SULFONANILIDES. I1
May 1967
4 ti3
TABLE I PHEXONE ISTERMEDIATES OCHRi
M 11
lit
R
P r e g n Yield, Crystn method“ % solventb
1.i 1 1 1.i 213 2.1 21: 213 3AZ 31: 313
3U 3.i
31 4 4 4 4 4 4 1U 2.i
3u 4
80 48 56 98 87 89 T9 76 84 87 86 68 77 70 85 95 94 86 88 62 70
B-C
55
A
95
A
h
B D ‘1
I I3
D
.\ .Z A A
.i .i
.Z h h
A .i R
h
_ _ _ (
Alp. “ C
l‘ortnula
136.5-137 109.5-110.5 95-98 225-226.5 deo 127.5-129 127-128 84-86 205.5-206.5 141.5-142.5 137.5-138.5 113.5-116.5 156.5-158.5 98-100 210-211 118,5-121,5 144-146 95.5-97.5 184.5-185.5 121.5-123,5 96,5-98.5 i9-81 146.5-147.5 166-168
Calrd
C-Found
66.41 67.36 68.21 48.8BC 74.66
66.17 67.33 67,Y 3 48.64 i4.W5
i5.27
i5.04
i 5 . 81 47.15 60.17 61.24 62.22 53.12
7 6 , 05 47.11 60.14 61.23 62.24 53.31 63.21 85.12 47.79 49.43
63, 1:i 35,08
48.23 48.52 50.71 41.15 51,82 66.41 74.66 60 17 48.25
50,75
41.35 52.12 66.01 74.44 60.11 47.48
r - c h I1 Calcd
4.83 5,30 Li3 2.64
6.2T 6.il 7.11 4.84 5.37
5 74 6.0Y 6.32
6.11 8.27 4.08 4.40
4,7:3 4 60 5.04 4.83 6.27 5.37 4 05
- --[A -
l‘ound Calcd 4.86 > , l e 5.60 4,Yl 5.49 4.68 2.61 i.12 6.32 5.81 6.86 5 . 4 Y 7.19 .5 20 4.YY 6.11 5 40 4.38 5.70 4.20 6.13 Y , 2 3 e 6.32 5.16 6.36 8 . 8 T e 3.86 4.53 4.36 4.68 3.40 5 03 7 5Ze 4.68 4.00 3.06 i.2ge 4.T6 5.16 6.56 5.81 3.39 4.38 4.28 3,52
Nl‘ound
.;.I6 4.Y7 4.76 7.21 5.8Y 3.28
jli 5.Y4 4.31 4 20 Y.48 5.24 9.W 4.52
7.71 3.2!J
7.52 4.17 7 49 5.21 5.80 4.30 3 32
Correspoiids to procedure given in Experimental Sect’ioti. A, 2-propanol; B, isopropyl ether; C, 2-butaiione; 11, ethanol. Hemihydrat.e. d The dimesylated comporiiid 5’-acet~yl-2’-ber1zylox~dimethariesulfor1ariilide, mp 180.5-182’, was also isolated. Anal. Calcd fur CliH1,KO,S2: C, 51.37; H, 4.82; K,3.53; S, 16.13. Found: C, 51.33; H, 4.99; S , 3.71; S, 15.86. e Sulfur. a
111general, the aiiiiriopherioiies (VI)were obtained by condensation of the pheriacyl bromides (V) with the appropriate secondary benzylamine or primary amine. For those aniinophenones (VI) where R, R1, and R:! are hydrogen, the phenacyl bromide (V) could be condensed with hexamethylenetetramine providing a quaternary salt which was then hydrolyzed in dilute acid to the primary amiriophenorie. Our observations support those of Suter arid Ruddy,6 that condensation of 1iex:inietliylerietetra~nine with a phenacyl halide oiily owurs when It is hydrogen. F‘or those primary phcncthariolamiries (I) where R is alkyl, the precursor amino ketones (VI) were prepared with a blocking group incorporated into the amino moiety. The benzhydryl blocking group was preferred over dibenzyl because it underwent a more facile hydrogenolysis. Purification of the aminophenories was often difficult since there is a tendericy for these substances to hydrate. In addition, compounds 28 and 31-33 possess two centers of carbori asymmetry. S o attempt was made to purify these aniiriopheriorics to the point where it was certain that only one racemate was present. III some instances, the amino ketones never did give satisfactory analyses, yet could be used for conversion to the phenethanolamines (I). The aminoacylhydroxysulfonanilides (VI) are listed in Table 11. Catalytic hydrogenation (Pd-C) of the aminophenones (T’I) resulted in reduction of the carbonyl group t o the sccoiidary hydroxyl function and removal of any 1)erizyl or benzhydryl groups present in the molecule. .ilternatively, the aminophenories (VI) can be reduced first with SaBH4 arid then the protective benzyl groups removed by catalytic hydrogenolysis. The resultant (2 -amino- 1-hydroxyalky1)hydroxyalkanesulfonanilides (1) are listed in Table 111. ( 6 ) L’. 31. Sutcr n i i ~ l.I. \ \ . ltuddy, J . A m . Chetn. Sur., 66, 747 (1944).
