A. POHLAND AND H. R. SULLIVAN
4458
tracted with two 100-ml. portions of methylene chloride, and the combined methylene chloride extracts were washed with two 50-1111. portions of 10% hydrochloric acid. The wash solutions along with the original aqueous solution were made basic with sodium carbonate, then extracted with five 100-ml. portions of methylene chloride. After the combined methylene chloride extracts were dried over anhydrous sodium sulfate, the solvent was removed by distillation. The residue, which contained both pyridine and thiazole, was distilled through a six-inch Vigreux column under reduced pressure. Pyridine was collected at 2-4 mm. in a receiver cooled with Dry Ice while 54 g. (76%) of 4-methyl5-(fl-hydroxyethyl)-thiazole(V) mas collected a t 110-116" (0.7 mm.), n% 1.5470. A pot residue of 7 g. remained. When the reaction was conducted in the same manner as described above except that 68 g. (1.O mole) of sodium formate was used in place of pyridine, the yield of thiazole was 68%. A sample of V was redistilled, and a center cut boiling a t 99-100' (0.20 mm.), n% 1.5477, was analyzed. Anal. Calcd. for CsHgNOS: C, 50.32; H , 6.33; N, 9.78. Found: C, 50.46; H,6.36; N, 9.59. Melting points of the picrate, m.p. 164-164.8', and the p-nitrobenzoate of V, m.p. 124 to 125', agreed with values previously reported in the literature.B Thioformamide.-In a 5-I., three-necked flask equipped with a mechanical stirrer and thermometer were placed 3 1. of tetrahydrofuran and 300 g. (6.67 moles) of technical
[CONTRIBUTION FROM
THE
Vol. it?
formamide. This solution was rapidly stirred while 330 g. (1.49 moles) of phosphorus pentasulfide was added in portions of about 50 g. during a period of one and one-half hours a t 30-35'. During the addition and for a short time thereafter, it was occasionally necessary to cool the flask in an ice-bath in order to maintain this temperature. After the reaction mixture had been stirred a t room temperature for six hours, a sticky solid which gradually formed in the reaction mixture was collected on a filter and discarded. Tetrahydrofuran was stripped from the filtrate under reduced pressure to leave a residue containing thioformamide, formamide and polymer. The residue was shaken with an equal part by weight of ether to dissolve thioformamide, leaving formamide and polymer undissolved. The ether solution was separated and concentrated under reduced pressure to give 201 g. (50%) of thioformamide. The crude thioformamide is of sufficient purity to react satisfactorily with I V but if desired, it can be recrystallized from ethyl acetate at Dry-Ice temperature to give pure thioformamide, m.p. 32.0 to 33.8'.
Acknowledgment.-The authors wish to thank H. B. Copelin and J. S. Showell for their advice and assistance in the early phases of this work. Microanalyses were performed by J. M. Bauer and J. M. Amery. NIACARA FALLS,NEW Yo=
LILLYRESEARCH LABORATORIES]
Analgesics : Esters of 4-Dialkylamin0-1,Z-diphenyl-Z-butanols BY A. POHLAND AND H. R. SULLIVAN RECEIVED APRIL25, 1953 Sixteen amino carbinols of the type C8H5CH2C(CsHs)OHCH(RL)CH(R2)N(R8)~ have been prepared and eight of these separated into their diastereoisomeric forms. The carbinols have been converted t o esters. Pharmacological studies in animals have shown that a number of these esters possess a high order of analgesic activity.
Acyl derivatives of 4-piperidinols1s2have been found to possess significant analgesic properties. These compounds (I) may be considered to be analogs of meperidine in which the ester function
possibly have greater analgesic activity, since the carbinols are devoid of activity. The present work is concerned with the preparation of 4-dialkylamino-l,2-diphenyl-2-butanoIsand their esters 111.
