4162
KERWIN, HALL,MILNES,WITT, MCLEAN,MACKO, FELLOWS AND [CONTRIBUTION FROM
THE
ULLYOT
Vol. 73
RESEARCH DIVISION, SMITH, KLINEAND FRENCH LABORATORIES]
Adrenergic Blocking Agents. 111. N- (Aryloxyisopropyl)-p-haloethylamines' BY JAMES F. KERWIN,GRISELLA C. HALL, FRANKJ. MILNES,IVAN H. WITT,~RICHARD A. MCLEAN, AND GLENNE. ULLYOT EDWARD MACKO, EDWINJ. FELLOWS A series of thirty-three N-(R)-N-(fl-phenoxyisopropyl)-@-haloethylamines, the intermediates for their preparation and methods of synthesis are described. Preliminary pharmacological data indicate that these 8-haloethylamines are potent adrenergic blocking agents following intravenous administration and that some are effective orally. Structural and chemical factors which may influence blocking ability are discussed. CICH2CH (OH)CHI During the investigation of the adrenergic block> ing action of N,N-disubstituted-/?-haloethylamines, ArON'i I one of our major objectives has been the developSOClZ ment of an orally active agent since such a coniArOCHzCH(0H)CH~--+ pound would be of major importance as a potentiI1 ally useful therapeutic substance. It was felt HzNCHzCH20H that structural modifications of intravenously acArOCHzCH(C1)CH, --f tive compounds might lead to increased oral efI11 ficacy. RX In the sympathomimetic amine series, the introArOCH2CH(CHa)NHCHzCHzOH + duction of an a-methyl group to convert phenethylIV amine into phenylisopropylamine results in an orsox2 ArOCHzCH(CH8)NRCHzCHIOH --+ ally active d r ~ g . ~This , ~ result appears to be assov ciated with the ability of the @-methylgroup to protect the amine from attack by amine oxidasea6 ArOCHzCH(CH3)NRCHzCHzX.HX Although the modes of action of the @-haloamines VI and the sympathomimetic amines are probably Addition of propylene chlorohydrin to the sodium quite differents?' the introduction of an a-methyl phenates in refluxing alcohol gave satisfactory yields group to convert N-benzyl-N-phenylethyl-P-chlo-of the ether alcohols (11) which were converted to roethylamine into the corresponding N-(@-phenyl- the chloro compounds by the method of Liberisopropyl)-@-chloroethylcompound markedly en- manng or by Darzens' procedure.'O Alkylation of hances intravenous activity. 3b We have extended 2-lxnzylaminoethanol with 1-phenoxy-2-chloroproour study of the effect of the a-methyl modification pane without a solvent at 160' formed the desired to N-(phenoxyethyl) -@-haloethylamines since a tertiary amine (V, Ar = phenyl, R = benzyl) in number of these have been reporteds to be active poor yield. Better results were obtained according adrenergic blocking agents when administered in- to the scheme shown above in which ethanolamine travenously to animals. was first monoalkylated and the group R was then We have found that N-(/?-phenoxyisopropy1)-@- introduced by reaction of IV with benzyl or substihaloethylamines are also active after intravenous tuted benzyl halides, @-phenoxyethylbromide, allyl administration and some members of the series bromide or ethyl iodide. Interaction of the aminohave an enhanced ability to produce, in animals, a ethanols (V) with thionyl chloride or thionyl broprolonged block after oral administration. For ex- mide proceeded smoothly in chloroform solution. -N-benzyl-@-chloro- N-(@-Phenoxyisopropy1)-ethanolamine (IV, Ar = ample, N-(@-phenoxyisopropyl) ethylamine is more active than the @-phenoxyethyl phenyl) was also prepared by reductive amination homolog when oral potencies are compared, al- of phenoxyacetone with ethanolamine. though the two are approximately equal in activity Alkylation of isopropanolamine with l-phenoxyby the intravenous route. 2-chloropropane produced two diastereoisomeric Most of the /?-haloethylamine hydrohalides racemic forms listed in Table V were prepared from phenols or aCeH,OCH&H(Cl)CHa f HdVCHzCH(0H)CHa ----t naphthol by the following method (1) Presented before the Division of Medicinal Chemistry at the 118th Meeting of the American Chemical Society in Chicago, Illinois, September, 1960. (2) Deceased. (3) (a) Kerwin, Herdegen, Heisler and Ullyot, THISJOURNAL, 73, 940 (1950); (b) Kerwin. Herdegen, Heisler and Ullyot, ibid., T I , 3983 (1950); Abstracts 116th Meeting American Chemical Society, page 23 L, 1949. (4) Piness, Miller and Alles, J . Am. Mcd. Assoc., 94, 790 (1930). (5) Chen, Wu and Henriksen, J . Pharmacol. E z p l . Thrrap., 86, 363 (1929). (8) Beyer, i b i d . , T I , 151 (1941). (7) Nickerson, i b i d . , 95, (Part II), 27 (1949). (8) (a) Rieveschl, Fleming and Coleman, Abstracts 112th Meeting American Chemical Society, page 17 K, 1947. (b) Nickerson and Gump, J . Pharm. E z p t . Thevap., 9'7, 25 (1949). (c) Henderson and Chen, Fed. P r o ~ . ,8, 301 (1949). (d) Gump and Nikawitz, THIS JOURNAL, T I , 3846 (1950).
