CZ208599A3 - Process for preparing [1S-[1a,2b,3b,4a(S)]]-4-[7-[[1-(3-chloro-2-thienyl) methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane carboxamide - Google Patents

Abstract

Preparation method [1 S- [1a, 2b, 3b, 4a (SO) -4- [7 - [[1-3-chloro-2- thienyl) methyl] propyl] amino] -3 H -imidazo [4,5-b] pyridine-3 yl] -N-ethyl-2,3-dihydroxycyclopentanecarboxamide (I) is that [S- [1a, 2b, 3b, 4a (S, j-AlP-amino-A) [[1- [3-chloro-2-thienyl) methyl] propyl] amino] -2- pyridinyl] amino] -N-ethyl-2,3- dihydroxycyclopentanecarboxamide reacts with the ester erthoformate or formamidine acetate or dimethylformamide dimethylformamide, preferably in the presence a catalytic amount of an inorganic or organic acid.

Description

The compound of formula I is a suitable cardiovascular agent, in particular an antihypertensive and an anti-ischemic agent, a cardiac protoactive agent that helps in ischemic problems of myocardial infarction caused by ischenic myocarditis, and an antilipolyte lowering agent. cho les tor o Iv. in blood plasma and a balance beam of triglycerides in blood serum.

BACKGROUND OF THE INVENTION

U3 No. 5,364,862 mentions a compound of formula I and related compounds as suitable abtihypertensive agents and anti-ischemic agents, and U.S. Pat. No. 5,151,134 discloses their suitability as cardioprotective and antilipolytic agents.

Methods for preparing the compound of formula I, related compounds and intermediates thereof are described in U3.

No. 5,364,552. (Spa.dn et al.), Issued Nov. 15, 12S4, and U.S. Patent No. 5,561,134.

The processes of the present invention provide improved yields, purity, ease of preparation and / or isolation of intermediates and the resulting product, and better reaction conditions suitable for industrial production as well as better processability of the product than previously described preparation processes.

Podstata vvnálczu

Embodiments of the invention are illustrated in Schemes I, II, III and IV.

♦ · · · · · · · ·

Scheme I

4 »································ · · · · ♦ ·

Scheme III

One embodiment of the process of the invention for preparing a compound of formula I is characterized in that [1S [1a, 2b, 3b,

4a (S ⁺ )]] - 4 - [[3-amino-4 - [[1- [3-chloro-2-thienyl] methyl] propyl] amino] -2-pyridinyl] amino] -N- Ethyl 1-2,3-dihydroxycycliorifanecarboramide (Compound IX) is reacted with formamidine acetic acid or orthoformate or dimethylformamide dimethylacetal, preferably in the presence of a catalytic amount of an inorganic or organic acid. The reaction is preferably carried out in an organic solvent or in a mixture of organic solvents, in aqueous in a mixture of organic solvent or solvents with water. In a preferred embodiment of the process according to the invention, the reaction is preferably carried out with iermamidine acetate in n-butyl acetate. In another particular embodiment of the processes of the invention, the reaction is preferably carried out with ethyl orthoformate in the presence of a catalytic amount of an inorganic or organic acid, preferably hydrochloric acid or caulphonic acid.

«··· *« ···

4 · ···· · ··· * · <

A preferred embodiment of the process of the invention for the preparation of a compound of formula I, preferably in crystalline form, comprises two steps of first forming the free base of a compound of formula IX from its hydrochloride salt, and reacting the obtained free base with acetic acid, both of which are carried out simultaneously without isolation and purification of the free base of compound IX.

A more preferred embodiment of the process of the invention for the preparation of the compound of formula I in crystalline form is characterized in that the dihydrochloride salt of compound IX is reacted with acetate forms without first forming the free base of compound IX.

Other embodiments of the process according to the invention for the preparation of ivory IX are characterized in that L 3aR- [3aa, 4a, 6a (R), Saa]] is hydrolyzed from -6- [3-amino-4 - [[1 - [ (3-Chloro-2-thienyl) methyl] propyl] amino J 2-pyrrolidinyl] amino] -N-thythyryl-2,2-diethyl- 4H-Cyclopentan-1,3-dioxol-4-carboxamide (Compound VIII), preferably in the presence of an organic solvent or a mixture of organic solvents, and an aqueous non-mineral or organic acid. Examples of suitable organic solvents include methanol, ethanol, isopropanol, ethyl acetate, toluene, tetrahydrofuran, tetracydropyran and dioxane. In a particular embodiment of the methods of the invention, the preferred solvent is non-ethanol or a mixture of toluene and isopropanol. When in accordance spccielzpůsobů} 'finding is preferred mixture for prosloučeniny VIII in compound IX, R ⁵ tetrahydrofv.r them perform management and HY drclýz Vosne;

: hydrochloric acid, methanol, ethanol, or isopropanol, or ethyl acetate or ethyl acetate and isopropanol and aqueous hydrochloric acid.

A further embodiment of the process according to the invention relates to the preparation of; of compound VIIIa and comprises the reduction of [3aR- [3aa, 4a, 6a (R ⁺ ), Saa]] - 5µl 4 - [[1 - [(3-chloro -2 -1 halo) methyl] ] propylamino] -3-nitro-2-pyridinyl] amino amino-ethyl-2,2-dinyl-4H-cyclopentyl-1, 3dioxole-4-carboxamide (compound VII), preferably in the presence of an organic solvent or a mixture of an orange solvent and water.

• to · to

Examples of suitable organic solvents include methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, tetrahydronyran and dioxane. In a particular embodiment of the methods of the invention

From about 26 ° C, the reduction is preferably carried out at a temperature in the range of about SC ° C, more preferably at the reflux temperature of the system in which the reduction is carried out. In a particular embodiment, the process of the invention is preferably about 65 ° C or the relusion temperature of the reduction system including methane.

The reduction of compound VII to compound VIII is carried out in the presence of known reducing agents or those described herein. Reducing agents suitable for this reduction include potassium horohydride in the presence of cuprous chloride, iron and aqueous hydrochloric acid, zinc and calcium chloride, platinum or palladium on chemically pure carbon in the presence of hydrogen, platinum on chemically pure carbon in the presence of ammonium formate, powdered zinc in the presence of ammonium acetate, and platinum on sulfated coal in the presence of ammonium formate. In particular embodiments of the methods of the invention, the preferred reducing agent is platinum on water-moistened coal or zinc powder in the presence of a substance capable of transferring hydrogen to the nitro group to be reduced, preferably ammonium acetate, or platinum on carbon in the presence of hydrogen.

An embodiment of the process according to the invention for the preparation of compound VII is characterized by reacting (R) -2-chloro-R [1 - [(3-chloro-2-thienyl) methyl] propyl] -3 -nitro-4-pyridinamine (compound V) with 2R, 3S-isopropylenedioxy-4R-amino-1S-ethylaninocarbonyl-cyclopentane (compound VI, preferably in the presence of an aprotic organic solvent. Aprotic organic solvents suitable for this reaction include aprotic organic ethers, aromatic. hydrocarbons, heteroaromatic hydrocarbons, aliphatic hydrocarbons and aprotic organic amides In a particular embodiment of the methods of the invention, the preferred organic solvent is toluene.

