USOO5675038A United States Patent 19 11 Patent Number: 5.675,038 Dolby et al. 45 Date of Patent: Oct. 7, 1997 54) LITHIUM AND AMNE DISSOLVING METAL Noordam et al. "Stereoselective synthesis (+)-pilocarpine, REDUCTION an imidazole alkaloid used in ophthalmology”. Recl. Trav. Chim. Pays-Bas 98, pp. 425-470, 75) Inventors: Lloyd J. Dolby; Nestor A. Fedoruk; Dey, A.N. “The Jaborandi Alkaloids. Part I. The Synthesis Shervin Esfandiari: Natalie C. of Homo-and isoHomo-pilopic Acids of r-Pilocarpine and Chamberlain, all of Eugene, Oreg.; r-isoPilocarpidine by New Methods and the Resolution of Michael E. Garst, Newport Beach, r-Pilocarpine". S. Chem. soc., (1937), pp. 1057-1065. Calif. Birch et al., "Reduction by Metal-Ammonia Solutions and Related Reagents”. Advanced Organic Chemistry, No. 8, pp. 73) Assignee: Allergan, Waco, Tex. 1-65 (1972). Benkeser et al. "Reduction of Organic Compounds by 21 Appl. No.: 685,902 Lithium in Low Molecular Weight Amines. VII. The Prepa 22 Filled: Jul. 18, 1996 ration of Dihydroaromatics. A Comparison of the Lithi um-Amine and Birch Reduction Systems". Journal of (51) Int. Cl. ............................. CO7C 291/00 Organic Chemistry, 28, pp. 1094-1096, 1972. (52) U.S. Cl. ........................... 564/253: 568/.303; 585/267 Kaiser, E.M., “A Comparison of Methods Using Lithium/ 58) Field of Search ............................ 585/267; 564/253; Amine and Birch Reduction Systems”. Synthesis, 1972, pp. 568/.303 39-415. 56 References Cited Primary Examiner-Mukund J. Shah U.S. PATENT DOCUMENTS Assistant Examiner-Bruck Kifle Attorney; Agent, or Firm-James M. Hoch; Robert J. Baran; 3,470.197 9/1969 VanDyke, Jr. .......................... 260/309 Martin A. Voet 5,055,467 10/1991 Albaugh....... S4/235.8 5,198,545 3/1993 Albaugh. ... 544/33 57 ABSTRACT 5,264449 11/1993 Albaugh. ..., 514/397 5,453,434 9/1995 Albaugh et al. ........................ 514/397 The invention is directed to a process for reducing or reductively cleaving an organic compound susceptible to OTHER PUBLICATIONS dissolving metal reduction comprising exposing the organic DeGraw, J.L. "Prostaglandins, An Improved Synthesis of compound to a solution of lithium in a polyamine including Pilocarpine.” Tetrahedron, vol. 28, 1972, pp. 967-972. at least two amino groups, selected from the group consist Koda et al., "Synthesis of Analogs related to Pilocarpine". ing of primary and secondary amino groups and mixtures Journal of Pharmaceutical Sciences, Dec. 1973, vol. 62, No. thereof, e.g. ethylenediamine and R-NH2, optionally con 12, pp. 2021-2023. taining a lower alkyl alcohol, wherein R is chosen from the Sauerberg et al., "Cyclic Carbamate Analogues of Pilo group consisting of ethyl, propyl, and butyl, including all carpine”. J. Med. Chem. 1989, 32, pp. 1322-1236. straight and branched chain isomers thereof, for a time Kondo et al. "Synthesis of y-Lactones By The Condensation sufficient to effect reduction. of 2-Alkene-1, 4-Diols With Orthocarboxylic Esters". Chemistry Letters, pp. 741-742, 1974. 35 Claims, No Drawings 5,675.038 1. 2 LTHUMAND AMNE DISSOLVING METAL from the solvent to form a radical which can in turn add REDUCTION another electron to form a further reduced anion and so forth until the reaction has reached completion. Alternatively, CROSS REFERENCE TO RELATED without an acidic proton source (i.e. a source of protons APPLICATIONS more acidic than ammonia or alkylamine) the reaction may proceed via a different route to form a less reduced or Commonly assigned U.S. patent application Ser. No. isomerically different product. 08/685,897, entitled "Process for Making Pilolactam and The use of lithium in a mixed solution of lower alkyl Derivatives Thereof" which has been filed on the same day amine and a polyamine, such as ethylenediamine, is a very as the present application in the names Lloyd J. Dolby, O Nestor A. Fedoruk, Sherwin Esfandiari, and Michael E. Garst potent reducing system which may be attributable to the is directed to a process of making an intermediate for the superior electron solvating ability of the ethylenediamine? synthesis of isopilolactam, pilolactam and derivatives alkyl amine solvent mixture. thereof. The contents of this copending application are A. J. Birch and G. Subba Rao reviewed many types of incorporated herein by reference in its entirety, dissolving metal reductions in a monograph entitled "Reduc 15 tion by Metal-Ammonia Solutions and Related Reagents" in BACKGROUND OF THE INVENTION Advanced Organic Chemistry, No. 8, pp. 1-65 (1972). R. A. Benkeser, et al., (Journal of Organic Chemistry; 28, FIELD OF THE INVENTION pp. 1094-96 (1962) described the use of low molecular weight amines in lithium metal reductions and compared the The invention described herein relates generally to the 20 field of reductive hydrogenation of organic compounds. In yields and regioisomers to reductions of the same group of particular, the invention relates to the treatment of organic compounds using Birch reduction conditions. compounds by lithium in a mixture of a lower molecular Edwin M. Kaiser wrote a review entitled “A Comparison weight amine and a