CoHsOCHzCH(CHa)NHCH&H(OH)CHs
These were separated by crystallization of the solid isomer from petroleum ether and the two forms were benzylated and the tertiary aminopropanols treated with thionyl chloride. The pyridyl analog of the parent compound was synthesized by the series of reactions CGHSCHSNHP CHjCH(Br)COOCzHs _____) LiAIHd C,)H,CHzNHCH(CHa)COOCzH,_ _ f PyBr CsHjCH?XHCH(CH3)CH?OH (9) Libermann, Nature, 160, 903 (1947). (10) Darzens, Comfit. rend.. 163, 1314 (1911).
N- (ARYLOXYISOPROPYL)-P-HALOETHYLAMINES
Sept., 1951
4163
of a 2-methyl or a 2-isopropyl group in the phenoxy ring of 513 resulted in compounds (674, 861, Table VI) ranking among the more potent intravenously I active adrenergic blocking agents of the P-haloamCsHsCHzNH ine type, these compounds were practically inactive PyOCH2CHCHa 1. HC1 orally. Alkyl substitution in the phenoxy ring of C s H b C K 2 L 2 C H a O H2. s o c l z the 688 series either markedly lowered or destroyed oral activity. However the effect on intravenous PyOCHzCHCHs potency was variable. Thus those substitutions CeHsCHz~CHaCHzC1.2Hc~ which had little effect are 2-methyl (783), 3-methyl (Py = 2-pyridyl) (845), 2-isopropyl (lOOl), 2-isopropyl-5-methyl Since the P-phenoxyisopropyl group appears to (973), and 3,4-dimethyl (883) ; however a 2-isoprogroup appeared to be optimum. Decreased acproduce desirable effects it was of interest to test a py1 tivity resulted from 4-methyl (730), 2-s-butyl (793), b-chloroamine containing two of these groups. The (901) and 4-t-butyl (974) substitutions. bis compound was prepared by hydrogenating the 4-s-butyl Large substituents such as a 4-phenyl (945), a 4crude ketimine formed from P-phenoxyisopropylcyclohexyl(924) or a 2-benzyl (1002) markedly lowamine and phenoxyacetone. The N-(&hydroxy- ered intravenous activity and resulted in orally inethyl) group was introduced by treating the second- active compounds. Substitution of the phenoxy ary amine with ethylene oxide. ring of 688 by 4-hydroxy (972), 4-methoxy (784) or Pharmacological Results.-Table V gives the 4-benzyloxy (835) had little effect on intravenous adrenergic blocking action of the P-haloethylamines activity but oral activity was markedly lowered or after both intravenous and oral administration. destroyed. Chlorine substitution in the 2- or 4Intravenous activity was determined in cats as positions (1025 and 853) lowered intravenous activpreviously described.3a ity somewhat and oral activity was no longer apparIn oral experiments 10 mg./kg. of the compound ent. was given to cats and after three hours a test dose In the phenoxyethyl series substitution in the (12.5 micrograms) of epinephrine was injected. If benzyl ring by a 2-methyl (790, Table VI) had lita depressor response occurred, three successive test tle effect on intravenous activity and if anything doses (50 mp., 500 pg. and 1 mg./kg.) were given. slightly decreased oral potency. On the other hand The numerical rating assigned as a measure of substitution in the benzyl group of the phenoxyisoblocking ability is a summation proportional to the propyl series by a 2-methyl markedly lowered oral amount of epinephrine reversed or blocked divided activity but only slightly decreased intravenous efby the number of animals employed. When the fectiveness. Chlorine substitution, 4-chloro (804), pressor effect of a given test dose of epinephrine 2,Pdichloro (805), 3,4-dichloro (803) destroyed oral was blocked but not reversed, the numerical value activity but only the 2,4-substitution markedly assigned was one-half the micrograms of epine- lowered intravenous activity. Methoxyl substiphrine administered. Experience has shown that tution in the 4-,or 3,4-positions of the benzyl of compounds with oral ratings below 1000 are not this series had little effect on intravenous activity consistently effective adrenergic blocking agents but essentially eliminated oral activity. following administration by this route. The values Substitution on the P-chloroethyl of 688 by a Precorded in Tables V and VI have been rounded to methyl resulted in two diastereoisomers (781 and the nearest hundred. While these ratings ex- 974, Table V). Both of these were only slightly press the relative order of activity they cannot be less active than 688 intravenously but they were orconsidered to denote an absolute value. ally ineffective. Previous work has shown that marked adrenergic Replacement of the phenoxy ring of 688 by cyblocking ability following intravenous administra- naphthoxy or 2-pyridyloxy (907 and 1137, Table V) tion is manifested in the N-benzyl-N-(P-phenoxy- decreased intravenous and eliminated oral activiethyl) -P-chlorethylamine seriessb A few of these ties. compounds have been tested in these laboratories Replacement of the benzyl group of 688 by: (a) in order to compare their blocking ability with that phenoxyethyl (806), if anything, increased intraof our compounds. The intravenous and oral ratvenous and slightly lowered oral activities; (b) ings are recorded in Table VI. Complete pharma- allyl (833) slightly lowered intravenous and oral cological data will be reported elsewhere. activities; (c) ethyl (1370) markedly lowered inDiscussion of Relationship of Structure to Activity.-The lack of correlation between intra- travenous and eliminated oral activities and (d) venous and oral activity, as shown by the data P-phenoxyisopropyl to give the bis-(P-phenoxyisofor 861 (Table VI), 688 and 806 (Table V), demon- propyl) compound (1273) had no effect on intravestrates that factors other than blocking ability nous but markedly lowered oral activity. On the basis of these results it appears that the cyalone play an important role in oral effectiveness. On comparison of N-benzyl-N-phenoxyethyl-P- methyl group in 688 contributes to oral activity. chlorethylamine (513, Table VI) with N-benzyl-N- Furthermore, the requirements for oral activity (P-phenoxyisopropy1)-P-chloroethylamine(688, Ta- seem to be rather precise since there is no correlable V) it appears that cy-methyl substitution in the tion between intravenous and oral activity. former has resulted in a compound with enhanced This is further emphasized by the fact that in the oral activity and that even the intravenous activity phenoxyisopropyl series the substitutions in the has been somewhat increased. While substitution phenoxy or benzyl groups markedly lowered or deCHz-CHz
PyOCHzCHCHt
L-01
-
KERWIN,HALL,MILNES,
4164
K'ITT,
MCLEAN,M A C K O , FELLOWS AND
VOl. 73
ULLYOT
TABLE I 1-PHEKOXU-2-PROPANOLSR- ~ ~ O C H ~ T H C H ~ OH R =
B.p. or m.p., OC.
