[CONTRIBUTION FROM T E E
DYSON P E R R I N S LABORATORY OF OXFORD
UNIVERSITY]
THE SYNTHESIS OF SOME NEW PHENYLURETHANS AS POTENTIAL LOCAL ANESTHETICS KENNETH HU"ON1 Received March 1, 1966
Phenylurethans of the type (A) seem, in general, to be more active as local anesthetics than the corresponding p-amino-benzoates (B).
a
NHC o o ( C H ),NR~ ~
* H t S o C O O (CH1)nNRZ
A
B
A number of them have been prepared by Rider, Cook, Shriner and others (1-3) and found to be of about the same toxicity. In spite of the large numbers of substituted benzoic esters of aminoalcohols which have been prepared, only four papers appear to have been published on the effect of introducing substituents into the phenyl group of the analogous urethans. Fromherz (4)stated that the introduction of a carbethoxy or ethoxy group in the p-position decreased the activity while leaving the toxicity unchanged; Donleavy and English ( 5 ) found that m-ethylthio- and m-butylthiophenylcarbamates, and Scott and Rider (6) found that the a-naphthyl- and p tolyl compounds were more active, toxic and irritating than the corresponding phenylcarbamates. Finally Horne, Cox and Shriner (3) prepared four p-aminophenylurethans of activity greater than cocaine, one of which was less toxic than novocaine, but which were all somewhat irritating. It was decided therefore to prepare a group of p-aminophenylurethans as these appeared to have promising properties; and also to investigate the effect of one or more methoxy groups in different positions, as they appear to improve the properties of the corresponding aminobenzoates; and one veratrylcarbamate prepared as a test had a promising preliminary pharmacological report. Two methods were used in the preparation of the urethans: (a) decomposition of the azide in an inert solvent, followed by reaction with aminoalcohol. (b) direct interaction of the azide and the hydrochloride of the aminoalcohol. EXPERIMENTAL PREPARATION OF AMINOALCOHOLS
2-Diethylaminoethanol (I) was obtained from the British Drug House, Ltd., and redistilled immediately before use, b.p. 60°/15 mm. 3-Diethylaminopropanol(IX)was prepared by the method described in Organic Syntheses (14, 28) for diethylaminoethanol, b.p. 79-81°/18 mm. 3-Diethylamino-1-methylpropanol,(11) b.p. 56-57"/5 mm., and 3-Diethylamino-l,2-dimethylpropanol,(111) b.p. 97-100"/38 mm. were kindly provided by Dr. E . Hoggarth of the Dyson Perrins Laboratory, Oxford. 2-Piperidinoethanol (V) Piperidine (8.5 g., 0.1 mole, redistilled, b.p. 105O), ethylene ohlorhydrin (8.05 g., 0.1 mole, redistilled, b.p. 127") and triethanolamine (45 g., 0.3 mole) 1
Preaent address: Hatfield School, Roe Green, Hatfield, Herts., England. 855
856
KENNETH HUTTON
VOL. 20
were well shaken together in a Claisen flask, the side arm of which had been stopped up, and were heated in an oil-bath until the reaction began (oil-bath a t 130'). The vigorous exothermic reaction raised the internal temperature to 150'. The reaction then was completed by standing the flask on the steam-bath for 1 hour, and the product was fractionated carefully; the portion boiling a t 75-110'/15 mm. was collected (7.5 g.) and then redistilled at 87'/15 mm. (100'/40 mm.). Yield: 7.1 g., 55%. Blicke and Marvel1 (7) obtained an 85% yield of the aminoalcohol (based on the amount of chlorhydrin) using a two-fold excess of amine. Previous workers did not state what yield was obtained, and a repetition of Ladenburg's method (8) gave only poor yields. S-Piperidinopropanol (VI) was prepared in 51% yield by the method of Brill and Leffler (9); no yield stated, b.p. 115'/25 mm. 8-Morpholinoethanol (IV) was prepared in 61% yield by a modification of the method described in Organic Syntheses (10) for diethylaminoethanol. The temperature used was 120-145" and the product was isolated by continuous extraction with ether; b.p. 115'/20 mm. 3-Morpholinopropanol (VII) was prepared similarly, b.p. 118'/15 mm. The yield was low owing t o inefficient extraction of the product. 