According to the invention, the reaction of compound V with compound VI is carried out in the presence of a base. Bases suitable for this reaction include aqueous alkali metal hydroxides, aqueous solutions

- 7 alkali metal carbonates, aqueous alkali metal bicarbonate solutions and aprotic organic amines. In a particular embodiment of the methods of the invention, the preferred base is a carbonate carbonate other.

with parting

Another embodiment of the process of the invention for preparation.

V s is characterized in that the hydroxyl group (F 1) -K-

Γ 4- (3-Chloro-2-thienyl) methyl] prepyl] -2-hydroxy-3-nitro-4-pyrimidine (compound IV) is replaced by a chloro group, preferably in the presence of an aprectic or organic solvent, Apric organic solvents which are suitable for this reaction, aprotic organiels include ethers, aromatic hydrocarbons, heteroaromatic hydrocarbons, aliphatic hydrocarbons and aprotic organic! amides. In a particular embodiment of the processes according to the invention it is preferred; toluene.

embodiments of this replacement include

The dies are those for oralyl chloride, phosphorus trichloride, phosphorus trichloride, thionyl chloride and phosphorus oxychloride.

Another embodiment of the invention relates to a process for preparing an elephant

L · G j? In the case of the value I ', it is caused by reacting 4-chloro-3-nitropyridin-2 (1E) -one (compound II) with (h) -3-chloro-trimethyl-1-2-thiophene ethanamine (compound III), preferably in the presence of an organic solvent or an organic solvent or water, or a mixture of the organic solvent or solvents with water. Examples of suitable organic solvents include methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, tetrahydropyran and dioxane. Examples of preferred solvents are methanol, ethanol, isoprepanol and a mixture of methanol, ethanol or isopropanol with water.

According to the invention, the reaction of compound II with compound III is carried out in the presence of a base. Bases suitable for this reaction include aqueous alkali metal hydroxides, aqueous alkali metal carbonate streams, aqueous alkali metal bicarbonate solutions, and aprotic organic amines. In a particular embodiment of the processes of the invention, the base is N, N-diisopropylethylamine.

Another embodiment of the invention relates to a process for the preparation of Siccin II, which comprises reacting a 4-liydro:

3-nitro-2 (III) -pyridone (compound XII) with a chlorine phosphorous or tissue chloride chloride axis, preferably phosphorous pentachloride, in the dark of an organic solvent and in the presence of bases. Organic solvents suitable for this reaction include pure organic ethers, aromatic hydrocarbons, heterearomatic ulilo, aliphatic hydrocarbons, halogenated hydrocarbons, and aprotic. About Ucs uc u c o o o v.

rr.v Λ 1 · _Ί : In UUX «. ..

> rganic amides. Examples of suitable organic '' '' '' ---, ----. +?

luene, methyl tert-butyl ether, dimethylformamide, ethyl acetate,

-b 1, J-. 1-butylacetate, 1-methyl-2-pyrrolidinone,

For special watering methods. According to the invention, the preferred organic solvent is toluene. In a particular embodiment of the methods of the invention, the preferred base is N, N-diisopropylethylamine.

A further embodiment of the process of the present invention for preparing the sicinic XII is to hydrolyse and deharbomylate 2-hydroxy-3-cyano-4-methypypyridine to form 2,4-dihydrosypyridine, followed by nitration of the 2,4- dihydrozypyridine. In a special embodiment of the processes according to the invention, said hydrolysis, decarboxylation and nitration simultaneously carry out, without the need for intermediate isolation and purification of said 2,4-dicyldypyridine, preferably by heating 2-hydroxy-3-cyanc-4-methouypyridine sequentially first. with phosphoric acid, then with glacial acetic acid and finally with nitric acid.

A preferred embodiment of the process of the invention for preparing the dihydrochloride salt of compound IX is to react compound II with compound III to form compound Γ. followed by the replacement of the hydroxyl group of compound IV with a group to form compound V which. then. reacting with compound VI to form compound VII, which is then reduced to compound VIII. Compound VIII is then added. hydrolyses in the presence of hydrochloric acid. All of these reaction steps are carried out simultaneously, without the need for intermediate isolations and purification of intermediates i.e. compounds VIII, VII, V and IV.

It is known that hyurezypyridines may also occur in the form of tautomeric pyrite! and that the pyridinones may also occur in the form of autosynthetic pyridines. Therefore, the compounds II, III, X. XI and XII may be in the form of the corresponding hydrouryridine or pyridene, or as a mixture of both.

The invention is illustrated in more detail by the following non-limiting examples;

i-riklaav rrcveaem v

- - * .......

Preparation of [1S (1α, 2b, 3b, 4a (3R))] -4- [7 - [[1- (3-chloro-2-thienyl) methyl] propyl] amino] -3H- imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2,3,3-dihydroxycyclopentanecarboxamide (compound I)

2C g -no leg of dihydrochloride chloride [1S- [1a, 2b, 3b, 4a (S ⁺ )] j4 - [] [3 - amino - 4 - [[1- - 3 - ch 1 oro - 2 - 1 h) 1-Methyl] -pyridine-2-pyridinyl] amino] -N-ethyl-2,3-dihydrose cyclinocarboxamide (Csine · safety IX) is suspended in 120 ml of water and the mixture is heated at 65 ° C to give a solution. The bag was added with 84.7 g of butyl acetate followed by 15.2 g of sodium carbonate in 54 g of water. The mixture was stirred, for approximately IC minutes at 55 ^± 5 ° C, then the resulting layers were separated by organic layer, washed with brine. 10.3 g of formamidine acetate are added to the organic layer and the mixture is stirred at 85 ± 5 ° C for about 2 hours. then the mixture is cooled to a temperature of "f * o"

- C and washed first with 5% aqueous sodium bicarbonate, then with water.

1.2 g of water, i.e. 55-5 ° C, were then added to the organic layer 1.2 g of water, after which the mixture was cooled to 21-2 ° C over approximately 2 hours. The mixture was then stirred for 12-24 hours, filtered, the resulting solid was washed with butyl acetate and dried under reduced pressure at 52 ° C under nitrogen for about 24 hours to give [13- [1a, 2b, 3b, 4a (S ⁺ )] - 4- [7 - [[1- (3-chloro-2-thienyl) methyl] propyl] amino] -3H-imidazo [4,5-b] pyridin-3-yl] -N - ethyl-2,3-dihydroxycyclopentanksrboxamide (compound I) in the form of a hydrate containing about 1.7% v / v. water.

1 H NMR (2CC MHz, DMSO) 0.915 (3H, t); 1.4 (311, t); 3.2-3.0 (4H, m);

4.91 (1H, d): 6.3 (1H, d): 6.6 (1H, bd); 3.9 (1H, d); 7.4 (1H, d);

7.8 (111, d); S, C 54 H, bt); 8.2 (111, s).

