IT8323005A1 - Process for the preparation of 2-hydroxy-5- {1-hydroxy-2- [(4-phenyl-2-butyl) amino] ethyl} benzamide - Google Patents

Description

DESCRIPTION

of the industrial invention entitled:

"Process for the preparation of 2-hydroxy-5- | 1-hydroxy-2- (4 phenyl-2-butyl) amino ethyl benzamide

SUMMARY

For the preparation of labetalol, that is 2-hydroxy-5- 1-hydroxy-2- (4-phenyl-2-butyl) amino ^ 7ethyl ^ benzamide, particularly useful as an antihypertensive, the direct bromination of 5-acetylsalicylamide is carried out, and Talkylation of the resulting bromoketone with 1-phenyl-3-amino butane, after which it leads to reaction with sodium borohydride.

DESCRIPTION

The present invention relates to the preparation of 2-hydroxy-5-hydroxy-2-4-phenyl-2-butyl) amino] ethyl benzamide, also known under the name dilabetalol, having a structural formula;

Labetalol? an important active pharmaceutical ingredient with activity? both 06 that j?> blocker of adrenergic receptors and thanks to these activities? combined in a single molecule constitutes an important innovation in the treatment of hypertension.

Numerous types of labetalol synthesis are described in the literature: Gold, E.H. and Chang, W. (Lunts, L.H.C. and Collin, D.T., German Patent Application No. 2032642 and European Patent No. 9702) which can be summarized as:

- Ammonolysis of methyl-2-hydroxy-5--hydroxy-2-? (1-methyl-3-phenyl-propyl) benziiamino ethyl ^ benzoate and subsequent catalytic hydrogenation to debenzylate the amino group.

- Ammonolysis of methyl-2-hydroxy-5 - [^ N-benzyl-N - (- 1-methyl-3-phenyl propyl) glycifj benzoate and subsequent catalytic hydrogenation for simultaneous reduction of the ketone group and debenzylation of the amino group.

- Alkylation of 4-hydroxy-3-carbamoyl-phenacylbromide with N- (1-methyl-3-phenyl propyl) phenyl-methylamine and subsequent catalytic hydrogenation to debenzylate the amino group.

- Alkylation of 4-benzyloxy-3-carbamoyl-phenacylbromide with N-Q-methyl-3-phenyl propyl) phenyl-methylamine and subsequent catalytic hydrogenation for simultaneous debenzylation of the amino and phenolic groups.

- Reductive catalytic alkylation of 5- (N, N-dibenzyl-glycyl) salicylamide in the presence of 4-phenyl-2-butanone.

- Azametino condensation of 2-hydroxy-5- (2-amino-1-hydroxyethyl) benzamide with 4-phenyl-2-butanone and subsequent reduction by catalytic hydrogenation.

How can you? it is easy to observe, these are synthesidelicates which involve a protective stage of 1-phenyl-3-amino butane or 5-acetylsalicylamide or both. In fact, this stage of protection, in addition to increasing the duration and complexity? of the synthesis, it also makes? a subsequent catalytic hydrogenation process is necessary, a process whose industrial problems and drawbacks (both as regards the cost of the catalysts and the nature of the plants to be used) are well known and evident.

Another problem intrinsically related to the acetalol molecule? the existence of four possible stereoisomers, namely (RR), (SR), (RS) and (SS), having activities? different in the blocking of receptors and. Among these? known that the isomer RR? the isomer pi? powerful as a blocking activity, while the SR isomer? the main person responsible for the activity? blocker of receptors? 6.

The realization of beta-beta forms having a predetermined ratio of certain isomers, in particular of the RR and SR isomers,? hitherto only possible by resorting to one of the above-mentioned processes with related drawbacks.

Main purpose of the present invention? hence that of carrying out a procedure for the preparation of formula (I) acetalol with which to solve the inconveniences and problems briefly mentioned above.

Another equally important object of the present invention? that of providing a process for the preparation ofabetalol in which the RR and SR isomers are present in predetermined ratios, in particular in the 50 / 5D ratio.