1,S-Dimorpholinopropanol-8(VIII) . Morpholine (17.4 g., 0.2 mole) and epichlorhydrin (9.25 g., 0.1 mole, b.p. 117') were heated together in an oil-bath until a violent reaction set in (oil-bath at 130'). When this had subsided, the mixture was heated t o 200' (slight bubbling) for one hour. On treatment with sodium hydroxide solution (30 g. in 60 cc. of water) and extraction with ether, a considerable amount of tar separated. After drying the extract over solid sodium hydroxide and evaporating the ether, 10 g. of a very viscous colorless oil, b.p. 215-220°/43 mm. was obtained. The dimorpholinopropanol was distilled at 183'/14 mm. and at 197-200"/24 mm., practically without loss. Yield, 40%. When the same quantities of the reactants were employed in the presence of dry potassium carbonate (35 g., 4 moles) and the mixture was refluxed for seven hours in an anhydrous solvent, the yields were 55% when ethyl alcohol was used, and 40% when benzene was used. The following derivatives of this new aminoalcohol were prepared (see Tables) :veratrylcarbamate dihydrochloride, p-nitrophenylcarbamate dihydrochloride, and the free base. PREPABATION OF AZIDES
p-Anisic azide. See Hutton (18). m-Anisic azide. ( a ) m-Anisic hydrazide. Methyl m-anisate (57 g., b.p. 131"/20 mm.) was boiled under reflux with 100% hydrazine hydrate (25 g., 30% excess) for 2 hours in a flask fitted with a ground-glass water condenser. The mass solidified on cooling and was collected and washed with ether; yield (crude), 39 g. of m-anisic hydrazide. It is very soluble in water, methyl alcohol, ethyl alcohol, benzene, chloroform, and ethyl acetate on heating; on attempted recrystallization from any of the above solvents, i t separated as an oil which solidified on standing. I n ether it was almost insoluble. On extraction with light petroleum in a Soxhlet, white silky crystals, m.p. 73' were eventually obtained, but even after 2 days only 1 g. had been extracted. It then was found that although it dissolves in boiling benzene t o the extent of 100 @;./lo0cc. of solvent, yet the solubility in cold benzene is only about 0.3%, and i t can therefore be crystallized with practically no loss by dissolving the crude product in 300 cc. benzene, filtering, and scratching t o form a nucleus. Yield: 55 g. (97%) of fine white silky needles, m.p. 90". It also crystallizes from fairly dilute aqueous solutions on prolonged cooling in the form of long colorless crystals. Anal. Calc'd for C ~ H I O N ~N, O 16.8. ~ : Found: N, 16.7. ( b ) m-Anisic azide. m-Anisic hydrazide (16.6 g.) was dissolved in warm 2 N nitric acid (100 cc. = 100% excess), cooled rapidly in a freezing-mixture t o obtain fine crystals, covered with a layer of alcohol-free ether (100 cc.) and stirred during the addition of a cooled 40% solution of sodium nitrite (19 cc. = 20% excess). When the reaction was completed (after about half an hour) the liquid was quite clear. The ethereal layer was separated, washed with sodium carbonate solution until free from acid, washed with water, dried over calcium chloride and the ether was evaporated a t room temperature t o give the azide as large
JULY
1955
SYNTHESIS O F NEW PHENYLURETHANS
857
