipine besylate, from m.p. 200-2ºC, whose NMR data agreed with the described for amlodipine besylate.

Preparative example one

Preparation of 3-amino-4- (2-tetrahydropyranyloxyethoxy) ethyl crotonate (VI with R2 = tetrahydropyranyl)

25 g of ethyl 4- (2-tetrahydropyranyloxyethoxy) acetoacetate (VII with R2 = tetrahydropyranyl), prepared according to a described method (cf. S. Yiu et al., Arch. Pharm. Med. Chem. 1999, vol. 332, pp. 363-7) and subsequently purified by distillation in 116 ml of toluene. 21.5 g of ammonium acetate was added and heated under the reduced pressure necessary to achieve reflux of toluene at a temperature of 50-60 ° C, removing the water formed in the reaction by means of a Dean Stark tube, replacing the distilled toluene when necessary After 3 h the reaction mixture was cooled to room temperature and washed with water (2x140 ml). The organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, obtaining 23.9 g of the title compound as an oil, which was used without purification in the next step.

Preparative example 2

Preparation of 4- (2'-tetrahydropyranyloxyethoxy) -2- (2-chlorobenzylideneacetoacetate ethyl (IV with R2 = tetrahydropyranyl)

In 50 ml of toluene 25.3 g of ethyl 4- (2-tetrahydropyranyloxyethoxy) acetoacetate (VII with R2 = tetrahydropyranyl) and 12.3 g of 2-chlorobenzaldehyde were dissolved, and then 1.0 g of acetic acid and 1.44 g of piperidine. The mixture was heated to about 60 ° C and emptied in the reactor to achieve reflux of toluene at said temperature, separating the water formed by a Dean Stark system. After about 5 h of reaction, an additional 1.0 g of the starting product (VII) was added and the reflux was maintained under the same conditions for a further 3 h, after which an additional 0.5 g of the product was added. starting (VII) and reflux was continued for a further 3 h. The toluene phase was washed with 25 ml of water and toluene was distilled off under reduced pressure to obtain 40.0 g of a crude oil, corresponding to the mixture of cis and trans isomers of the title product, which was used without purification in the next step.

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Preparative example 3

1,4-dihydro-2 - [(2-tetrahydropyranyloxyethoxy) -methyl-6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl (III_ {a})

In 130 ml of isopropyl alcohol dissolved 7.5 g of 2- (2-chlorobenzylidene) acetoacetate methyl and 5.1 g of the compound obtained in Preparative Example 1, and heated at reflux for 19 h. Then the evaporated solvent under reduced pressure and a crude oil of weight was obtained 12.9 g containing the title product. An aliquot was purified  of 2 g of said oil by column chromatography [column of 2 cm in diameter and 20 cm in height, filled with silicagel in diameter particle 0.040-0.063 mm; eluent: hexane / ethyl acetate 3:11, 0.5 g of the product being isolated from title, characterized by the following analytical data:

1 H-NMR (CDCl 3, 250 Hz, ppm): 6.90-7.5 (m, 5H, ArH, NH); 5.40 (s, 1 H, CH); 4.77 (q, 2H, CH2); 4.65 (m, 1 H, CH); 4.18 (m, 2H, CH2); 4.12-3.5 (m, 6H, CH2); 3.62 (s, 3H, CH3); 2.35 (s, 3H, CH3); 2.0-1.5 (m, 6H, CH2); 1, 15 (t, 3 H, CH3).

Preparative example 4

1,4-dihydro-2 - [(2-tetrahydropyranyloxyethoxy) -methyl-6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl and 5-methyl (III_ {a})

5.0 g of the compound obtained were dissolved in the Preparative Example 2 and 1.0 g of 3-aminocrotonate of methyl in 25 ml of isopropyl alcohol, and the mixture was heated at reflux for 24 h. Then, the solvent was evaporated under pressure reduced, obtaining an oil with the title product.

