| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 21, 1992 |
| PATENT TITLE |
Process for cyclic amino acid anticonvulsant compounds |
| PATENT ABSTRACT | An improved process for the preparation of cyclic amino acids by a novel synthesis is described where a dinitrile derivative is converted in two steps to the desired products, as well as valuable intermediates used in the process |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | August 10, 1990 |
| PATENT REFERENCES CITED |
EPO Search Report 90 116 264.4 (citing all listed references). Justin Liebigs Annalen Der Chemie, vol. 688, 1965 pp. 113-121. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A process for the preparation of a compound of Formula I ##STR34## or a pharmaceutically acceptable salt thereof wherein n is an integer of one to three, which comprises: Step (a) (1) reacting a compound of Formula V ##STR35## wherein n is as defined above with a compound of formula R--OH wherein R is alkyl of from one to six carbon atoms, in a solvent and an acid to afford in situ, after removal of excess acid, a compound of Formula IV ##STR36## wherein n and R are as defined above; (2) adding water and then adjusting the pH with an aqueous base to about 4 to 4.5, adding water immiscible solvent and removing the aqueous phase to afford in situ a compound of Formula III ##STR37## wherein n and R are as defined above; (3) adding a phase transfer agent and an aqueous base in situ to a compound of Formula III, stirring, removing the water immiscible solvent and adding an equivalent of an acid to afford a compound of Formula IIa ##STR38## wherein n is as defined above; or treating a compound of Formula IIa with an alkali metal alkoxide, alkaline-earth metal alkoxide, ammonia, or an amine in the presence of a solvent to afford a compound of Formula IIb ##STR39## wherein R.sup.1a is an alkali metal, alkaline-earth metal, ammonium, or amine cation and n is as defined above; Step (b) reacting a compound of Formula IIa or Formula IIb with hydrogen in the presence of a catalyst selected from the group consisting of: rhodium on carbon containing palladium, rhodium on carbon containing platinum, rhodium on calcium carbonate containing palladium, rhodium on alumina containing palladium, palladium on carbon, palladium on carbon in the presence of a mineral acid, Raney nickel, Raney nickel and a base, Raney cobalt, lithium aluminum hydride, rhodium hydrido complex, ruthenium hydrido complex, borane methyl sulfide complex, iron, cobalt, nickel and rhodium and a solvent to afford a compound of Formula I; or alternatively, after removing the water immiscible solvent in step (a)(3) treating in situ a compound of Formula VII ##STR40## wherein R.sup.1b is an alkali metal or alkaline-earth metal and n is as defined above with hydrogen in the presence of a catalyst selected from the group consisting of: rhodium on carbon containing palladium, rhodium on carbon containing platinum, rhodium on calcium carbonate containing palladium, rhodium on alumina containing palladium, palladium on carbon, palladium on carbon in the presence of a mineral acid, Raney nickel, Raney nickel and a base, Raney cobalt, lithium aluminum hydride, rhodium hydrido complex, ruthenium hydrido complex, borane methyl sulfide complex, iron, cobalt, nickel and rhodium to afford a compound of Formula I; Step (c) and converting the resulting compound of Formula I to a corresponding pharmaceutically acceptable salt and optionally converting the corresponding pharmaceutically acceptable salt to a compound of Formula I. 2. A process according to claim 1 wherein the acid in Step (a)(1) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid. 3. A process according to claim 2 wherein the acid is hydrochloric acid. 4. A process according to claim 1 wherein the solvent in Step (a)(1) is selected from the group consisting of toluene, ethyl acetate, methylene chloride, ethanol, and methanol. 5. A process according to claim 4 wherein the solvent is toluene. 6. A process according to claim 1 wherein the base in Step (a)(2) is selected from the group consisting of an alkali metal hydroxide, alkali metal carbonate, alkaline earth metal hydroxide and alkaline earth metal carbonate. 7. A process according to claim 6 wherein the base is sodium hydroxide. 8. A process according to claim 1 wherein the water immiscible solvent is selected from the group consisting of toluene, ethyl acetate, methylene chloride, hexane, heptane, octane, isooctane, and tertiary butyl methyl ether. 9. A process according to claim 8 wherein the water immiscible solvent is toluene 10. A process according to claim 1 wherein the stirring in Step (a)(3) is for about five minutes to about five hours. 