@ADRENERGIC BLOCKING AGENTS. I
September 1988
1001
isopropoxide in i-PrOH presumably proceeded bimolecularly to give an intermediate +diamine 74, which, by elimiriation of isopropylamine, gave the pyrrolidine 75.
CH(CHJ2 75
74
Reduction of bromomethyl 2-naphthyl ketone with SaBHd gave the bromohydrin 76, which with ethanolic IiOH gave the epoxide 77. Treatment of the epoxide or the bromohydrin (which with base forms the epoxide) with, for example, isopropylamine (method C) gave a mixture of 5 and its position isomer 78, in the ratio 4 : l . These particular compounds were separated by fractional crystallization. I n the case of 2, 10, 18, 32, 37, arid 42, also made solely by this route, no special search was made for the primary alcohol isomers. Compounds 10 and 18 mere later shown by nmr to be free from the position isomers. 0
/ \
ILCII(OH)CH~BI* +RCH-CHz + 76 77 IICII(OII)CHzSHCH(CH~)z RC€I[~HCII(CI13)ylCHiOH 5 78 OCOPh
+
RCHCHZBr 79
The action of isopropylamine on the benzoate of the bromohydrin 79 was studied in an attempt to replace the bromine atom by the isopropylamino group directly, without the intermediate formation of the epoxide, thus eliminating the possibility of formation of 78. The bromine atom in the benzoate 79 was relatively inert to at tack by isopropylamine. Under forcing conditions 5 could be obtained, but none of its 0-benzoyl derivative was detected. The reaction probably proceeded via the epoxide after initial aminolysis of the benzoyl group. h useful intermediate in the synthesis of 5 and related N-substituted derivatives was 2-amino-1-(2naphthy1)ethanol (l),which was conveniently prepared by reduction of aminomethyl 2-naphthyl ketone 801° with SaBH4. Reductive alkylation of 1 with an aldehyde or ketone was carried out using either Pt-HZ (method D) or S a B H 4 (method E) as reducing agent. Cse of methyl vinyl ketone as alkylating agent in method E gave the tertiary amine 44 and not the secondary amine 26; the reaction had proceeded by addition of 1 to 2 moles of the unsaturated ketone and subsequent reduct ion of the carbonyl groups. The dimethylamino analog 39 was obtained by reductive alkylation of 1 with formaldehyde and formic acid.I1 Aminomethyl ?-naphthyl ketone (80) was also reductively alkylated with acetone by methods D and E to give pronethalol (5). The amino alcohol 1 and the amino ketone 80 are probable intermediates in several preparative methods which follow. The route shown below suffers from the disadvantage that the intermediate 2-hydroxyiminoacetylnaphthaleiie 81 can not be obtained in good yield. The preparation of 81, mp 93-94", in 50yoyield by the (11) I I T Clark?. 1% Sur , 56. 4571 ( I ~ ) 3 3 )
i Gillesple, and S. Z. \Veisshauq. J . d m . Chem.
action of amyl nitrite on 2-acetonaphthone under basic conditions has previously been described. l 2 Repeated experiments, under similar and slightly modified conditions, have given yields of about 20% of pure product, mp 105". 2-Saphthoic acid, a further product of the reaction, is formed even under carefully controlled conditions, and is not readily separated from the desired product by fractional crystallization. Separation is best achieved by adjusting the pH of an aqueous alkaline solution of the mixture (pH 11) to pH 7.5 when 2hydroxyiminoacetylnaphthalene, the weaker acid, is precipitated. At pH 4.5, 2-naphthoic acid separates. The reaction between amyl nitrite arid 2-acetonaphthone in the presence of HC1 has been investigated. In one experiment, in which a large amount of HC1 was used, 2-naphthoic acid was the only product. With catalytic amounts of HC1 a mixture of the hydroxyimiiiomethyl ketone 81 and 2-naphthoic acid was ohtained from which 81 was separated in 21y6 yield. SlaterI3 has pointed out that ketones of the type PhCOCH, are sensitive to excess HC1 during isonitrosation, whereas those of type PhCOCH2CH, are reasonably stable. The reduction of hydroxyiminomethyl ketones to &amino alcohols is well k n o ~ n .When ~ ~ the catalytic reduction of 81 mas carried out with a P t catalyst in the presence of an excess of a ketone (method F) the intermediate amino alcohol (or amino ketone) was reductively alkylated iu situ to give the S-alkyl derivative. When an aldeh!.de was used to provide the alkyl group it was necessary to use only 1 molar equiv if a mono-Salkyl derivative ( e . g . , 7) was required; with excess aldehyde an S,S-dialkyl derivative ( e . q . , 43) was obtained. Four methods used for the preparation of pronethalol involve reductive alkylation of the amino alcohol 1 (or the amino ketone 80) formed in situ from (a) 2-naphthaldehyde cyanhydrin, (b) 2-naphthoyl cyanide, (e) azidomethyl %naphthyl ketone, and (d) diazomethyl %naphthyl ketone.'6 I n each case reduction in glacial acetic acid solution in the presence of excess acetone using a 20% I'd-C catalyst gave 5 in about 20% yield. The method of Fodor and I icld h>. eatal> tic. ittluctive miinatioii of the g l cixal ~ with iwprop) 1:tiiiirie (method G ) , or i l l tjti?; >.icltl u-iiig SaBHi (method H). The c:Ltal>-tic recluetioil prcsurnahly proceeds uia the iiiteriiiediates 83 ;tiid 73. 111 one slow catalj-tic reduction the aminopyrrole 84, formed by condensation of two molecules of 73, separated out. The structure of 84 follows tronn the nmr rpectrum which eliminates the dihydrop> r:izinr alternative 85.