- 10 Example 2

Preparation of [IS-Γ la, 2b, 3b, 4a (3 ^T)]] - 4- [7-Γ [1- (2-3chIcro thieny1) methyl] propyl] amino] -3H-imidazo] 4,5 b] pyridin-3-yl] -N-ethyl 12,3-dihydroxycyclopentanecarboxamide (Compound I)

To 54.3 g of n-butyl acetate was added at room temperature

4.5 g (43 m). The mixture was heated to ICC ^c C god nir.ut 21 was added 8.4 g (15 rrnC ac) ro legs wire dihydro och ar Lorido 3.3 L 10,25,35,40-C (3 R) 13- 44] 3-amino-4 - [[1-] 3-chloro-2-thienyl) methyl] propyl] amino] -2-pyridinyl] amino] -N-ethyl-2,3,3-dihydronoylpentanharboxamil ( compound IN). The mixture was stirred at 100 ° C for 1 hour, then cooled to room temperature. SC ° C and add sc CC ml of 8% w / w. aqueous sodium bicarbonate solution. The drift was stirred for 5 minutes and the resulting layers were maintained at a separate temperature. Crganad 50 C, was washed with 45 0.42 g of activated carbon and water. The organic layer was then stirred at 75 ° C for 45 minutes. After filtering the reaction mixture, the filtrate was cooled to 22 ° C over 1 hour at which temperature it was heated; Stir for 2 hours. The resulting solid was filtered off and washed with 6 ml of n-butyl acetate. The white product was dried at 3 ° C with nitrogen overnight to afford Compound I.

Example 3 * Preparation of [IS-IIIa, 2b, 3b, 4a (S ⁺ )]] - 4-] 7-([1- (3-chloro-2-thienyl) ethyl] propyl] amino] -3H- imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2,3-hydroxycyclopentanecarboxamide (Compound I) (Compound I)

To 25.2 g of t-butyl acetate at 51 g (27 mmol) of formamide acetate. The mixture was warmed to 0 ° C at 94 ° to ⁰ ° C at room temperature, and sus (15 mmol) of compound dihydrochloride monohydrate of 30.5 g of n-butyl acetate was added to the zither of the room, washing the remainder of the nzo slurry. The mixture was stirred at 100 ° C for 30 minutes, cooled to 80 ° C and 90 ml of 8% w / w sodium carbonate carbonate was added. The mixture was then stirred for 5 minutes, the layers separated and the organic layer held above 60 ° C. se oromvie 45 2 vodv. The mixture is cooled to the bottom of the hydrate solution, at which

11 c. 0.42 g of activated carbon is stirred for 45 minutes

r.ři tenlcte 75 ° C the filtered and cooled over 1 hour to a HRI ^B C. Temperature:

The solid is filtered off, washed with 5 ml of n-butyl acetate Compound I.

vznia.

Preparation of [3aR < 3ac, 4a3a (R '), 5ss]] - S- [] 3-anino-4 - [[1 - [(3-chloro-2-thienyl) methyl] preyl] amino] -2-pyrodenyl] amino] -K-ethy Itetracydro-2,5-dimethyl-4Z'-cyclopentyl-1,3-dicro-2-4-carbononide (s)

Charge to the reaction vessel 12.4 g] 3aE- [3aa, 4a, 5a (R '), 6aa]] -S-] -4-Γ [1-Γ (3-chloro-2-thienyl) methyl l] prepyl] amino] -3-nitro-2-pyridinyl] amino] -n-ethyl-triazol-2,2-dimethyl-4K-cyclopentyl-1,3-dicuole-1-carbouamide (compound VII), 32.4 g of methanol and δ.5 _{c of} wet (32.4%) activated carbon with 5% platinum. To the mixture, 10.0 g of ammonium formate was added to the mixture.

mixture heated 4 hours at approx li žne 55 ° C, cooled to fence 23 ° C and filter; is through a filter aids (SulhaFloc 300), m.p. rá pro pro Rinses 130, 4 g e t h a l c e t. The filtrate is washed first

ml of 5% aqueous sodium bicarbonate solution, then with a saturated aqueous sodium chloride solution. The organic layer was evaporated under reduced pressure at 5 ° C to give compound VIII as a foam which was used for the next reaction without further processing.

Example 5

Preparation of p 13-p 1a, 2b, 3b, 4a (S)]] - 4 - [[3-amino-4 - [[1- [3-chloro-2-thienyl] methyl] propyl] amino 2-Pyridinyl-1-amino] -N-ethyl-2,3-biphenylcyclopentanecarbamide (compound Id) to 11.2 g of compound VIII in ISO g of tetrahydrofuran was added 7.3 ml of concentrated hydrochloric acid over 2 minutes. The mixture was stirred for 15 hours, then cooled to 0-3 ° C and stirring was continued for an additional 1 hour. The mixture was filtered and formed; The solid is washed with tert-butyl ether at 0 to 3 ° C, after which time

It is dried under reduced pressure and a temperature of 55-5 ° C for 12 hours with nitrogen introduced. Compound IX is thus obtained as the dihydrochloride monohydrate, m.p. 135 ° C. 1 S (31), m / z 467 50 50%) diNiS (5 CCl 2, DHSO) <3 0.91 (1E, t); 1.05 (1E, t); 1.55 (2E, m); 2.30 (1H); 3.11 (1E); 4.01 (2H); 6.24 (1H); 5.36 (1H); 6.98 (1E);

7.37 (1E); 7.48 (1E); 12,47 (1U)

Example 5

Preparation of (R) 1 - [(3-Chioro-2-thienyl) methyl] propyl] -2-hydronyl-3-nitro-4-pyridinamine (Compound IV)

14.5 g of (E) -3-chloro-a-ethyl-2-thiophenethanamine (Compound III) was gradually added to a 3-liter 1-neck flask equipped with a mechanical stirrer, thermocouple, nitrogen inlet, and condenser. , 10.0 g of 4-chloro-3-nitropyridin-2 (1H) -one (compound IP), 35 g of 2-propanol (IFA) and 25 µl of N, N-diisopropylethylamine (DIFEA Snes was stirred for 7 hours at The reaction mixture was concentrated to 41.4 syrup, which was dissolved in 425 ml of ethyl acetate and the solution was washed first. 125 ml of water, then twice with 50 ml of 5N ammonium chloride solution each time and dried, filtered, concentrated and the precipitated solid was filtered to give compound IV, m.p. 150 DEG-152 DEG C. Mass spectrum and twice with 50 ml each. e rust saturated sodium sulfate. Ho flux NNK, 1 'e ^c, o T

m / z 328 (6 %). ^] Ε: ΗΏ (500 HHz, DLI3C) δ 0.0 3.05 (1H, m); 5, δ (1E, 8.8 (1H, d); 11.1 (1H) Shit! 7

Preparation of (H) -2-chloro-N- [1 - [(3-chloro-2-thienyl) methyl] propyl] -3-nitro-4-pyridinamine (Compound V)

A solution of 0.1 mole of (H) -N- [1 - [(3-chloro-2-thienyl) methyl] propyl] -2-hydroxy-3-nitro-4-pyridinamine (compound IV) in 100 mL of toluene, containing 2 equivalents of DIFEA hydrochloride is heated to 4.