Press., mm.
n%
Yield,
%
Empirical formula
C
Calcd.
Analyses, %
H
C
Found
H
2-CH1" 86-88 2 1.5199 64 CloH1402 72.26 8.49 71.99 8.76 3-CH3 114 5 1.5211 84 C10H1102 72.26 8.49 72.37 8.38 4-CH3 101-106 4 82 CloHlrOz 72.26 8.49 72.34 8.35 2-(CHa)eCH 98 3 1.5118 68 ClzHl~Oz 74.19 9.34 74.14 9.36 105-110* 2 76 C13H2002 74.96 9.68 75.03 9.57 4-(CH )sC 2-CaHsCHz 56.5-S'iC 7% Ci@HisO? 79.31 7.49 79.20 7.45 2-(CH3)2CH-5-CH3 94-97 2 1.5100 72 C13H2002 74.96 9.68 75.18 9.58 3,4-diCHs 110-113 3 1,5226 80 CllHleOn 73.30 8.95 73.30 9.09 4-CH30 ti3-64d 73 C10H1403 65.91 7.74 65.80 7.57 4-CeHsCHyO 104-1 05" 60 Cl&H1.303 74.39 7.02 74.25 6.86 2-c1' 109-114 3 1.5382 69 GH1102CI 57.92 5.94 58.63 5.93 4-Cl' 125-130 6 1.5378 63 GHllOzC1 57.92 5.94 58.17 6.04 (u-C&I~OCH&H(OH)CH~ 59-63' 55 CI3H1402 77.20 6.98 77.31 6.76 0 The p-nitrobenzoate ester melted a t 95.5-96'. Anal. Calcd. for C17H17N05: C, 64.75; H, 5.43. Found: C, 64.51; Recrystallized from benzene and H, 5.50. b M.p. 44-46' from petroleum ether. ' Recrystallized from Esso hexane. petroleum ether. e Recrystallized from benzene. f The p-nitrobenzoate ester melted a t 97-97.5'. Anal. Calcd. for CisHl4NO5CI:C , 57.23; H, 4.20. Found: C, 57.52; H, 4.46. The p-nitrobenzoate ester melted a t 76.6-77'. Anal. Calcti. for C~~HllNOsCl: C, 57.23; H, 4.20. Found: C, 57.19; H, 4.03.
TABLE I1 1-PHENOXY-2-CHLOROPROPANES ~ ~ - O C H Z C H ( C ~ ) C H S
R R =
B.p.orm.p., OC.
Press., mm.
Yield, l t 2 b
%
94-95 5 1.5207 66 94-95 3 1.5160 70 96.5-98 5 1.5166 72 1.5199 75 76.5-77 2 76-78 2 1.5100 74 118-124 4 69 104-110 2 1.5070 78 100-103 0.3 1,5071 43 75-76" 81 4646.5" 6t 4-C6Hll 80.5-81" 58 2-C6HsCH* 2-(CH3)2CH-5-CHs 90-9 1 3 1.5090 53 96-98 3 1.5197 97 3.4-diCH3 91-95.5 1 1.5243 83 4-CHsO 66-67.6" 83 4-CoHbCHz0 2-c1 112-114 i) 1.5346 67 4-C1 37-3gb 73 a-CloH7OCHzCH(C1)CHa 117-120 0.2 1.5962 70 Recrystallized from petroleum ether a Recrystallized from alcohol.
€I 2-CH3 3-CH3 4-CH3 2-(CHs)2CH 2-GHsCH(CHs) 4-CaH&CH( CH3) 4-(CHsW 4-CsH5
stroyed the ability to produce an adrenergic block after oral administration while in the phenoxyethyl series substitution of a 2-methyl in the benzyl group (compound 790) if anything only slightly decreased oral activity. One additional fact is noteworthy. Replacement of the &chlorine by bromine (1000, Table V) essentially eliminated oral effectiveness. While this may a t &st appear startling it may be associated with the greater reactivity of the 8bromo compound which could result in its being destroyed before it can be absorbed into the blood stream from the gastrointestinal tract and distributed in the body. It has been amply demonstrated here and in previous ~ o r k , ~that " * ~structural factors axe exceedingly important in contributing to blocking ability per se once the agent gets into the blood stream. However, we feel that it is
Formula
C
Calcd.
