448
N Hllt2 lieNo. 1
I1
2 3
I1
4
II H H H H
€I
5 6 I
8
12
H II I1 ClIs
1:3
("d
14
cH I
1 .j 16 17 18 14
CHI CHI CHs
20 22
CHI C"? < 131
2 :3
C HI
21 25 26 27
CH3 CH1
!j
10 11
cm CHI
21
("a
("1
Ai = water, R
=
diniethvlformaniide.
216-218 189-190 200-201 179-180
,\ .\
!IO !IO
I>>
:::j
('
,jij
205-207 205-208 232-233 242-243
.I
.4 $5 :i k
li6-1i8 183-183 181-183 185-186 217-218 223-224 221-222 238-239 252-253 240-241 229-230
190-191 145-14T 16i-168 167-169 193-19.5
.\ .\
I) 1.; \
:3s
1,:
42
1'
- iJ .
\
4.4
4i
1,: I3
62 3 :i 78
I1 .\ I
,we were led t o investigate the report by Bramauti and Di Paco2 of possible hypoglycemic activity of ?J-[(4-tolylsulfonyl)earbamoyl]leucine. We wish to report the synthesis of some new K-[(4-tolylsulfonyIjcwbamoyl] amino acids. Prior synthesis2 of such compounds involved the reaction of the ethyl esters of leucine and a-aminobutyric acid with 4-tolylsulfonyl isocyanate or 4-tolylsulfonylurethan, followed by alkaline hydrolysis. The reaction of 4-tolylsulfonylurea wit,h amines in acetic arid and with glycine ethj-1 ester hydrochloride as a melt to give S-substituted K'-tolylsulfonylureas has also been r e p ~ r t e d . ~We have found that heating 4-tolylsulfonylurea with amino acids in acetic acid affords t>he title compounds in fair yield. These results are summarized in Table I. The cornpounds showed no hypoglycemic activity. Experimental Section4 4-Tolylsulfonylurea was prepared according to Kharag, Yavlinskii, and Savin.6 Compounds 2-5 were prepared using the -__11) Author to uliom inquiries s!iould be addressed. ( 2 ) Q. Hramanti and G. F. Di Paco, Ann. Chirn. (Rome), 51, 1202 (1981). (3) A. G . Georgiev, Compt. Rend. Acad. Bvlgare Sci., 14, 603 (1961);
Chern. Abstr., 68, 55466 (1963).
:i1
*ti ti7 -n
I .a
07 2 ,-, 82
-ilii_
evaporated in C ~ C ZtoI ~give an oil. The oil was diqsolvrtl i n : I +:[Iurated KHCO, solution, the. d u t i o i i uxs filtered, and the filtr:it'c: was acidified with 3 -\'HC1 to give a gum. The gunk was ~varheti with water, dried, dissolved i i i a niiriimuni amount of ethyl acetat,e, and treated with petroleurn ether ( b p 30-60") to givc a n amorphous solid d i i c h , after drying, weighed 9.2 g.
(4j Melting points were i o k m on a Fisher-Johns block and are curr .inaiyses are b y Midwest M c r o l a h , Inc., Indianapolis, Ind. ( 5 ) I. AI. Ktiarag, If.D. 1-avlinskii, and 13. AI. Savin, IT.H.B.R. l'alent 128,015 (1960); Chern. ALstr,, 56, 352:ib (1961). (6) I. Smith in "Cliromatographir and Electrophoretic 'Techniqiics." \ u l . I , I. Smith, Ed.. 2nd ?(I, Interscience f'ul~lisliers~I n i , . , N e w l o r k , N. Y., 1960: (a) 11 9.5; ibj p 9i. ( , i )J. P. Greenstein and AI. \\ inil A , "i 'lieinistry of t lie .\mino .u i : i r p p 893, ins;; 'L? .JiJliii Wiley and Sons, Inc.. K e w T o r k . N . \. , 1961: irp 906, 932.
