FR2483922A1 - PROCESS FOR THE PREPARATION OF BAMIFYLLINE - Google Patents

PROCESS FOR THE PREPARATION OF BAMIFYLLINE Download PDF

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Publication number
FR2483922A1
FR2483922A1 FR8110558A FR8110558A FR2483922A1 FR 2483922 A1 FR2483922 A1 FR 2483922A1 FR 8110558 A FR8110558 A FR 8110558A FR 8110558 A FR8110558 A FR 8110558A FR 2483922 A1 FR2483922 A1 FR 2483922A1
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Prior art keywords
benzyltheophylline
bamifylline
ethyl
ethylethanolamine
approximately
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FR8110558A
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French (fr)
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FR2483922B1 (en
Inventor
Rene Rachel De Ridder
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A Christiaens SA
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A Christiaens SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Process for the preparation of bamifylline or 7-(N-ethyl-N- beta -hydroxyethylaminoethyl)-8-benzyltheophylline hydrochloride. According to the invention, a mixture of 8-benzyltheophylline, N-ethylethanolamine, dichloroethane and sodium carbonate is heated under reflux such that, in a single stage, 7-(N-ethyl-N- beta -hydroxyethylaminoethyl)-8-benzyltheophylline results, which can be converted into its hydrochloride.

Description

La présente invention est relative à un procédé de préparation de 7-(N-éthyl-N-#- hydroxy éthylamino-éthyl ) -8-benzylthéophylline ou Bamifyl- line qui est un produit connu de formule

Figure img00010001

possédant-des propriétés pharmaceutiques intéressantes notamment pour le traitement de diverses maladies, telles que le collapsus du système respiratoire, 1' angine de poitrine, les dépressions respiratoires, 1'asthme et diverses maladies pulmonaires.The present invention relates to a process for the preparation of 7- (N-ethyl-N - # - hydroxy ethylamino-ethyl) -8-benzyltheophylline or Bamifylline which is a known product of formula
Figure img00010001

having advantageous pharmaceutical properties, in particular for the treatment of various diseases, such as collapse of the respiratory system, angina pectoris, respiratory depression, asthma and various pulmonary diseases.

I1 est connu (voir le brevet belge n 602.888) de préparer la Bamifylline, par voie industrielle en faisant réagir de la 7 -( -chloro ou bromo-éthyl)-8-benzylthéophylline (formule II) avec de la N-éthyléthanolamine (formule III) en présence de carbonate de sodium anhydre, selon la réaction suivante

Figure img00010002
It is known (see Belgian Patent No. 602,888) to prepare Bamifylline, by the industrial route by reacting 7 - (-chloro or bromo-ethyl) -8-benzyltheophylline (formula II) with N-ethylethanolamine (formula III) in the presence of anhydrous sodium carbonate, according to the following reaction
Figure img00010002

Dans ce procédé connu, effectué à l'échelle industrielle, on chauffait pendant 7 heures le mélange suivant - 192,5 kg de 7-(y ( -chloroéthyl)-8-benzylthéophylline
(578,4 moles) obtenue de la manière décrite dans le
brevet belge nO 602.887 - 70 litres de N-éthyléthanolamine (718 moles) - 45 kg de carbonate de sodium anhydre (424,5 moles).In this known process, carried out on an industrial scale, the following mixture was heated for 7 hours - 192.5 kg of 7- (y (-chloroethyl) -8-benzyltheophylline
(578.4 moles) obtained as described in the
Belgian patent no. 602.887 - 70 liters of N-ethylethanolamine (718 moles) - 45 kg of anhydrous sodium carbonate (424.5 moles).

Après isolement et purification du produit de la réaction, le rendement atteignait 57 à 65%. After isolation and purification of the reaction product, the yield was 57 to 65%.

Outre les pertes mécaniques, cette réaction donnait lieu à la formation d'une proportion importante d'un produit secondaire inactif, à savoir la 7-vinyl-8benzylthéophylline de formule

Figure img00020001
In addition to the mechanical losses, this reaction gave rise to the formation of a large proportion of an inactive secondary product, namely 7-vinyl-8benzyltheophylline of formula
Figure img00020001

Ce produit secondaire était obtenu à raison de 25 à 30 et à raison de 40 à 45,' respectivement dans le cas où l'on utilisait une 8-bromo-théophylline chloro- ou bromoéthylée en position 7. This secondary product was obtained at a rate of 25 to 30 and at a rate of 40 to 45, 'respectively in the case where a chloro- or bromoethylated 8-bromo-theophylline was used in position 7.

Or, on a trouvé à présent que l'on peut obtenir de la Bamifylline, en un seul stade, avec un rendement remarquable, c'est-à-dire sans production simultanée de 7-vinyl-8-benzylthéophylline. Now, it has now been found that Bamifylline can be obtained, in a single stage, with a remarkable yield, that is to say without simultaneous production of 7-vinyl-8-benzyltheophylline.