Analyses, 5% H
CpHilOCl 63.35 6.50 CIoHi30Cl 65.04 7.10 CloHlaOCl 65.04 7.10 CioHi3OCl C1, 19.20 Ci2H17OCl 67.75 8.06 C1, 15.64 C1sHlg0Cl CISHloOC1 68.86 8.45 C18HlsOC1 68.86 8.45 C15H160Cl 73.02 6.13 C15HziOCl 71.27 8.37 C16H17OC1 73.69 6.57 C13HieOCl 68.86 8.45 CiiHiSOC1 66.49 7.61 CIoH1302Cl 59.85 6.53 Ci6Hi70zC1 69.43 6.19 GHioOC12 52.71 4.92 CgHloOClz 52.71 4.92 ClaHlaOCl C1, 16.07 after distillation, b.p. 84-90" a t
CFound
K
63.30 6.95 65.02 7.17 65.03 7.10 C1, 19.03 67.90 8.22 C1, 15.63 69.23 8.54 68.99 8.96 73.52 6.15 71.11 8.13 74.04 6.93 68.98 8.35 66.49 7.65 60.10 6.38 69.80 6.18 52.95 4.86 52.73 5.14 Cl, 16.11 2 mm.
probable that rather exacting requirements regarding solubility and chemical reactivity must be met to attain oral effectiveness.
Experimentalll Generous samples of l-phe.noxy-%propanol, 1-(2-s-butylphenoxy)-2-propanol, I-( 4-s-butylphenoxy)-2-propanol, 1(4-biphenyloxy)-2-propanol and 1-(kyclohexy1phenoxy)%propanol were supplied by the Dow Chemical Company. p-Methoxybenzyl chloride13 and 3,4-dimethoxybenzyl bromide's were prepared by methods described in the literature. l-Aryloxy-2-propanols.-All the compounds listed in Table 1 were prepared by essentially the procedure described for 1-(3,4-dimethylphenoxy)-2-propanoI. A solution of 112 g. (2.8 moles) of sodium hydroxide in 125 ml. of water was added to 350 g. (2.8moles) of 3,4-di(11) Melting points are corrected, boiling points are uncorrected. (12) Haller and Bauer, Compt. r e n d , 183, 23 (1911). (13) Haworth, Perkin and Rankin. .I Chcm. Soc , 11'7, 1444 (1925)
N- (ARYLOXYISOPROPYL) -@-HALOETHYLAMINES
Sept., 1951
4165
TABLE I11
N-(~ARYLOXYISOPROPYL)-AMINO ALCOHOLS~ O C H ~ C H ( CNHCH~CH~OH H ~ ) R ' W R = TI 2-CHI 3-CHa 4-CHr 2-(CHa)rCH Z-CzH&H(CHs) +-CaH&H(CHs) 4-( CHsj S C 4-CaHs 4-CsH11 2-C'HaCHa P-(CH&CH-I-CHa 3,4-di-CH1 4-CHaO 4-CaHrCHn0 2-CI 4-C1
M.p., OC. 70.5-72 57.5-59 57-58 69-71 52-54 69.5-71.5 c
49-50 141-142 45-46 76.5-77 d
60-61.5 63-55 121-122 8
63.5-64
Other N-aryloxy amino alcohols a-CioH7OCH;CH(CHs)NHCHLHaOH 70-71.5 CsH'OCHaCH(CHdNHCHzCH69.5-71(A) (CH:)OH' (B)
Yield, Recry.'
'70 solvn.
58 62 69 75 46 59 62 74 89 53 29 34 68 57 76 52 62
H B, P B, P B, H H H
60
B, P
22 19
H
Formula
CiiHirNOn CizHitNOn CiaHioNOz CizHitNOa CirHzaNOn CisHlsOzN CisHaiNOn H CiaHasNOn E CitHaiNOn P Ci.rHztNOa B, P CiaHaaNOa CisIIasNOz B, P CisHniNOn B, P CiaHiBNOa B CiaHzsNOr CiiHiaNOzCl B, P CiiHisNOaCl
Analyses, % CCalcd.H CFoundH 67.66 68.86 68.86 68.86 70.85 71.67 71.67 71.67 75.24 73.60 75.75 71.67 69.92 63.97 71.73 57.51 57.51
8.77 9.15 9.15 9.15 9.77 10.02 10.02 10.02 7.80 9.81 8.12 10.03 9.48 8.50 7.67 7.02 7.02
CiaHioNOa
73.44
7.81
CizHirNOa CizIIioNOz
68.86 68.86
9 . 1 5 68.88 9 . 1 5 68.71
M.P.,* OC.
I¶ydrochlotide C1- analyses Calcd. Found
Formula
67.60 9 . 0 2 103.5-104.5 69.02 9 . 1 2 101.5-103.4 68.82 8 . 6 0 84-86 8 . 9 9 100-102 68.78 70.94 9.75 71.73 9.79 71.63 9 . 8 8 95-97 72.03 9,94 75.24 7.79 73.72 9 . 9 1 134-135 75.75 8.23 71.51 1 0 . 0 3 118-120 69.97 9.42 64.04 8 . 3 5 108.5-109.5 71.70 7.56 7 . 4 5 115-117 58.01 57.77 7 . 2 6 71-75
CiiHisNOnCl CizHaoNOaCl CinHaoNOzCI CizHsNOzCI
15.30 14.43 14,4;3 14.43
CisHzsNOClz
12.32 12.38
CirHz1N0zCl
11.30 11.40
CiaHasNOzCI
12.32 12.23
CizHroNOaCl
1 3 . 5 5 13.50
73.43
CiaHaNOzCI
1 2 . 5 8 12.57
CizHsNOEl CizHzoNOnCI
14.43 14.55 14.43 1 4 . 4 8
7.90
119-121.6
9 . 0 5 135-13! 8 . 8 9 07-99'
15.15 14.3!4 14.36 14.43
CiiHirNOzCIz 1 3 . 3 2 13.35 CiiHirNO~CIn
a Solvents as follows: H = Esso hexane, B = benzene, P = petroleum ether, E = ethanol, combinations denote recrystallization from mixed solvents. * Hydrochlorides were recrystallized from alcohol and ether unless noted otherwise. B.p. Anal. Calcd. for C,IHuN02C12: C, 166-178" (3 mm.). B.p. 127-128' (0.4 mm.). e B.p. 136-141' (0.7 mm.). 49.63; H, 6.44. Found: C, 49.75; H, 6.27. Racemates A and B. * B.p. 114-115' (0.7 mm.); n% 1.5182. Recrystallized once from acetone and thrice from alcohol and ether.