The preparation of the hydroxyiiitropheriories for the two series of compounds required diff ererit synthetic procedures. For the meta series, 4’-hydroxyphenones were nitrated with red fuming nitric acid at -25’ to yield the 4’-hydroxy-3-1iitrophenones.~ These phenolic phenones were allowed to react with benzyl chloride in the presence af KOH t o give the 4’-benzyloxy-3’nitropheriones (11). Most of the phenethaiiolaniiiie* (I) were prepared from intermediates wherein the phenolic hydroxyl group had been converted to the benzyl ether. For the 7,ieta series, the entire ~ ~ U C I I ( * C : of reactions, depicted in Scheme I, can be acc.onipli4iccl without protectiiig the phenolic hydroxyl group. For the p a m series, initial consideration was given to the direct acylation of ?’-alkoxy- or 2’-benzyloxyalliaiiesulfonanilides. The results from this approach were equivocal. A sevorid unsuccessful attempt, involving diazotization of 4’-acetyl-%’-aminoniethanesulforiariilide (VII) gave an alkali-insoluble material, the structure of which is apparently the triazolc VI11 (Scheme 11).8
I
VI1
SO-CH, \.I11
‘l’tic sytit’licsis of ::’-lJctizyloxy-3’-iiit roacctopheiioiie was successfully accomplished in the manner illustrated in Scheme 111. (7) P. D. Rartlett a n d E. N. Trachtenberg, ihid.. 80, ,5808 (1958): F. C. Brown, ibid., 68, 272 (1946). (8) K. Srtsse, R. Wegler, a n d F. Grewe. U. S. P a t e n t 2,943,017 ( J u n e 28, 1060), h a v e described the preparation of a nuinlwr of analogous tnetliaiicsulfonyllriaeoles Ly diazotization of l‘-atninotnelliatiesulfoiiatiili~~~.
c2 CG' ' z
SULFONASILIUE~. 11
M a y 1967
2 L
D
e a
-4.
:I'-
w
.1
a
465
niay 1967
SUL~WNANILIDEY. I1
A niixturc of 2.7 g (0.01 niole) of the 3-benxyloxy-4-nitrobenzoic acid and 2.0 g (0.01 mole) of PClj was heated on a steam bath until HC1 evolution ccased. The niixture was diluted with 50 ml of ccl4 and filtered, and the residue from the concentrated filtrate was crystallized from heptane; yield 2.5 g (85%) of 3-benzyloxy-4nitrobenzoyl chloride, mp 96-100”. Anal. Calcd for C14HloClN04: C, 57.65; H,3.46; N, 4.80; C1, 12.15. Found: C, 57.53; H, 3.48; N,4.91; C1, 12.07. 3-I3enzyloxy-4-nitrobenzoyl chloride (29.2 g, 0.1 niole) was treated with diethyl ethoxymagnesium malonate (prepared from 0.11 g-atom of Mg and 0.11 mole of diethyl malonate) according to the manner described by Reynolds and H a i ~ s e r ,providing ~ 16.8 g (62%) of 3’-benzyloxy-4’-nitroacetophenone, mp 90-97’. Crystallization was effected from isopropyl ether, mp 96.5-
467
An alkali-iiisoluble material M a5 isolated in addition to the desired product; mp 176-177.5O, after crystallization from 2propanol. Elemental analyses indicated this to be the diniesylated product, 4’-acetyl-2’-benzyloxydimethanesrilfonanilide. Anal. Calcd for C17H,gNOsS~: C, 51.37; H, 4.82; N, 3.53; S, 16.13. Found: C, 51.28; H, 4.92; 21, 4.02; S, 15.92. Benzyloxybromoacylalkanesulfonanilides (V). Procedure 4. 2’-Benzyloxy-5‘-(2-bromobutyryl)methanesulfonanilide.-A solution of bromine (22.2 g, 0.139 mole) in 100 ml of CHC13 was added dropwise to a stirred solution of 48.1 g (0.139 mole) of 2’-benzyloxy-5’-brityrylmethanesulfonanilideand 0.2 g of dibenzoyl peroxide in 650 ml of CHC13. After stirring for 30 min a t room temperature, the mixture was washed with water, then saturated NaHC03 and again with water. The CHC13 solution was dried (hIgs04) and concentrated a t reduced pressure. The 98.5’. Aminobenzyloxyphenones (111). Procedure 2A. 4’-Aminoresidue was taken into 2-propand and scratched to induce crystal3’-benzyloxyacetophenone.-A sample of 6.7 g (0.025 mole) of lization, and the solid was collected; yield 55.8 g (94%), mp 3’-benzylosy-4’-nitroacetophenone in 200 ml of methanol was 93-96’. Recrystallization from 2-propanol allowed recovery of reduced in a Parr hydrogenator with 0.2 g of PtO, as catalyst. 