NEWCOMPOUNDS
May 1966
449
TABLE I N- [ (4-'~OLYLSULFONYL)CARBAhlOYL]AJIINO A i C I U S RCHCOZH I
kHCONHSO&eH&H3-4
R
XU,
Mp,
O C
Recrystn solrenta
Purified yield, Formula
C
44.11 46.15 49.68 56.34
1 2 3 4
5
189-190
c
173-175
D
%---
----Calcd,
70
H
70---
--Found,
S
4.44 10.29 4.93 9 . N 5.77 8.91 5.01 7.73
C
43.86 46.49 49.89 56.19
H
N
4.79 5.07 5.81 5.26
9.96 9.64 9.02 7.45
56.85 4.77
10.47
56.88 4 . 9 3 10.67
47.71 6.29
11.92
48.01 6.26
H
6
H2N(CHn)a
14
Ci4H21N3OjS.0.5HeO
NH
11.68
11
189-190 J3 44.20 5 . 8 3 18.41 44.35 6 . 0 5 18.50 45.34 4 . 6 8 8 . 1 4 178-178 B 45.35 4 . 6 4 8 . 2 1 ... 131-132 A-B 51.21 6 . 1 4 8 . 5 3 ,51.09 6 . 1 8 8.59 b Identical v-ith a A = ethanol, B = water, C = dissolved in XaOH and reprecipitated with HC1, D = methanol-water-ether. the compound prepared by alkaline hydrolysis of ~ - ~ ~ 4 - t o ~ y ~ s ~ ~ l f o n y l ~ c a r b a m ~ethyl y l ] gester.3 l y c i l l e c In this case the ester was employed as indicated in the Experimental Section. The compound is N- [(Ctolylsulfoiigl)carbamoy1]-6-amiiiocaproicacid.
7 8 9
H,N&Tu'II(CIIn)s HOkXCHz),
analytical sample was prepared by recrystallizing a small portion of t h e solid twice from ethyl acetate and benzene; mp 139-141'. A n a l . Calcd for C ~ ~ H ~ T N ~C,O 55.34; ~ S : H, 5.70; N, 8.80. Found: C, 55.62; H, 5.92; N, 8.88. N~-[(4.T0lyI~~lfonyl)~arbamoyl] lysine (6).-The crude Wbenzyloxycarbonyl-N2-[(Ptolylsulfonyl)carbamoyl]lysine (9.0 g), prepared above, was dissolved in a mixture of 200 ml of methanol and 50 ml of water containing 1 ml of glacial acetic acid. The mixture was shaken with 0.8 g of lOy0Pd-C in a Parr apparatus until 1 mole of hydrogen/mole of compound was absorbed (1 hr). The mixture was filtered, the filtrate was evaporated in vacuo to almost dryness, and acetone was added to yield a white solid which was dried to give 3.7 g of product, mp 170". Recrystallization from methanol-water-ether yielded 1.9 g, mp 17317-5". Further recrystallization did not raise the melting point. N- [(4-Tolylsulfonyl)carbamoyl]glutamic Acid (8).--A mixture of 0.046 mole (11.1 g ) of L-glutamic acid diethyl ester hydrochl0ride7~ and 0.02 mole (4.3 g ) of 4-tolylsulfonylurea was heated at, 100-110" for 3.0 hr. The resulting oil was taken up in 150 ml of water, extracted with three 75-ml portions of ether, dried (Drierite), and evaporated to give an oil. The oil was taken up u.ith 1 ;V Na2COa and extracted with ether. The aqueous layer was acidified with 3 A: HCl and extracted with ether, and the ether was evaporated to give an oil which, upon treatment with water, yielded 13.4 g of a solid. The solid was treated with 100 ml of a 10% ethanolic KOH solution a t 0' and then allowed to stand overnight a t room temperature. T h e mixture was concentrated in vacuo, the residue was dissolved in 100 ml of water and acidified to congo red with concentrated HC1 to yield a solid. T h e solid was dissolved in a saturated KzC03 solution, reprecipitated with 3 J\- HCl, and recrystallized from water to give 4.1 g of product, mp 178-179". Further recrysta.llizrttion did not raise the melting point.