Preparative example 5

1,4-dihydro-2-f (2-hydroxyethoxy) methyl-6-methyl-4- (2-chlorophenyl) -3,5-pyridinedicarboxylate of 3-ethyl 5-methyl (IIIb)

In 8.3 ml of ethanol, 8.3 g of the crude compound (IIIa) (purity 85-90% measured by HPLC) obtained in any of Preparative Examples 3 or 4, and 53 ml of 1 N hydrochloric acid was added. The mixture was left. with stirring at room temperature for 5 h. It was extracted with xylene (1x35 ml and 2x19 ml). The combined organic phases were washed with an 8% sodium bicarbonate solution (16 ml) and subsequently with water (16 ml). It was concentrated under reduced pressure up to one sixth of the initial volume and 1.8 ml of heptane The solution was cooled and the product was recovered by filtration, obtaining 3.21 g (52%) of the title compound, characterized by the following analytical data:

1 H-NMR (CDCl 3, 250 Hz, ppm): 6.90-7.5 (m, 5H ArH, NH); 5.37 (s, 1 H, CH); 4.72 (q 2H, CH2); 4.02 (m 2 H, CH 2); 3.82 (t, 2H, CH2); 3.65 (m 2H, CH2); 3.58 (s, 3H, CH3); 2.29 (s, 3H, CH3); 1.15 (t, 3H, CH3).

13 C-NMR (CDCl 3, 60 Hz, ppm): 168.1; 167.2 (CO) 145.7; 145.6; 144.2; 132.3; 131.4; 129.2; 127.3; 126.8; 103.8; 101.4 (aromatic C and RCH = CHR ') 72.6; 68.0; 61.5; 59.7; 50.7; 37.2; 19.1; 14.2 (aliphatic C).

Claims (15)

1. Compound of general formula (II) 6 where R is a selected radical of the group formed by (C 1 -C 4) - alkyl, phenyl and mono- or disubstituted phenyl radicals (C 1 -C 4) -alkyl. 2. Compound according to claim 1, wherein R is selected from the group consisting of methyl, phenyl and 4-methylphenyl. 3. Compound according to claim 2, wherein R It is methyl. 4. Compound according to claim 2, wherein R It is phenyl. 5. Compound according to claim 2, wherein R It is 4-methylphenyl. Method for obtaining the compound (II) defined in any one of claims 1 to 5, characterized in that it comprises reacting the alcohol of formula (III_ {b}) 7 with a sulfonic acid chloride of formula Cl-SO_ {2} -R in a inert solvent, where R has the same meaning as in claims 1 to 5. 7. Method of use of the compound (II) defined in any of claims 1 to 5, characterized in that it comprises reacting (II) with ammonia, replacing the sulfonate group (

 \ hbox {-OSO2 -R} 

) by the ammonium group (-NH 3 +) 8. Method according to claim 7, wherein the reaction is carried out with a solution of ammonia in water or in mixtures of water and a monoalcohol aliphatic- (C 1 -C 6). 9. Method according to claim 7, wherein the reaction is carried out with ammonia gas under pressure in a non-aqueous solvent. Method according to claim 9, characterized in that the non-charged solvent is selected from the group consisting of an aliphatic monoalcohol- (C 1 -C 6), benzene, toluene, xylene, an aliphatic ether- (C_ { 4} -C_ {6}) and mixtures thereof. Method according to any one of claims 7 to 10, characterized in that the reaction medium is subsequently basified and amlodipine (I) is formed. 8 12. Method according to claim 11, characterized in that the amlodipine (I) is separated from the reaction medium and subsequently reacted with the appropriate amount of a pharmaceutically acceptable acid to obtain the corresponding salt. 13. Method according to claim 12, where the pharmaceutically acceptable acid is maleic acid and the Salt obtained is amlodipine maleate (1: 1). 14. Method according to any of claims 7 to 10, characterized in that the amlodipine salt with the HO-SO2 -R sulfonic acid is isolated directly from the reaction medium without basifying it. 15. Method according to claim 14, where R is phenyl.