yellow rhombs which melted below 30". If the hydrazide was not quite pure, the ether not quite free from alcohol, or the ethereal solution not washed quite free from acid, then the azide could not be obtained as a solid; and if this was so, then the diethylaminoethyl urethan hydrochloride prepared from i t could not be obtained crystalline either. Naegeli, Tyabji, and Conrad (11) prepared the azide by the action of sodium azide on the acid chloride and gave m.p. 22.5" but no yield. On the first occasion on which this preparation was attempted, acetic acid was used t o dissolve the hydrazide, and no ether was added. An oily solid (ca. 7 9.) was precipitated, which was washed with ether (the ethereal solution on evaporating gave the azide) and crystallized from ethyl alcohol (ca. 1% solution) to give white needles, m.p. 195.5-196.5". Yield: 1.3 g. from 16.6 g. of hydrazide. Two further crystallizations from the same solvent gave m.p. 198". It was practically insoluble in water, and on heating with solid sodium hydroxide gave a faint smell of hydrazine. Anal. Calc'd for C1sHlsNzOl (di-m-anisoyl hydrazine), C, 64.0; H, 5.3; N, 9.4. Found: C , 63.6; H, 5.3; N, 9.4. o-Anisic azide. o-Anisic hydrazide was prepared according t o the method of Kalb and Gross (12). The hydrazide (6.6 g.) was dissolved in 2 N hydrochloric acid (40 cc. = 100% excess), cooled t o 0", and treated with 40% sodium nitrite solution (9 cc. = 10% excess). A red oil separated, and was taken up in ether (20 cc.), washed with water and dried over sodium sulfate. It appeared t o be decomposing in solution even a t room temperature because bubbles of gas were evolved continuously. Stoermer (13) said: "One of my pupils found that on heating the azide in benzene, the oily isocyanate is formed", but gave details neither of the preparation nor of the properties of the azide. Since p-anisic azide has m.p. 68", and m-anisic azide m.p. 22.5", o-anisic azide might well be expected to be an oil a t room temperature. (0-Nitrobenzazide also has a much lower m.p. than the m- or p compounds.) Piperonylic azide. ( a ) Piperonylic hydrazide. Methyl piperonylate (23 g.) b.p. 155'/20 mm. undecomposed) was heated with 100% hydrazine hydrate (9 g. = 50% excess) in a flask fitted with a ground-glass reflux condenser. At the end of half an hour the contents set solid and were collected. Yield: 22 g. of crude piperonylic hydrazide, m.p. 166". It was recrystallized from boiling ethyl alcohol (solubility 3.5 g./100 cc. of solvent) as white rhombic crystals, m.p. 173-174', from boiling water (solubility 4.5%) as white needles, m.p. 175-176", and from methyl alcohol (solubility 4%), m.p. 175-176". Anal. Calc'd for C9H8N203:N, 15.6. Found: N, 15.9. ( b ) Piperonylic azide. Piperonylic hydrazide (6.1 g.) was dissolved in warm glacial acetic acid (20 cc.), cooled t o O", and treated drop by drop with 40% sodium nitrite solution (6 cc.). When the addition was complete, piperonylic azide separated as a white flocculent precipit,ate which was collected, washed well with water, and dried t o constant weight in a vacuum desiccator. Yield, 5.6 g., m.p. 78" (87%). It turned yellow on standing even in a vacuum desiccator. Anal. Calc'd for CaHJ?sOs: N, 22.0. Found: N, 21.5. (c) Dipiperonyl urea. I n the preparation of morpholinoethyl piperonyl carbamate, part of the product was insoluble in ether. After repeated washings with ether the insoluble portion had m.p. 279-280", and was identified as dipiperonylurea. Anal. Calc'd for ClsHt2N2Ol: N, 9.3. Found: N, 9.3. Veratric azide. Veratric hydrazide [40 g., prepared in 85% yield by the method of Brunner and Wohrl (14)] was dissolved in glacial acetic acid (200 cc.), cooled in ice, and treated drop by drop with a 40% aqueous solution of sodium nitrite (35 cc.). Towards the end of the reaction, oeratric azide was precipitated in clouds, and the precipitation was completed by the addition of more water. It was collected, washed well with water, and dried in a vacuum desiccator. Yield: 38 g. (go%), m.p. 72.5-73.5'. It is very easily soluble in benzene in the cold (more than 20%), and decomposes completely on heating therein for 2 hours. A small portion was recrystallized for analysis from carbon tetrachloride (50% solution), m.p. 74". Anal. Calc'd for C ~ H ~ N ~N, O I20.3. : Found: N, 20.4.