9 «·

13 to 60 ° C and with stirring, 20.6 g of phosphorus pentachloride are added over 10 minutes. The reaction mixture was stirred at 60 ° C until the reaction was complete (3 hours). After cooling to a temperature of &lt; 0 ° C, 245 g of 2N sodium chloride solution was added at a rate such that the temperature of the reaction mixture was kept below 10 ° C. The biphasic reaction mixture was stirred at G ° C for 1-2 hours, then allowed to warm to room temperature over ncc. The lower aqueous layer was separated by burning the organic layer, which was evaporated under reduced pressure, and the residue purified by chromatography using a 25:75 mixture of ethyl acetate and hepan to afford compound V. 13 (m). / from 345 (10%).

XhhR (500 kHz, CDCl ₃ / CD ₃ CD) δ 1.0 (3H, t); 1.5-1.6 (2h, m); 2.6-3.2 (2h, m); 3.8 (1h, m); 6.5 (3H, bd); 6.6 (1H, a); 7.15 (1H, d); 7.9 (lh, p

Example 8

Preparation [33E-3aa, 4a, 6a (R ⁺ ), 6aa]] -6 - [[4 - [[1 - [(3-chloro-2-thienyl) methyl] propyl] amino] -3-nitro-2. -pyridinyl] amino] -β-ethyltetrahydro-2,2-dimethyl-4I-1-cyclopenta-1,3-diouole-4-carboxamide

To a solution of 0.1 mole of (E) -2-chloro-N- [11 (3-chloro-2-thienylmethyl) propyl] -3-nitro-4-pyridinamine (compound V) in 100 ml of toluene was added in one 28.5 g of fine-grained potassium carbonate and 33.7 g of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbenylcyclopentane (compound VI) are added in portions, and the suspension is heated at 98 DEG and 2 DEG for 6 hours. C. When the reaction is complete, the suspension is cooled to room temperature and water (230 g) is added with stirring The aqueous layer is separated and the organic layer is added with stirring

14.5 wt. ammonium chloride solution, and the lower aqueous layer is separated again. After the addition of 10 DEG C., the layers were separated again. The toluene solution was evaporated under reduced pressure and the residue purified by chromatography using 60: 40: 5 parts of acetate, heptane and triethylamine as eluent to give compound VII. Mass Spec (FA3-LRF), (h + h) ⁺ 538 (ICC%)

X 1 NH (500 kHz, ΟΠΟίθ) δ 1.0 (3K, t); 1.15 (3H, t); 1.6 (1H, m); 1.75 (1H, m); 2.6 (1H, m); 2.8 (1H, m); 3.1 (211, m); 3.35 (2 H, m);

5.95 (1H, d); 6.85 (1H, d); 7.1 (1H, d); 7.8 (1H, d); 9.25 (III, d);

9.55 (2 H, d).

- 14 Example S

Preparation. 3aR- [3aa, 4a5a (R ⁺ ), 6aa]] - .beta.-β- [3-amino-4 - [[1- (3-chloro-2-thienyl) methyl] propyl] amino] -2-pyridinyl] amino 1-X-Ethyltetrahydro, 2-dimethyl-4 H -cyclopenta-1,3-dioxole-4-carboxamide (with Mull and Cinema VIT.)

To a solution of 0.09 µl of Compound VII in 85 µl of toluene? followed by the burning of a burner for 15 minutes adds 24 g of nonwoven, 18 g of I? A and 54 g of ammonium tannate. Then take in small proportions

Γ Γ · -

mm. ávání crdot ?. The reaction mixture was stirred for 30 minutes and then the heterogeneous drift was cooled to ⁰ ° C with 35 ° C powder.

-.- n

u. .to action:

about tc fence 4G

C. The resulting gray salts were filtered at 0 ° C and washed with toluene. The filtrate under reduced pressure and the residue was purified by chromatography on evaporation, heptane and triethylamine.

□ use of SO: 1C: 5 parts and the formation of Compound VIII. 13 (1H + H) ⁺ 508 (ICC K).

W m (5CO KHz, DMSO) δ C, 9 (3H, t); 1.0 (3K, t); 1.7-1.4 (3 H, m);

? tky lac!

2.35 (1H, m); 2.25 (2 H, m); 3.1 (2 H, n); 5.75 (1K, d); 6.0 (1K, i); 7.0 (IIId); 7.25 (1H, d); 8.15 (1H, m)

Example IC

Cascade Preparation of [1S- [1a, 2b, 3b.4a (S ⁺ )]] - 4 - [[3-amino-4 - [[1-L-3-chloro-2-thienyl) methyl] propyl] amino 2-Pyridinyl-1-amino-2-ethyl-2,3-dihydrocyclocentanecarboxamide (Compound IX)

To a 1 liter round-bottomed flask equipped with a mechanical stirrer, a thromocouple, a nitrogen inlet and a condenser was charged 23.3 g of (R) -3-chloro-α-ethyl-2-thiophenethanamine (compound III) in succession. hydrochloride form. 18, C g of 4-chloro-3-nitropyridin-2 (1H) -one (compound II), 35 g of 2-propanol (IA) and 33.3 g of anriva 5

H, K-diisopropylethylamine (DIFEA). The mixture was stirred at 70 ± 2 ° C for 7 hours. Fa! The reaction mixture was allowed to return to room temperature (22 ° C). In the morning, the reaction mixture was stirred at room temperature. 240 g of toluene and an azeotropic IrΛ / toluene mixture were distilled off under reduced pressure at 80 to SC. The remaining IPA is checked for gas flow rate.

The reaction mixture was left overnight

When the level of ilA falls below 0.1%, the resulting two-phase liquid / liquid containing (R) -X- [1-Γ (3-chloro-2-thienyl 1) · and · · ·

- 15 υ (Compound IV) is added for 10 minutes, the mixture is heated to 0 ° C (2 to 3 hours), then cooled to '° C and a total of 245 g of 2N aqueous sodium hydroxide solution added Low: 14 ° C. RVE Ithylo] propyl] -2-hydro :: y-3-nitro-4-r.yridinamin C ^C C n, with stirring, cooled to God 6 :: ychloridu and phosphorus. Reaction to completion at such a rate, the phase mixture is stirred for 1 to 2 hours; the temperature is allowed to rise overnight at 0 ° C, then not.

• n ~!, - e · ^J - r, -1ir,? l · no f. A · ', lot of lUÍST!

In the morning, the lower aqueous layer was separated from the organic layer containing (R) -2-chloro-K- [1 - [(3-chloro-2-thienyl) methyl] prenyl] 3-nitro-f-pyridinamine (Compound V n) 28.5 g of fine-grained potassium carbonate are added in one portion, followed by 33.7 g of 2R, 33-isopropylidene-4R.-amino-13-ethylamino carboxylic acid 1 cyl: of pentane (compound VI). The resulting suspension is heated for 2 to 3 hours at heat Co

After completion, 230 g of deioni was added with stirring and 14.5% w / w was added to the organic layer with stirring. aqueous ammonium chloride solution, after which the lower aqueous layer is again removed. ICC g of deionized vocg is added. and the layers separated again.