dR'
\/ OH(-OCOR)
R 2 a - C H 2 /
I
I1
'CH( I11
R3)CH(R4)S(R5)2
is reversed. Similar open chain esters (11) have R' 0 been prepared by other investigator^^-^ but I/ according to the published pharmacological results, -C-CH-CH-K( R5)z have failed to show any promising analgesic activity. A 4 In our laboratories compounds of the type II IV have been under investigation as possible analgesic of 3-dialkylamino-1,l-disubstances. Esters The intermediate 8-dialkylaminopropiophenones phenylpropanols were found to exhibit weak and a-alkyl-8-dialkylaminopropiophenones (IV analgesic properties. These esters are unstable in where R 1is H or CH3, RSis H or CHI or CzHa and aqueous solution, being readily hydrolyzed to the R' is H) were prepared by means of the Mannich carbinol.3 It was felt that more stable esters might reaction. The P-dialkylaminobutyrophenones (IV (1) K. A. Jensen, F. Lindquist, E. Rekling and C. G . WolBbrandt, where R1and Ra are H, R4is CHI) were prepared Dansk Tids. Farm., 17, I73 (1943). by addition of the secondary amines to phenyl (2) A. Zieringand J. Lee, J . Org. Chem., l a , 911 (1947). propenyl ketones6 (3) A. C. Kjaer and P. V. Petersen, A d a Chem. S c a d , 6, 1145 These aminoketones were allowed to react with (1951). (4) J. H.Burckhalter and S . H. Johnson, Jr., THISJOUXNAL, 78, benzylmagnesium chloride to yield the carbinols 4827 (1951). (Table I). The ketones containing an asymmetric (5) M. B. Slomka and F. W. Schullrr. .I. Am. Phnrm. Assoc , 41, HI8 (1951). (6) n. Shmpiro, J Or8 C h c n , 14, 8.39 (1949).
''
k3
ANALGESICS : ESTERSOF 4-DIALINLAMINO-1 ,2-DIPHENYL-2-BUTANOLS
Sept. 20, 1953
4459
TABLE I 4-DIALKYLAMINO1,2-DIPHENYL-2-BUTANOLS
a
-CHz
Isomer
RI
/ \
H 156-157 H 232-233 H a 231-232 H 197-199 B H ff 255-256 H 153-154 B H ff 204-205 H ff 188-189 H 202-203 B H a 219-220 H 221 dec. B H CY 224-225 H 180-181 P H ff 219-220 ff 231-232 CH3 ff 199-200 CH3 176-177 CH3 B CY 217-2 18 CH3 212-213 CH3 B a Reference (7)reports base b.p. 138-139' (0.2 mm.). mental. Reference (7)reports b.p. 138-139' (0.1 mm.). e Piperidine. f Pyrrolidine. Morpholine.
Nitrogen Calcd. Found
Ionic chlorine Calcd. Found
11.60 11.42 4.58 4.38 CiaHz3NO.HCl 10.25 10.40 4.05 4.20 C21HnNO.HCl 11.08 11.11 4.38 4.57 CisHz6NO.HCl 11.08 11.39 4.38 4.26 CipHzsNO.HC1 4.20 4.42 10.62 10.72 CzoHnNO*HCl 4.20 4.32 10.62 10.54 C?oHnNO.HCl 4.03 4.08 10.19 10.14 CziHzoNO.HC1 10.25 10.10 4.05 4.13 CzIHnNO*HCl 10.25 10.09 4.05 3.86 CziHp7NO.HCl 3.87 3.81 9.80 9.85 CziHzTN02.HCl 3.87 3.92 9.80 9.84 CziHz?NOz.HCl 9.85 9.71 3.89 4.13 CnHz,NO*HCl 9.85 9.53 3.89 4.03 C22H&O.HCl 9.48 9.32 3.75 3.46 CzaHaiNO.HC1 11.08 11.10 4.38 4.36 CigHzsNO.HC1 10.25 10.50 4.05 3.95 CziHgN0.H C1 10.25 10.09 4.05 4.17 C21HUNO.HCl 3.89 3.91 9.85 9.61 CnHzgNO.HC1 9.85 9.70 3.89 3.73 Cz?HzgNO.HCl Reference (7) reports base m.p. 85". Described in ExperiFree base melts at .96-97'. Reference (6) reports 94-95'.