858
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KENNETH HUTTON
Trimethylgallie azide. This was obtained in 78% of the theoretical yield from the hydrabut was not recrystallized from ethanol as sugzide by the method of Pepe (15), m.p. &io, gested, because of its great solubility in that solvent. I-Furoic azide. This was obtained in 67% of the theoretical yield from the hydrazide by the method of Curtis and Leimbach (16). p-Nitrobenzazide. The azide was prepared by diazotizing a suspension of the hydrazide in dilute nitric acid. Curtius, Struve, and Radenhausen (17) said a 'solution' in nitric acid, but in fact the azide is only sparingly soluble therein. It is necessary t o recrystallize the azide from methyl alcohol (solubility ca. 30 g./lOO cc. of alcohol at 60°), in order t o remove a small amount of hydrazide which contaminates the precipitated azide. Yield: 78%. PREPARATION O F URETHANB
A . Decomposition of the azide followed b y reaction with an aminoalcohol. The method used was the same in each case, and the amounts of substances reacting, the yield, properties, and analyses of the products, together with any comments, are tabulated in Table I. TABLE I URETHANHYDROCBLORIDES FROM AZIDESAND AMINOALCOHOLS X-NH-CO-O-
-
Analysis Azidea X
41coholb
R
iield,e %
M.P., 'C.
*4 B C D D E E E E E E E E E F G H
Found
Calc'd .___
A A
Empirical Formula
I I1 I11 I I I IV I I I1 I11 V VI IV VI1 VI11 I I I
H H
IX I1
H H
I11
H
IV
H
VI11
v
6V 6@
161 156-157
N
c1
N
CI
9.33 58.0c
8.ld
9.39 58.2O
8. Id
9.3
11.7
9.4
12.0
9.0 8.5 54. lc
11.4 10.9 7.4d
7.7
9.7 10.0
h
33
122
i
w 65 811 16". 62p
189-190 207.6208.5 165.5 204.6205.5
11.2 8.9 8.5 10.7 54. lc 7.5d 7.7
9.8
9
61r 908
62 60" 15" 10"
170.5-171.5 136-137 210.5-211.5 185 217-218 153
8 . 1 10.3 56.6" 7.6d 10.2 8.1 7.8 9.7 14.8 8.7 52.gC 7.4d
8.1 56.5" 8.3 7.9 8.7 52.@
10.1 9.9 15.2 7.3d
211.5
13.2
11.2
13.0
11.2
212-213 204
12.6 12.2
10.7 10.3
12.6 12.2
10.6 10.5
206.5 234 d. 241dd 243
11.7
9.8 10.8
11.6
9.4 11.0
12.6
10.7
12.5
10.6
8.0d
2.
35u 650 12z 42aa 20" 226b 50°C
60e6 750 50ff
240.5 d.
15.2
15.4
a Abbreviations for the azides are as follows: A , p-anisic; B, m-anisic; C, o-anisic; D, piperonylic; E, veratric; F, trimethylgallic; G, 2-furoic; H, p-nitrobenzoic. Abbreviations
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1955
SYNTHESIS OF NEW PHENYLURETHANS
859
TABLE I-Continued for the amino alcohols are as follows: I, 2-diethylaminoethanol; 11, 3-diethylamino-lmethylpropanol; 111,3-diethylamino-l,2-dimethylpropanol;IV, 2-morpholinoethanol; V, 2-Piperidinoethanol; VI, 3-piperidinopropanol; VII, 3-morpholinopropanol; VIII, 1,3dimorpholinopropanol-2; IX, 3-diethylaminopropanol. Value for carbon. d Value for hydrogen. e In the following footnotes, the crystalline form (from alcohol) and the solubility (%) in boiling absolute alcohol are given for each compound. f Large, colorless, Anal. Calc'd : rectangular plates; 15%. See previous paper; picrate, m.p. 131", C2~H~IzsNaOlo. N , 14.3; Found: N, 14.0.0 White needles, 18%. Non-crystalline, white, sticky oil. White needles, 50%. 2 Non-crystalline red oil, deposited very few, exceedingly hygroscopic needles on standing. Free urethan very insoluble in ether. k White needles, 10%. White needles, 1.5%. 111 White needles, 20%. n Identical with that obtained from the amino alcohol hydrochloride; different from the corresponding ester hydrochloride, m.p. 155"; mixture m.p. 147.5'. From the hydroch1oride.p White needles, 10%. q Noncrystalline, white, sticky, deliquescent solid; liquified immediately after precipitation. White needles, 14%; somewhat hygroscopic when impure. 8 Large, transparent, rhombic plates, 30%; somewhat hygroscopic. t Small, rod-shaped crystals. 