methylphenol dissolved in 400 ml. of alcohol. The solution was stirred and refluxed while 263 g. (2.8 moles) of propylene chlorohydrin was added dropwise over a two-hour interval. After an additional three hours of refluxing, the reaction mixture was allowed to cool and filtered. The salt cake was washed with a little alcohol, most of the alcohol was removed from the filtrate under reduced pressure and the crude product was dissolved in approximately an equal volume of benzene. The benzene solution was extracted with 10% sodium hydroxide solution, washed with water and distilled. Some of the solid ether alcohols separated from the reaction mixture when it was allowed to cool; these were collected, washed with water and recrystallized. I-Aryloxy-2-chloropropanes.-The general procedure is illustrated by the following preparation. 1-(3-Methylphenoxy)-2-propanol(272g., 1.64 moles) was placed in a one-liter flask provided with a gas delivery tube dipping beneath the surface of the liquid, dropping funnel and condenser. The alcohol was cooled by an ice-bath and a slow stream of dry air was introduced while 146 g. (1.23 moles) of thionyl chloride was added over a two-hour period. Air was bubbled through the dark solution for three hours a t room temperature and then another 146 g. of thionyl chloride was added over a half-hour interval. The next morning two ml. of dry pyridine was added and the solution was heated on the steam-bath for three hours. The cooled reaction mixture was poured into a liter of water, 300 ml. of benzene was added and the aqueous phase was withdrawn. Sodium bicarbonate solution was used to wash the benzene solution free of acid. After a final wash with water, the solution was dried over magnesium sulfate, filtered and distilled. Comparable yields were obtained when one mole of pyridine per mole of alcohol was employed. For example, 198 g. (1.7 moles) of thionyl chloride was added dropwise t o a stirred cooled solution of 277 g. (1.4 moles) of 1-(2-isopropyl-5-methylphenoxy)-2-propanoland 134 g . (1.7 moles) of dry pyridine in 300 ml. of chloroform. After the addition was completed, the solution was refluxed for 1.5 hours, cooled and poured into water. The chloroform layer was separated, washed with sodium bicarbonate solution and water, dried and distilled. Solid ether alcohols were treated in the same manner with dry benzene or chloroform as solvent. The yields, physical
constants and analyses of the 2-chloropropanes are given in Table 11. 2-( @-Aryloxyisopropy1amho)-ethanols. Method A.-In a typical experiment 58 g. (1.44 moles) of ethanolamine was heated to boiling in a 500-ml. flask equipped with stirrer, dropping funnel and condenser while 89 g. (0.48 mole) of l-(2-methylphenyl)-2-chloropropane was added dfopwise with stirring. During the latter part of the additlon two phases were formed. After the addition of the chloro compound the reaction mixture was refluxed for three hours, then cooled and poured into 300 ml. of water. The water-insoluble oil was extracted into 400 ml. of ether and the ether solution was extracted with 2 N hydrochloric acid until a clear solution was obtained when a sample of the extract was made basic. The combined extracts were made strongly alkaline with sodium hydroxide solution and extracted with three portions of ether. After the solution was dried over anhydrous potassium carbonate, the solvent was distilled. As the last traces of ether were being removed under reduced pressure, the amine solidified. Method B.-A solution of 50 g. (0.33 mole) of phenoxyacetone and 20 g. (0.33 mole) of ethanolamine in alcohol No. 30 was shaken with Raney nickel under a hydrogen pressure of 3 atmospheres. Approximately 0.23 mole of hydrogen was absorbed. The solution was filtered, the alcohol evaporated under reduced pressure and the residue diluted with water. The organic layer was extracted into ether, and the ether removed in vacuo. Recrystallization of the solid from Esso hexane yielded 26 g. of product, m.p. 65-69'. Purification by formation of the hydrochloride, recrystallization and liberation of the free base gave 18.8 g . (25%) of material melting at 70.5-72'. N-(~-Phenoxyisopropyl)-l-amino-2-propanol .-The reaction of 0.75 mole of 1-phenoxy-2-chloropropane with 2.25 moles of isopropanolamine was conducted as described in Method A above. The crude product was taken up in ether, dried and distilled t o yield 87 g. (56%) of oil, b.p. 120-125' (3 mm.). Anal. Calcd. for C ~ Z H ~ ~ C, O ~68.86; N : H , 9.15. Found: C, 68.59; H, 8.95. A solution of the distillate in petroleum ether was cooled to -20', whereupon the solid racemic form (Isomer A) crystallized. A second recrystallization from petroleum ether produced 35 g. (22%) of crystals, m.p. 69.5-71'.