p-ADRENEKGIC BLOCKING AGESTS. I
September 1968
Infusion rate, rg/kg/min
hip, OC, Crystn solventb
EtOAc EtOAc 11eOH EtOAc hIeOH EtOAc lIeOI3 EtOAc JIeOII IIeOII EtOAc l\IeOII EtOAc Ale011 EtOhc EtOAc 1leOII
+ P (40) + EtOAc + P (40) + EtOAc + lle2C0 + lIe2CC) + EtOAc + P (40) + EtOAr + EtOAc
P (GO) EtOAc lIe0II
+ EtOAc
of amine Analyses
o r salt
C, H, lV
106-107 81-82 131-132 94-95 149-130 108-109 202-203 112-113 l78-17U 142-143 73-74 1.54-1 35 112-1 13 167- 168 141-142 14i 238-239
C, H, N C, H, C1, N C, H, N H, iT; Cz C, H, N C, H, C1, N C, H, S C, HI C1, S C, H, C1, S C, h, N C, H, ?j C, H, N C, H, S C, H, N C, H, N C, €-I,C1, N
C, H, N C; H; N
94-93 122-123 198-199
C, H,
loor?
200 50
% change in heart rate
7% inhib of tachycardia
+6 -4
53 - 34
- 29
50 25
-8
6*i
24
50 0 , .5 mg i v
0 -9
-50 33
0
44
0
.5R
20 100 A0 20 mg id1 (toxic) 100 100
+8 +6
"
--I
-i i
36 * 3i 19
?j
MeOII
229-23Obb
CnH,,ClNO
C, H, C1, N
100
- 13
17
EtOAc
100-101
Ci?Hi?SO?
C, H, ?i
500
-2
62
232-233
CZoH,oClSO?
C, H, C1, S
MeOH EtOAc RleOH P (60) AleOH
+ EtOAc
+ EtOAc + EtOAc EtOAc MeOH + EtOAc EtOAc RleOH + EtOAc EtOAc MeOH + EtOAc EtOAc MeOH + EtOAc MeOH + EtOAc MeOH + EtO.lc bIeOH + EtOAc
11.7-116 137-138 128-129 167- 168 111 210-211 130-131 203-204 131-132 174- 17.5 1.5 1-1.52 184-18.5 19,5-196 129-130
C, H, N C, H, C1, N H, X ; Cdd C, H, C1, iT C, H, N C, H, C1, N S C, H, N C, H, N C, HI C1, 9 N C, H, C1, N C, H, C1, N C, H, N, HL)
20 me id1
0
18
100 100 200 100 50
$4 -3
50
-2
31
50
- 13
6.5
100
-3
54
- 12
60 44
0
0
-
5011
I 1
-7
100
56 28 43 . 6i 62
154 CnH&lXO C, H, C1, N 800 -i 3-5 Isolated by the method used for 16. reported mp 59-60'. The letters A and B distinguish the two possible racemates C: calcd, 73.8; found, 73.2. u' Either l-pheriylbiitail-3-oile or 1-phenvlbut-1-en-3-one may he used as the ketone component. h* Lit.% mp 211-212". e c Isolated by CHC1, eutrartion. d d C : calcd, i 8 . 8 : found, 78.3. ee Norephedrine was iised as amine component. f / Biological results were extremely variable. p-Hydroxyvliorephedri~re was used as amine component. * h Free base was redllred using Pt catalyst. 2
the two possible racemates were separated by fractional crystallization.zz The separation was readily monitored by observing the hydroxyl frequency at about 1070 cm-I in the ir spectrum.
through catheters in the femoral veins. Standard amounts of isoproterenol [ 1-(3,4dihydroxyphen\-1)-2isopropylaminoethanol] (I) mere administered intravenously at intervals of approximately 10 min. The amounts of I administered depended upon the sen-
Biological Results and Discussion The results of the screening testz3given in Table I were obtained as follows. Cats were anesthetized with chloralose (SO mg/kg iv) and their heart rate and blood pressure were recorded. Drugs were administered (22) T h e four optical isomers of 5 1 will he discussed in a later puhlication. (23) Biological testing was carried o u t hy Dr. J. \V. Black a n d hlr. D. Illinlop. For further information see .J. \T'. Black, \V. A . M. Duncan, and R . G . Shanks, Brzl. J . P h w m w d , , 26, 577 (1965).
