United States Patent Office Patented Oct.3,839,423 1, 1974 1. 2 SUMMARY OF THE INVENTION DEMETHYLATON3,839,423 PROCESS In fulfillment of thee ababove andd other objects, this iin Bennie J. FE Greenwood, and Eugene J. Fornefeld, vention provides an N-demethylation process wherein a Indianapolis, Ind., assignors to Eli Lilly and Company, secondary amino compound is produced by reacting a Indianapolis, Ind. 5 tertiary N,N-dimethylamine of the formula No Drawing. Filed Dec. 19, 1973, Ser. No. 426,263 CH Int, C. C07c 85/04 / U.S. C. 260-490 10 Clains Q-N 0. CH3 ABSTRACT OF THE DISCLOSURE wherein Q is (a) A novel of N-demethylation procedure between a ter- (a) C2H5 tiary amine and a haloalkyl chloroformate, to yield a Hé-O-Ak carbamate, followed by reductive removal of the re- H Sulting carbamate to yield a secondary amine. Analgesic 15 substances including noracymethadol and d-norpropoxy- - -CH.-- phene are produced. CH

BACKGROUND OF THE INVENTION 20 Most useful analgesic compounds are tertiary amines. Or When the tertiary amines are converted to secondary (b) O amines, the compounds usually lose the greater part of o–Alk B their analgesic activity. Thus, for example, the highly d CH effective analgesics, morphine, codeine, and methadone, 25 -, -- all tertiary amines, when converted to the corresponding E CH. H. secondary amino compounds, lose substantially all of their analgesic activity. Certain secondary amines such as those preparable by the processes of the present in vention, however, do possess useful analgesic activity 30 themselves or can be converted to useful analgesic sub- w stances such as noracymethadol carbamates, U.S. Pat. and Alk is C-C alkyl, with a haloalkyl chloroformate 3,755,416, by standard chemical procedures. to produce a haloalkyl carbamate. Reductive cleavage of Methods described in the art useful for the N-demethyl- the carbamate under non-hydrolyzing conditions produces permanganate,ation of tertiary Ber. amines 29, 1575include (1896), oxidation Liebig with Ann. potassium Chen... 35 Himula es.when secondaryQ is (a), are: the compounds E.E.E. are known, the genfor Chen.708, 210 S. (1967); 74, 'sa. or pitypotassium ferricyanide,E"Wii, J.ethylo, Anner. ericallyC2H, the as compoundsacymethadols are and called when propoxyhenes. Q is (b), and The Alk see is phenyl chloroformates followed by hydrolysis, Tet. Lett. 40 E. aCS thus E. ar valuable aS analgesic 1971 57-58; J. Med. Chen. 15, 208 (1972); and forma- R or as intermediates for preparing analgesic tion of an alkylazodicarboxylate reaction product fol- Substances. lowed by hydrolysis, U.S. Pat. 3,213,128. The oxidative DETALED DESCRIPTION demethylation procedures suffer from the defect that large volumes of solvents are required and the yields More specifically, the present invention provides a of product are low. In addition, the hydrolysis of carba 45 process for the preparation of secondary amines (I) mates produced by the above chloroformate procedures CH, is difficult and in some cases none of the desired second- Q-N ary amine can be obtained. In both of the chloroformate Yh I wascases employed. cited above, Hydrochiotic hydrolytic acid cleavage was used of the in thecarbamate method 0 wherein Qis of the first reference, and a mixture of 1:4, 50% aque- (a) CH5 O ous potassium hydroxide-ethanol in the method of the Iid-O--Alk second chloroformate reference above. The dialkylazodi- H carboxylate method gives varying yields of the secondary CH amine product contaminated with small quantities of the {O)- -un-- tertiary amine. CH The 2,2,2-trichloroethoxycarbonyl amine protecting group is described in Tet. Lett. 27, 2555-2557 (1967) and J. Org. Chem. 36, 1259 (1971). The 2-iodoethoxycarbon- 60 Or yl amine protecting group is described in