3%. Small, rhombic plates, 15%; difficult t o obtain pure from alcohol. Finally obtained as stellate clusters of needles from somewhat moist dioxane. v Microcrystalline powder; exceedingly hygroscopic, hence low yield. Crystallized from absolute methanol by addition of ether. Rosettes of white needles, 20%. Exceedingly hygroscopic when precipitated, but not after purification from absolute alcohol. Non-crystalline, red, sticky oil. The isocyanate, formed on heating the azide, has a very pungent smell. y Pale yellow, transparent rhombs from 90% aqueous alcohol, 1% [Horne, Cox, and Shriner (3) from the isocyanate, a less convenient method]. Conglomerates of prisms, 3y0; precipitated as a liquid which later solidified. Large, pale yellow, transparent hexagonal prisms, 7%. bb Pale yellow rosettes of needles, 10%; very hygroscopic when impure. cc Microscopic, pale yellow needles, 0.5%; very flat solubility curves for all solvents, hence difficult t o purify. dd In uacuo. 8 8 Star-shaped clusters of pale yellow needles from 90% aqueous alcohol, 1%. Free urethan, m.p. 106".ff Yellow plates (parallelograms of 35" angle), very sparingly soluble in alcohol. Solubility in hot water, 40 @;./IO0cc. The free urethan, m.p. 155156". Anal. Calc'd for ClaH~sNdOs:C , 54.8; H, 6.6; N , 14.2. Found: C, 54.9; H, 6.9; N , 13.8. It was soluble t o 16% in hot alcohol, 7% in hot ether. 0
2
The dry azide (1/30 mole), and pure xylene (125 cc.) which had been distilled over sodium, were placed in a 250 cc. quickfit round-bottomed flask with a reflux condenser and calcium chloride tube and heated in an oil-bath until bubbles of gas appeared (oil-bath a t about 110"). The temperature then was kept constant until evolution of gas had ceased, when the temperature was raised t o the boiling point for a few minutes in order to ensure the completion of the decomposition. The mixture was allowed t o cool, the theoretical amount-or, in some cases, an excess of up to 50%-of the appropriate aminoalcohol was added, and the whole waa warmed t o 50" for one hour. The condenser then was reversed, and the xylene and any excess aminoalcohol were removed under reduced pressure by heating on the steam-bath for one hour. The residue in the flask was dissolved, after cooling, in very carefully purified dry ether (200 cc.) filtered from any insoluble solid-the disubstituted urea-and added slowly to an equal quantity of pure dry ether saturated with dry hydrogen chloride at 0".A precipitate, bulky and somewhat sticky, was obtained {yellow in the case of the nitro-derivatives; in other caaes more or less white) and the ether was decanted at once. The urethan hydrochloride then was recrystallized from absolute alcohol, or, if necessary, from other solvents. B . Reaction of an azide directly with an aminoalcohol hydrochloride. Pure xylene (50 cc., distilled over sodium) waa saturated with dry hydrogen chloride a t 0" in a flask fitted with an inlet tube and reflux condenser and protected from the atmosphere by calcium chloride tubes, and treated with equivalent amounts of the azide and diethylaminoethanol (1/30 mole) dissolved in xylene (50 cc.). A messy white precipitate of the hydrochloride was
860
VOL. 20
KENNETH HUTTON
TABLE I1
1
Alcohola
I IX I1 I11 V IV VI11
yieldla (Once% recrystallized)
6OC
M.P., o c . (pure)
j
Analyses Formula
I
Calc'd
N
I
Found C1
1
N
1
C1
2 12-21 4
CiaH2zClzNs02
13.0
21.8
13.4 21.6
241.5 238-24Oj 236.5 d . 243 d. 230
CiaHz~ClzN30z ClsH2eC12N302 C14H23C12N30~ Ci3H2IClzNa02
11.9 11.5 12.5 12.4
20.1 19.4 21.2 20.9
11.4 11.6 12.5 12.2
d
40* 75f 820
55h 50'
19.7 19.1 20.8 20.3
