[CONTRIBUTION FROM
THE
RESEARCH LABORATORIES, SCHOOLOF PHARMACY, UNIVERSITY OF MARYLAND]
AMINO ALCOHOLS. XIII. THE SYNTHESIS OF ALIPHATIC AMINO ALCOHOLS OF PHARMACOLOGICAL INTEREST (1) WALTER C. GAKENHEIMER
AND
WALTER H. HARTUNG
Received October 6, 1943
Barger and Dale (2) state that for compounds to produce a rise in blood pressure they must have the minimum skeleton Ar-C-C-N, where Ar is an aromatic nucleus. More recently, Gunn and Gurd (3) have shown that the cycle may be hydroaromatic, and they claim no important qualitative difference between 8-cyclohexylethylamine and p-phenylethylamine. Hexahydropropadrin, or 1-cyclohexyl-2-aminopropan-l-oll is also known to have pressor activity (4). Physiologically active compounds with hydrogenated rings frequently retain their characteristic activity when the cycle is opened (5). Blicke and Zienty (6) found that the antispasmodic value of methyl-di-p-cyclohexylethylamineis altered only quantitatively by opening the ring in the l , 2 position to produce methyldioctylamine. Barger and Dale (2) observed that the physiological response of cyclohexylamine was slower in appearing and was more prolonged but otherwise resembled the pressor activity obtained with n-hexylamine. Consequently, what will be the effect if the ring of hexahydropropadrin is opened at various places in the cycle? Pressor activity is known to exist in aliphatic amines (2,7) beginning with n-butylamine, reaching the maximum with n-hexylamine and still apparent in the higher homologs. Dunker and Hartung (8) state that “the introduction of the hydroxyl leads to a decrease in toxicity and activity as compared to the non-hydroxylated amine”. Accordingly, it appeared desirable to prepare for pharmacological examination a series of aliphatic amino alcohols of general structure RCHOHCHNH2R’, and consisting of eight or nine carbon atoms since, in the aromatic amino alcohols, activity is found in arylethanolamines and arylpropanolamines. The open-chain amino alcohols were obtained by the reduction of the corresponding nitro alkanols. These intermediates were synthesized by the method of Vanderbilt and Hass (9). Of the ten nitro alcohols listed in Table I, Nos. 1,2, 3, 9? and 10 have been previously reported (10). Efforts to hydrogenate catalytically the aliphatic nitro alcohols with palladium were unsuccessful. Raney nickel in an acid medium (acetic and carbonic acids) at room temperature was satisfactory. In neutral medium no trace of the desired amino alkanol could be isolated; instead, most of the nitrogen could be accounted for in the form of primary and secondary amines with smaller alkyl groupsl indicating that the nitro alkanol chain underwent fission, e.g.: RCHOHCHN02R’
neutral solvent 3 R’CHzNH2 Raney nickel
+ R‘CH2NHCHzR
That the fission occurs with a partially hydrogenated product is indicated by dowing the nitro alcohol to stand at room temperature for seventy-two hours 85
86
W. C . QAKENHEIMER AND W. H . HARTUNQ
with (a) the corresponding amino alcohol; (b) hydrochloric acid; (c) sodium hydroxide; (d) Raney nickel, whereupon the nitro alcohol remained unaffected, and by treating the amino alcohol with hydrogen a t temperatures as high as 85", and pressures as high as 300 pounds per square inch in the presence of Raney nickel, without decomposition. Electrolytic reduction of 3-nitroheptan-4-01 was very successful. TABLE I NITROALCOHOLS SYNTHESIZED B.P..
COMPOUND
1. 3-Xitroheptan-4-01, . . . . . . . . . . . . . 2. 2-Nitro-2-methylhexan-3-01. . . . . . . . . . . . . . . . . . . 3. 5-Witrooctan-4-01, . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. l-~itro-3-et~hylpentan-2-01. ................... 5. 2-Nitro-4-ethylhexan-3-01, . . . . . . . . . . . . . . . . . . . . 6. 1-Xitroheptan-2-01 7. 2-Sitrooctan-3-01, . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. 3-Xtrononan-4-01, . .............. 9. 1-Nitrooctan-2-01'. . . . . . . . . . . . . . . . . . . . . .,. . . . . . 10. 2-Nitrononan-3-01. . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFRACTIVE INDEX AT 22
'c
"e.
122-123/18 mm. 122-123/21 mm. 123-124/13 mni. 109-111/26 mm. 118-120/22 mni. 11&120/24 mm. 133-134/22 mm. 142-143/23 mm. 130-132/24 mm. 134-136/23 mm.