In fact, with a product in which only the isomers RR and SR sipu are represented in the 50/50 ratio? reach a pharmaceutical form cIJ and ?? blocker pi? active and therefore usable in dosages? low, with all the obvious advantages.

These objects are achieved with the process of the present invention for the 2-hydroxy-5-1-hydroxy-2- (4-phenyl-2-butyl) -aminq 7ethylbenzamide diformula (I) synthesides characterized by: a) direct bromination of 5 -acetylsalicylamide, with the introduction of bromine in position? algroup ketone;

b) alkylation of the resulting 4-hydroxy-3-carbamoyl-phenacyl bromide with 1-phenyl-3-aminobutane;

c) reaction of the resulting 2-hydroxy-5- [N- (1-methyl-3-phenylpropyl) amino 7-acetyl benzamide with alkali metal borohydride, preferably sodium, to obtain the desired product (I). The process according to the invention can? therefore summarize in the following diagram:

In the process defined above, the direct bromination of 5-acetylsalicylamide is preferably carried out in methylene chloride and allowing the mixture to reflux until completion of the reaction.

In turn, the dialkylation phase of the bromoketone is carried out at a low temperature not exceeding 10 ° C, and in an alcoholic solvent, such as ethanol, or chlorinated.

If the dialkylation step is carried out starting from (R) - (-) - 1-phenyl-3-aminobutane, an intermediate is obtained, i.e. (R) - (+) - 2-hydroxy-5-N- (1-methyl -3-phenylpropyl) amm inq_ / acetylbenzamide which in turn, brought to react with sodium boroidide, provides a mixture of (RR) and (5R) isomers, in particular in the 50/50 ratio.

The importance of this last result and aspect of the present invention? diper s? evident and? already? been commented on.

In the synthesis according to the invention, therefore, the direct bromination of 5-acetylsalicylamide is carried out, with the introduction of the bromine in the ketone group without any appreciable bromination in the ring and without having to proceed with the protection of the phenolic group. The alkylation of bromoketone is then carried out using 1-phenyl-3-aminobutane, thus operating on the unprotected primary amine, unlike what? described throughout the literature referring to betalol. In this regard, it is important to point out that in the operating conditions of the present invention the formation of products deriving from the double alkylation of the amine is never noticed.

If the alkylation process is not carefully controlled the main product of the reaction? a dimer showing the structure indicated below, confirmed by the properties? physico-chemical (NMR, MS, IR, elemental analysis)

Some examples are now given which illustrate the invention without constituting an undue limitation.

EXAMPLE

a) 4-hydroxy-3-carbamoyl-phenacylbromide

950 ml of methylene chloride and 50 g (0.279 moles) of 5-acetylsalicylamide are loaded into a 2-liter flask equipped with a stirrer, reflux cooler, dropping funnel and thermometer.

The suspension is brought to reflux. A solution obtained from 44.4 g (0.278 moles) dibromo and mi65 methylene dichloride is dripped off, keeping the mixture under reflux, in about 60 minutes.

After the addition of the bromine, it keeps the mixture under reflux for another 30 minutes.

The suspension is cooled to 20 ° C and then filtered.

The white crystalline solid is then washed with dimethylene chloride, then with ethanol and then with water.

It dries at 50 ° C under a residual vacuum of 20 mmHg.

70 g (yield 97.2%) are obtained, with a melting point of 206? C (dee.). The product can be recrystallized from ethyl alcohol.

The NMR spectrum (in D --DMSO) shows bands at 4.992H (s), 7.16

IH (d, j = 4 p.p.m.), 8.232H (d, d, j = 1-4 p.p.m.), 8.26 IH (s all., Disappears by deuteration), 8.76 IH (d, j = 1 p.p.m. ), 8.80 1H (s all., Disappears for uteration).

By thin layer chromatography (TLC on silica gel - eluent: benzene / ethyl acetate / N-hexane / isopropanol 30/20/20/5 v / v) the main spot is highlighted which has the same Rf (0.45) of a standard sample.

b) 2-hydroxy-5 - ^? N- (1-methyl-3-phenylpropyl) amino7-acetyl? benzamide hydrochloride

In a two-liter flask equipped with a stirrer and a thermometer, I charge 1000 midyalcoolethyl and 300 g of 98% dil-phenyl-3-aminobutane (1.970 mol).

