Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen bonded directly to ring carbon of the purine ring...
Patent
1995-09-29
1998-04-14
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen bonded directly to ring carbon of the purine ring...
C07D47308
Patent
active
057393311
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is a process for the preparation of a compound of formula: ##STR1## in which
A is a xanthine ring or a compound comprising a xanthine ring (a xanthine ring derivative),
B is a hydrocarbon group,
C and D are identical or different hydrocarbon groups optionally bearing one or more hydroxyl groups, or of a salt of such a compound. In this process, a xanthine ring or a xanthine ring derivative is reacted with a molar excess of a substance X.sub.1 --B--X.sub.2 where X.sub.1 and X.sub.2 are electrophilic groups, in the presence of a molar excess of an amine of formula: ##STR2## and the compound formed is optionally converted into a salt thereof.
THE PRIOR ART
It is known from Belgian Patent BE-A-602,888 to prepare bamifylline, namely a compound of formula II.
According to this patent, bamifylline is prepared by reacting, in a first step, 8-benzyltheophylline with 1,2-dichloroethane or 1,2-dibromoethane to give 7-(.beta.-chloro- or .beta.-bromoethyl)-8-benzyltheophylline (formula I). ##STR3##
In a second step, the product (I) is reacted with 2-ethylaminoethanol in the presence of sodium carbonate, to form bamifylline (II) in a yield of 57 to 65% according to the following scheme: ##STR4##
This reaction gives rise to the formation of the derivative 7-vinyl-8-benzyltheophylline (III) as side product, in a large amount (25 to 43%).
It is known from Belgian Patent BE-A-883,654 to prepare bamifylline in a single step with good yield by heating to reflux a reaction mixture consisting of 8-benzyltheophylline, N-ethylaminoethanol, sodium carbonate and 1,2-dichloroethane.
This process, which makes it possible to avoid the formation of the vinyl side product (III), ##STR5## has, however, the drawbacks of a very long reaction time (52 hours) and of formation of about 7% of the derivative 7-chloroethyl-8-benzyltheophylline (I) as side product. The reaction temperature in the process according to this patent is 80.degree. C.
In the process according to the invention, the reaction is carried out at a temperature above 90.degree. C. and at a pressure above 10.sup.5 Pa.
It has been noted that the process according to the invention allowed the rate of conversion of the nucleophilic ring to be increased, and quite unexpectedly allowed an excellent selectivity to be obtained for the conversion of the xanthine ring or of the xanthine derivative into ##STR6##
Although a person skilled in the art might have expected that the rate of the 8-benzyltheophylline+N-ethylaminoethanol+1,2-dichloroethane reaction at 90.degree. C. would be greater than the rate of this reaction at 80.degree. C., the person skilled in the art could not expect that the process according to the invention would make it possible furthermore to ensure a selectivity of greater than 90% for the reaction to give bamifylline. The reason for this is that those skilled in the art know that by increasing the temperature of a reaction, not only is the desired reaction promoted, but so are side reactions giving unwanted side products.
Thus, quite unexpectedly, it has been noted that by applying the process according to the invention to the manufacture of bamifylline (8-benzyltheophylline+N-ethylaminoethanol+1,2-dichloroethane), it has been possible to obtain an 8-benzyltheophylline conversion of greater than 99%, after a reaction time of 2 to 5 hours (instead of 52 hours for the process according to BE-A-883,654) and a molar yield of bamifylline relative to the number of moles of 8-benzyltheophylline of greater than 90%, or even higher (>95%).
BRIEF DESCRIPTION OF THE INVENTION
The invention relates to a process for the preparation of a compound selected among the group consisting of bamifylline and etamiphylline, in which a mixture comprising: 8-benzyltheophylline; ##STR7## with C and D selected among the group consisting of hydrocarbon groups containing and one hydroxyl group and hydrocarbon groups containing from 1 to 4 carbon atoms and two hydoxyl groups out at a temperature higher than 90.degree. C. and under a pressure highe
REFERENCES:
Van Nostrand's Scientific Encyclopedia (7th Edition) (1995), pp. 18-19.
March, "Advanced Organic Chemistry" (1968), pp. 217-221.
Parmantier Michel
Thyrion Fernand
Yang Hong
Berch Mark L.
S.A. Nycomed Christiaens N.V.
LandOfFree
Process for converting a xanthine ring or xanthine ring derivati does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for converting a xanthine ring or xanthine ring derivati, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for converting a xanthine ring or xanthine ring derivati will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-636215