center yielded predominantly one diastereoisomer. For example, P-dimethylaminoisobutyrophenone yielded 75% of the a-carbinol and only 15% of the @-isomer. Four of the carbinols have been previously rep~rted,~,' but possible diastereoisomers were not isolated. Instead the free bases, isolated by distillation, were dehydrated to the 1,2-disubstituted-4-dialkylamino-2-butenes.' The amino carbinol hydrochlorides were acylated a t steam-bath temperatures using an equal weight of acetic or propionic anhydride and five times the weight of pyridine as a solvent. In cases where acylation could not be effected in this manner, less pyridine was used, and the reaction mixture refluxed at higher temperatures. The carbinols in ether solution were also acetylated by ketene. The higher acyl and benzoyl derivatives were prepared by the reaction of the acid chloride with the carbinols in toluene solution. The physical properties of the esters are summarized in Table 11. Carbinols and their acyl esters with substituted Dhenvls (comDound I11 were R' is CHn or H. R2 is H br Cl) wire prepared. These are summakzed in Table 111. In contrast to the esters of 3-dialkylamino-1,ldiphenylpropanols (I1 where R is C~HI,R1 is alkyl) , these acyl derivatives were quite resistant to hydrolysis. After 45 minutes reflux of a 5% aqueous solution, over 90% of the q4-dimethylamino - 1,2 - diphenyl - 3 - methyl - 2 - propionyloxybutane hydrochloride was recovered unchanged. A 24-hour hydrolysis a t reflux temperature, yielded 36% of unchanged ester along with both the a(7) W. G. Stoll, Ch. J. Morel and Ch. Frey, H d u . Chim. Acla, 88, 1184 (1950).
CH(R1)CH(Ra)Ra Molecular formula
M.P., OC. HCI
.
and the @,Fdimethylamino-1,2-diphenyl-3-methylbutanols. Preliminary pharmacological evaluation, using the rat-tail burn technique, has shown that a number of the esters are worthy of further study. Subcutaneous doses of 10 and 20 mg./kg. of a,4dimethylamino - 1,2 - diphenyl - 3 - methyl - 2propionyloxybutane hydrochloride in rats produced analgesic action similar to that of 1 and 2 mg./kg. of methadone hydrochloride. In anesthetized dogs, 1-2 mg./kg. intravenously or up to 20 mg./kg. subcutaneously caused no respiratory depression. The diastereoisomer, @,4-dimethylamino-l,2diphenyl-3-methyl-2-propionyloxybutane, is devoid of analgesic action. a,l,2-Diphenyl-3-methyl-2propionyloxy-4-pyrrolidinobutane, an analog in which pyrrolidine has replaced dimethylamine, is equally active as an analgesic. However, the acetyl compound, cr,2-acetoxy-l,2-diphenyl-3methyl-4-pyrrolidinobutane, is approximately twice as potent.
Experimental8 Aminoketones.-Many of the aminoketones used in this work have been fully described in the literature.s-l* The free bases of the 8-aminopropiophenonesand 8-aminobutyrophenones are unstable to distillation. For use in the Grignard reactions, the pure hydrochlorides were treated with excess cold dilute alkali and the bases dried in ether solution with magnesium sulfate. The Mannich bases from pro(8) Melting points and boiling points are uncorrected. (9) C. Mannich and 0.Heilner, Bcr., 66, 356 (1922). (IO) J. H.Burckhalter and R. C. Fuson, THIS JOURNAL, 70, 4186 (1948). (11) A. W.Ruddy and J. S. Buckley, Jr., ibid., 74, 718 (1960). (12) J. H. Burckhalter and S. H. Johnaon, Jr., ibid., 78, 4827 (1962).
Vol. i5
A. POHLAND AND H. R. SULLIVAN
'4400
TABLE I1
ESTERS O F 4-DIALKYLAMINO-1,2-DIPHENYL-2-BlJTANOLS C ~
Isomer
a! a!
P P a a!
P P a!
u a!
P a! a!
P P ff
a
P ff ff
a ff
B a ff
RZ
H H H H H H H H H H H H H H H H H H H H H H H H CHI CHI CHI CHx CH3 CHE CH3 Described in Experimental.
R4
X p . , "C.