11. A process according to claim 1 wherein the phase transfer agent in Step (a)(3) is methanol. 12. A process according to claim 1 wherein the base in Step (a)(3) is an alkali metal hydroxide. 13. A process according to claim 12 wherein the base is sodium hydroxide. 14. A process according to claim 1 wherein the acid in Step (a)(3) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid. 15. A process according to claim 14 wherein the acid is hydrochloric acid. 16. A process according to claim 1 wherein the catalyst in Step (b) is selected from the group consisting o rhodium on carbon containing palladium, rhodium on carbon containing platinum, rhodium on calcium carbonate containing palladium, rhodium on alumina containing palladium, palladium on carbon, palladium on carbon in the presence of a mineral acid, Raney nickel, and Raney cobalt. 17. A process according to claim 16 wherein the catalyst is rhodium on carbon containing palladium. 18. A process according to claim 17 wherein the catalyst is 0.5% to 10% rhodium on carbon containing 1% to 10% palladium. 19. A process according to claim 1 for the preparation of 1-(aminomethyl)-cyclohexaneacetic acid and pharmaceutically acceptable salts thereof. 20. A process according to claim 1 wherein the alkali metal in Step (a)(3) is selected from the group consisting of sodium, potassium, and lithium. 21. A process according to claim 20 wherein the alkali metal is selected from the groups consisting of sodium and potassium. 22. A process for the preparation of a compound of Formula III ##STR41## wherein R is alkyl of from one to six carbon atoms and n is an integer of one to three which comprises: Step (a) reacting a compound of Formula V ##STR42## wherein n is as defined above with a compound of Formula R--OH wherein R is as defined above, in a solvent and an acid to afford, in situ, after removal of excess acid, a compound of Formula IV ##STR43## wherein n and R are as defined above; Step (b) adding water and then adjusting the pH with an aqueous base to about 4 to 4.5, adding a water immiscible solvent and removing the aqueous phase to afford, after removal of the water immiscible solvent a compound of Formula III. 23. A process according to claim 22 for the preparation of the compound of formula: ##STR44## wherein R is alkyl of from one to six carbon atoms. 24. A process according to claim 23 for the preparation of ethyl 1-cyanocyclohexaneacetate. 25. A process for the preparation of a compound of Formula II ##STR45## wherein R.sup.1 is hydrogen, an alkali metal, an alkaline-earth metal, ammonium, or amine cation and n is an integer of one to three, which comprises: Step (a) (1) reacting a compound of Formula V ##STR46## wherein n is as defined above with a compound of formula R--OH wherein R is alkyl of from one to six carbon atoms, a solvent and an acid to afford in situ, after removal of excess acid, a compound of Formula IV ##STR47## wherein n and R are as defined above; (2) adding water and then adjusting the pH with an aqueous base to about 4 to 4.5, adding a water immiscible solvent and removing the aqueous phase to afford in situ a compound of Formula III ##STR48## wherein n and R are as defined above; (3) adding a phase transfer agent and an aqueous base in situ to a compound of Formula III, stirring, removing the water immiscible solvent and adding an equivalent of an acid to afford a compound of Formula IIa ##STR49## wherein n is as defined above; (4) treating a compound of Formula IIa with an alkali metal alkoxide, alkaline-earth metal alkoxide, ammonia, or an amine in the presence of a solvent to afford a compound of Formula IIb ##STR50## wherein R.sup.1a is an alkali metal, alkaline-earth metal, ammonium, or amine cation and n is as defined above. 26. A process according to claim 25 wherein the stirring in Step (a)(3) is for about five minutes to about five hours. 27. A process according to claim 25 for the preparation of a compound selected from the group consisting of 1-cyanocyclohexaneacetic acid, sodium 1-cyanocyclohexaneacetate, and potassium 1-cyanocyclohexaneacetate. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION U.S. Pat. Nos. 4,024,175 and 4,087,544, which are herein incorporated by reference, disclose novel cyclic amino acids of Formula A ##STR1## wherein R.sub.1 is a hydrogen atom or a lower alkyl radical and n is 4, 5, or 6 and the pharmacologically compatible salts thereof. The compounds disclosed in the above United States patents are useful for the therapy of certain cerebral diseases, for example, they can be used for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. Additionally, they bring about an improvement of cerebral functions and thus are useful in treating geriatric patients. Particularly valuable is 1-(aminomethyl)-cyclohexaneacetic acid (gabapentin). Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunction with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases, such as epilepsy, schizophrenia, Parkinson's disease, Huntington's Chorea, and dyskinesia (Saletu, B, et al, International Journal of Clinical Pharmacology, Therapy and Toxicology, 24, pages 362 to 373 (1986)). Gabapentin was designed as a GABA analog that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man. The aforementioned compounds of Formula A including gabapentin have been prepared, from a compound of formula ##STR2## wherein R.sub.2 is an alkyl radical containing up to eight carbon atoms and n is as defined above, by well known standard reactions such as, for example, the Hofmann, Curtius, or Lossen rearrangements, into the amino derivatives of Formula A. Although these reactions provide the target compounds they require a large number of synthetic steps and in some cases involve potentially explosive intermediates. U.S. Pat. No. 4,152,326 discloses cyclic sulphonyloxyimides of formula ##STR3## wherein R.sub.2 is a saturated, straight-chained, branched or cyclic lower aliphatic radical or an unsubstituted or substituted aryl radical and n is 4, 5, or 6 which can be converted into a compound of Formula A. Again, similar to the previous processes, this process requires a large number of synthetic steps to obtain a compound of Formula A. Finally, all of the previous processes require as the penultimate step conversion of an intermediate salt of the target compound to an amino acid of Formula A. The object of the present invention is an improved process for preparing the compounds described above by using a novel synthesis. Further, we have unexpectedly found that the particularly valuable gabapentin can be prepared from a novel intermediate without the need for proceeding through an intermediate salt in the penultimate step and in fewer steps and higher yields than the previous methods. Moreover, the present method proceeds from inexpensive starting materials and is amenable to large-scale synthesis. SUMMARY OF THE INVENTION Accordingly, a first aspect of the present invention is an improved process for the preparation of a compound of Formula I ##STR4## and pharmaceutically acceptable salts thereof wherein n is an integer of one to three, which comprises: Step (a) (1) reacting a compound of Formula V ##STR5## wherein n is as defined above with a compound of formula R--OH wherein R is alkyl of from one to six carbon atoms, in a solvent, and an acid to afford in situ, after removal of excess acid a compound of Formula IV ##STR6## wherein n and R are as defined above; (2) adding water and then adjusting the pH with an aqueous base, adding a water immiscible solvent, and removing the aqueous phase to afford in situ a compound of Formula III ##STR7## wherein n and R are as defined above; (3) adding a phase transfer agent and an aqueous base in situ to a compound of Formula III, stirring, removing the water immiscible solvent, and adding an equivalent of an acid to afford a compound of Formula IIa ##STR8## wherein n is defined as above; or treating a compound of Formula IIa with an alkali metal alkoxide, alkaline-earth metal alkoxide, ammonia, or an amine in the presence of solvent to afford a compound of Formula IIb ##STR9## wherein R.sup.1a is an alkali metal, alkaline-earth metal, ammonium, or amine cation and n is as defined above; Step (b) treating a compound of Formula IIa or Formula IIb with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula 1; or alternatively, after removing the water immiscible solvent in step (a)(3) treating in situ a compound of Formula VII ##STR10## wherein R.sup.1b is an alkali metal or alkaline-earth metal and n is as defined above with hydrogen in the presence of a catalyst to afford a compound of Formula I; Step (c) and if desired, converting the resulting compound of Formula I to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula I by conventional means. A second aspect of the present invention is an improved process for the preparation of a compound of Formula I. ##STR11## and pharmaceutically acceptable salts thereof wherein n is an integer of one to three, which comprises: Step (a) reacting a compound of Formula V ##STR12## wherein n is as defined above with a compound of Formula R--OH wherein R is alkyl of from one to six carbon atoms, in a solvent and an acid to afford in situ, after removal of excess acid, a compound of Formula IV ##STR13## wherein n and R are as defined above; Step (b) adding water and then adjusting the pH with an aqueous base, adding a water immiscible solvent, and removing the aqueous phase to afford, after removal of the water immiscible solvent, a compound of