HU205090B - Process for produicng hyigh purity polymorphous modification of 1,4-bis/3-(3,4,5-trimethoxy-benzoyloxy)-propyl/-perhydro-1,4-diazepine dihydrochloride monohydrate - Google Patents

Abstract

The present invention relates to 1,4-bis [3- (3,4,5-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate for the preparation of a high purity polymorph by recrystallization from an organic solvent. According to the invention, 1,4-bis [3- (3,4,5-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate is present in an organic solvent having a dielectric constant of 20-40, preferably It is dissolved in C 1-4 alkynyl nitrile, C 1-4 nitroalkane, C 2-4 diols or mixtures thereof at temperatures above 30 ° C, preferably at the boiling point of the solvent or solvent mixture, optionally removing the insoluble impurities which may be present by filtration. After cooling to 25-30 ° C, the excellent impurities were removed by filtration and the filtrate was crystallized at a temperature below 25 ° C, preferably 0-5 ° C. EN 205 090 B Scope of the description: 4 pages

Description

The present invention relates to a process for the preparation of a polymorph of a 1,4-bis [3- (3,45-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate, commonly known as dilazep dihydrochloride. in high purity by recrystallization from an organic solvent.

More particularly, the present invention relates to a process for the preparation of a unitary crystalline drug of pharmaceutical purity by recrystallization of a mixture of any other crystalline modifications obtained by any means.

It is known from U.S. Patent 3,523,685 that 1,4-bis [3- (3,4,5-trimethoxy-benzoyloxy) -propyl] -perhydro-1,4-diazepine dihydrochloride monohydrate is a coronary vasodilator. Recent biological studies have also shown other beneficial vascular effects.

According to known processes for the preparation of dilazep (U.S. Patent 3,523,685; Japanese Patent Laid-open Nos. 53-144 591, 56-158 773, 57-106 668 and 51-095 086), the final product is purified by repeated use of ethyl alcohol. recrystallization is used. However, recrystallization from ethyl alcohol yields only chromatographically non-uniform material having a melting point of 195-200 ° C. This product no longer meets the very strict requirements. For medical use, dilazep dihydrochloride is required to be chromatographically uniform, melting above 200 ° C, which corresponds to a particular polymorphic crystalline moiety.

To meet the increased quality demands, U.S. Patent No. 3,438,289. U.S. Patent No. 4,863,198 discloses a purification process consisting of washing a highly basic impurity from a solution of crude dilazep base in a water-immiscible solvent with an aqueous solution of a medium organic or inorganic acid, followed by washing the dilazep salt in the organic phase the dihydrochloride salt is prepared. This is recrystallized from ethyl alcohol to give a uniform dihydrochloride monohydrate salt by chromatography, with a yield of 72% relative to the crude product.

The melting point and morphological properties of the resulting material are not described.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a simpler, low-loss, operationally feasible method for purifying the crude product of dilazep dihydrochloride, while providing the desired crystal type.

It has been found that the impurities of dilazep dihydrochloride in solvents of defined polarity are much less soluble than dilazep dihydrochloride, so that they can be removed by fractional crystallization. Therefore, according to the present invention, 1,4bis [3- (3,4,5-trimethoxybenzyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate is prepared in a dielectric constant organic solvent, preferably Dissolved in C 1-4 alkylnitrile, C 1-4 nitroalkane, C 2-4 nuts or mixtures thereof at temperatures above 30 ° C, preferably at the boiling point of the solvent or solvent mixture, if necessary, insoluble impurities are removed by filtration; After cooling to 30 ° C, the precipitates are removed by filtration and the product crystallized from the filtrate at temperatures below 25 ° C, preferably 0-5 ° C.

The process of the invention uses an organic solvent having a dielectric constant of 20-40 at 20'C. Acetonitrile has a particularly preferred dielectric constant at 20 ° C for this purpose

38.3 - 812 times the weight of dilazep dihydrochloride, propionitrile dielectric constant at 20 'C is 27.6-15-19 times, and nitromethane dielectric constant at 20' C is 39.45- 8 times, and mixtures of these solvents as shown in Table 1.

Preferably, the hot solution of the crude dilazep dihydrochloride is treated with 0.05 to 0.1% by weight of activated carbon or Kieselgel 60 adsorbent and then filtered, for example, on a G-4 pore size filter to remove any suspended impurities.

At high heavy metal contents, the solution is also treated with 0.005% by weight ethylene diamine tetraacetic acid complexing agent. The complexing agent is mixed with the adsorbent in solution.

The pre-purified solution was cooled to 25-30 ° C. At this temperature range, impurities are separated from the solution and can be removed by repeated filtration.

The impurities of crude dilazep dihydrochloride are alkylamines and / or their hydrochloride salts, which are essentially basic in nature but / or hydrochloride salts of the following synthesis pathway, and high molecular weight polymer alkylaminoalkyl compounds based on DC Alurolle Kieselgel 60 thin film, butanol: 60% glacial acetic acid. Running at 15:25 gives Rf = 0.05, 0.23 and 0.34.

The impurity at 25-30 ° C is generally 8-15% by weight of the starting crude product.