To a toluene solution of [3sR- [3aa, 4a, 6a (R ⁺ ), 8aa]] - S - [[4 [11- [(3-chloro-2-thienyl) methyl] propyl] amino] - 3-nitro-2-pyridinyl] -N-ethyl-ethyl-2,2-dihydro-4K-cyclopentyl-1,3-diimino-4-carbonanide (compound VII) 24 and methanol, 18 g of IPΛ and 54 g of ammonium acetate are added under stirring. Then, 35 g of zinc powder is added in small portions until the evolution of the purified water develops. Water layer with <

While maintaining the temperature of the reaction mixture by adding zinc, the reaction mixture was stirred at 40 ° C for 30 minutes, then the heterogeneous mixture was cooled to 0 ° C. The gray colored salts were filtered off and washed with toluene. Filtrate (en3aR- [3aa, 4a, 5a (R ⁺ ), 6aa)] - S- [Γ3-anino-4 - [[1 - [(3-chloro-2-thienyl) methyl] propyl] amino] 2-Pyridinyl] amino] -N-ethyltotracydro-2,2-dimethyl-4H-cyclopenta-1,3-dic-1-4-carbamide (BUT) was used directly in the next reaction.

ko ne; IRA a

To the toluene solution of compound VIII was added 100 g of halo at a temperature of 50 ° C to 3 ° C. During some c • · • * τι &

31 g of concentrated hydrochloric acid are slowly added over a few minutes. when the reaction of Compound VIII is complete, the reaction temperature is reduced to 22 t 2 ° C with the mixture not boiling overnight. In the morning, the mixture was cooled, cooled to a lot of C and washed with ethyl acetate. SNES Cancer RACH 1 hour RRI this temperature and then the precipitated solids were filtered off and transferred it first with cold (0 ^DEG C.) IPA etkylacetátom then at room temperature. Filter the filtered white cake at 40 ± 3 ° C for 1 hour under reduced pressure. thereby obtaining the drugs [13-βa, 2b, 3b, 4a (3 ⁺ )] - 4- [β-amino-4 - [[1- (3-chloro-2-thienyl) methyl] methyl] chloride] propyl] amino] -2-pyridinyl] amino] -N-ethyl-3-dihydrouycyclopentanecarboxsmide as a monohydrate of melting point - Op

J.JO U.

Example 11

Preparation of 4-chloro-3-nitro-pyridin-2 (1H) -one (compound II). Into a 150 ml flask, add 10.0 g (0.054 mol)

2,4-dihydrouy-3-nitropyridine (compound XII) and 30 ml of toluene. The mixture was heated to 47 ° C with gentle stirring. Then, 4.4 g (0.028S mol) of phosphorus oxychloride (PCCl3) was added via syringe pump over 10 min, increasing the reaction temperature to 49 ° C. 2.22 g (0.017 mole) of Ν, Ν-diisopropylethylamine (DIFEA) was then added over the course of IC minutes while the temperature of the reaction mixture was raised to 51 ° C.

- 4 g (0.0239 mol) of chloride chloride longer than 2.2 (0.017 mol) DIPEA by God for 10 minutes. The third dose,

More phosphorous is added over ten minutes, followed by 4 &apos;

(0.0239 mol) phosphorus oxychloride was added over 10 minutes followed by a third addition, 2.2 g (0.017 mol), DIPEA over 10 minutes. The last addition, 4.4 g (0.0289 mol) of phosphorus oxychloride over 10 minutes (total 17.7 g of phosphorus oxychloride is added) is followed by the last addition of 2.2.0 (0.017 mol of DIPEA over 10 minutes (total DIPEA addition) The reaction mixture was then stirred at 50 ° C for 5 hours until chromatographic analysis showed complete conversion of Compound XII. The reaction mixture was allowed to cool to 20 ° C over 30 minutes before being allowed to cool for 1.5 hours. water (50 ml) was added to raise the temperature of the reaction mixture to 47 DEG C. The mixture was then stirred for 4 hours while stirring at room temperature.

- 17 keeps the temperature at 25 ° C. After filtration, the reaction product is washed twice with 15 ml of water each followed by twice with 1 of toluene each time to give compound II for drying.

O. 19

Example

Preparation

2,4-dihydrinyl-3-nitropyrimidine (compound III);

A mechanical stirrer, a rim and a reflux condenser, are introduced in an argon atmosphere of 90 ml (151.3.

g) Removal of phosphoric acid and 30 ° C (0.20 mol) of 3-cyano-4- ethoxy-2 (IE) -pyridinone (compound K). The mixture was then heated in an oil bath at 175-180 ° C for 23 hours. Then the reaction mixture was cooled to 71 ° C, £0 ml (4,54.5 g) of glacial acetic acid was added and the mixture was then heated at 9 ° C for about 10 minutes. 8.3 ml) of 1.52 g of nitric acid, giving a slight heat evolution, and the mixture was then heated at SG to 95 ° C for 2 hours. 90 ml of water are then added to the mixture and heating is continued at 90 ° C for 1 hour. With stirring, the mixture is then slowly cooled to room temperature, filtered through a fritted Buchner funnel and the filter residue is washed with water to give compound sloučenina, mp 258 ° C.

NEB (Dk 1 SO) δ 7.44 (1E, d); 6.0 (1H, d); 3.5 (2H)

Example 13

Preparation of [1S- [1a, 2b, 3b, 4a (3 ⁺ )]] -4 - [[3-amino-4-4 [1- [3-chloro-2-thienyl] methyl] propyl] amino] -2-pyridinyl] amino] -N-ethyl-2,3-dihydrouycyclopentanecarbonamide (compound IX)

21.6 g (2.71 mmol) of activated charcoal with 5% platinum (Degussa F 101 BA /, 7), g (100 ml), are gradually introduced into a 3-necked round-bottomed flask under stirring with a mechanical stirrer. 543 mmol of ammonium formate, 110 ml of an ethyl acetate solution of compound VII containing 29 g of compound VII (54.3 mmol) and 65 g of methanol. The black suspension was heated at 30 ° C for 6 hours, then cooled to room temperature and filtered through Celite filter aid to collect insoluble matter.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The filter cake was washed twice with 5 [mu] l of ethyl acetate each time. 40 ml of concentrated hydrochloric acid are added to the combined filtrates with stirring over a few minutes and the dream is heated for 3 hours.

to-l. ^ ε filtering followed by drying at teploJ ^M C in a vacuum oven to give the dihydrochloride monohydrate in three of compound IX as a white solid HEI RRI; ra va [1S (1α, 2b, 3b, 4a (3 ')) - 2'-3-amino-4-Z [1- (3-chloro-2-thienyl) methyl] propyl] amino] -2-py 1-amino] -N-ethyl-2,3-di-cyclopentanecarbosamide (Compound IX) was a 1-m &lt; 6 &gt; -multidot of charcoal (Aldrich, Degussa &lt; RTI ID = 0.0 &gt; F1 &lt; / RTI &gt; toluene solution 8.8 g of compound VII (13.6 mmol) in 50 toluene. The reaction mixture was shaken at room temperature under 52 psi of hydrogen for 15 hours. The resulting black suspension was filtered through a Celite filter aid to give a solution of: VIII. 20 g of 2-propanol, 57 g of toluene and 7.4 g of concentrated hydrochloric acid are added in succession at 20 DEG C. and the reaction mixture is then heated to 45 DEG C. with stirring with a mechanical stirrer. After heating at this temperature for 2 hours, the red-yellow colored precipitate is filtered and washed with 20 ml of 2-propanol. The filter cake was dried at 45 ° C for 6 hours to give Compound IX dihydrochloride monohydrate.