HCI
Method
CHa 227-228 CzHs 188-189 C3H7 169-170 CBHS 204-205 dec. CH3 157-158 CHa 187-188 CzHs 170-171 CH3 205-206 dec. CzHj 187-188 dec. CHI 156-157 CzHs 169-170 CH3 155-156 CzHs 175-176 CHI 191 CH, 202-203 dec. C2HS 196-197 dec. CzHj 169-170 CHa 195-196 CsHs 190-191 CHI 177-178 CzHs 160-161 CH3 215-216 CzHj 191-192 CHs 190-191 CHI 210-211 CzH6 210-211 CH3 203-204 CzHs 200 GH6 187-188 CH3 225-226 (22% 229-230 dec . Piperidine. Pyrrolidine.
piophenone and butyrophenone were stable t o distillation a t reduced pressures. The new Mannich ketones are described below. ~-Dimethylamino-o-methylisobutyrophenone Hydrochloride.-By the procedure of Maxwell13 95 g. (0.64 mole) of o-methylpropiophenone, 68 g. (0.83 mole) of dimethylamine hydrochloride, 26 g. (0.87 mole) of paraformaldehyde, 100 ml. of ethanol and 1 ml. of concentrated hydrochloric acid yielded 70 g. (46%) of product recrystallized from ethyl acetate-methanol solution, m.p. 134-135'. Anal. Calcd. for C~~HIONO.HCI: N, 5.80; C1, 14.67. Found: N, 5.56; C1, 14.83. p:Pyrrolidinoisobutyrophenone .-A ieaction mixture containing 107.6 g. (1.3 moles) of pyrrolidine hydrochloride, 134 g. (1.0 mole) of propiophenone, 39 g. (1.3 moles) of paraformaldehyde, 200 ml. of ethanol and 2 ml. of concentrated hydrochloric acid was refluxed for 12 hours. The ethanol was removed in vacuo and the residue dissolved in water. The aqueous solution was washed with ether and then made basic by the addition of excess concentrated ammonium hydroxide. The oil was taken up in ether, dried over magnesium sulfate, and distilled. The product boiled a t 117118' (0.30 mm.); +D 1.5302,94 g. (44%). p-Dimethylaminobutyrophenone Hydrochloride.-This compound has been prepared in crude form by Shapiro.6 The ptocedure has been modified t o give good yields of the Dure product. A solution containing 6.8 g. (0.15 mole) of dimethylamine in 50 ml. of toluene Was stirred and, Faded
Molecular formula
B B D" D C B Aa B. Be B B B B C" A A A A
A A A C A C B B A A A
B A
Nitrogen Calcd. Found
Ionic chlorine Found Calcd.
4.03 3.87 3.73 3.42 3.61 3.87 3.73 3.87 3.73 3.73 3.59 3.73 3.59 3.59 3.61 3.49 3.49 3.47 3.35 3.47 3.35 3.49 3.37 3.49 3.87 3.73 3.61 3.49 3.49 3.49 3.37
10.19 9.80 9.43 8.67 9.14 9.80 9.43 9.80 9.43 9:43 9.09 9.43 9.09 9.09 9.14 8.82 8.82 8.78 8.48 8.78 8.48 8.82 8.52 8.82 9.80 9.43 9.14 8.82 8.82 8.82 8.52
3.82 3.95 3.44 3.15 3.66 3.59 3.63 3.89 3.73 3.66 3.75 3.54 3.30 3.83 3.57 3.74 3.41 3.44 3.50 3.41 3.35 3.56 3.29 3.66 3.67 3.66 3.72 3.54 3.78 3.50 3.32
10.34 9.78 9.46 8.56 9.25 9.71 9.54 9.74 9.61 9.58 9.19 9.23 9.02 9.01 9.06 8.77 8.87 8.70 8.63 8.70 8.18 8.66 8.74 8.64 10.02 9.18 8.85 8.83 9.05 8.94 8.29