polyamine including at least two amino of Methods Using Lithium/Amine and Birch Reduction groups, selected from the group consisting of primary and 25 Systems" Synthesis, 1972 pp. 391-415) which also com secondary amino groups and mixtures thereof, e.g. pares reports of yields and conditions for these two reaction ethylenediamine, to effect reduction. types. SUMMARY OF THE INVENTION BACKGROUND OF THE ART The invention is directed to a process for reducing or Reductions using alkali metals in ammonia or lower alkyl 30 reductively cleaving an organic compound susceptible to amines are synthetically useful reactions for the reduction of dissolving metal reduction comprising exposing the organic organic compounds. The metals commonly employed compound to lithium in a mixed solution of a polyamine include the alkali metals-lithium, sodium and potassium including at least two amino groups, selected from the group as well as calcium and magnesium and occasionally zinc and 35 consisting of primary and secondary amino groups and iron. The alkali metals and calcium dissolve into solutions in mixtures thereof, wherein said polyamine comprises from 2 liquid ammonia (b.p. -33°C.), in low molecular weight to 4. e.g. 2, nitrogen atoms and from 2 to about 30, e.g. from amines such as methylamine and ethylamine, or in certain 2 to about 20 carbon atoms, and may be selected from the ethers such as 1,2-dimethoxyethane. Reactions with metal group consisting of alkyl and cycloalkyl amines such as solutions in liquid ammonia often use a cosolvent such as ethylenediamine, N,N'-dimethylethylenediamine. ether, tetrahydrofuran, or 1,2-dimethoxyethane to increase piperazine, diaminopropane, diaminobutane, dimethyl the solubility of the organic substrate in the reaction mixture. diaminobutane, tris-(aminoethyl) amine, etc., e.g This sometimes has the disadvantage of resulting in a two ethylenediamine, and R-NH wherein R is selected from phase reaction mixture. the group consisting of lower alkyl radicals. having from 2 The Birch reduction is perhaps the best known form of 45 to 6 carbon atoms, preferably ethyl, propyl, and butyl, these metal reductions and utilizes sodium metal, liquid including all straight and branched chain isomers thereof, ammonia, and an alkyl alcohol such as n-butanol or optionally containing a lower alkyl alcohol, for a time t-butanol. The Benkeser reduction is another form of the sufficient to effect reduction. reduction which utilizes lithium metal and a lower alkyl The present process for reducing susceptible organic amine along with one of the already mentioned alcohols. 50 chemical compounds uses lithium metal as an electron These reductions as a class are called dissolving metal source, the above lower alkyl amines as solvent and the reductions; this term being descriptive since the metals above polyamine, e.g. ethylene diamine (1.2- dissolve into solution which is generally blue in color as a diaminoethane), as the cosolvent. Lithium is dissolved in the result of ionization of the metal atoms. alkyl amine along with at least one equivalent of said A proton source (frequently ethanol, isopropanol. 55 polyamine, e.g. ethylenediamine, per gram-atom of lithium. t-butanol, or water) may be necessary and present in the Optionally, a lower alkyl alcohol can be added to the reaction medium, and is added concurrently with the com solution to improve yields of desired products. A discussion pound to be reduced, or is added during the isolation. of these protonation mechanisms and reaction kinetics can An early hypothesis that dissolving metal reductions were be found in the review on dissolving metal reductions by effected by reaction of the "nascent'hydrogen liberated from Birch, et al. (vide supra). reduction of the hydroxylic solvent by the metal with the Examples of compounds susceptible of being reduced or molecule being reduced has since been dismissed as unten reductively cleaved by this system (products follow in able. In fact, the formation of hydrogen gas during these parentheses) are: anisoles (methoxycyclohexadienes), naph reactions is normally an undesirable side reaction which thalenes (isotetralins). O.B-unsaturated ketones (ketones), makes the use of excess metal necessary, Presently it is 65 ketoximes (amines), aldoximes (amines), thioanisoles believed that "solvated" electrons in the solution add to the (thiophenols), reduction of tertiary amides, cleavage of Substrate to form a radical anion which can add a proton sulfonate esters (to the alcohols) and reductions of 5,675,038 3 4 p-toluenesulfonamides (to amines, or in the case of tertiary solved into the solvent, the reaction is considered to have sulfonamides to the thiophenol). finished. Time spans of between 5 minutes and 24 hours are typically required. DETALED DESCRIPTION OF THE Once the reaction is complete, the solvent phase is cus INVENTION tomarily removed under reduced pressure, typically on a Preliminary experiments with lithium in lower alkyl rotary evaporator, which allows recovery of the solvents amines alone, such as in n-propylamine or isopropylamine from the reaction mixture.