Example

Preparation of [1S- [1a, 2b, 3b, 4a (3 ⁺ )]] - 4-7 - [[1- (3-chloro-2-thienyl) -butyl] propylamine] -3H-imidazo £ 4.5 -b] pyridin-3-yl] -N-ethyl-2,3-dihydride; cyclopentanecarbouamide (compound I)

To a 3-necked round-bottomed flask equipped with a condenser and magnetic stirrer was added 2.2 g (3.8 mmol) of dihydrochloride monohydrate of compound IX and 12 g of deionized water; The resulting suspension is heated to 65 ° C and an aqueous solution of 1.7 g of sodium carbonate in 5 g of deionized water heated to rt is added. 65 ° C. The organic phase precipitated as a light red-yellow-yellow oil. To the biphasic salt is added 6.5 µl (41 mol) of triethyl orthonate and the bottom layer is removed. Add SO _{from 1} L of concentrated hydrochloric acid and heat the solution for 5 hours at SO C, then cool to 70 ° C and add 1 C mL of n-butyl acetate. The resulting organic layer of sc p.rony is first saturated with sodium carbonate,

temperature.

then lead and brine, then cool not. The mixture is stirred at room temperature for 15 hours. Filtration followed by drying from.

c ·? 4 1; η -Γ ** .m Λ H r \ {· 1 * -? - * - O g *> ’· * Π Π Π v v v v V v V V V V V V V V V V V > -. λχ ti v-? <, _ x, u. d? xv l.v V i> x i -v. -u · i-1 ad

Preparation of [1S <1a, 2b, 3b, 4a (3 ')]] -4- [7 - [[1- (3-chloro-2-thienyl) methyl] propyl] amino] -SH-imidazof 4,5 -b] pyridin-3-yl] -N-ethyl-2,3-dihydrozycyclopentanecarboxamide (compound I)

Cooled into a round-bottomed 3-necked flask; and magnetic stirrers, 2.0 g (3.5 mmol) of note dihydrochloride hydrate of compound IX and 12 g of deionized water are added in succession. The resulting slurry was heated to 65 ° C and aqueous aq. flow 1.6 g sodium carbonate in 6 g deionized water heated to 1 fence 65 ° C. Then, G, C ml (54 mmol) of triethyl orthoformate was added to the biphasic mixture with a lower aqueous phase, the niche phase was washed with 5 µl of deionized water, and the lower phase was separated. After the addition of 42 mg of ((1S, imol)) (IP) - (-) - 10-camphorsulfonic acid, the solution was heated at SC ° C for 2 hours and stirred at 25 ° C for 15 hours. The reaction mixture was then added. again heated to rrr ·, On ~ _c pgpgx after n-butyl lacetate. The organic phase formed;

nacez se

Cr; * 'O!?

Wash first with saturated sodium carbonate solution, then with water and brine, cool the organic phase to 16 ° C for 16 hours, filter and dry at 56 ° C.

Example 17

Preparation of [1- G- [1a, 2b, 3b, 4a (S ⁺ )]] - 4- [7 - [[1- (3-chloro-2-, thienyl)]. methyl] propyl] amino] -3H-imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2,3-dicydroxycaclopentanecarboxsmide (compound I)

In a 3-necked round-bottomed flask fitted with a mechanical microsphere, thermocouple, nitrogen-charged and condenser, sc

9999

9 9

9 9 acoustically introduces 3.4 of the compound IX in the form of nickel for 2 to 4 hours at 22 ° C.

dihydride monohydrate, 34 .mu.g of n-butyl acetate, and 4.5 g of ammonium acetate. The suspension sc zazafařívání temperature CC ^U C on completion of 'the reaction (disappearance of the compound C in the SS ^{in the} n

1X, the reaction drench was cooled to 3 ° C and washed first with native. lukewarm: reztck.cn sodium bicarbonate, puck 45 g towing water. After the aqueous layers are removed. UlVRl-C luui _v , o - n> o i. J χ c of οι. z <2 · * · * - ^: and heated with stirring 45 gently filtrate and filtrate with?

at 70, cooled to r, Q 0

c. The suspension was stirred at room temperature for 2 hours. You say that the cloth is re-lit, rinsing the steel mill. It is dried in a vacuum oven at a temperature of 50 ^b C.

It will be appreciated by those skilled in the art that the invention is well suited to achieving the objectives of the invention, and not to be merely exemplary, but to be exemplary only, without the invention being limited thereto.

and the resulting ones, the methods of their manufacture are only industrial usability

The compound of formula (I) will find use in medicine as a suitable cardiovascular drug with, in particular, an antihypertensive, anti-ischemic and cardioprotective effect to assist in ischemic problems and myckardial infarction caused by ischemic mycoplasmia. and plasma cholesterol and blood serum triglycoritl levels.

Law Office

VVOKCKA CVO-IVK KALENSKÝ

PARTNER! mA ϋϋ '' mA 'Halkova 2 ueska i epuoiiKa / W

Vtifijl ·

Claims (13)

