Catalytic Hydrogenation of (pseudo)Ephedrine and Phenylpropanolamine

Introduction

A note on nomenclature utilized in the various syntheses. The literature variously refers to amphetamine as beta-phenylisopropylamine, 1-phenyl-2-aminopropane, beta-aminopropylbenzene, deoxynorephedrine, desoxynorephedrine, PhCH2CH(NH2)CH3 or PhCH2CH(NH2)Me. Methamphetamine is variously referred to as beta-phenylisopropylmethylamine, 1-phenyl-2-methylaminopropane, N-methyl-phenylisopropylamine, alpha-,N-dimethyl-phenethylamine, N-methylamphetamine, deoxyephedrine, desoxyephedrine, PhCH2CH(NHCH3)CH3 or PhCH2CH(NHMe)Me. The dextro isomer of phenylisopropylamine and phenylisopropylmethylamine is the d, (+), D or S isomer; the levo isomer is the l, (-), L or R isomer. The racemic mixtures may be referred to as d,l or (±) or (+,-) or DL.

Reduction of either (-)-ephedrine or (+)-pseudoephedrine will yield the dextro (+)-methamphetamine. The stereospecificity of the reduction results from mechanistic factors as well as the diastereoisomeric nature of the ephedrines. Ephedrine and pseudoephedrine are 1-phenyl-1-hydroxy-2-methylamino-propane; each contains two chiral centers at the No. 1 and No. 2 carbons of the propane chain. Reduction to methamphetamine eliminates the chiral center at the No. 1 carbon.

Recommended Reading

Organic Synthesis:

• Dictionary of Organic Compounds with cumulative supplements.
• Organic Syntheses and/or Collected Organic Syntheses (multi-volume sets).
• Reagents for Organic Synthesis (Volumes 1-15), Fieser et al.

Catalytic Hydrogenation:

• Practical Catalytic Hydrogenation: Techniques and Applications, Freifelder (1971).
• Catalytic Hydrogenation in Organic Synthesis: Procedures and Commentary, Freifelder (1978).
• Catalytic Hydrogenation in Organic Syntheses, Rylander (1979).

Catalytic Reduction of Ephedrine, Pseudoephedrine and Phenylpropanolamine

Those interested in the catalytic reduction of ephedrine and related compounds may find the following references useful; review of foreign language references and foreign patents is limited to the Chemical Abstract citations.

Reduction With Palladium/Barium Sulfate--Bromo or Chloro Ephedrine Reduced to Methamphetamine:

Emde, Concerning Diastereoisomers. I. Configuration of Ephedrine; II. Steric Inversion of Ephedrine with Hydrochloric acid; III. Chloro- and Bromo-Ephedrine. Helv. Chem. Acta., 12, 365-99 (1929); C.A. 23: 3452-4 (1929).

(+) Desoxyephedrine:

A solution of 3 g. sodium acetate in 40 cc. water is made neutral to litmus with a few drops of acetic acid. 2 g. of Pd-BaSO4 (palladium-barium sulfate) catalyst is added, with 9.8 g. of (+)-bromopseudoephedrine hydrobromide (or 7.2 g. of (+)-chloropseudoephedrine hydrochloride), and agitated under hydrogen at room temperature. About 90% of the theoretical H2 is absorbed in 2-3 hours, the catalyst is filtered off, and the product is steam distilled from the filtrate after addition of sodium hydroxide. There remains a small residue of (+)-didesoxyephedrine (probably 2,5-bis-methylamino-3,4-diphenylhexane, [PhCHCH(NHCH3)CH3]2), b.p.0.6mm. 165°. The steam distillate is neutralized with HCl (to methyl red) and crystallized from absolute ethanol (solubility 1:4). Yield, 80-90%.

Purification was achieved by extraction of the base from the steam distillate with diethyl ether, drying (e.g., potassium hydroxide), and distillation under a high vacuum. The hydrochloride salt had m.p. 172°.