Suivant l'invention, on prépare de la
Bamifylline, en un seul stade, en chauffant au reflux un mélange réactionnel constitué de 8-benzylthéophylline et de N-éthyléthanolamine, de carbonate de sodium et de 1,2-dichloroéthane.According to the invention,
Bamifylline, in a single stage, by heating at reflux a reaction mixture consisting of 8-benzyltheophylline and N-ethylethanolamine, sodium carbonate and 1,2-dichloroethane.

Le rendement de la réaction atteint plus de 9096 et, lorsque la réaction est terminée, on obtient une petite proportion (environ 6%) de 7 -/3-chloroe'thyl- 8-benzylthéophylline qui est récupérable. The reaction yield reaches more than 9096 and, when the reaction is complete, a small proportion (about 6%) of 7 - / 3-chloroe'thyl-8-benzyltheophylline is obtained which is recoverable.

L'homme de métier ne pouvait s'attendre à ce que l'on puisse obtenir, en un seul stade réac- tionnel, de la Bamifylline, en partant directement de 8-benzylthéophylline et sans passer par la phase intermédiaire de préparation du composé de formule II, c'est-à-dire de 7- (p -chloro ou bromoéthyl)-8 benzylthéophylline. Those skilled in the art could not expect that Bamifylline could be obtained in a single reaction stage, starting directly from 8-benzyltheophylline and without going through the intermediate phase of preparation of the compound of formula II, that is to say of 7- (p -chloro or bromoethyl) -8 benzyltheophylline.

L'exemple suivant illustre la préparation, à l'échelle industrielle, de Bamifylline par le procédé suivant l'invention. The following example illustrates the preparation, on an industrial scale, of Bamifylline by the process according to the invention.

EXEMPLE
On chauffe à reflux pendant 52 heures le mélange suivant 100 kg de 8-benzylthéophylline (370 moles) 36 litres de N-éthyléthanolamine (environ 350 moles) 300 litres de 1,2-dichloroéthane (environ 738 moles) 71 kg de carbonate de sodium (environ 667,5 moles)
Après 24 heures de chauffage au reflux, on ajoute encore 36 litres de N-éthyléthanolamine.EXAMPLE
The mixture is heated under reflux for 52 hours the following mixture 100 kg of 8-benzyltheophylline (370 moles) 36 liters of N-ethylethanolamine (approximately 350 moles) 300 liters of 1,2-dichloroethane (approximately 738 moles) 71 kg of sodium carbonate (approximately 667.5 moles)
After 24 hours of heating at reflux, another 36 liters of N-ethylethanolamine are added.

Lorsque la réaction estterminée, on refroidit le mélange réactionnel et on y ajoute de l'eau pour dissoudre les sels minéraux. When the reaction is complete, the reaction mixture is cooled and water is added to it to dissolve the mineral salts.

La phase organique (1.,2-dichloroéthane) est alors extraite avec de l'acide chlorhydrique, puis écartée. Cette phase organique contient environ 5 à 6% de 7-( 13 -chloroéthyl)-8-benzylthéophylline. The organic phase (1., 2-dichloroethane) is then extracted with hydrochloric acid, then discarded. This organic phase contains approximately 5 to 6% of 7- (13 -chloroethyl) -8-benzyltheophylline.

La phase acide est neutralisée avec du carbonate de sodium, la base ou 7-(N-éthyl-N- hydroxyéthylamino-éthyl ) -8-benzylthéophylline en est extraite par un hydrocarbure aliphatique halogéné, tel que le dichlorowéthane. The acid phase is neutralized with sodium carbonate, the base or 7- (N-ethyl-N-hydroxyethylamino-ethyl) -8-benzyltheophylline is extracted therefrom by a halogenated aliphatic hydrocarbon, such as dichlorowethane.

Après évaporation à sec du dichlorométhane, la base est dissoute dans un alcanol, tel que le méthanol, puis transformée en chlorhydrate dans les conditions habituelles de tranformation d'un composé organique azoté en un sel d'addition avec un acide. After evaporation to dryness of the dichloromethane, the base is dissolved in an alkanol, such as methanol, then transformed into hydrochloride under the usual conditions of transformation of an organic nitrogen compound into an addition salt with an acid.

Le chlorhydrate obtenu est purifié par cristallisation dans du méthanol. Le chlorhydrate désiré ou Bamifylline qui fond à environ 185-186 C est obtenu avec un rendement industriel de 81%, ce rendement atteignant 91% lorsqu'on utilise, le produit récupérable de formule II.  The hydrochloride obtained is purified by crystallization from methanol. The desired hydrochloride or Bamifylline which melts at around 185-186 C is obtained with an industrial yield of 81%, this yield reaching 91% when the recoverable product of formula II is used.