formed. The mixture was allowed to stand for two hours, and then was heated on the steambath for half an hour during which time slight bubbling occurred; i t then was heated in an oil-bath a t 150" for two hours when further slight bubbling took place. It was cooled, and the solid product was collected by filtration, dried on the steam-bath, and recrystallized. The products thus obtained were identical with those prepared by the previous method. They are indicated by an asterisk in Table I. Hydrogenation of nitrourethans to aminourethans (Table 11).The appropriate p-nitrophenyl urethan hydrochloride (ca. 5 g.) was dissolved in the minimum amount of water a t 50", (100 cc. or more), filtered from any insoluble matter (if a crude specimen was used), cooled in ice, sodium carbonate was added (1.2 g. = 100% excess), and the mixture was extracted with ether (100 cc. or more) until the aqueous solution was colorless. The ether was evaporated, and the product (which was sometimes crystalline) was taken up in ethyl alcohol and hydrogenated a t room temperature a t about 2.5 atmosphere over Raney Nickel. Absorption of hydrogen was usually completed after 2% hours, but was in some cases incomplete (ca. 60% of theory) probably owing t o incomplete extraction of the urethan. The catalyst was removed by repeated filtration, the solution was evaporated to dryness and taken up in pure dry ether, dried if necessary over potassium carbonate, cooled and added t o pure ether saturated with dry hydrogen chloride at 0". The precipitated di- (or tri-) hydrochloride was often very hygroscopic, and the best procedure was found in such cases t o be t o evaporate off the ether and excess hydrogen chloride.
Acknowledgments. The author wishes to thank the Department of Scientific and Industrial Research for a grant, Magdalen College, Oxford for a Senior Demyship, Mr. F. Hall and Dr. Weiler for analyses, Messrs. J. Raventos and
JULY
1955
SYNTHESIS OF NEW PHENYLURETHANS
861
J. Dee of I.C.I. (Dyestuffs Division) for some pharmacological tests, and Professor Sir Robert Robinson for helpful advice and encouragement. SUMMARY
Twenty-one new urethan hydrochlorides have been prepared which are likely to be active as local anesthetics. They are principally veratryl- and p-aminophenyl carbamates derived from a number of diff went aminoalcohols, including diethylaminoethanol, piperidinoethanol, and morpholinoethanol. They were prepared either by decomposing the corresponding azide in an inert solvent and then reacting the product with the aminoalcohol, or by direct interaction of the azide and the aminoalcohol hydrochloride. Such pharmacological results as have been received show that some compounds are fairly active without being very toxic. OXFORD, ENGLAND LIST OF REFERENCES (1) RIDER,J . Am. Chem. Soc., 62, 2583 (1930). (2) COOKAND HILL,J . Am. Chem. SOC.,62, 1995 (1940). (3) HORNE,Cox, AND SHRINER, J . Am. Chem. SOC.,66,3435 (1933). (4) FROMHERZ, Naunyn-Schmiedeberg’s Arch. exptl. Pathol. Pharmakol., 76, 257 (1914). (5) DONLEAVY AND ENGLISH, J . Am. Chem. SOC.,62, 2966 (1940). (6) SCOTT AND RIDER,J . Am. Chem. SOC., 66, 804 (1933). (7) BLICKEAND MARVELL, J . Am. Chem. SOC.,64, 429 (1942). (8) LADENBURG, Ber., 14, 1877 (1881). (9) BRILLAND LEFFLER, J . Am. Chem. SOC.,66, 365 (1933). (10) Organic Syntheses, 14, 28 (1934). (11) NAEGELI, TYABJI,AND CONRAD, Helv. Chim. Acta, 21, 1139 (1938). (12) KALBAND GROSS,Ber., 69, 727 (1926). (13) STAERMER, Ber., 42, 3133 (1909). (14) BRUNNER AND WBHRL, Monatsh., 63, 374 (1934). (15) PEPE,J . prakt. Chem., 126, 241 (1930). (16) CURTIUS AND LEIMBACH, J . prakt. Chem., 66, 24 (1902). (17) CURTIUS,STRUVE,AND RADENHAUSEN, J . prakt. Chem., 62, 232 (1895). (18) HVTTON, J . Org. Chem., 20, 808 (1955).