Chloropseudoephedrine-HCl [PhChClCHMeNHMe·HCl]:

1. 60 cc. CHCl3 (chloroform) and 60 g. PCl5 (phosphorus pentachloride) are placed in a wide-mouth glass-stoppered bottle, and after cooling with ice 40 g. of powdered (-)-ephedrine hydrochloride is added in 0.5 g. portions in about 10 minutes, shaking vigorously after each addition. The bottle is then shaken mechanically for 2 hours. The reaction mass is then decanted into a 750 cc. beaker, leaving the excess PCl5 in the bottle. After rinsing with 20 cc. chloroform, 500 cc. diethyl ether is added and the product allowed to stand. The product crystallizes out, is filtered under suction, washed with acetone and dried in a vacuum desiccator. Yield, 99.4%. A few recrystallizations from ethanol yields optically pure product.
2. Similarly, using 20 cc. thionyl chloride (SOCl2), 20 cc. chloroform and 10 g. of (-)-ephedrine hydrochloride. The reaction is slower, and after 30 minutes 100 cc. diethyl ether is added and the crystallized chloroephedrine is treated as above. Yield 93%.
3. Similarly from 2 g. of (+)-pseudoephedrine hydrochloride, 5 cc. of CHCl3 and 4 cc. SOCl2. The addition of 100 cc. diethyl ether precipitates 2.15 g. of yellowish chloropseudoephedrine hydrochloride product. Free (+)-chloropseudoephedrine is a yellow oil with a strong odor similar to that of pseudoephedrine, too unstable to be purified for analysis.

(+)-Bromopseudoephedrine-HBr:

(+)-Bromopseudoephedrine-HBr was obtained from 12.9 g. of (-)-ephedrine hydrobromide, 50 g. PBr5 and 60 cc. chloroform. After 3 hours of shaking, the product is decanted off and treated with 500 cc. of ether and filtered off. Yield, 98% of pure product. For those interested, this article also contains procedures and data on the steric inversion of ephedrine, chloroephedrine and bromoephedrine.

Reduction With Calcium Hydride-Palladium and HCl--Chloroephedrine reduced to methamphetamine:

Gero, Some Reactions of 1-Phenyl-1-chloro-2-(methylamino)propane. I. Reactions with Metals and with Hydrogen. J. Org. Chem., 16, 1731-5 (1951); C.A. 46: 6606g (1952).

1-Phenyl-1-chloro-2-methylaminopropane was reduced to methamphetamine in yields ranging from 10(86%. Propenylbenzene was formed in a side reaction in amounts ranging from a trace (reduction with calcium hydride-palladium and hydrochloric acid) to 77% (reduction with zinc and hydrochloric acid). Whether the propenylbenzene is further reduced to propylbenzene was not investigated.

Hydrogenation with zinc and hydrochloric acid:

22 g. 1-phenyl-1-chloro-2-methylaminopropane was dissolved in 100 ml. concentrated hydrochloric acid. To this solution 65 g. of zinc dust moistened with water was added. When the reaction subsided, it was kept going by adding more hydrochloric acid. When all the zinc was dissolved, the solution was distilled with steam as long as propenylbenzene came over. The solution was then made alkaline and the steam distillation continued as long as the distillate was alkaline. The alkaline distillate was extracted with diethyl ether, the ether dried with sodium sulfate and saturated with hydrogen chloride gas. The precipitated desoxyephedrine hydrochloride was washed with ether and dried. Yield 2.3 g. (12%), m.p. 171°.

Hydrogenation with zinc in the presence of palladium and hydrochloric acid:

The hydrogenation was performed in the same manner except that the zinc was previously immersed in a solution of 0.65 g. of palladous chloride in 2 ml. of concentrated hydrochloric acid and 80 ml. of hot water, after a few minutes filtered, and washed with water. Desoxyephedrine hydrochloride was obtained in 34% yield.

Hydrogenation with zinc-copper and hydrochloric acid:

The hydrogenation was carried out likewise but the zinc was first immersed in a solution of 50 g. of cupric sulfate in 1200 ml. water until the blue color disappeared, filtered, and washed with water. Desoxyephedrine hydrochloride was obtained in 10% yield. Hydrogenation with zinc-copper in the presence of palladium and hydrochloric acid: The copper-plated zinc was palladized as described above and utilized in the same manner. Desoxyephedrine hydrochloride was obtained in 26% yield.