J. Chem. Soc. (b) O 1965, 7136-7139. Removal of an N-benzyl group using trichloroethyl chloroformate is disclosed in J. Org. Chem. O-C-Ak 38, 3281 (1973); however neither the trichloroethyl chlo- H roformateused to displace nor the a 2-iodoethylmethyl group chloroformate from a tertiary have amine been 65 {O)--H-i-ch, ch, h heretofore. It is an object of this invention to provide an N-de methylation procedure which avoids the drawbacks of the N-demethylation procedures presently available in the 70 art. 3,839,423 3 4. and wherein Alk is C-C alkyl, by reacting a tertiary reaction. Thereafter, slow distillation of the organic sol amine of Formula II vent from the reaction mixture is carried out at atmos pheric pressure during a one hour period, thereby concen trating the reaction mixture to approximately half-volume. 5 Longer reflux periods, although not believed necessary, are CPI I not deleterious to the reaction. Although we do not wish wherein Q has the same meaning as hereinabove, with a to be bound by the particular mechanism proposed, it is haloalkyl chloroformate of the formula postulated that an intermediate acyl quaternary compound O is formed which is thermally decomposed to the carbamate O during the heating period. C-C-O-CHR, The second step of the present process involves reduc wherein R is CHI or CCl3, namely, 2,2,2-trichloroethyl tive removal of the haloalkyl group using a metal reduc chloroformate or 2-iodoethyl chloroformate. The final ing agent, such as zinc dust, in an alcohol, such as metha product of the reaction is a haloalkyl carbamate (III) nol, or in a weakly acidic medium. A carboxylic acid such as acetic acid or formic acid may be used as a solvent, or, preferably, the acid may be combined with a polar organic C-O-CH-R cosolvent such as dimethyl sulfoxide or dimethylform amide. It will be obvious to those skilled in the art that other organic solvents which contain a labile hydrogen III 20 may be used with the zinc dust, and dilute mineral acids wherein Q and R are the same as defined above. may be used in combination with an organic co-solvent Reduction of the carbamate of Formula III with a as a proton source for the zinc. Also, those skilled in the dehydrohalogenating/reducing agent yields directly the art will recognize that there are equivalent reducing agents desired secondary amino compound (I). This secondary which will remove a halogen from the haloalkyl protect amino compound may be isolated by standard procedures. ing group thereby effecting carbamate removal. The compound of Formula I is preferably isolated as The preferred conditions for reductive removal of the its acid addition salt by adding one molar equivalent of a carbamate group comprise adding an excess of zinc dust carboxylic or mineral acid in an appropriate solvent such (most preferably a one and a half molar equivalent ex as acetone or ethyl acetate. The maleate salt of norpro cess) in formic acid (most preferably a one molar equiv poxyphene I (b), Alk is ethyl), for example, is readily 30 alent excess). A large volume of dimethylformamide is crystallized, allowing for ease of isolation and purifica preferred, preferably 10 to 15 times the volume of the tion. The noracymethadols II (a) are readily isolated as formic acid used. their hydrochloride salts prepared according to standard In isolating the secondary amine from the above re procedures. Other secondary amine salts of the above com action, care must be taken to avoid high temperatures and pounds can be prepared by reconversion to the correspond high (alkaline) pH's, since the free bases of the final ing free base at reduced temperatures by treatment with product (I) are converted intramolecularly by excess heat mild alkali, followed by acidification of the free base with or