70 58 76 51 49 55 43 59 69 57
1.4436
1.4524 1.4515
a Cerf de Mauny (Bull. sac. chim., 7, 133 (1940); Chern. Abstr., 34, 5413 (1940)) gives the boiling point as 135"/10 mm.
TABLE I1 Animo ALCOHOLS SYNTHESIZED
___ BENZAMIDES
COXPOUND
1. 2-Amino-4-ethylhexan-3-01., . . 2. 3-Aminoheptan-4-01, . . . . . . . . .
YIELD,
%
69 54 75 3. 1-Aminooctan-2-01. . . . . . . . . . . 41 4. 5-Aminooctan-4-01. . . . . . . . . . . 66 5. 3-Aminononan-4-01, . . . . . . . . . . 38
B.P.,
"c.
METH-
OD'
110-112/27 mm. 98-99 /20 mni. 130-132/26 mm. 118-119/26 mm. 116-118/27 mm.
X.P., "C.,
151 145
1
NITROGEN ANAL.
j 5.62 5.95
Found%
5.68, 5.62 5.91, 5.96
158 5.62 5.51, 5.59 149-150 5.62 5.47, 5.56 161 5.32 5.34, 5.39
* A-Catalytic
reduction with Raney nickel and acetic acid. B-Catalytic reduction with Raney nickel and carbonic acid. C-Electrolytic reduction.
Table I1 contains information pertaining to the amino alcohols synthesized. Hass and Vanderbilt (11) have described previously 3-aminoheptan-4-01 and 5-aminooctan-4-01; the other three are unreported. EXPERIMENTAL
Preparation of the nitro alcohols. The method used was essentially that of Vanderbilt and Hass (9). Immediately prior t o use, these products were redistilled and a three-degree cut utilized.
ALIPHATIC AMINO -4LCOHOLS
87
When treated in the manner designed for the preparation of urethans (12), all of the nitro alkanols reacted with a-naphthylisocyanate to produce di-a-naphthylurea. Bickel and French (13) report a similar observation with other alcohols. Reduction of the nitro alcohols. ( a ) Catalytic hydrogenatzon, acetic acid medium. Twelve grams of glacial acetic acid and 0.2 mole of nitro alcohol were dissolved in enough absolute alcohol t o make 100 cc. One gram of Raney nickel was added and the mixture reduced a t room temperature with a n initial hydrogen pressure of a t least 500 pounds per square inch. The pressure drop was theoretical. After the catalyst had been removed by filtration, the alcohol was allowed t o evaporate spontaneously. The residue was extracted with 10% hydrochloric acid. After washing the acid extract with toluene, i t was made strongly alkaline with 40y0 sodium hydroxide. The amino alcohol which separated was removed; the r:maining aqueous portion was extracted with ether, and this ethereal solution was added to the unpurified amino alcohol. The solution was dried for 18 hours over anhydrous magnesium sulfate. Distillation a t reduced pressure yielded the amino alcohol as a waterwhite liquid. ( b ) Catalytic hydrogenation, carbonzc acid medzum. The use of solid carbon dioxide reported by Vanderbilt (14) results in the production of carbonic acid which combines with the amine as i t is produced. Two-tenths mole of the nitro alkanol was dissolved in enough absolute alcohol t o make 100 cc. and 1 g. of Raney nickel was added to this solution. Two hundred grams of solid carbon dioxide was placed in the bomb before sealing. After two hours the pressure became constant at 240 pounds per square inch and the system was assumed to be in thermal equilibrium. Hydrogen was admitted until the pressure rose a t least an additional 600 pounds per square inch. After shaking for three hours, the pressure dropped approximately 7070 of the theoretical decrease. Additional agitation of 24 hours failed t o produce a further change. The nickel mas removcd, the alcohol evaporated a t reduced pressure, and the product isolated as described above. ( c ) Electrolytic reduction.' The reduction was carried out in a 1500 cc. beaker using a lead mode, separated from the cathode by a porous cup, and a lead cathode, 15 X 14 cm. The cathode plate was coated with spongy lead just before reduction by placing i t in a hot, acidified suspension of lead chloride with a lead anode and passing a current through the cell until thc cathode was covered with a gray coat of the spongy lead. The electrolyte consisted of 10% sulfuric acid, approximately one liter being used in the cathode compartment The porous cup serving as the anode compartment mas kept filled n-ith the acid. Seventy-one grams of 3-nitroheptan-4-01 was added t o the cathode compartment, the catholyte was continuously