Hydrogenation with palladized aluminum and hydrochloric acid:

Aluminum powder (9 g.) was washed successively with benzene, methanol, water, then immersed in 30 ml. of 0.1% sodium hydroxide solution. After two minutes, 100 ml. of water was added and the aluminum filtered and washed with water. A solution of 0.2 g. palladous chloride in 200 ml. hot water was then poured on the aluminum and left overnight. The palladized aluminum was filtered and washed with water and added to a solution of 22 g. of 1-phenyl-1-chloro-2-methylamino- propane in a mixture of 200 ml. of concentrated hydrochloric acid and 200 ml. water. The reaction was slow to start but became gradually quite vigorous and had to be moderated by outside cooling. When the reaction stopped, the unreacted aluminum was dissolved in concentrated hydrochloric acid, the mixture distilled with steam, and treated as before. Desoxyephedrine hydrochloride was obtained in 44% yield.

Hydrogenation with calcium hydride and hydrochloric acid in the presence of Pd:

11 g. 1-phenyl-1-chloro-2-methylaminopropane was dissolved in 100 ml. methanol. To this solution was added a solution of 0.25 g. of palladium chloride in 7.5 ml. hot concentrated hydrochloric acid (Solution A). Calcium hydride (11 g.) was covered with 100 ml. of methanol and Solution A was added at such a rate that the temperature of the reaction mixture stayed at 35-40°, with outside cooling if necessary. When the initially vigorous hydrogen development subsided, enough concentrated hydrochloric acid was added to bring the pH to about 3 and the mixture was stirred for 30 minutes. The clear solution was filtered from the palladium black and washed with 200 ml. of water. Then 250 ml. was distilled off to remove the methanol and whatever propenylbenzene might have been formed (no more than a trace was ever found), the residue made alkaline, and treated as in previous experiments (yield 86%).

Reduction with Palladium/Barium Sulfate--Ephedrine Perchlorate Ester and Sulfate Ester Reduced to Methamphetamine:

Rosenmund et al., Concerning the Preparation of beta-Aryl-Alkylamines. Berichte, 75B, 1850-9 (1942); C.A. 38: 1219(1) (1944).

It was found the group ArCH(OH) (Ar = aryl; in other words the group of compounds containing a benzylic alcohol moiety) is easily reduced catalytically to ArCH2 in acetic acid or propionic acid in the presence of HClO4 (perchloric acid). Thus RCH2CHMeNH2 (where R is a radical such as the phenyl group and Me is a methyl group) is readily obtained from RCH(OH)CHMeNH2. Reductions of beta-arylalkanolamines were carried out in acetic acid with Pd-BaSO4 (palladium on barium sulfate) in the presence of 0.5-1 cc. 70% HClO4 at 80-90°; the yields of the (-arylalkylamines were 60-80%. Concentrated H2SO4, ZnCl2-HCl or BF3-acetic acid may be used, but HClO4 is the most efficient activator. Ephedrine is reduced in the presence of HClO4 in 30 minutes, with concentrated H2SO4 in 40 minutes to give the hydrochloride salt of (+)-phenylisopropyl- methylamine, m.p. 172°. dl-Ephedrine is reduced in 10 minutes; the hydrochloride salt m.p. 134°.

Reduction With Palladium--Ephedrine Sulfate Ester Reduced to Methamphetamine:

Kindler et al., The Mechanisms of Chemical Reactions. X. Preparation of Phenyl- and Cyclohexylalkylamines by Hydrogenation. Justus Liebigs Ann. Chem., 560, 215-21 (1948); C.A. 43: 1025g (1949).

It was found the hydrogenation of ephedrine to the corresponding amine is faster with strong acids, such as H2SO4 and HClO4. Amino alcohols (such as ephedrine and phenylpropanolamine) were hydrogenated only slowly in the absence of acid. The use of H2SO4-H2O was better than that of H2SO4, avoiding reduction to H2S and catalyst poisoning. The use of HClO4 in large amounts caused reduction of C6H5 to C6H11 (the benzene ring was reduced to a cyclohexane ring). (+)-Phenylisopropylmethylamine (PhCH2CHMeNHMe) was prepared in 95% yield as the crude hydrochloride salt from 4 g. ephedrine hydrochloride, 90 cc. acetic acid, 4.7 g. 84% H2SO4, and 1 g. palladium wool. M.p. 166-8°, m.p. 182° (from chloroform and ethyl acetate).