strong alkali to the undesired amide IV a different acid to form a new salt. In the first step of the present process, the quantity of 40 g the haloalkyl chloroformate employed can vary from an C-Alk equimolar amount to a large excess. The reaction is pref erably carried out, however, using a slight excess of the CH3 IV haloalkyl chloroformate. The reaction between the halo wherein Z is alkyl chloroformate and the tertiary amine is carried out at a temperature in the range 60-180° C., preferably in (a) C2H5 the range 80-100° C. Upon completion of the carbamate formation, the excess haloalkyl chloroformate may be de composed with a carboxylic acid, such as formic acid, in the presence of a hydrogen chloride scavenger such as triethylamine or pyridine. 50 To permit proper mixing of the reactants, an inert organic cosolvent is preferred, although excess haloalkyl chloroformate may be employed as the solvent. Inert co O solvents refer to those solvents which will not interact with the reagents employed. Acceptable inert organic co 55 (b) OH H solvents include aromatic hydrocarbon solvents, such as {O)--gi-- benzene, toluene, xylene, and the like, ethereal solvents GH, CH3 H such as 1,4-dioxane, butyl propyl ether, dipropyl ether, tetrahydrofuran and the like, halogenated hydrocarbon 60 solvents such as 1,1,2-trichloroethane, chloroform, 1,1,2,2- tetrachloroethane, and the like, esters of carboxylic acids such as ethyl acetate, butyl acetate, and the like, and ketones such as 2-butanone, 3-pentanone and the like. The and wherein Alk is the same as defined hereinabove. Such preferred solvent for the first step of the process is benzene. a reaction is hereafter referred to as an O->N acyl migra The reaction is preferably carried out by addition of tion. the haloalkyl chloroformate to a refluxing solution of the It is an advantage of the novel process of this inven starting tertiary amine in the organic cosolvent, and the tion that the desired secondary amine is produced in high chloroformate is added dropwise to the reaction at such yield. In addition to producing high yields of product, a a rate that an even reflux rate is maintained. The evolu 70 further advantage of the present process over existing tion of methyl chloride, postulated as the by-product of demethylation methods is the high degree of purity of the the reaction, is no longer visible after about a one half product, which contains no detectable amount of tertiary hour further reflux period following completion of the amine. This high degree of purity is made possible by the chloroformate addition. However an additional reflux fact that acid-base extractions are carried out at two dif period of 1 to 2 hours is preferred for best results in the 75 ferent stages during the purification of the secondary 3,839,423 5 6 amine product or an intermediate therefor. Since the ammonium hydroxide to make the solution slightly basic. carbamate of Formula III is neutral, it is possible to effect d-Propoxyphene, being insoluble in the aqueous alkaline its separation by acid extraction of the basic tertiary amine layer, separated and was extracted with two portions of of Formula II from which it is derived. Later in the diethyl ether. The ether extracts were combined; the com process, the basic secondary amine of Formula I, ultimately bined extracts were washed with water and then dried over produced, can be dissolved in dilute aqueous acid and any magnesium sulfate. The dried ether solution was filtered, unreacted neutral carbamate of Formula III can be re and then the filtrate was concentrated in vacuo. d-Pro moved as an organic solvent soluble material. Another ad poxyphene remained as a solid residue and, without fur vantage of the process of this invention is the avoidance