stirred, and a current of about 15-17 amperes and about 8 volts was passed through the cell. As the reduction took place, the nitroheptanol, which was suspended in the catholyte, went into solution. After several hours, 47 g. more nitroheptanol was added and reduction continued. Only a small amount of oily material remained a t the end of the reduction. The reduction cell was cooled in a water-bath during the operation, the temperature remaining a t 35". The catholyte was filtered and extracted with toluene. The catholyte was then made strongly alkaline with 40% sodium hydroxide and then solid sodium hydroxide was added. The oil which separated was collected and combined with ether extractions of the alkaline solution. The extract was dried over sodium hydroxide and then distilled. O m d a t i o n of 5-aminooctan-4-01. T h a t the amino alcohols have the structure assigned is confirmed by the oxidation of 5-aminooctan-4-01. A sample weighing 5.872 g. was shaken for one hour with 37, solution of potassium permanganate acidified with sulfuric acid; the excess permanganate was reduced with sodium sulfite and the resultant mixture filtered. The filtrate was made alkaline with 10% sodium hydroxide and refiltered. This solution was then evaporated on a water-bath. The dry crystals thus obtained were dissolved in the 1 The electrolytic reduction was carried out by Dr. Glenn E. Ullyot of the Research Laboratories, Smith, Kline, and French, Philadelphia, Pa., t o whom the authors express thanks.
88
W. C. GAKENHEIMER AND W. H. HARTUNG
minimum amount of 50% sulfuric acid, and ether was used t o extract 5.1 g. of butyric acid, whose identity was proved through the anilide (13). This represented a 71% yield of butyric acid on the assumption t h a t two molecules of butyric acid are produced from one molecule of the amino alcohol, and since the yield is greater than 5070, proves the assumption. Preparation of the monobenzoyl derivatives of the amino alcohols. These compounds were synthesized by shaking calculated quantities of the amino alcohol and benzoyl chloride i n excess 20Y0 sodium hydroxide solution, and recrystallizing the resulting mass from toluene and then from 50% aqueous alcohol. The properties of the amides are included in Table 11.
It was hoped that pharmacological data might be included in this paper, but because of present conditions such studies are being delayed. CONCLUSIONS
1. In the preparation of open-chain amino alcohols of pharmacological interest,, five new nitro alkanols were synthesized. 2. The electrolytic reduction of nitro alkanols gives good yields of corresponding amino alkanols. 3. Raney nickel, in the presence of carbonic or acetic acid, will catalyze the hydrogenation of the nitro alkanols to the corresponding amino alkanols. 4. When the reduction is carried out in neut,ral solvent, the carbon chain of the nit,ro alcohol undergoes fission of the alkane chain with the formation of primary and secondary amines. Evidence indicates that the fission takes place with some partially hydrogenated product. BALTIMORE, MD. REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
(11) (12) (13) (14)
For Amino Alcohols, XII, see JAROWSKI AND HARTUNG, J . Org. Chem., 8,564 (1943). AND DALE,J . Physiol., 41, 19 (1910). BARGER GUNNAND GURD,J . Physiol., 97, 453 (1940). unpublished. HARTUNG, BUTH,KULZ,AND R O S E N M U N D , 72,19-28 B ~ ~ . , (1939). BLICKE AND ZIENTY, J . Am. Chem. SOC.,61, 771-773 (1939). ALLES,Univ. Calif. Pub. Pharmacol., 2, 1-32 (1941). DUNKER AND HARTUNG, J . Am. Pharm. ASSOC., 30,619 (1941). AND HASS,Ind. Eng. Chem., 32, 34 (1940). VANDERBILT U. S. Patent, 2,139,121; Chem. Abstr., 33, 2149 (1939). TINHAS AND VANDERBILT, DALL, Ind. Eng. Chem., 33, 65 (1941). SPRANG AND DEQERING, J . Am. Chem. Soc., 64, 1063 (1942). BOUVEAULT AND WAHL,Compt. rend., 134, 1226 (1902). SCHMIDT, Ber., 68, 2430 (1925). HAWAND VANDERBILT, U. S. Patent, 2,164,271. SHRINER AND FUSON, “The Systematic Identification of Organic Compounds”, Second Edition, John Wiley and Sons, New York City, 1940. BICKEL AND FRENCH, J . Am. Chem. SOC.,48, 747 (1926). U. S. Patent, 2,157,391 (May 9,1939). VANDERBILT,