50.5 g (8570), mp 95.5-97.5”. Aminoacylbenzyloxyalkanesulfonanilides (VI) (Table 11). After removal of the catalyst and evaporation of the solvent, the 5 ’-( 2-Benzylmethylaminopropionyl)-2’-benzyloxymethanesulfonresidue was triturated with cold 2-propanol and the solid was Crystallization was anilide (7).-Solid 2’-benzyloxy-5’-(2-bromopropionyl)methanecollected; yield 4.2 g (707,), mp 72-80’. sulfonanilide (8.2 g, 0.02 mole) was added to a stirred solution of effected from 2-propanol; yield 3.9 g (65%), nip 79-81”. Procedure 2B. 3’-Amino-4’-benzyloxybutyrophenone.-A 5.0 g 10.041 mole) of benzylmethylamine in 75 ml of acetonitrile, slurry of 56.5 g (0.189 mole) of 4’-benzyloxy-4’-iiitrobutyro- and the mixture was stirred a t room temperature for 3 hr. phenone in 700 ml of absolute ethanol was refluxed with stirring. The mixture was concentrated a t reduced pressure, the residue To this hot solution was first added 5 teaspoons of Raney nickel, h s stirred in 300 ml of anhydrous ether and the benzylmethylamine hydrobromide was removed by filtration. The ethereal and then a s h t i o n of 28.4 g (0.566 mole) of 99% hydrazine hydrate in 30 ml of ethanol was added dropwise over 20 min. The solution was evaporated, the residue was triturated with isomixture was refluxed an additional hour, then filtered through propyl ether, and the solid was collected by filtration; yield 7 . 5 g (83%), mp 117-121”. Crystallization from 2-propanol allowed Celite. The filtrate was concentrated a t reduced pressure and recovery of 5.3 g (59yo,, mp 119-121’. the residue was triturated with cold 2-propanol and filtered; 2’-Benzyloxy-5‘-( 2-isopropylaminoacetyl)butanesulfonanilide yield 45.1 g (SU?;), mp 83-85’. A crystallization from isopropyl Hydrochloride (13).-A mixture of 8.8 g (0.02 mole) of 2’-benzylether yielded 40.0 g (79y0),mp 84-86’. Acylbenzyloxyalkanesulfonanilides (IV). Procedure 3A. oxy-5’-( 2-bromoacety1)biitanesulfonanilideand 2.4 g (0.04 mole) 5’-Acetyl-2‘-hydroxybutanesulfonanilide.-Butanesulfonyl chloof isopropylamine in 50 ml of acetonitrile was stirred a t room ride (56.2 g, 0.30 mole) was added dropwise with stirring to a temperature for 30 min. The solution was diluted with 300 ml cooled solution of 3’-amino-4’-hydroxyacetophenone hydroof anhydrous ether and the isopropylaniine hydrobromide was removed by filtration. The ethereal filtrate was acidified with chloride (47.0 g, 0.30 mole) in 375 ml of pyridine. After stirring for 2 hr a t 2 5 O , the solution was poured into 2.5 1. of ice water. ethanolic HCl, the supernatant solution was decanted, and the residue was triturated with 2-propanol. The solid was collected The precipitate was collected and washed successively with by filtration; yield 4.7 g (52%), mp 165-175’. Crystallization water, dilute HC1, and water. The moist solid was dissolved in 2 1. of 0.5 IY XaOH, and the filtrate was acidified with 6 .V HC1. from 2-propanol and then from acetonitrile-isopropyl ether alThe white solid was collected, washed with water, and air dried; lowed recovery of 4.3 g (477,), mp 173.5-176.5”. 2‘-Benzyloxy-5’- 12-(diphenylmethylamino)butyryl] methaneyield 64 g (79%,), mp 148-154”. Cryst,allization from 2-propnnol yielded 55.0 g (€is%), mp 156.5-158.5’. sulfonanilide Hydrochloride (4).-To a solution of 3.7 g (0.02 5 ’-Acetyl-2’-benzyloxymethanesulfonanilide.