"ODC
H(OH)CH~x H c H ( c H ~*)
HO I
sitivity of the cat used and was generally between 0.25 and 0.5 pg/kg. The injection of isoproterenol caused an increase in heart rate and the mean of five responses was termed the control tachycardia. The test compound was administered by continuous intravenous
0-ADRESERGIC BLOCKING AGEA-TS. I
September 1968
residne was washed with EtOAc and then crystallized from MeOH-EtOAc. Isopropylaminomethyl 2-naphthyl ketone hydrobromide formed plates, nip 268', yield 27 g (4473. Anal. (CI5HLBBrNO) C , H, Br, X. The hydrogen oxalate melted a t 234-233" (from EtOH). Anal. (Cl,Hl,S06) C, H ; X : calcd, 4.4; found, 4.9. 1-Methyl-2-phenylethylaminomethyl 2-Naphthyl Ketone.-A mixture of bromomethyl 2-naphthyl ketone (10 g, 0.04 mole), 1-methyl-2-phenylethylamine(5.4 g, 0.04 mole), and NeOH (50 ml) was kept at room temperature for 18 hr and then the lIeOH was evaporated. The residiie was stirred with a little EtOAc and the solid which did not dissolve was isolated and then crystallized from a mixture of lIeOH and EtOAc. l-lIethyl-2minomethyl %naphthyl ket,one hydrobromide had ', yield 1.95 g ( 1 2 . i T ) . dnal. (C?lIIpsBr?r'O) C, TIj S ; Br: calcd, 20.8; foiind, 20.2. 2-Isopropylamino-l-(2-naphthyl)ethanol (5).-Isopropylaminomethyl 2-naphthyl ketone hydrobromide ( 5 g) was shaken with E t 2 0 (100 ml) and NaIIC03 solution ( 1 0 5 , 23 ml), and then the Et& extract was dried. LAH ( 2 g) was added during 1.5 min to the dry E t 2 0 solution at room temperature, and after 30 min the mixture was heated under refliix for 12 hr. The excess of LAH was decomposed by adding ice and the organic material was isolated with EtzO. The extract, gave 5, mp 106". 3,4-Dihydroxy-l-isopropyl-3,4-di( 2-naphthy1)pyrrolidine (75). -A soliition of isopropylaminomethyl %naphthyl ketone hydrogen oxalate (0.4 g) and aluminum isopr3poxide (1.3 g) in dry i-PrOH ( 2 5 ml) was slowly distilled during 7 hr to remove l\lerCO and then the solution was evaporated t,o dryness. The residue was made alkaline with 1 S NaOH and then extracted with EtzO. The extract gave 75 as prisms: mp 146', from EtOAc-petroleum ether (bp 60-80'); nmr (CL)C13), T 2.2-3.0 (multiplet, Ar-€I, 14), 5.7 (OH, 2), 6.53 (AB quartet, CH2 of pyrrolidine, 4),7.04 (septet, isopropyl CH, l ) , 8.75 (doublet, isopropyl CHs, 6 ) . Anal. (CnH27NOa) C, H, S., Method B. 2-Amino-l-(2-naphthyI)ethanol(l).-NaBH4 (10 g) was added diiring 25 min to a stirred suspension of aminomethyl 2-naphthyl ketone hydrobromidelo ( 2 5 g) in >le013 (250 ml) a t 5". After 1 hr the lIeOII was evaporated and the residlie was made alkaline with 1 S NaOH and then extracted with CIICI,. The extract gave 1, mp 118O, yield 15.3 g (89%). Method C. 2-Isopropylamino-l-( 2-naphthy1)ethanol ( 5 ) and 2-Isopropylamino-2-(2-naphthyl)ethanol (78).-A solution of 2-bromo-1-(2-naphthyl)ethanol(220 gj 0.873 mole) and i-PrNHp (200 nil, 2.35 moles) in EtOH (400 ml) was heated under reflux for 3 hr and then the EtOH and the excess of i-PrSHz were evaporated. EtOAc (200 ml) was added to the hot residual oil and the crude 2-isopropylamino-1-( 2-naphthy1)ethanol hydrobromide, mp 172-174", which separated on cooling, was collected. The filtrate was retained. The crude hydrobromide was converted to the criide free base which was then converted to the hydrochloride. This was recrystallized from hIeOH-EtOAc and gave pure 2-isopropylamino-l-(2-naphthyl)ethanol hydrochloride, nip 184'. The corresponding free base (5) is characterized by ir absorption bands at 1086, 1070, and 1018 em-' arid by the absence of srich bands at 1058 and 1032 cm-I (in cIIcl3 so111tion): iinir (CCl, trifliioroacetic acid (TFA)), T 2.1-2.8 (midtiplet, Ar-TI, i ) ,.5.15 (X part of ABX, OCH