Formula III ##STR14## wherein n and R are as defined above; Step (c) treating a compound of Formula III with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula VI ##STR15## wherein n is as defined above; Step (d) hydrolyzing a compound of Formula VI in a conventional manner to afford a salt of a compound of Formula I; Step (e) and converting the salt of a compound of Formula I to a compound of Formula I by conventional means and, if desired, converting the resulting compound of Formula I to a corresponding pharmaceutically acceptable salt by conventional means. A third aspect of the present invention is an improved process for the preparation of a compound of Formula III ##STR16## wherein R is alkyl of from one to six carbon atoms and n is an integer of one to three which comprises: Step (a) reacting a compound of Formula V ##STR17## wherein n is as defined above with a compound of Formula R--OH wherein R is as defined above, in a solvent and an acid to afford, in situ, after removal of excess acid, a compound of Formula IV ##STR18## wherein n and R are as defined above; Step (b) adding water and then adjusting the pH with an aqueous base, adding a water immiscible solvent and removing the aqueous phase to afford, after removal of the water immiscible solvent a compound of Formula III. A fourth aspect of the present invention is an improved process for the preparation of a compound of Formula II ##STR19## wherein R.sup.1 is hydrogen, an alkali metal, an alkaline-earth metal, ammonium, or amine cation and n is an integer of one to three, which comprises: Step (a) (1) reacting a compound of Formula V ##STR20## wherein n is as defined above with a compound of Formula R--OH wherein R is alkyl of from one to six carbon atoms, in a solvent and an acid to afford in situ, after removal of excess acid, a compound of Formula IV ##STR21## wherein n and R are as defined above; (2) adding water and then adjusting the pH with an aqueous base, adding a water immiscible solvent and removing the aqueous phase to afford in situ a compound of Formula III ##STR22## wherein n and R are as defined above; (3) adding a phase transfer agent and an aqueous base in situ to a compound of Formula III, stirring, removing the water immiscible solvent and adding an equivalent of an acid to afford a compound of Formula IIa ##STR23## wherein n is as defined above; (4) treating a compound of Formula IIa with an alkali metal alkoxide, alkaline-earth metal alkoxide, ammonia, or an amine in the presence of a solvent to afford a compound of Formula IIb ##STR24## wherein R.sup.1a is an alkali metal, alkaline-earth metal, ammonium, or amine cation and n is as defined above. A fifth aspect of the present invention is an improved process for the preparation of a compound of Formula VI ##STR25## wherein n is an integer of one to three which comprises: Step (a) reacting a compound of Formula V ##STR26## wherein n is as defined above with a compound of formula R--OH wherein R is alkyl of from one to six carbon atoms, in a solvent and an acid to afford in situ, after removal of excess acid, a compound of Formula IV ##STR27## wherein n and R are as defined above; Step (b) adding water and then adjusting the pH with an aqueous base, adding a water immiscible solvent and removing the aqueous phase to afford, after removal of the water immiscible solvent, a compound of Formula III ##STR28## wherein n and R are as defined above; Step (c) treating a compound of Formula III with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula VI. A sixth aspect of the present invention is a novel intermediate of formula ##STR29## wherein R is alkyl of one to twelve carbon atoms, which is useful in the preparation of a compound of Formula I. A seventh aspect of the present invention is a novel intermediate of formula ##STR30## wherein R.sup.1 is hydrogen, an alkali metal, an alkaline-earth metal, ammonium, or amine cation and n is an integer of one to three, which is useful in the preparation of a compound of Formula I. DETAILED DESCRIPTION OF THE INVENTION In this invention, the term "alkyl" means a straight or branched hydrocarbon group having from one to twelve carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, and the like. "Alkali metal" is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like. "Alkaline-earth metal" is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, magnesium, and the like. "Phase transfer agent" means a solvent which is mutually soluble in the aqueous phase and organic phase and includes, for example, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, and the like. The compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention. Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S. M., et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)). The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for purposes of the present invention. Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, S. M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66, pp. 1-19 (1977)). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acids for purposes of the present invention. Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. U.S. patent application Ser. No. 188819 now U.S. Pat. No. 4,894,476 discloses gabapentin monohydrate and a process for producing the gabapentin monohydrate. A preferred compound of Formula I prepared by the improved process of the first aspect of the present invention is: 1-(aminomethyl)-cyclohexaneacetic acid A preferred compound of Formula I prepared by the improved process of the second aspect of the present invention is: 1-(aminomethyl)-cyclohexaneacetic acid A preferred compound of Formula III prepared by the improved process of the third aspect of the present invention is: ##STR31## wherein R is alkyl of from one to six carbon atoms. Preferred compounds of Formula II prepared by the improved process of the fourth aspect of the present invention are: 1-cyanocyclohexaneacetic acid; sodium 1-cyanocyclohexaneacetate; and potassium 1-cyanocyclohexaneacetate; A preferred compound of Formula VI prepared by the improved process of the fifth aspect of the present invention is: 2-azaspiro[4.5]decan-3-one A preferred novel intermediate of the sixth aspect of the present invention are: ethyl 1-cyanocyclohexaneacetate Preferred novel intermediates of the seventh aspect of the present invention are: 1-cyanocyclohexaneacetic acid; sodium 1-cyanocyclohexaneacetate; and potassium 1-cyanocyclohexaneacetate. As previously described, the compounds of Formula I are useful for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. The process of the present invention in its first aspect is a new, improved, economical, and commercially feasible method for preparing a compound of Formula 1. Furthermore, the process can be carried out in a two-pot procedure requiring only isolation of the penultimate intermediate and the final product. The process of the present invention in its first aspect is outlined in Scheme I: ##STR32## A compound of Formula IIa is prepared from a known dinitrile of Formula V. In the preparation of a series of .alpha.,.alpha.-disubstituted succinimides via cyano imidoester intermediates Schafer, H. (Liebigs Annalen der Chemie, 668, pages 113 to 121 (1965)) reported "a special stability" to hydrolysis of the cyano imidoesters to cyano esters. We have unexpectedly and surprisingly found that by removing excess acid after formation of the cyano imidoester in situ in the present process that hydrolysis in situ to the cyano ester proceeds smoothly and with negligible formation of succinimide by-product. Thus, a compound of Formula V, wherein n is an integer of one to three is treated with about one equivalent of a compound of formula R--OH wherein R is alkyl of from one to six carbon atoms, for about one to five days in a solvent such as, for example, toluene, ethyl acetate, methylene chloride, ethanol, methanol, and the like and about one to three equivalents of an inorganic or organic acid such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and the like at a pressure of about 2 mm to about 50 pounds per square inch gauge (psig) and about -20.degree. C. to about 55.degree. C. to afford, after removal of excess acid, a compound of Formula IV wherein n and R are as defined above which is not isolated. Preferably the reaction is carried out by adding about two equivalents of anhydrous hydrogen chloride at a pressure of about 3 mm to about 10 mm Hg and about 10.degree. C. to an evacuated flask containing the dinitrile of Formula V in toluene containing about 2 equivalents of ethanol or methanol, stirring for two days and removing excess acid by distillation. Water is added and the pH is adjusted to about 4 to about 4.5 with an aqueous base such as, for example, an aqueous alkali or alkaline earth-metal hydroxide or carbonate, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, and the like. The mixture is stirred for about one to about 36 hours at about 0.degree. C. to about 50.degree. C. and a water immiscible solvent such as, for example, toluene, ethyl acetate, methylene chloride, hexane, heptane, octane, isooctane, tertiary butyl methyl ether, and the like is added to afford, after removal of the aqueous phase, a compound of Formula III wherein n and R are as defined above, which is not isolated. Preferably the reaction is carried out by adjusting the pH with aqueous sodium hydroxide, stirring for about 24 hours, and adding toluene. A phase transfer agent such