of ther purification, was dissolved in 2400 ml. of benzene. the expensive and explosive dialkylazodicarboxylate, used O The solution was dried by refluxing with a Dean-Stark for example in U.S. Pat. 3,213,128, in the process for the water separator for one hour. Next, to the refluxing stirred preparation of I (a). A further advantage of the present benzene solution was added 1000 g, of trichloroethyl chlo invention is that carbamates which are formed as inter roformate in dropwise fashion at such a rate as to main mediates are readily cleaved under very mildly acidic/ tain an even reflux. After completion of the addition, the reducing conditions. As will be apparent to those skilled 5 reaction mixture was refluxed for an additional two hours in the art, the conventional acid hydrolysis of the carba and then concentrated to half-volume by distilling off mate group would also result in removal of the ester benzene over a one hour period. The concentrated reac group. Conventional basic hydrolysis of a carbamate can tion mixture was then allowed to stand at 25° C. for 16 also cause the O->N acyl shift previously discussed. hours. Each compound of Formulas I, II and III, for example, 20 The reaction mixture was next cooled to a temperature can exist in four diastereoisomeric forms occurring as two in the range 0-5 C. To decompose the excess trichloro racemates or racemic mixtures, each of which can be re ethyl chloroformate, 25 ml. of formic acid was added solved into dextro and levorotatory isomers. The two race followed by 50 ml. of triethylamine, both being added in mates have been arbitrarily designated as the o- and 3 dropwise fashion. Subsequently, the reaction mixture was racemates, the designation oz- having been given to that 25 stirred for 30 minutes and the reaction temperature racemate, or diastereoisomeric pair, having the least allowed to rise to 25 C. The reaction mixture was then soluble hydrochloride salt, while the other, having the poured into sufficient water and diethyl ether to dissolve more soluble salt, is called the 6-racemate. In the case of all the products present. 4-N-methyl-N-(2,2,2-trichloro compounds of Formula I (a), the noracymethadols, the ethoxycarbonyl)amino-3-methyl - 1,2 - diphenyl-2-pro o- and B-racemates have substantially the same analgesic 30 pionoxybutane formed in the above reaction was soluble activity; however, the d- and the 1- forms of each race in the ether layer which was separated, washed with 1N mate differ in the amount of analgesic activity they possess. aqueous hydrochloric acid and then twice more with wa Thus, the dextrorotatory isomer of the ox-diastereoisomeric ter. The ethereal solution was dried over magnesium sul pair of the compound of Formula I (a) has a greater fate, and the ether was evaporated therefrom in vacuo. analgesic activity than the levorotatory enantiomorph. 35 The residue was triturated with a small volume of n-hex If the or and 6 isomers of the compounds of Formula II ane and the resulting solution reconcentrated in vacuo, are separated, the steric configuration is retained during thereby removing the last traces of ether. A large volume the N-demethylation process of this invention; thus, the of n-hexane was added to dissolve the resulting residue, N-desmethyl product has the same configuration as its di and the resulting solution was cooled to 0 C, 4-N-meth methylamino starting material. The ox-d and c-1 secondary 40 yl-N-(2,2,2 - trichloroethoxycarbonyl)aminol-3-methyl-1, amines in the noracymethadol series, I (a), are more active 2-diphenyl-2-propionoxybutane crystallized and was sepa analgetically than the corresponding tertiary amines II rated by filtration, m.p. 82-84 C., weight -2136 gm. (a) from which they are prepared. (See Eddy, Chem. and Analysis.