--;\Iethariesul- mole) of diphenylmethylamine in 25 ml of acetonitrile was added fonyl chloride (4.4 g, 0.039 mole) was added dropwise to a stirred 4.3 g (0.01 mole) of 2’-benzyloxy-5’-( 2-bromobutyry1)methanemixture of 10.7 g (0.039 mole) of 3’-amino-4‘-benzyloxyacetosnlfonanilide. The mixture was refluxed for 24 hr and then phcnone hydrochloride in 50 ml of pyridine. After stirring for chilled, 200 nil of anhydrous ether was added, and the diphenylmethylamine hydrobromide was removed by filtration. The 4 hr at room temperature, the solution was poured into 500 ml of ice water and the solid was collec,ted by filtration; yield 10.6 g ethereal filtrate was acidified with ethanolic HCl, and the sepa( 9 7 % ) of the 5’-acetyl-2’-benzyloxymethanesulfonanilide 3’rated solid was collected by filtration; yield 5.0 g (88%), mp amino-4’-beneyloxyacetophenone salt, mp 109-111 ’. Crystal179-181”. Crystallization from acetonitrile-isopropyl ether lization from 2-propanol yielded 10.2 g of the salt, melting point yielded 4.5 g (79’%), mp 186.5-188.5’. unchanged. 4‘42-Aminoacetyl)-2’-benzyloxymethanesulfonanilideHydroAnal. Calcd for CIGFIli~04S.CljH~5N02: C, 66.41; I€, 5.75; chloride (35).-A solution of 8.0 g (0.02 mole) of 2’-benzyloxy-4’S , 5.00; S, 5.72. Found: C, 66.99; H, 5.85; N, 5.38; S, 5.19. (2-bromoaretyl)methanesulfonanilide and 4.2 g (0.03 mole) The salt (10.2 g) was stirred with 50 ml of 10% NaOH solution, of hexamethylenetetramine in 150 ml of CHCL was stirred at the insoluble material was filtered, washed with water, and dried; room temperature for 3 hr. The accumulated precipitate was Recrystallization from 2-propanol yield 5.0 g, mp 124-128’. collected by filtration and washed with CHC1, and then acetone; gave the purified starting aniline derivative, mp 127-129’. A yield 7.2 g (SS%), mp 157-160’. The quaternary complex was mixture melting point of this substance with 3’-amino-4’hydrolyzed by heating with 50 ml of 95% ethanol and 8 ml of benzyloxyacetophenone was not depressed, and the infrared concentrated HC1 until solution was affected. On cooling, the spectra of the two were identical. amino ketone hydrochloride crystallized and was collected by Acidification of the alkaline filtrate with HCl yielded 5.0 g filtration. The solid was triturated with 15 ml of cold water, of solid, mp 140-142’. Crystallization from 2-propanol yielded filtered, and dried a t reduced pressure; yield 4.4 g (59% over-all), 4.8 g (75% baaed 011 recovered starting material) of anilide prodmp 196.5-198”. uct, mp 141.5-142.5’. Hydroxyalkanesulfonamidophenethanolamines ( I ) (Table 111). Procedure 3B. 4’-Acetyl-2’-benzyloxymethanesulfonanilide. 2’-Hydroxy-5’- [ 1-hydroxy-2-( isopropylamino)ethyl] butanesulfon-A solut,ion of 5.6 g (0.049 mole) of methanesulfonyl chloride in anilide hydrochloride (52).-A solution of 4.3 g (0.0094 mole) 40 ml of benzene was added dropwise to a stirring solution of of 2’-benzyloxy-4’-(2-isopropylaminoacetyl)butanesulfonanilide 11.7 g (0.049 mole) of 4’-amino-3’-benzyloxyacetophenoneand hydrochloride (13) in 100 ml of 90% ethanol with 0.5 g of 10% 9.8 g (0.098 mole) of triethylamine in 160 ml of benzene. After Pd-C was subjected to 3.5 kg/cm* hydrogen pressure in a Parr stirring for 4 hr a t 25’, the precipitate was collected, washed with hydrogenator. Consumption of the calculated quantity of benzene, and then triturated with 300 nll of water; yield 6.0 hydrogen was complete after shaking the mixture a t room temg, mp 143-147”. An additional 2.5 g of product, mp 143-147’, perature for 4 hr. After removal of the catalyst and evaporation was obtained by acidifying a 10% NaOH extract of the benzene of the solvent, the oily residue was triturated with 50 ml of cold filtrate: total yield 8.5 g (5570). Crystallization was effected 2-propanol to obtain a durry of a white solid. After dilution with from 2-pr0l)al~l,1111) 146.5-147.5’. 50 ml of isopiopyl ether, the solid was collected by filtration;
1.0
~icsl(l;;.IS g (9l(,i1, inp 146.>-14b3. Ci allizatioii from et h~iiicil-isopriJpylether yielded 2.6 g (73\