as, for example, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, and the like, and an aqueous base such as, for example, an aqueous alkali or alkaline earth-metal hydroxide or carbonate, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate and the like are added to the previous water immiscible solvent containing a compound of Formula III and stirring is continued for about five minutes to about five hours at about 0.degree. C. to about the reflux temperature of the solvent. The water immiscible solvent is removed and an equivalent of an inorganic or organic acid such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid and the like is added to afford a compound of Formula II wherein n is as defined above. Preferably the reaction is carried out in methanol and aqueous sodium hydroxide for about four hours at about 40.degree. C., removing the toluene and adding an equivalent of concentrated hydrochloric acid at about 0.degree. C. to about 5.degree. C. A compound of Formula IIa is treated with hydrogen in the presence of a catalyst such as, for example, rhodium on carbon containing palladium, rhodium on carbon containing platinum, rhodium on calcium carbonate containing palladium, rhodium on alumina containing palladium, palladium on carbon, palladium on carbon in the presence of a mineral acid such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, and the like, Raney nickel, Raney nickel and a base such as, for example, an alkali metal hydroxide, ammonium hydroxide and the like, Raney cobalt, metal hydrides such a, for example, lithium aluminum hydride, rhodium hydrido complex, ruthenium hydrido complex, borane methyl sulfide complex and the like, and metals such as, for example, iron, cobalt, nickel, rhodium, and the like in a solvent such as, for example, methanol, ethanol and the like at about -20.degree. C. to about 50.degree. C. to afford a compound of Formula I wherein n is as defined above. Preferably the reaction is carried out with 0.5% to 10% rhodium on carbon containing 1% to 10% palladium in methanol at about room temperature. Additionally, a compound of Formula IIa is treated with an alkali metal alkoxide such as, for example, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tertiary butoxide, and the like, an alkaline-earth metal alkoxide such as, for example, magnesium ethoxide, and the like, ammonia, an amine capable of forming a salt with a carboxylic, acid such as, for example, triethylamine, pyridine, and the like in the presence of a solvent such as, for example, tetrahydrofuran, and the like to afford a compound of Formula IIb. Preferably the reaction is carried out with sodium methoxide or potassium tertiary butoxide in tetrahydrofuran. A compound of Formula IIb is converted to a compound of Formula I using the methodology previously described for preparing a compound of Formula I from a compound of Formula IIa. Additionally, a phase transfer agent and an aqueous base are added to the water immiscible solvent containing a compound of Formula III as previously described. The water immiscible solvent is removed and a compound of Formula VII wherein R.sup.1b is an alkali metal or alkaline-earth metal and n is as defined above is converted in situ to a compound of Formula I using the methodology previously described for preparing a compound of Formula I from a compound of Formula IIa or Formula IIb. The process of the present invention in its second aspect is a new, improved, economical and commercially feasible method for preparing a compound of Formula I. The process of the present invention in its second aspect is outlined in Scheme II. Thus a compound of Formula V is converted into a compound of Formula 111 as previously described. A compound of Formula III is isolated and treated with hydrogen in the presence of a catalyst using the methodology previously described for preparing a compound of Formula I from a compound of Formula IIa or Formula IIb to afford a compound of Formula VI wherein n is as defined above. A compound of Formula VI is converted to a salt of a compound of Formula I by conventional acid or basic hydrolysis such as, for example, acid hydrolysis with hydrochloric acid, sulfuric acid and the like or basic hydrolysis with sodium hydroxide, potassium hydroxide and the like and subsequently converted to a compound of Formula I by conventional methods such as, for example, ion exchange techniques. Additionally, in the first aspect of the invention any formed by-product of Formula VI may be converted as previously described to a compound of Formula I. A compound of Formula V may be prepared by methodology described by Schafer, H., Liebigs Annalen der Chemie, 688, pp 113 to 121 (1965). |
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