--Calc. for C24H23NOACl3 (percent): C, Ind. 1462-1469 (1959). The a-d secondary amine of the 57.55; H, 5.63; N, 2.80. Found (percent): C, 57.64; H, norpropoxyphene series II (b)) is analgetically active also 45 5.80; N, 2.69. (Nickander, R. and Smits, S., Abstracts Fall 1973 Meeting Following the above procedure, ox-d-4-dimethylamino-3- Amer. Soc. for Pharm. and Exp. Ther.). methyl-1,2-diphenyl-2-acetoxybutane was treated with tri d-Norpropoxyphene, I (b), has been described as the chloroethyl chloroformate to form oz-d-4-(N-methyl-N- major metabolite of d-propoxyphene, II (b) wherein Alk (2,2,2-trichloroethoxycarbonyl)amino - 3 - methyl-1,2- 50 diphenyl-2-acetoxybutane; m.p. 96-98 C. is ethyl J. Pharm. Exp. Therap. 125, 14 (1959) and Analysis.-Calc. for C23HasnO4Cls (percent): C, Life Sci. 12, 463-473 (1973). 56.75; H, 5.38; N, 2.88. Found (percent): C, 56.52; H, Illustrative of the haloalkyl carbamates formed as 5.20; N, 2.87. intermediates in the present process are the following: Also following the above procedure, a-l-acetylmethadol 4-N-methyl-N-(2-iodoethoxycarbonyl)amino]-1,2- 55 was reacted with trichloroethylchloroformate to form the diphenyl-3-methyl-2-propionoxybutane, ox-l-noracetylmethadol trichloroethyl carbamate ox-l-3- 4-N-methyl-N-(2-iodoethoxycarbonyl)amino 1,2- acetoxy-6-(N-methyl - N - (2,2,2-trichloroethoxycarbon diphenyl-3-methyl-2-butyroxybutane, yl)amino-4,4-diphenylheptane. 3-acetoxy-6-EN-methyl-N-(2-iodoethoxycarbonyl) EXAMPLE 2 3-propionoxy-6-(N-methyl-N-(2,2,2-trichloroethoxyaminol-4,4-diphenylheptane, - 60 carbonyl)aminol-4,4-diphenylheptane. d-Norpropoxyphene Maleate Salt 3-butyroxy-6-N-methyl-N-(2-iodoethoxycarbonyl) A solution of 1500 gm. of 4-(N-methyl-N-(2,2,2-tri aminol-4,4-diphenylheptane, and the like. chloroethoxycarbonyl)aminol-3-methyl-1,2-diphenyl-2- The general procedures employed in the preparation of 65 propionoxybutane, from Example 1, in 3000 ml. of DMF compounds of this invention are illustrated in the follow and 200 ml. of formic acid was prepared and cooled to ing examples. --5 C. Four hundred and fifty three grams of powdered zinc was added in portions. After the addition had been EXAMPLE 1. completed, the reaction mixture was stirred for an addi 4-N-methyl-N-(2,2,2-trichloroethoxycarbonyl)amino 70 tional hour at about 0° C. The reaction mixture was 3-methyl-1,2-diphenyl-2-propionoxybutane then filtered to remove excess zinc. The filtrate, containing d-norpropoxyphene formed in the above reaction, was To 1690 gm. of d-propoxyphene hydrochloride (o-d-4- poured into 10 liters of water, and 600 ml. of 12N hydro dimethylamino-3-methyl-1,2-diphenyl-2-propionoxybutane chloric acid was added. Insoluble zinc salts were removed hydrochloride) in 3 liters of water was added sufficient 75 by filtration. The acidic filtrate, containing d-norpropoxy 3,839,423 7 phene as a salt, was extracted twice with ethyl acetate to wherein Q is remove any starting material, 4-N-methyl-N-(2,2,2-tri chloroethoxycarbonyl)aminol - 3 - methyl-1,2-diphenyl 2-propionoxybutane. The ethyl acetate extracts were com CE5 O O bined, and the combined extracts in turn were extracted twice with 1N hydrochloric acid. The aqueous acid layers 5 Hi-O--Alk O-5–Alk were combined with the original acidic extract, and the combined extracts were cooled to 0° C. and then basified -C-C-C-H. or -C| CE-C-|| with 14N ammonium hydroxide. d-Norpropoxyphene, KO)--CH-)-&H, or {O)--H-ki, &H, h being insoluble in aqueous base, separated and was ex 10 tracted with ethyl acetate. Two more ethyl acetate ex tracts of the aqueous basic layer were made. The ethyl acetate extracts were combined; the combined extracts were washed with water at 0° C., cooled to -5° C., and dried. 