Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1990-01-12
1993-10-05
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
546348, 562105, C07D 7500, C07D 700, C07D21318, C07C30915
Patent
active
052507114
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to amine salts of alkane-1,n-dicarboxylic acid mono-(2-sulfato-ethyl)amides I, their preparation and use as intermediates for the preparation of water-soluble esters of corticosteroids of Formula VII. Water-soluble esters of corticosteroids are known to be useful as injectable anti-inflammatory agents.
INFORMATION DISCLOSURE
Sulfonate containing prodrugs containing ester prodrugs of corticosteroids having the Formula VI, wherein St represents a corticosteroid moiety bonded to the carbonyl via the 21-hydroxy group of said corticosteroid are disclosed in U.S. Pat. No. 4,472,392. These compounds are also described by Anderson et al, J. Pharm. Sci. (1985), 74; pp. 365,375 and 382.
Corticosteroids such as methyl prednisolone can be converted into pharmaceutically useful water soluble derivatives by esterification with suberic acid-mono(2-sulfatoethyl-N-methyl)-amide monosodium salt ("suleptanic acid mono sodium salt"). Conventional processes for preparation of suleptanic acid involve treatment of suberic acid and N-methyl taurine with a coupling agent such as dicyclohexylcarbodiimide in a homogeneous, one-phase solution. Since, in a homogeneous solution, the two carboxylic acid groups of suberic acid have equal probability of reacting with N-methyl taurine, these processes afford statistically random mixtures of unreacted suberic acid, monoamide, and bisamide. Also, these conventional processes afford suleptanic acid in the monosodium salt form, which is hygroscopic. Thus, isolation in the anhydrous state required for esterification with the corticosteroid is quite laborious. Also, conventional processes for esterification of corticosteroids with the monosodium salt of suleptanic acid require very polar organic solvents such as dimethylformamide (DMF) because of the insolubility of suleptanic acid monosodium salt in less polar organic solvents. Separation of the desired corticosteroid suleptanate ester from the solvent DMF requires multiple extractions. Thus, conventional processes for preparation of suleptanate esters of corticosteroids are uneconomical.
SUMMARY OF THE INVENTION
The present invention provides:
A compound having the Formula I wherein R.sub.1 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.8 -alkyl and phenyl; R.sub.2 is C.sub.1 -C.sub.8 alkyl or (R.sub.2).sub.3 when taken together with the nitrogen atom is pyridinyl; and n is an integer of from 4 to 20.
A compound having the Formula VI wherein R.sub.1 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.8 alkyl and phenyl; R.sub.2 is ethyl; n is an integer of from 4 to 20; and St is the residue of a corticosteroid and n is an integer of 4 to 20.
Also provided is a process for preparing the compounds of Formula I wherein R.sub.1 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.8 alkyl and phenyl and R.sub.2 is C.sub.1 -C.sub.8 alkyl or (R.sub.2).sub.3 when taken together with the nitrogen atom is pyridinyl which comprises (a) contacting a solution of the compound having the Formula II wherein R is selected from the group consisting of C.sub.1 -C.sub.8 alkyl and phenyl, C.sub.1 -C.sub.8 alkoxy, and substituted phenyl in a water-immiscible organic solvent with a water solution of the amine of the Formula III to prepare a compound of Formula IV; (b) treatment of an aqueous solution of the compound of Formula IV with a trialkylamine hydrohalide and hydrogen halide, and (c) recovery of the compound of Formula I from the reaction mixture formed in (b).
This process affords unexpectedly high yields of monoamides and unexpectedly low yields of bisamide. Condensation of n-methyl taurine with 1.25 molar equivalents of bis pivalic anhydride II by prior art, conventional processes is expected to afford a statistically random mixture of products (45% suberic acid, 60% monoamide, and 20% bisamide). However, the process described in this invention affords monoamide in 80.7% yield and bisamide in 4.7% yield (Example 1).
The invention further provides
REFERENCES:
patent: 3089881 (1963-05-01), Hershberg et al.
Jones Aldrichimica Acta. 9(3) 1976 pp. 35-45.
Shah Mukund J.
The Upjohn Company
Ward E. C.
Williams, Jr. Sidney B.
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