Claims (7)

REVENDICATIONS 1.- Procédé de préparation de Bamifylline, caractérisé en ce qu'on chauffe au reflux un mélange de 8-benzylthéophylline, de N-éthyléthanolamine et de 1,2-dichloroéthane en présence d'une base minérale et on transforme la 7-(N-éthyl-N-t -hydroxy- éthylamino-éthyl)-8-benzylthéophylline obtenue en son chlorhydrate.1.- Process for the preparation of Bamifylline, characterized in that a mixture of 8-benzyltheophylline, N-ethylethanolamine and 1,2-dichloroethane is heated to reflux in the presence of a mineral base and the 7- ( N-ethyl-Nt -hydroxy-ethylamino-ethyl) -8-benzyltheophylline obtained in its hydrochloride. 2.- Procédé suivant la revendication 1, caractérisé en ce que la base minérale est du carbonate de sodium.2.- Method according to claim 1, characterized in that the mineral base is sodium carbonate. 3.- Procédé suivant l'une ou l'autre des revendications précédentes, caractérisé en ce qu'on extrait la phase organique obtenue à l'aide d'acide chlorhydrique, on neutralise la phase acide obtenue avec du carbonate de sodium, on extrait la 7-(Néthyl-N- ss -hydroxyéthylamino-éthyl )-8-benzylthéophyl- line de la phase neutralisée au moyen de dichlorométhane, et on transforme ce dernier composé en chlorhydrate.3.- Method according to either of the preceding claims, characterized in that the organic phase obtained is extracted with hydrochloric acid, the acid phase obtained is neutralized with sodium carbonate, extracted the 7- (Nethyl-N- ss -hydroxyethylamino-ethyl) -8-benzyltheophylline of the phase neutralized by means of dichloromethane, and the latter compound is converted into the hydrochloride. 4.- Procédé suivant l'une ou l'-autre des revendications précédentes, caractérisé en ce qu'on chauffe au reflux un mélange contenant, par environ 100 parties en poids de 8-benzylthéophylline, environ 300 parties en volume de 1,2-dichloroéthane, environ 72 parties en volume de N-éthyléthanolamine et environ 71 parties en poids de carbonate de sodium.4.- Method according to either of the preceding claims, characterized in that a mixture containing, by approximately 100 parts by weight of 8-benzyltheophylline, approximately 300 parts by volume of 1.2 is heated to reflux. -dichloroethane, approximately 72 parts by volume of N-ethylethanolamine and approximately 71 parts by weight of sodium carbonate. 5.- Procédé suivant la revendication 4, caractérisé en ce qu'une partie de la N-éthyléthanolamine est ajoutée au mélange réactionnel pendant la réaction.5.- Method according to claim 4, characterized in that part of the N-ethylethanolamine is added to the reaction mixture during the reaction. 6.- Procédé de préparation de Bamifylline, en substance, tel que décrit plus haut notamment dans l'exemple.6.- Method for preparing Bamifylline, in substance, as described above in particular in the example. 7.- Bamifylline obtenue par le procédé suivant l'une ou l'autre des revendications précédentes. 7.- Bamifylline obtained by the process according to either of the preceding claims.
FR8110558A 1980-06-05 1981-05-27 PROCESS FOR THE PREPARATION OF BAMIFYLLINE Granted FR2483922A1 (en)

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BE883654 1980-06-05

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FR2483922B1 FR2483922B1 (en) 1983-12-02

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6117998A (en) * 1996-11-19 2000-09-12 Link Technology Incorporated A1 adenosine receptor antagonists
US7202252B2 (en) 2003-02-19 2007-04-10 Endacea, Inc. A1 adenosine receptor antagonists
US7247639B2 (en) 2003-06-06 2007-07-24 Endacea, Inc. A1 adenosine receptor antagonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE602888A (en) * 1960-04-22 1961-10-23 Manuf Prod Pharma New 8-benzylxanthine derivatives and their preparation.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE602888A (en) * 1960-04-22 1961-10-23 Manuf Prod Pharma New 8-benzylxanthine derivatives and their preparation.
FR1124M (en) * 1960-04-22 1962-02-12 Manuf Prod Pharma New derivatives of 8-benzylxanthines.

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6117998A (en) * 1996-11-19 2000-09-12 Link Technology Incorporated A1 adenosine receptor antagonists
US6489332B1 (en) 1996-11-19 2002-12-03 Endacea, Inc. A1 adenosine receptor antagonists
US6495687B1 (en) 1996-11-19 2002-12-17 Endacea, Inc. A1 adenosine receptor antagonists
US7202252B2 (en) 2003-02-19 2007-04-10 Endacea, Inc. A1 adenosine receptor antagonists
US7423041B2 (en) 2003-02-19 2008-09-09 Endacea, Inc. A1 adenosine receptor antagonists
US7247639B2 (en) 2003-06-06 2007-07-24 Endacea, Inc. A1 adenosine receptor antagonists
US7902360B2 (en) 2003-06-06 2011-03-08 Wilson Constance N A1 adenosine receptor antagonists

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FR2483922B1 (en) 1983-12-02
DE3120909A1 (en) 1982-04-08

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