? A Τ Ξ íí T C V Process for the preparation of [13-βa, 2b, 3b, 4a (3 ')]] - 4- [7- [11-chloro-β-thienyl) methyl] propyl] amino] -3K-inidazoC 4,5- k] pyridine-3- in 1] -N-ethyl-2,3,3-dihydro-cyclopentanecarboxanide, characterized in that [13a-1a, 2b, 3b, 4a (S ^{+ 2} )] 4- [[3 _ει · _{· .ι} η ο-4- [l-Γ Γ 3 chlcro- £ -thienyI) methyl] propyl methyl] amino] -2-pyridinyl] amino] -k-etky1-2,3- the dihydroxycyclopentanecarboxamide is reacted with a c-formate ester, formamidine acetate or dimethylformamide dimethylformamide. Process according to claim 1, characterized in that the reaction is carried out with formamidine acetate. A process according to claim 1, wherein the hydrolyzed [3aE-C 3aa, 4a, 6a (E '), 6aa]] - 6 - [[3 amino-4-Γ 1- ( 3-Chloro-2-thienyl) methyl] propyl] amino] -2-pyridinyl] amino-1-methyl-2,2-dimethyl-4H-cyano cl-a-1,3-dioxo14-carboxamide to give said [IS-Γa, 2b, 3b, 4a (ο ⁺ ))] -4--[3 amino-4 - [[1- [3-chloro] -2-thienyl) methyl] propyl] amino] -2-pyridinyl-1-ylamino] -N-ethyl-2,3-dihydroxycyclohexanecarboxamide. A process according to claim 3, characterized in that the hydrolysis is carried out in the presence of aqueous acids; hydrochloric acid. 5. Preparation method [1S- [1a, 2b, 3b, 4a (S)]] - 4 - [[3-απι1 '· Γ] 4-f [1- (3-chloro-2-thienyl) ethyl] propyl] amino] -2-pyridinyl] amino] -2-ethyl-2,3,3-dihydrozycyclopontanesecarboxamide, characterized in that by hydrolyzing Γ3a ?- [3aa, 4a, 8a (E ⁺ ), 6aa]] 6 - [[3-amino-4 - [[1 - [(3-chloro-2-thienyl) methyl] propyl] amino] -2-pyridinyl] amino] -N-ethyltetrahydro -2,2-dimethyl-4H-cyclopenta-1,3-dicxole-4-carboxamide. 4 4 A method according to claim 3, characterized in that [3aR- [3aa, 4a, 6a (R '), 6aa]] is reduced to -6- [[4- [E 1Ε (3-chloro-2)]. -thienyl 1) methyl] pyrimidine-3-nitro-2-pyrrolidinyl-amino] -N-ethoxycarbonyl-2,2-dihydro 1-41-cyclopenta-1,3-di-o-4-harbomamide to give the above [3sR- [3aa, 4a, 3a (h), 6aa]] - 3 [[3-amino-4] -E Γ - [(3-Chloro-2-thienyl) -methyl] -propyl] -amino] -2-pyridinyl] -amino] -N-methyl-tetrahydro-2,2-dimethyl-4E-cyclopentyl-1,3-dioxol-4 -carboxamide. 7. The process of claim 6 wherein the reduction is carried out in the presence of platinum on water-moistened coal and ammonium formate, or in the presence of zinc and ammonium acetate, or in the presence of platinum on carbon in the presence of hydrogen. b. Zrms oo Sea \ ^T y i. 3an - E 3aa, 4a, δ and (R), 3aa]] - 6 - E [3-Amino-4 - [[1 - [(3-chloro-2-thienyl) methyl] propyl] anino] -2-pyridinyl] amino] -N-hydroxyethyl ether -2,2-Dimethyl-4H-cyclopent and -1,3-dihydro-4-carbonamide, characterized in that E 3 AR-E 3aa, 4a, 6a (R ⁺ (Axis)] -5-E [4 - [[1 - [(3-chloro-2-thienyl) methyl] pyridin-3-yl] -3-nitro-2-pyridine 1] amino] -Ethyl-11-methyl-2,2-dimethylethyl-4H-cyclopentyl-1,3-diol-4-carboxamide in the presence of platinum on water-moistened coal and ammonium formate. G. Preparation of Γ 3aR- [3aa, 4a, 6a (R ⁺ ), 6aa]] -6-E-3-amino-4-E-1 - [(3-chloro-2-thienyl) methyl] propyl [amino] -2-pyridinyl] amino] -R-ethyl-tetrahydro-2,2-dimethyl-4H-cyclopentan-1,3-diozoxo-4-carboxamide, characterized in that it reduces [ 3aR- [3aa, 4a, 6a (R ⁺ ), 6aa]] -6 - [[4 - [[1- (3-chloro-2-thienylmethyl) propyl] amino] -3- nitro-2-pyridinyl] amino] -R-ethanol 2,2-Dimethyl-4H-cyclopenta-1,3-dioxol-4-carboxamide in the presence of zinc and ammonium ethane. 10 ,. Preparation method [3aR- [3aa, 4a, 6a '(R'), 6aa]] - 6 - [[3 · amino -4 [1 - [(3-chloro-2-thienyl) 1] (Methyl) propyl] amino] -2,2-pyridinyl amino] -H-ethyl-tetrahydro-2,2-diethyl-4H-cyclopenta-1,3-dioxol 9 · 9 · · · · · · · · · · · · · · · · 23 by re-4-carboxamide characterized by [3α- [3aa, 4a, 6a (R ⁺ ), 6aa]] - 6 - [[4 - [[1 - [(3-chloro-2-thienyl)] (i) Chloro] propyl] amino] -3-nitro-2-pyridinyl] amino] -h-ethyl Itetrahydre 2,2-dihydro-1H-cyclopentyl-1,3- di-4-carboxamide in the presence of coal and hydrogen alloys. 11. The method of claim 6, wherein said method comprises: The reaction is carried out by reacting 23,3S-isopropylidene-4-hydroxy-13-ethylaminocarbonylcyclopentane with (R) -2-chloro-NC p - [(3-chloro- 2-chloro-methyl] propyl] -3-nitro-4-pyridinanine to give the said [3au- [3aa, 4a, 3a (P. ⁺ ), 6aa]] -δ - [[4 - [[1 - [( 3-Chloro-2-thienylmethyl] propyl] amino] -3-nitro-2-pyridinyl] amino] -h-ethyl-tetrahydro-2,2-dithiyl-4h-cy-tilt α-1,3- dioxo 1-4-carboxamate. Process according to claim 11, characterized in that the reaction is carried out in the presence of toluene and of the scavenger and the alkali metal. Method of Preparation: / [3aR- [3aa, 4a, 6a (Γ. ⁺ ), 6aa]] -5L-4-Γ [1-Γ (3-chloro-2-thienyl) methyl] propyl] amino] -3-nitro-2-pyrimidinyl] amino] -N-ethylhydroxy-2,2-dimethylamino-11-cyano-1-ope a 3-dioxol-4-carboxamide, characterized in that (R) -2-chloro-NC 1 - [(3-chloro-2-thienyl) methyl] propyl] -3-nitro -pyridinsain reacts with 2Ώ. 33-Isopronylenedio [eta] &lt; 4 &gt; -R-amino-1-ethylaminocarbonylcyclohexane in the presence of an alkali metal carbonate. 