The solution is cooled to 0 ° C.

Then 100 g (0.387 moles) of 4-hydroxy-3-carbamoylphenacylbromide are added, maintaining the temperature at 0/5 ° C, in the time of four hours. The reaction solution is then kept under stirring at 0/5 ° C for one night.

100 ml of concentrated hydrochloric acid are added, the product is left to crystallize under stirring.

The white crystalline precipitate is separated by filtration, washed with alcohol and dried at 5Q <n> C under a residual vacuum of 20 mmHg.

120 g of dry product are obtained (yield: 85.3%) with a melting point of 220-222 <D> C.

By alkalizing the madridireaction waters, the unreacted phenylaminobutane is recovered.

20/1 v / v) highlights the main spot which has the same Rf (0.36) as a standard sample.

c) 2-hydroxy-5- 1-hydroxy-2- (4-phenyl-2-butyl) amino] 7ethyl benzamide

In a two-liter flask equipped with a stirrer and Sicilian thermometer, at room temperature, 1200 ml of water, 200 ml of 30% sodium hydrate solution (2 moles) and 350 g (0.96 moles) of 2-hydroxy-5-N- (1-methyl-3-phenylpropyl) amino-7acetyl-benzamide hydrochloride

The mixture is kept stirred until the reaction intermediate is completely dissolved.

30 g of 95% sodium borohydride (0.75 moles) are then loaded in portions, in about four hours. Once the reductant has been reached, it is left under stirring, again at room temperature, for one night, taking care to check the end of the reaction by TLC (eluent: chloroform / methanol / ammonia 75/25 / 2.5 v / v).

The solution is decoloured with charcoal.

The labetalol base is precipitated with diluted acetic acid up to the isoelectric pH (10.5).

5i filters the white precipitate obtained, silvae with distilled water to neutral pH and dry at 60 ° C under a residual vacuum of 20 mmHg.

270 g of dry product are obtained (yield: 85%) with a melting point of 139-141 ° C.

For high-pressure liquid chromatography (HPLC) the dansyl derivative synopses two peaks, the ratio of which? about 1: 1.

The product obtained, examined in TLC (eluent chloroform / methanol / ammonia 75/25 / 2.5 (v / v), shows the presence of a main spot having the same Rf (0.63) as a standard sample.

The labetalol base thus obtained is transformed into the corresponding hydrochloride.

400 ml of acetone and 50 g of labetalol base are placed in a one-liter flask. The mixture is stirred and 15 midi concentrated hydrochloric acid are charged.

The suspension is heated under reflux for 30 minutes and then cooled to 15DC.

The solid is separated by filtration, washed on the filter with acetone and dried at 50 ° C under a residual vacuum of 20 mmHg.

52 g of pure product are obtained (yield: 94%) with a melting point of 180-181 ° C.

Mass spectrum shows M / E spikes: 310 (3% M <+> -18), 292 (3% 310 - 17), 162 (70% 310 - 140), 91 (100% M <+> -237) .

d) Preparation of: (R) - (+) - 2-hydroxy-5- ^ Z.N- (1-methyl-3-phenyl-propyl) -amino] acetylbenzamide hydrochloride.

In a two-liter flask equipped with a stirrer and a thermometer, they add 1000 midi alcohol ethyl and 300 g of 98% (R) - (-) - 1-phenyl-3-aminobutane (1.970 mol).

The solution is cooled to 0 ° C.

Then 100 g (0.387 moles) of 4-hydroxy-3-carbamoyl-phenacylbromide are charged, maintaining the temperature at 0 ° / 5 ° C, in the time of four ares. The reaction solution is then kept under stirring at 0/3 ° C for one night.

100 ml of concentrated hydrochloric acid are added, the product is left to crystallize under stirring.

The white crystalline precipitate is separated by filtration, washed with alcohol dried at 50 ° C under a residual vacuum of 20 mmHg.