Morpholine. t o 10' during the dropwise addition of 14.6 g. (0.10 mole) of phenyl propenyl ketone. The reaction was allowed t o stand overnight at room temperature and was then extracted with cold dilute hydrochloric acid. The acid aqueous layer was made basic with dilute ammonium hydroxide. The resulting oil was dried in ether solution over magnesium sulfate. The hydrochloride was prepared in ether using anhydrous hydrogen chloride and recrystallized from methanol-ethyl acetate solution, m.p. 134-135" dec.; 15 g. (66%). Anal. Calcd. for C1zH1,NO.HC1: N, 6.15; C1, 15.57. Found: N, 6.16; C1, 15.77. 8-Piperidinobutyrophenone Hydrochloride .-Following the procedure for the dimethylamino compound, 58.4 g. (0.4 mole) of phenyl propenyl ketone and 51.2 g. (0.60 mole) of piperidine in 150 ml. of toluene yielded 87 g . (81%) of the product which melted a t 157-158". AmZ. Calcd. for ClsHz1NO.HCl: N , 5.03; C1, 13.24. Found: N, 5.09; C1,13.20. 8-Pyrrolidinobutyrophenone Hydrochloride .-Following the procedure for the dimethylamino compound, 58.4 g. (0.4 mole) of phenyl propenyl ketone and 43 g. (0.6 mole) of pyrrolidine in 150 ml. of toluene yielded 40 g. (39%) of the product which melted a t 120'. Anal. Calcd. for C14HiSNO.HCl: N , 5.52; C1, 13.97, Found: N, 5.70; C1, 14.00. Preparation of a- and j3,CDimethylamino-1 ,Z-diphenylJmstbyL?=-k~at,trcnol Hydtecalarides,-BenzrVlmaOnocium chldh
Sept. 20, 19.53
AANAI,GESICS:
ESTERS OF 4-DIALKYLAMINO-1
,2-DIPHENYId-2-BUTANOLS
446 1
TABLE I11 4-DIMETHYLAMINO-1,2-DIARYL-2-BUTANOLS AND
ESTERS
R'
R 2 a - C H 2 Isomer
R'
CY
CHI CHs CH, CH, CH3 H H
CY
c u H
C P B
Y
H
R=
Ra
R4
H H H H H CI
H CHsCO C2HjCO
c1
H H H CH, CHs H H
c1
CH3
H
c1
CHI
CH:jCO
H CH3CO H CHaCO
C2HjCO H C2HjCO
H H
/ \
CH-R3)CH2N( C H B ) ~
M.P., "C. HC1 Method
169-170 228-229 197-198 234-235 180-181 163-165 215-216 dec. 231-232 dec. 205-206 dec. 208-209 dec. 221-222 190-192
B
Molecular formula
CisH24ClNO.HCl C22H2sClN02.HCl
Nitrogen Calcd. Found
Ionic chlorine Calcd. Found
4.38 3.87 3.73 4.20 3.73 4.12 3.66
4.42 3.84 3.67 4.36 3.48 4.06 3.40
11.08 9.80 9.43 10.62 9.43 10.42 9.27
11.14 10.09 9.31 10.75 9.33 10.42 9.34
3.95
3.93
10.01
10.03
3.54
3.52
8.95
8.76
3.41
3.22
8.64
8.45
3.95 3.41
3.79 3.31
10.01 8.64
10.01 8.97
ride was prepared from 127 g. ( I mole) of benzyl chloride, mole) of a,4-diethylamino-l,2diphenyl-3-methyl-2-butanol 30.8 g. (1.25 moles) of magnesium and 1400 ml. of ether. in 50 ml. of ether was allowed t o react with excess ketene.14 The Grignard solution was stirred a t room temperature The hydrochloride was prepared from the ether solution during the dropwise addition of 95.5 g. (0.5mole) of p-di- and anhydrous hzdrogen chloride and recrystallized from methylaminoisobutyrophenone. The reaction mixture was acetone, m.p. 191 ; 4.0 g. (60%). stirred and refluxed for one hour and then decomposed with Anal. Calcd. for C23H31N0z.HCl: X, 3.59; C1, 9.09. 190 ml. of saturated ammonium chloride solution. The Found: N, 3.83;C1,9.01. ether was decanted from the granular solid and dried over Method D for 2-Butyryloxy-4-dimethylamino-1,2-diphenmagnesium sulfate. The hydrochloride was prepared in Hydrochloride .