Reduction With Palladium--Ephedrine and Phenypropanolamine with HCl (Gas) Reduced to Methamphetamine and Amphetamine:

Metzger, Bases of the 1-Phenyl-2-aminopropane Series, German Pat. No. 968,545, Mar. 6, 1958; C.A. 54:7654b (1960). 1-Phenyl-2-methylamino-propan-1-ols were catalytically hydrogenated in the presence of palladium, glacial acetic acid and dry hydrohalide gas.

60 g d,l-ephedrine hydrochloride in 600 cc glacial acetic acid containing 30 HCl gas was hydrogenated at 90° in the presence of 50 g palladium black (note: this is a very high catalyst ratio), the catalyst separated, the solvent evaporated, and the residue made alkaline to give 95% d,l-deoxynorephedrine. Similarly prepared were D-deoxyephedrine (d-methamphetamine) and D-deoxynorephedrine sulfate (d-amphetamine).

Note that there is evidently an error in the Chemical Abstracts translation. Reduction of ephedrine would be expected to give deoxyephedrine; reduction of phenylpropanolamine (norephedrine) would be expected to give deoxynorephedrine.

Reduction With Palladium/Carbon--Sulfate Esters Reduced to Amines:

Dobke et al., Amines. Brit Pat 509,661, July 19, 1939; C.A. 34: 3761(6) (1940).

Amines were produced from esters of 1-aryl-2-amino-1-propanols and their N-substitution products by catalytic hydrogenation in a nonaqueous medium, preferably under pressure. Among the examples given, 1-phenyl-2-methylamino- 1-propanol (ephedrine) is stirred into alcohol and hydrogenated by aid of a palladium black carrier catalyst at about 50° and 4 atm. to give the theoretical yield of 1-phenyl-2-aminopropane.

Temmler-Werke, Amines. Fr Pat 844,227, July 20, 1939; C.A. 34: 7297(1) (1940).

A method for the preparation of amines from 1-aryl-2-aminopropanol esters or their N-substituted derivatives by catalytic hydrogenation consists of effecting the hydrogenation in a nonaqueous medium and preferably under pressure. The yield is quantitative. Among examples, racemic 1-phenyl-2-methylaminopropane, b.p.20mm. 92-94°, is obtained by dissolving 4 parts of the sulfuric ester of racemic pseudoephedrine in 200 parts of alcohol, subjecting the solution to a hydrogenating operation under a pressure of 3 atm. at 50°, in the presence of a catalyst composed of palladium and carbon, eliminating the catalyst by filtration after the absorption of the calculated amount of hydrogen, concentrating the filtrate, treating it with diluted H2SO4 and precipitating the amine by means of an alkali.

Reduction with Platinum--Halide Ester Reduced to Methamphetamine and Amphetamine:

Dobke et al, Amines. Ger Pat No 767,186, Jan. 31, 1952; C.A. 49: 15958b (1955).

Hydrogen halide esters of the 1-aryl-2-aminopropanols or their N-substituted products in the form of their hydrohalides were hydrogenated under pressure in a non-aqueous medium and in the absence of buffering agents to give the corresponding amines in good yields.

(+)-1-Phenyl-1-chloro-2-methylaminopropane hydrochloride 21 suspended in ethanol 120 and admixed with a platinum catalyst is hydrogenated with 3 atm. hydrogen at room temperature. Working up the hydrogenation mixture in the usual manner gave (+)-1-phenyl-2-methylaminopropane hydrochloride, m.p. 172° (from ethanol) in almost quantitative (100%) yield. Similarly prepared was d,l-1-phenyl-2- aminopropane, b.p.20mm. 93-95°, from d,l-1-phenyl-1-chloro-2-aminopropane.

Reduction With Platinum/Carbon--Chloroephedrine Reduced to Methamphetamine:

Nakajima, 1-Phenyl-2-methylaminopropane. Japanese Pat. No. 2307, May 15, 1951; C.A. 47: 5437h (1953). Chloroephedrine hydrochloride (PhCHClCH(NHMe)·HCl) (10 g.) was reduced in 50% methanol with 1 ml. 5% PtCl3 , 0.2 g carbon, and hydrogen without pressure absorbed the theoretical amount of H2. The product was filtered and distilled. Yield 7 g. PhCH2CH(NHMe)Me·HCl (methamphetamine hydrochloride), m.p. 172°.