KERWIN,HALL,MILNES,WITT,MCLEAN,MACKO, FELLO ws
4166
AND
VOl. 73
ULLYOT
li R' = benzyl R =
H 2-CH1 3-CHa 4-CH1 2-(CHa)zCH P-CzH&H(CHa) 4-CnHrCH(CHs) 4-tCHa)aC 4-CsHa 4-CaHii 2-CdbcHY 2-(CH:)nCH-5-CHa 3,4-diCH1 4-CHsO 4-CsHsCHz0 2-CI 4-Cl R = H , R' = 4-C1CsH&Hz 2,4-ClzC~HdCHz 3.4-ClzCaHaCHz ~-CH~OC~HICHI 3,4-(CHsO)zCsHaCHz CsHsOCHzCHz CsHsOCHaCH(CH8) CHs=CHCHz CzHs
B.p. or
m.p., OC. 150-151 157-163 154-161 159-163 183-186 172 165-172 66.5-67.5* 222-232 215-216 2 11-216 170-174 63.5-66' 171-177
Press., Yield, mm. % 0.25 85 66 19 .2 .2 82 . I 68 .35 55 .25 81 63 29 .3 . .J 70 42 .2 6!! .4 81 .z 61 . Y
Formula CisHzaNOs CrtHaaNOz
Analyses, % Calcd. Found C H C H 75.75 8.12 75.34 8.26 76.22 8 42 75.76 6.33
CitHzsNOz CaiHloNOn CazHaiNOa CnzHaiNOz CaaHaiNOa CzrHvNOz CidHaa NOz CasHrNOz CzrHaiNOz CaHsrNOn CioHzsNOs
76.22 77.02 77.38 77.38 77.38 79.74 78 43 79.9G 77 38 76 64 72 33
47d
170-179 174-177
.3
17
. _>
60
165-170
.3
-,.1
8.61 9.00 8.91 9.21 9.26 7.63 8.91 8.02 9.16 CzaHazNOnCI 8.06 CioHzsNOzCl 7 . 6 7 CioHasNOaCl CI~HIPNO:CI CisHaaNOnCIn 6 7 . 5 0 6 . 9 3 67.40 6.94 8.42 8.93 9.15 9.15 9.15 7.53 9,03 7.79 9.15 8.,50 7 !I9
75.90 76.98 77.37 77.55 77.33 79.76 78.51 79.99 77.26 76.64 71.99
Hydrochloridea M.p., 'C.
C1- analyses Calcd. Found
98-99.5 85.87 112.5-114.5
10 56 10.55 10.56 10.54 10.56 10.44
96-98 121-123 104.5-106 110-111.5 146-148
9.38 9.24 10.13 10.13 10,OX 9.97 8.29 8.44 e
67.59 6 . 9 3 67.49 6.68 61.02 5.98 61.38 6.01
G:!
J
(it,
142-157 188 189 160-167 180-183 122-124 121-122
Formula
.-
70
f
.8
3.4
G0 64
.'.1
87
.'L
.7 .6
39 3 fi 31
72.35 72.92 71.45 69.92
.z
50
CneHzsNOz
.2 .2
81 68
CIsHnbNOz 76.22 8.42 76.62 8.17 C I O H Z ~ S O Z 76.22 8.42 76.13 8.76
7.88 7.99 8.26 9.00 9.48
69.40 72.15 72.91 70.88 70.02
8.23 7.82 8.33 9.09 9.22
CsHsCHzN(R)CHzCH(R') OH R = Rf= ~-C~OHIC)CHZCH(CH?) H 193-198 C~HIOCHZCH(CHS) CHa A 142-149 {B 148-152 (5-CsH4N)OCHzCH(CHa)' H 138-146
.3-.5 48
CirHzzNaOa
78.77 7.51 78.71 7.63
71.30
7.74 70.70
7.64
Hydrochlorides were recrystallized from alcohol and ether. Recrystallized from alcohol. Recrystallized from Esso hexane. d Isolated as the hydrochloride salt. e Calcd. : C, 60.68; H, 6.51. Found: C, 60.68; H, 6.33. Distilled base was not analyzed but was used directly t o prepare the j3-chloroethylamine. 0 The dipicrate, recrystallized from alcohol, melted a t 131-132'. Anal. Calcd. for CesHzshT601s: C, 46.78; H. 3.79; N, 15.05. Found: C, 47.00; H, 4.32; N, 15.17. a
The original petroleum ether filtrate was diluted with diethyl ether and saturated with dry hydrogen chloride. The salt was collected, recrystallized from acetone and then three times from alcohol and ether t o yield 35 g. (19%) of Isomer B hydrochloride. The purified hydrochloride was converted to the free base which distilled as a colorless viscous oil, b.p. 114-115" (0.7 mm.), n% 1.5182. N,N-Disubstituted Amino Alcohols.-Most of the compounds listed in Table IV were prepared in the same manner as follows: A mixture of 78.7 g. (0.35 mole) of 2-[0-(4-methoxyphenoxy)-isopropylamino]-ethanol,24.2 g. (0.175 mole) of anhydrous potassium carbonate, 44 g. (0.35 mole) of benzyl chloride and 150 ml. of alcohol was stirred and refluxed for nine hours. Approximately 100 ml. of alcohol was removed by distillation, the concentrated mixture was refluxed an additional five hours and then diluted with 300 ml. of water. The organic layer was extracted into ether, the solution was dried over anhydrous magnesium sulfate, filtered and distilled. The 4-benzyloxy compound was not distilled. The hydrochloride was formed by passing dry hydrogen chloride into a dried ether solution of the crude product. The other hydrochlorides in Table IV were prepared from the distilled bases. The 4-methoxybenzyl, 3,4dimethoxybenzyl and 8-phenoxyethyl compounds were prepared by a slightly ditferent procedure as illustrated by the following typical experiment. A solution of 28 g. (0.12 mole) of 3,edimethoxybenzyl bromide, 48 g . (0.24 mole) of 2-( 0-phenoxyisopropy1amino)ethanol and 100 ml. of toluene was refluxed for two hours. The cooled mixture was diluted with 200 ml. of ether, the oil which separated gradually solidified and was removed by filtration. The filtrate was shaken with 100 ml. of 5% bo-