5 A solution of 348 g. of maleic acid in the minimum volume of acetone required for solution at 25° C. was added to the cold dry ethyl acetate solution of d-norpro and wherein Alkis C1-C3-alkyl poxyphene obtained as above. The resulting solution was or an acid addition salt thereof comprising the steps of: thoroughly mixed. The maleic acid salt of d-norpropoxy A. reacting a haloalkyl chloroformate of the formula phene precipitated and was collected by fitration, m.p. 20 159-160° C., wt. 906 g. Analysis.-Calc. for CHNO (percent): C, 68.01; H, 7.08; N, 3.17. Found (percent): C, 67.81; H, 7.09; N, 3.19. wherein R is -CH2 or -CCl3 with a tertiary amine Following the above procedure, ox-d-4-(N-methyl-N- 25 of the formula (2,2,2-trichloroethoxycarbonyl)amino - 3 - methyl-1,2- diphenyl-2-acetoxybutane was treated with zinc dust and CH3 formic acid in DMF and the product was converted to the maleic acid salt of ox-d-4-methylamino-3-methyl-1,2- 30 N diphenyl-2-acetoxybutane, m.p. 130-131 C. CH Analysis.-Calc. for C2HNO (percent): C, 67.43; H, 6.84; N, 3.28. Found (percent): C, 67.64; N, 6.78; N, wherein Q is the same as above, at a temperature of 3.06. 60-180° C. to produce a haloalkyl carbamate of the Also following the above procedure, a-l-3-acetoxy-6- N-methyl - N - (2,2,2-trichloroethoxycarbonyl)aminol formula 4,4-diphenylheptane was treated with zinc dust and formic acid in DMF to prepare 3-acetoxy-6-methylamino-4,4-di phenylheptane (o-1-noracetylmethadol), isolated as its hy O 40 8-O-CH-R drochloride salt, m.p. 234-235 C., oxid=67.8 (C.=1, 1. H2O). Q-N EXAMPLE 3 CE d-Norpropoxyphene Hemi-citrate Salt 45 wherein Q and R are the same as above, B. removing the carbamate group by reduction with To a slurry of 1186 g. of d-norpropoxyphene maleate zinc dust, and in three liters of cold water and one liter of cold ethyl C. then isolating the secondary amine thus formed acetate was added one liter of cold (0-5 C.) 14N aim either as the free base or as an acid addition salt monium hydroxide. Sufficient solid sodium chloride was 50 thereof. added to the aqueous alkaline layer to separate the re 2. The process of Claim 1 wherein an inert organic co Sulting emulsion. d-Norpropoxyphene free base was in solvent is used for Step A. soluble in the alkaline solution and was separated. The 3. The process of Claim 2 wherein the inert organic free base was extracted with three equal volumes of ethyl cosolvent is benzene. acetate. The ethyl acetate extracts were combined, washed 55 4. The process of Claim 1 wherein a carboxylic acid twice with water (5 C.), and then dried. The d-nor and an inert cosolvent are used for Step B. propoxyphene solution thus obtained was treated with a 5. The process of Claim 4 wherein the inert cosolvent solution of 310 gm. of citric acid monohydrate in 700 ml. is dimethylformamide. of acetone (which solution had been previously dried 6. The process of Claim 4 wherein the carboxylic acid over magnesium sulfate). d-Norpropoxyphene hemicitrate 60 used in Step B is formic acid. crystallized rapidly, and was separated by filtration and 7. The process of Claim 1 wherein: dried in vacuo. M.p. 152-154 C., wt., 1100 g. Q is Analysis.--Calc. for CashN2O (percent): C, 68.39; H, 7.41; N, 3.32. Found (percent): C, 68.14; H, 7.17; N, 65 3.20. We claim: 1. A process for the preparation of a compound of the -O-C-Alk formula: H 70 (O) ".

( CH3 75 8,839,423 9 O 8. The process of Claim 7 wherein the product is iso- 10. The process of Claim 9 wherein the product is first lated as its hydrochloride salt. isolated as its maleate salt. 9. The process of Claim 1 wherein: Q is References Cited 5 UNITED STATES PATENTS Q 3,021,360 2/1962 Pohland ------260-490 o-e-Alk 3,213,128 10/1965 Fornefeld et al. ------260-490 ^ >--CH-CH- o CH, CH3 O VIVIAN GARNER, Primary Examiner U.S. C. X.R. 260-471 C