HU201929B - Process for producing crystalline 2-(1-pentyl-3-guanidino)-2-(2-methyl-4-imidazolyl)-thiazoledihydrochloride trihydrate - Google Patents

Abstract

The present invention relates to crystalline 2- (1-pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) thiazole dihydrochloride trihydrate. 2- (1-Pentyl-3-guanidino) -2- (2-methyl-4-imidazolyl) thiazole is optionally crystallized from a dilute aqueous hydrochloric acid solution which is optionally diluted with a water miscible organic solvent. EN 201929 B Scope of the description: 4 pages, 2 drawings, Figure 3 -1-

Description

This invention relates to crystalline 2- (1-pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) -thiazole dihydrochloride trihydrate.

U.S. Patent 4,560,690 to Reiter discloses 2- (1-pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) -thiazole and various analogues thereof which exhibit anti-gastric ulcer activity. Further details are given in the above-mentioned patent for pharmaceutical compositions and the method of inhibiting gastric ulcer with these compounds.

Reiter prepared these compounds according to Scheme I, wherein R is benzyl or C 1 -C 5 alkyl and R ^{1 is C} 1 -C 5 alkyl. The products were isolated in the form of their dihydrobromide salts and then converted to the preferred dihydrochloride salts via the free base.

The present invention relates to a process for the preparation of crystalline 2- (1-pentyl-3-guanidino-4-imidazolyl) -thiazole dihydrochloride trihydrate. This compound has distinct advantages over the former anhydrous dihydrochloride produced by Reiter, which is amorphous, less easily purified, and has properties that generally render it less suitable for use in medicine and humans,

The starting material for the preparation of crystalline dihydrochloride trihydrate can be prepared according to the above-described U.S. Patent 4,560,690 or by the procedure described in Hungarian Patent Publication No. T / 50814.

The crystalline 2- (1-pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) -thiazole dihydrochloride trihydrate of the present invention is prepared from dilute aqueous hydrochloric acid, optionally in a water-miscible solvent such as acetonitrile. It is obtained by crystallization at C. If desired, the product is recrystallized from aqueous solvents such as a mixture of water and acetonitrile at a temperature above 50 ° C and at ambient pressure to keep the trihydrate in crystalline trihydrate form. at temperatures above 70 ° C (e.g. 70 ° C and ambient pressure) it slowly loses hydration water but is readily recovered when stored at room temperature and high relative humidity. .

The following examples illustrate the invention.

Example 1

2- (l-pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) thiazole dihydrochloride trihydrate

Procedure A)

In a 3-necked 50 mL flask equipped with a condenser, thermometer and mechanical stirrer, 15.0 g (172 mmol) of pentylamine and 10.0 g (23.8 mmol) of 2-guanidino-4- (2 -methyl-4-imidazolyl) -thiazole dihydrochloride time is measured. The thick slurry is heated to reflux (104 ° C) under nitrogen and the reaction mixture is considered homogeneous at about 90 ° C. The reaction mixture was refluxed for 19 hours. Thin layer chromatography and high performance liquid chromatography indicated that the reaction was complete. The thick brown syrup was cooled to 50 ° C and 130 ml of acetone followed by 12 ml of concentrated hydrochloric acid were added. A solid begins to precipitate. The suspension was cooled to room temperature and granulated for 1 hour. The off-white solid was filtered off, washed with acetone and air-dried at room temperature. The crude dry solid weighed 6.93 g (48.8%).

The crude product was dissolved in 80 ml of a 1: 1 mixture of acetone-water at 45 ° C and 1.0 g of activated carbon was added. The carbon-treated solution was filtered through a funnel lined with diatomaceous earth, and the filter pad was washed with another 11 mL of acetone: water (1: 1). The filtrate was transferred to a clean flask and cooled in an ice bath. Concentrated hydrochloric acid (32 mL) was added slowly. After the addition of about 20% of the concentrated sol, the solid begins to precipitate. When the acid addition is complete, the solid is granulated for 1 hour at room temperature. The white solid was washed with acetone and air-dried to give 5.85 g (41.5% overall yield) of the crystalline trihydrate dihydrochloride salt. Examination under the polarization microscope shows needle-like crystals. The differential thermogravimetric curve shows high heat absorption at 107-109 ° C, which remains unchanged after drying under vacuum without heat transfer.

Elemental analysis based on the formula C13H20N6S-2HCl-3HzO:

date:

c 37.22% H 6.74% N 20.4% s 7.64% cl 16.90% H? O 12.87%; found: C 36.97% H 6:57% N 19.89% S 7.82% cl 16.83% H2O 13:32%. THE product Above 50 ° C at temperature

loses water when looted. For example, the water content at 70 ° C decreases to 5.69% over a week. At room temperature and 84% relative humidity, the trihydrate re-forms within two weeks.