dium hydroxide solution, washed with water, dried over anhydrous potassium carbonate and distilled. Ethyl a-Benzylmhopropionate.-Three moles (321 8.) of benzylamine was heated to its boiling point while 271 g. (1.5 moles) of ethyl a-bromopropionate was added with stirring over a three-hour interval. The mixture was refluxed an additional 1.5 hours, poured into ice and water and made basic with 40% sodium hydroxide solution. The organic layer was extracted into ether, dried and distilled to yield 115 g. (37%) of product, b.p. 116-117.5' (5 mm.). Anal. Calcd. for C ~ ~ H I , O ~C, N :69.53; H, 8.27; X, 6.76. Found: C, 69.47; H, 8.30; N, 6.94. 2 Bemylamino - 1 - propanol.-Twenty-one grams (0.55 mole) of lithium aluminum hydride and 750 ml. of ether was stirred in a flask equipped with mercury sealed stirrer, dropping funnel and condenser while 115 g. (0.55 mole) of ethyl a-benzylaminopropionate in 200 ml. of ether was added dropwise a t a rate to cause gentle refluxing. After the addition was completed, the mixture was refluxed for 45 minutes, cooled and 100 ml. of water added cautiously. The reaction mixture was then poured into 2 liters of 10% sulfuric acid, t h r ether layer was separated and discarded. The aqueous acid solution was made strongly basic with 40% sodium hydroxide solution and extracted twice with 150-ml. portions of benzene. Removal of the solvent left a solid which weighed 55 g. and melted at 6 4 6 6 " after recrystallization from hexane. The slightly colored material was converted t o the hydrochloride in ether solution and the salt was recrystallized from alcohol and ether. Conversion of the hydrochloride to the free base and recrystallization from hexane gave 41 g. (45%) of colorless crystals, m.p. 68-68.5'. A y Z . Calcd. for CIOHI~NO: C, 72.69; H, 9.15. F o u ~ l d : c, t 2 60; 13, 9.05.
-
Sept., 1951
N-(ARYLOXYISOPROPYL)-@-HALOETHYLAMINES
4167
4168
KERWIN, HALL,MILNES,WITT,MCLEAN,MACKO, FELLOWS AND ULLYOT
Vol. 73
* Amount of drug which when injected into cats causes a fall 0 Hydrohalides were recrystallized from alcohol and ether. See text for explanation of numbering system. Total chlorine. E Acid in blood pressure after 1mg./kg. of epinephrine. sulfate salt, recrystallized from alcohol and ether. f Organic chlorine. 0 Free base was liberated from its hydrochloride and DibenamineSmith, Kline and French Laboratories trademark Dihydrochloride. distilled, b.p. 113-116' (0.2 mm.). for N,N-dibenzyl p-chloroethylamine hydrochloride. A solid isomer of N,N-bis-( p-phenoxyisopropy1)-aminewas obtaincd in the following manner. The amine (124 g.) was converted into the neutral sulfate in alcohol solution and the salt was recrystallized twice from alcohol. Seventeen and one-half grams of the less soluble isomer, m.p. 172.5-174', was collected and converted to the free base. Evaporation of an ether solution or the base left 14 g. of solid which melted a t 46.5-47.5' after recrystallization from petroleum R' ether. Adrenergic blocking action Intravenous Oral rating Anal. Calcd. for C ~ ~ H ~ S X O ~ 75.75; : H, 8.12. dose in at 10 Found: C, 75.68; H , 7.75. X-0. R R mg./kg. mg./kg. N,N-Bis-( ,%phenoxyisopropyl)-ethanolamine.-ThirtyH 1.5-5 1200 518 H two grams (0.11 mole) of N,N-bis-( 8-phenoxyisopropy1)1 400 2-CHs 14 674 amine, 10 g. (0.22 mole) of ethylene oxide and 2 g. (0.11 1-2.5 100 2-(CHs)?CH H 861 mole) of water were heated in a sealed vessel a t 100" for 2-CH3 2.5;s 1000 790 H seven hours and then a t 120' for six hours. The reaction mixture was dissolved in ether, dried over potassium carbon2-Benzylamino-l-(2-pyridyloxy)-propane .-Sodium (5.5 ate and distilled. The tertiary amine distilled as a viscous g., 0.24 mole) was added to a solution of 39 g. (0.24 mole) of oil, b.p. 18C-183° (0.2 mm.), wt. 14 g. (39%). The pic2-benzylamino-1-propanoland 250 ml. of dry xylene. When rate, recrystallized from alcohol, melted a t 141-142'. the initial reaction had subsided, the mixture was refluxed Anal. Calcd. for CioH~NaOio: H, 10.03. Found: N, for three hours until all the sodium had reacted. Thirty- 10.01. nine grams (0.24 mole) of 2-bromopyridine was added t o the N,N-Disubstituted p haloethylamine Hydrochloride.cold mixture which was heated slowly and finally refluxed 8The preparation of N-( @-phenoxyisopropy1)-N-benzylfor four hours. The cold xylene solution was extracted with water and then with 2 .V hydrochloric acid. Sodium chloroethylamine hydrochloride serves to illustrate the hydroxide was added