120 g of dry product are obtained (yield: 85.3%).

In a two-liter flask equipped with stirrer and thermometer, 1200 ml of water, 200 ml of sodium hydrate solution at 30% (2 moles) and 350 g (0.96 moles) of R - (+) are charged at room temperature. -2-hydroxy-5- [N- (1-methyl-3-phenylpropyl) amin ^ acetyl benzamide hydrochloride.

The mixture is kept stirred until the reaction intermediate is completely dissolved.

30 g of 95% sodium borohydride (0.75 moles) are then loaded in portions, in about four hours. Once the addition of the reducing agent is finished, it is left under stirring, again at room temperature, for one night, taking care to check the end of the reaction by TLC (eluent: chloroform-methanol / ammonia 75/25 / 2.5 v / v).

The solution is decoloured with charcoal.

The labetalol base is precipitated with acetic acid diluted to isoelectric (10.5).

The obtained white precipitate is filtered out, silicaed with distilled water up to neutral pH and dried at 60 ° C under a residual vacuum of 20 mmHg.

270 g of dry product are obtained (yield: 85%) with a melting point of 159-160 ° C.

HPLC: ratio of isomers RR / SR = 48.37 / 51.63.

The RR-SR basic labetalol thus obtained is transformed into the corresponding hydrochloride, according to the modalities. already? views, with 94% yield.

With the product obtained by the process of the present invention, in the variant which leads to a mixture of 50/50 diisomers (RR) and (SR), it is possible, as already? mentioned, prepare more pharmaceutical compositions? effective, at par? dosage with respect to the traditional compositions based on abetalol, or minor compositions

Claims (15)

characterized by aglistadids: a) direct bromination of 5-acetyl salicylamide, with the introduction of the bromine in position? algroup ketone; b) alkylation of the resulting 4-hydroxy-3-carbamoyl-phenacylbromide with 1-phenyl-3-aminobutane; c) reduction of the resulting 2-hydroxy-5- [N- (1-methyl-3-phenylpropyl) amino acetyl-benzamide with borohydride of an alkali metal to obtain the desired compound (I). 2) Process according to claim 1, characterized in that said step (a) is carried out in an inert organic solvent, causing the mixture to reflux until the reaction is completed. 3) Process according to claim 2, characterized in that said organic solvent? dimethylene chloride. 4) Process according to claim 1, characterized in that the bromoketone alkylation step (b) is carried out at a low temperature, not higher than 10 ° C. 5) Process according to claim 4, characterized in that said temperature? about 0? C. 6) Process according to claim 4, characterized in that the alkylation is carried out in an alcoholic to chlorinated solvent. 7) Process according to claim 6, characterized in that said alcoholic solvent? ethanol. 8) Process according to claim 1, characterized in that said step (b) dialkylation is carried out with (R) - (-) - 1-phenyl-3-aminobutane, with the obtainment of (R) - (+) - 2-hydroxy -5- [N- (1-methyl-3-phenylpropyl) amino7acetyl ^ benzamide. 9) Process according to claim 8, characterized in that (R) - (+) - 2-hydroxy-5- [N- (1-methyl-3-phenylpropyl) amino] Jacetyl benzamide is subjected to reduction with alkaline borohydride, with formation of a mixture of isomers (RR) and (SR) of compound (I). 10. Process according to claim 9, characterized in that said isomers are present in the ratio 50/50 in said mixture. 11) 2-hydroxy-5- [N - (1-methyl-3-phenylpropyl) amino] acetyl benzamide and its hydrochloride, useful as intermediates in the process according to claim 1. 12) Isomer (R) - (+) - 2-hydroxy-5- [- (1-methyl-3-phenylpropyl) amino] / - acetyl ^ benzamide and its hydrochloride. 13) Mixture of isomers (RR) and (SR) of the compound of formula (I) when obtained with the procedure of claim 9. 14. Mixture according to claim 13, characterized in that said isomers are present in said mixture in the ratio 50/50. 15) Pharmaceutical composition, characterized by containing as the active ingredient the mixture of isomers of the compound of formula (I) according to claim 14.