During filtration, the main product remains in solution and crystallization begins only upon cooling at 0-25 ° C, preferably 0-5 ° C, and after 8-12 hours cooling, 78-85% of the main product precipitates. solution.

The stoichiometric dilazep dihydrochloride monohydrate is obtained by drying at 95 ° C, 5xl0 ⁴ mbar.

Morphologically uniform according to the invention, showing the infrared characteristics of the crystal types, 2450 cm ^-1, 1720 cm ^-1, 1590 cm ^-1 and 1230 cm ^-1 absorption maxima values obtained.

The crystals obtained according to the invention are chromatographically uniform, melting above 200 ° C and having a transmittance of greater than 98% in a 5% aqueous solution.

The advantages of the process according to the invention can be summarized as follows:

The process can be carried out on an operational scale with simple technological operations.

The product obtained is of medical purity, namely:

(a) Chromatographic unit, DC Alurolle Kieselgel

EN 205 090 Β thin film, butanol: glacial acetic acid: water 60:15:

running mixture of _Rf = 0.38 value occurs.

b) Melting point higher than 200 ° C.

c) Transmittance greater than 98% in 5% solution.

(d) It is morphologically uniform.

The invention is illustrated in detail by the following examples:

Example 1

36.9 g of 92% 1,4-bis (3,4,5-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate, contaminant hydrochloride salt, and opacifying agents The crude product containing the crude product was dissolved in 400 ml of acetonitrile at the boiling point of the solvent, at this temperature 2.0 g of activated carbon was added and the carbon solution was filtered through a G-4 pore size glass filter. The filtrate was then allowed to stand until it cooled to 28 ° C and crystallization began. After 10 minutes, filter again on a G-4 filter and allow the clear filtrate to stand at 0-5 ° C for 10-12 hours. White powder, a well-filterable material separates out, which was dried for 1 hour 5xl0 ⁴ Pa in vacuo at 95 ° C.

This gave 30.8 g (83.5%) of a chromatographically uniform product, m.p.> 200 ° C, which exhibited 98.8% transmittance in 5% aqueous solution.

Example 2

10.0 g of 95% 1,4-bis [3- (3,4,5-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate, salts of amino compounds as impurities and anti-ulcer Dissolve the crude product containing the substances in 50 ml of nitromethane at the boiling point of the solvent, add 1.0 g of Kieselgel 60 adsorbent at this temperature and reflux for 15 minutes. It was then filtered through a G-4 glass filter, cooled to 25 ° C, and after crystallization began, it was repeatedly filtered through a G-4 glass filter. The solution was allowed to stand at 10 ° C for 24 hours and the precipitated pure product was filtered. The drying takes place at 95 ° C for 5xl0 ⁴ mbar for 1 hour to yield C-melt, a chromatographically pure product (7.8 g, 78%), 200.9 °, which is a 5% aqueous solution at 98% shows transmittance.

Example 3

10.0 g of 90% 1,4-bis [3- (3,4,5-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate, contaminated with salts of amino compounds and anti-ulcer substances The crude product containing the crude product was dissolved in propionitrile (180 mL) at the boiling point of the solvent and proceeded as in Example 1 below.

Purification afforded 8.5 g (85%) of a chromatographically uniform product, m.p. 201.4 ° C, having a transmittance of greater than 99% in 5% aqueous solution.

4-7. example

Purification was carried out as described in Example 1 using the solvent mixtures shown in Table 1.

Table 1 /

Example number: Solvent (ml) Production % acetonitrile propionitrile nitromethane 4 ¹ - 50 5 83 5th 50 - 50 76 6th - 80 20 80 7th 80 - 20 78

4-7. Examples 1 to 8 are based on a crude product having a purity of about 90% and the final product is of pharmacopoeial quality.

Example 8

The procedure of Example 1 was followed except that the crude product was dissolved in 350 ml of ethylene glycol instead of 400 ml of acetonitrile.

30.3 g (82.1%) of a chromatographically uniform product, m.p. 200.6 ° C, is 99% transmittance in 5% aqueous solution.

Example 9

The procedure of Example 1 was followed except that the crude product was dissolved in propylene glycol (propane-1,2-diol) (380 ml) instead of 400 ml acetonitrile.

30.4 g (82.4%) of the product is chromatographically uniform, m.p. 200.8 ° C, exhibiting 99% transmittance in 5% aqueous solution.

Claims (1)

PATENT CLAIMS Process for the preparation of a high purity polymorph of 1,4-bis [3- (3,4,5-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate by recrystallization from an organic solvent, characterized by: 1,4-bis [3- (3,4,5-trimethoxybenzoyloxy) propyl] perhydro-1,4-diazepine dihydrochloride monohydrate in an organic solvent having a dielectric constant of 20-40, preferably 1-4. dissolved in C alk alkilnalkylnitrile, C 1-4 nit nit nit nitroalkane, C2--- nuts or mixtures thereof at a temperature above 30 ° C, preferably at the boiling point of the solvent or solvent mixture, the optional insoluble impurities are removed by filtration if desired; After cooling to <RTIgt; C, </RTI> the remaining impurities are removed by filtration and the product crystallized from the filtrate at temperatures below 25 ° C, preferably 0-5 ° C.