-A reaction mixture containing ether solution using anhydrous hydrogen chloride. After ylbutane two recrystallizations from m:thanol-ethyl acetate (4:1), 5 g. (0.019 mole) of 1,2-diphenyl4-dimethyIaminobutanol, 5 ml. of butyryl chloride and 75 ml. of toluene was warmed the a-isomer melted a t 231-232 ; 120 g. (75%). one hour on a steam-bath. The product was collected on a The mother liquor was concentrated on a steam-bath to a ter and recrystallized from methanol-ethyl acetate soluremove the methanol and ether was added to incipient crystallization. The crude p-isomer separated on cooling, m.p. tion, m.p. 169-170'; 5.75 g. (82%). Anal. Calcd. for C22H2oN02.HCl: N, 3.73; C1, 9.43. 193-194" ; 35 g. The p-isomer was recrystallized twice from Found: N, 3.44; C1,9.46. methanol-ethyl acetate-ether solution, m.p. 197-199'; Hydrolysis of CY ,4-Dimethylamino-l,2-diphenyl-3-methyl25 g. (15%). Reparation of the Esters: Method A for a,4-Dimethyl- 2-propionyloxybutane Hydrochloride .-A solution of 10 g. amino-l,2-diphenyl-3-methyl-2-propionyloxybutane Hydro- of a4-dimethylamino-l,2-diphenyl-3-methyl-2-propionylchloride .-A reaction mixture containing 50 g. (0.156mole) oxybutane hydrochloride in 200 cc. of water was refluxed of a,4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol hy- for 45 minutes and then concentrated in vacuo to dryness. drochloride, 50 g. of propionic anhydride and 50 ml. of pyr- The residue was recrystallized from methanol-ethyl acetate idine was heated a t reflux for five hours. The reaction solution, m.p. and mixed m.p. 167.5170' with starting temperature rose to 140' during this time. The reaction material, wt. 9.50 g. mixture was cooled t o 50' and ether was added to incipient Another run, with the addition of one drop of concencrude product separated on further cooling, trated hydrochloric acid, was refluxed for 24 hours and then turbidity. m.p. 161-166 ; 57 g. After two recrystallizations from concentrated in vacuo to dryness. The residue mas fracmethanol-ethyl acetate solution the product melted a t 170- tionally crystallized from methanol and methanol-ethyl 171'; 41 g. (70%). acetateether t o yield 2.75 g. of starting ester hydrochloride Anal. Calcd. for C22H29N02.HC1:N , 3.73; C1, 9.43. melting a t 166-168°, 2.22 g. of ~~,4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol hydrochloride melting a t 231Found: N, 3.63; C1, 9.54. 232', and 1-10 g. of /3,4-dimethylamino-l,2-dipheny1-3Method B for ~,4-Dimethylamino-l,2-diphenyl-3-methyl2-propionyloxybutane Hydrochloride .-A reaction mixture methyl-2-butanol hydrochloride melting a t 196-198'. containing 2 g. of p,4-dimethylamino-l,2-diphenyl-3- Acknowledgment.-The authors are indebted to methyl-2-butanol hydrochloride, 2 ml. of propionic anhy- Mr. E. B. Robbins for the preliminary pharmadride and 10 ml. of pyridine was warmed on a steam-bath for two hours. Ether was added t o incipient turbidity. cological results and to Messrs. W. L. Brown, The crude product was recrystallized from acetone-ether H. L. Hunter and W. S. Schenck for the microsolution, m.p. 187-188' dec.; 1.50 g. analyses. Anal. Calcd. for C2zH29N02.HC1:N, 3.73; C1, 9.43. INDIANAPOLIS,INDIANA Found: N, 3.73; C1. 9.61. Method C for (2 ,2-Acetoxy-4-diethylamino-1,2-diphenyl-3- (14) R. Adams, "Organic Reactions," Vol. 111, John Wiley and methylbutane Hydrochloride.-A solution of 5.36 g. (0.017 Sons, Inc., New York, N. Y.,1946, p. 132.
TF
