Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1994-11-14
1996-08-27
Kumar, Shailendra
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C07C23568, C07C23706
Patent
active
055502881
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US93/05613 filed Jun. 11, 1993.
BACKGROUND OF THE INVENTION
Compounds of the general Formula I have been described as effective long lasting cardiac antiarrhythmic agents. ##STR1##
Of particular interest are the compounds of Formula I wherein variable n is zero, compounds generally described as .alpha.-aminoacylanilides. Tocainide, an example of an .alpha.-aminoacylanilide, is a commercially marketed antiarrhythmic agent.
Synthetic preparations of compounds of the Formula I wherein n is zero have been previously described (see for example U.S. Pat. No. 4,218,477).
Of the known synthetic routes the preferred preparation of the .alpha.-aminoacylanilides comprises synthesis of the suitably substituted .alpha.-haloacylanilide followed by reaction of the haloacylanilide and ammonia gas in a suitable organic/aqueous solvent. The reaction of the haloacylanilide typically proceeds in high yield; however, because the terminal nitrogen of the product, .alpha.-aminoacylanilide, is comparable in nucleophilicity to ammonia, a byproduct of the Formula II may form in amounts which are unacceptable for pharmaceutical applications. ##STR2##
Small amounts of byproducts of the Formula II may be removed, or reduced to be within acceptable pharmaceutical limits, by recrystallization of the reaction product or washing the reaction product with a suitable organic solvent. However, this additional step presents added economic costs and the potential utilization of environmentally harmful solvents.
An alternative amination procedure utilizes aqueous ammonia in high dilution without an organic cosolvent. While the amount of the above described byproduct is reduced under this reaction condition, it is still present in such amounts as to require further purification as previously described. This second procedure is also unacceptable because of the enormous size of the vessels which would be required for implementation on a manufacturing scale. Thus, there now exists a need for a simple, economic procedure for preparing .alpha.-aminoacylanilides from .alpha.-haloacylanilides wherein the dimeric byproduct of the reaction is substantially reduced or eliminated.
It is an object of the instant invention to provide an improved process for the preparation .alpha.-aminoacylanilides by amination of the corresponding .alpha.-haloacylanilides with a solution of ammoniun carbamate in aqueous ammonia. It has been surprisingly discovered that under these conditions the unwanted dimer byproduct has been essentially eliminated from the crude reaction product.
The .alpha.-aminoacylanilide compound of Formula I produced by the process of the present invention is useful per se as an antiarrhythmic agent, such as disclosed in U.S. Pat. No. 4,218,477. It is also understood that the compound of Formula I may be further modified and that such modification may lead to other pharmaceutical agents, such as disclosed in U.S. Pat. No. 4,169,106 and PCT application WO 91/12265.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of a compound of the Formula I: ##STR3## wherein: R.sup.1 is H lower alkyl or aryl; selected from the group consisting of Cl, Br, I, F, NH.sub.2, --NH--(lower alkyl), --N(lower alkyl).sub.2, CO.sub.2 H, --CO.sub.2 --(lower alkyl), lower alkoxy, NO.sub.2, CF.sub.3, lower alkylthio or OH; selected from: H, lower alkyl, lower alkoxy, Cl, Br, I and F; and ##STR4## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined hereinabove; and methylsulfonyloxy; temperature from 40.degree. to 80.degree. C.
One embodiment of the process of the instant invention is that process in which the molar ratio of ammonium carbamate to the acylanilide of the Formula III is selected from a range of 3.0/1 to 3.5/1 and the molar ratio of ammonia in the aqueous ammonia to the acylanilide of the Formula III is selected from a range of 12/1 to 15/1.
One class of this embodiment is the process wherein the temperature is from 55.degree. to 70.degree.
REFERENCES:
patent: 2851494 (1958-09-01), Ehrhart et al.
patent: 3210412 (1965-10-01), Chapman
patent: 4169106 (1979-09-01), Diamond et al.
patent: 4218477 (1980-08-01), Boyes et al.
"New Antiarrhythmic Agents. 1. Primary alpha-Amino Anilides", Eugene W. Byrnes, et al., Journal of Medicinal Chemistry, 1979, vol. 22, No. 10, pp. 1171-1176.
"New Antiarrhythmic Agents. 2. Amide Alkyl alpha-Amino Xylidides", Paul D. McMaster, et al., Journal of Medicinal Chemistry, 1979, vol. 22, No. 10, pp. 1177-1182.
The Merck Index, 10th Edition, Compound No. 518, p. 76 (1988).
Kumar Shailendra
Merck & Co. , Inc.
North Robert J.
Winokur Melvin
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