14. The process according to claim 11, wherein the hydroxy-left (Π) -N- [1 - [(3-chloro-2-thienyl) methyl] propyl] -2-hydroxy- 3-nitro-4-pyridinamine is replaced by a chloro group to give the above (F) -2-chloro-b- [1 - [(3-chloro-2-thienyl) methyl] propyl] -3-nitro-4 -pyridine? min. 15. The process of claim 14 wherein said replacement is performed in the presence of phosphorus oxychloride. • · · - 24 13. A process for the preparation of (Π) -2-chloro-C 1 - [(3-chloro-2-thienyl) methyl] propyl] -3-nitro-4-pyrilinanine, in which 3 that sc hyrcxy left groups. ' (R) -N--1 - [(3-chloro-2-thienylmethyl) propyl] -2-hydroxy-3-nitro-4'-amino-amino is replaced by chloro. characterized in that 4-chloro-3-nitropyridin-2 (1-thi) -one is reacted with (II) -3-chloro-α-ethyl 1-2-thiophenethananine to give (Z) -a - [1- (3-chloro-2-thienyl) methyl] propyl] -2-hydroxy-317. Way after. of claim 14, n. init r o -4-pyridine mamine. IS. The process of claim 17 wherein the reaction is carried out in the presence of isopropanol and Κ, Ν-diisopropylethylamine. 12. A process for the preparation of (R) -N--1 - [(3-chloro-2-thienyl) methyl] prepyl] -2-hydroxy-3-nitro-4-pyridinamine, characterized in that The process of claim 1, wherein 4-chloro-3-nitropyridin-2 (1H) -one is reacted with (Π) -3-chloro-α-ethyl-2-thiophenethylamine. .20. The method of claim 17, wherein the 4-hydroxy-3-nitro-2 (1H) -pyridone is reacted with phosphorus oxychloride to provide said 4-chloro-3-nitropyridine-2 (II-I). ) -on. 21. A process for the preparation of 4-hydroxy-3-nitro-2 (111) -pyrimidine by hydrolyzing and decarboxylating 2-hydroxy-3-cyano-4-methoxypyridine to form 2,4-dihydroxypyridine followed by nitration of said 2,4-dihydroxypyridine El Process according to claim 21, characterized in that the hydrolysis, decarboxylation and nitration are carried out in a single step, without the need for isolation and purification of the intermediate intermediate 2,4-dihydrc pyridine. ·· ···· ·· - 2ο 23. Process for the preparation of the di-acid chloride salt [13 [1a, 2b, 3b, 4a (S ⁺ .)]] -4 - [[3-aciro-4- [1,1- [3-chloro-2-thienyl]] (I) methyl] propyl] amino] -2-pyridinyl] amino] -N-ethyl-2,3-dihydronycyclopentenecarbosamide, 4-chloro-3-nitropyridin-2 (1 H) -ene is reacted with (R) -3-chloroacetyl-2-thiophenethanamine to give (R) -N- [1 - [(3- chloro-2-thienyl) methyl] propyl] -S-hydroxy-3-nitro-1-pyridinamine, then the (R) -R- [1 - [(3-chloro-2-thienyl) methyl] pi group 'pollin' 2-hydroxy-3-nitro-4-pyridinamine is replaced by a chloro group to give (14) -2-chloro-R - [1- [3- (3-chloro-2-thienyl) methyl] propyl] -3-nitro-4-pyridinamine and then (R) -2-chloro-N-] 1 - [(3-chloro-2-thienyl) methyl] propyl] -3-nitro-4-pyridinamine is reacted with 22,3S-isopropylidene-4R-amino- 13 with reading-amino carbonyl pent and 1 cycle can not give [3a] 3aa, 4a, 3a (R ^T), Gaa]] -3 - [[4- [[Ι-Γ (3-chloro o-2-thienyl) methyl] propyl] amino] -3-nitro-2-pyridinyl] amine, then [3aE- [3aa, 4a, 3a (R ⁺ ), 6aa] 1-3-Γ [4 - [[1- [(3-Chloro-2-thienyl-uretyl] propyl] amino] -3-nitro-2-pyridinyl] amine is reduced in R 3aR- [3aa, 4a, 5 a (R ⁺ ), Gaa]] - 6-η 3 - * amino-4 - [[1 - [(3-chloro-2-thienyl) methyl] propylamino] -2-pyridine 1-amino] -H-α-hydroxy-ethoxy-2,2-dimethyl-4H-cyclohexyl-3,3-1,3-diozol-4-carbarbamide, whereupon [ 3aR- [3aa, 4a, Ga (R & apos ^; ), Gaa]] 5- [Γ 3-amino-4 - [[1- [(3-chloro-2-thienyl.) Methyl] propyl] anino] -2-pyridinyl] amino] -N-ethyl-tetrahydro-2,2-diethyl-4E-cycloponta The 1,3-dione-4-carbosamide is hydrolyzed in the presence of hydrochloric acid, which reaction steps are carried out without the need to isolate and purify the intermediates formed in each scale, i.e. [3aR- [3aa, 4a, 6a (R '), 6aa] ] -5-] [3-Amino-4 - [[1 - [(3-chloro-2-thienyl) methyl] propyl] amino] -2-pyridinyl. amino] - N -ethyl-tetrahydro-2,2-dimethyl-di-cycloponta-1,3-di-ol-4-carboxamide, [3aR- [Saa, 4a, 6a (R ⁺ ), oaa] - 6 - [[4- [r (3-Chloro-2-thienylmethyl) prenyl] amino] 3-nitro-2-pyridinyl, 1] amino] -N-ethyl-tetrahydro-2,2 (4) -2-chloro-N- [1 - [(3-chloro-2-thienyl) methyl] propyl] -3-nitro-dimethyl-4K-cyclopentyl-1,3-diozole-4-carboxamide; 4-pyridinamine or (R) -N- [1 - [(3-chloro-2-thienyl) methyl] propyl] -2-hydroxy-3-nitro-4-pyrrole come with us nu. . . 24,2Preparation method [1S- [1a, 2b., 3b, 4a (S ⁺ )]] r-4 - [.7-LU (3-chloro-2-llyny 1) net 1] propy 1] ami η o] - 3T-I - i dazo [4,5 - b] pyridine - 25 ·· ······ · · · · 3-yl] -N-ethyl-2,3-dihydroxy cyclopentanecarboxamide in crystalline form; A process for preparing a free base [1f- [1a, 2b, 3b, 4a, 5]] - 4 - [[3-anino-4 - [[1- [3-chloro-2-thicnyl) methyl]] propyl] amino] -2-pyridinyl] amino] -N-methyl-2,3-dihydrones of cyclopentanecarboxamide from the dihydrochloride salt of the compound, whereupon the free base is reacted with formamidine acetate, which reactions are carried out in a single step without the need for isolating and purifying said free policy. c t * 7 e _n T.-t ¼ _r 0¼9b ZI of \ 1 1 ζί_Γ 7 r Γ 1 _, »Li ^; vG O »· 'xj. * In -.i .ix p <* ij · - '· f jj "CT \ O / ^l ** JJ w · u (3-chloro-2-thienyl) methyl] propyl] amino] -3H-imidazo [4,5-b] pyridine 3-yl] -N-ethyl-2,3-dihydronycyclopentanecarboxamide in crystalline form, characterized in that pIS-β, 2b, 3β · 4α (S ⁺ )]] -4- [β-amino] 4 - [[1- (3-Chloro-2-thienyl) methyl] propyl] amino] -2-pyridinyl] amino] -N-ethyl-2,3-dihydroxycyclopentanecarbamide dihydro chloride is reacted with octanol f. ormamid inu. 26. (R) -N- [1 - [(3- 1-Chloro-2-thienyl) methyl] propyl] -2-hydroxy-3-nitro-4-pyridine. . . 27. [13- [1a, 2b, 3b, 4a. (S ⁺ )]] - 4 - [[3-amino-4 - [[1- [3-chloro-2-thienyl] methyl] prepyl] amino] -2-pyridinyl] amino] -N-ethyl-2,3-dihydroxy-cyclopentanecarbone and mi.