-23 HU

Elemental Analysis Found:

C 37.02%, H 6.66%, N 19.83%,

H 2 O 13.45%.

When dried under vacuum at 65 ° C to constant weight, the resulting anhydrous product is amorphous by microscopic examination. During the differential thermogravimetric examination, no snow absorption was observed at 107-109 ° C.

HPLC analyzes were performed on a microBONDAPAK C18 column (7.8 mm internal diameter x 30 cm) using a UV detector (254 nm). A 1: 1 mixture of aqueous buffer and methanol (1 ml / min) was used as eluent. The buffer contained 0.05 M potassium dihydrogen phosphate, 0.01 M sodium hexanesulfonate and 0.1% triethylamine, the pH of which was adjusted to 3.0 with phosphoric acid.

TLC analysis was carried out on Merck silica gel plates (60F-254) using methanol: water: diethylamine (20: 4: 1 by volume) as eluent.

201929 B 4 has the same physical properties as the product obtained by Method A. Optionally, the product obtained is washed with a small amount of acetone or stirred with 60 ml of acetonitrile for 2 hours and then filtered again to facilitate drying.

The product is recrystallized if desired by dissolving 3.4 g of the trihydrate in 34 ml of water at 50 ° C. Aceto10 nitrile (180 mL) was added to the resulting solution while maintaining its temperature at 50 ° C. The mixture was cooled slowly to 20 ° C with stirring. Crystallization begins at 32 ° C. The product is obtained in the form of a trihydrate (water content 12.95%) having the same physical properties.

Example 3

Preparation of 100 mgA capsule containing 2- (1-pentyl] -3-guanidino) -4- (2-methyl-4-imidazolylthiazole)

Procedure A)

Procedure B

The amorphous dihydrochloride of 2- (1-pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) -thiazole is prepared according to Example 5 of U.S. Patent No. 30 4,560,690. According to the description, 8.1 g of dihydrobromide salt are dissolved in 150 ml of water at 50 ° C. A solution of 8.86 g of Na2CO3 ^- H2O 35 in 80 ml of water is added with stirring for 1 hour. Stirring was continued for another half hour at room temperature, the base was collected by filtration and dried in vacuo for 48 hours, not completely anhydrous. The material was taken up in 200 ml of acetone, filtered to give a clear solution which was acidified with 3.4 ml of 12N hydrochloric acid and diluted with 100 ml of fresh acetone.

The precipitated material was filtered off, dried at 60 ° C under vacuum for 24 hours to give 6.3 g'amorphic dihydrochloride, elemental analysis for Οΐ3Η2θΝ58 · 2Η01 · 0.5Η2θ

gave a good result. calculated: 50 C, 41.71% H 6.19%, H 22:45%; found: C 41.90%, H, 6.20% N 22:55%; 41.60% 23.6% 22:48%.

3.01 g of this product are dissolved in 75 ml of water with stirring. To the solution was added 0.3 g of activated carbon, the mixture was stirred for 15 minutes and then filtered. 25 ml of concentrated hydrochloric acid were added to the filtrate. Within a few minutes, 60 crystallization begins. The crystalline title product is granulated for one hour and then collected by filtration, washed with 4 ml of water and dried for 18 hours to give 2.9 g of a water content of 12.6%; 65

The following substances are thoroughly mixed in the indicated weight ratio:

2- (1-Pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) -thiazole dihydrochloride trihydrate 144.9 * lactose anhydrous 173.8 starch 1500 173.8 magnesium stearate 7.5 * A 144, 9 mg of dihydrochloride trihydrate is equivalent to 100 mg of anhydrous free base, i.e., 100 mg of activity (100 mgA).

Suitable hard gelatin capsules are filled with 500-500 mg of the above mixture to provide 100 mgA of active ingredient. These capsules exhibit good chemical and physical stability when stored under challenging conditions (96% release in water over 15 minutes by standard dissolution techniques).

mgA capsules containing the active ingredient were similarly prepared using a mixture of 72.5 parts dihydrochloride trihydrate, 211.2 parts anhydrous lactose, 211.2 parts 1500 starch and 5.1 parts magnesium stearate.

Claims (2)

PATENT CLAIMS A process for the preparation of crystalline 2- (1-pentyl-3-guanidino) -4- (2-methyl-4-imidazolyl) -thiazole dihydrochloride trihydrate, characterized in that 2- (1-pentyl-3- guanidino) -4- (2-methyl-4-imidazolylthiazole) is crystallized from a dilute aqueous hydrochloric acid solution which is optionally diluted with a water-miscible organic solvent. A process according to claim 1 wherein the aqueous acid is diluted with acetonitrile. Published by the National Office for Inventions, Budapest Responsible: Dr. Gabriella Szvoboda Head of Department R 4977 - KJK