to the acid solution and the base was general method. Dry hydrogen chloride was introduced into 20 g. (0.067 extracted into ether. Thirty-seven grams (6470) of product, b.p. 104-116' (0.2-0.3 mm.,, was obtained on distilla- mole) of N-( p-phenoxyisopropyl )-N-benzylethanolamine tion. A portion of the liquid was redistilled and the frac- dissolved in 50 ml. of dry chloroform until the solution was tion boiling at 137-139" (1 mm.1; ? z * ~ D1.5518 was analyzed. acid to moistened congo paper. Nine grams (0.076 mole) of thionyl chloride in 50 ml. of chloroform was added slowly Anal. Calcd. for C l b H d i O : C, 74.35; H, 7.49. Found: while the solution was cooled in an ice-bath. The solution C. 74.10; H, 7.65. was then heated on a water-bath a t 50-60' for two hours N-[ B-( 2-Pyridyloxy)-isopropyl]-N-benzylethanolamine after which the solvent was removed under reduced presA mixture of 28.5 g. (0.12 mole) of 2-benzylamino-l-(2sure. Crystallization of the oily residue was induced by pyridy1oxy)-propane, 10.5 g. (0.24 mole) of ethylene oxide trituration with ether and the hydrochloride was recrystaland 2.1 g. (0.12 mole) of water was heated in a closed vessel at lized from alcohol and ether. 100' for four hours and then a t 120' for another four hours. The N-( p-phenoxyisopropy1)-N-benzyl-p-bromoethyl hyEther was added, the solution was dried and distilled. drobromide was prepared in the same manner from thionyl p-Phenoxyisopropyl&e.-A solution of 75 g. (0.5 bromide. mole) of phenoxyacetone, 53 g. (0.5 mole) of benzylamine in N-[ p-( 4-Hydroxyphenoxy)-isopropyl] -S-benzyl-p-chloro100 ml. of alcohol was hydrogenated over platinum oxide ethylamine hydrochloride was prepared by debenzylation15 catalyst a t approximately 3 atmospheres pressure. The of the corresponding 4-benzyloxy compound as follows. calculated amount of hydrogen was absorbed in three hours Four grams (0.009 mole) of N-[ p-(4-benzyloxyphenoxy)at room temperature. The N-benzyl-8-phenoxyisopropyl- isopropyl]-N-benzyl-P-chloroethylaminehydrochloride was amine was not isolated, but to the filtered solution was refluxed for 3 hours in 13 cc. of concentrated hydrochloric added 0.5 mole of Concentrated hydrochloric acid and 10% acid and 13 cc. of alcohol No. 30. Removal of the solvent palladium-on-charcoal catalyst. Further hydrogenation under reduced pressure left an oil which solidified on trituraa t 3 atmospheres and room temperature removed the benzyl tion with ether. Recrystallization of the solid from alcohol group. The filtered solution was concentrated to dryness, and ether gave 2 g. (66%) of the 4-hydroxy compound. the residual hydrochloride was dissolved in water and the N,N-Bis-(phenoxyisopropy1)-pchloroethylamine hydrobase liberated with sodium carbonate. The amine was ex- chloride was not obtained in solid form. The oily salt was tracted in ether, dried over potassium carbonate and dis- extracted with sodium bicarbonate solution and ether, the tilled to give 90% of colorless liquid, b.p. 55-62" ( 0 . 3 mm.); organic layer way separated and dried over potassium carXZOD 1.5227." bonate. Addition of the ethereal sulfuric acid to the ether N,N Bis ( p phenoxyisopropy1)-amine.-Twenty-four solution of the free base precipitated a crystalline acid sulgrams (0.16 mole) of p-phenoxyisopropylamine and 24 g. fate which was recrystallized from alcohol and ether. (0.16 mole) of phenoxyacetone were heated a t 110-120" (inAcknowledgments.-The authors are indebted side temperature) for two hours. The crude imine was dis solved in alcohol and hydrogenated over platinum oxide to Ruth Savacool, Rita Fox and Frances McCarcatalyst at 65' and 50 lb. After filtering, the solution was ron for the analyses. We are also grateful to Dr. distilled to yield 30 g. 166%) of secondary amine, b.p. 160Slrillialn Gump of Givaudan-Delawanna, Inc., for 162' (0.2-0.3 m m . ) The picrate was prepared i n alcohol solution and waq re- supplying us with compounds 752, G74, 8G1 and crystallized from acetone, m.p. 159-162'. 790 and for his kind permission to include these Am!. Calcd. for CuHzsNiOs: N, 10.89. FoWld: S , compounds in this report. 11.07. PHILADELPHIA, PENNA. RECEIVED FEBRUARY 14, 1951 TABLE
VI
c,
- -
.-
- - -
(14) Hurd and Perlitz, THIS JOURNAL, 68, 38 (1946), report b. p. 117-120' (18 m.), 7@D 1.6287.
(15) Druey, Dull. soc. rhim., [ 6 ] 2, 1737 (1936).