Substituted 2-Phenoxypropionic and -butyric Acids and Derivatives E. M A G N I E XF. , TEsrr.i, A N D
s. L. SHIPIKO
U . S . V i t a m i n and Pharmaceutical Corporation, Yonkers, S e w York
10701
Received January 26, 1966 We have prepared a series of 0-phenoxy-substituted propionic arid butyric acid derivatives. Among the derivatives are the esters, acids, hydroxamates, and amides. These compounds were tested for possible use as hypocholesteremic agents. Some of these compounds had moderate activity in lowering of serum
cholesterol in guinea pigz. The most active compoiindb were 8, 12, 13, 17, 37, 39,43, and 51 (Table I). Experimental Section' Preparation of Esters and Acids.-The esters were prepared by refluxing equimolar amounts of the phenol, a-bromo ester, and K2COa in acetone. The esters were obtained by vacuum distillation. The acids were obtained by hydrolysis of the esters in refluxing 2 S NaOH for 1 hr followed by neutralization and filtration of the insoluble acids. The amides were prepared by three methods. Method 1. N-(4-Carbethoxy)phenyl-2-o-allylpropionamide (9).-To a solution of 6.6 g (0.04 mole) of ethyl p-aminobenzoate 111 30 ml of dry ether was added 4.5 g (0.02 mole) of 2-0-allylphenoxypropioiiyl chloride while maintaining the solution a t 0". After 2 hr, the amine hydrochloride was filtered off. The filtrate was evaporated to dryness and the product distilled to obtain 3.2 g of bp 212-214' (0.03 mm), n P 3 D 1.5714. Method 2. N-(4-Pyridyl)-2-o-phenylphenoxybutyramide(51). --4 mixture of 2..5 g (0.01 mole) of 2-o-phenylphenoxybut,yric acid, 0.94 g (0.01 mole) of 4-aniinopyridine, and 2.1 g (0.01 mole) lohexylcarbodiiniide in 40 nil of acetonitrile was stirred for 3 hr a t 25", then allowed to stand overnight. The dicyclohexylurea (2.3 g ) m-as filtered off, and the filtrate was evaporated to dryness in Llacuo. The amber-colored residue was dissolved in dry ether, and excess HCl was passed into the solution. The crude hydrochloride (2.0 g ) was crystallized from ethanol-ether to give 1.6 g, mp 176-178". Method 3. N-Methyl-N'-2-o-allylphenoxypropionylpiperazine (12).-A mixture of 7.0 g (0.03 mole) of ethyl 2-o-allylphenoxypropionate, 3.0 g (0.03 mole) of N-methylpiperazine, and 0.1 g of sodium in 2 ml of ethanol was refluxed until no more ethanol v a s removed in a Dean-Stark trap (approximately 2 hr). The mixture was cooled and partitioned between ether and 3 N HC1. The water extract was saturated with K z C O ~and , the product was extracted into ether. After removal of the ether, the product was distilled to yield 4.9 g of material with bp 142-144" (0.04 mm). This product solidified on stauding and was crystallized from hexane to yield 2.3 g, mp 84-88'. 2-o-Allylphenoxybutyrohydroxamic Acid (14).-A solutioir containing 0.02 mole of hydroxylamine was prepared from 1.39 g (0.02 mole) of hydroxylamine hydrochloride and 0.46 g (0.02 g-atom) of sodium in 50 ml of ethanol. After removal of the Tu'aC1, 2.48 g (0.01 mole) of ethyl 2-o-allylphenoxybutyrate was added. The solution was allowed to stand a t room temperature for 40 days. The solvent was removed in vacuo leaving a solid residue of 2.5 g, mp 111-118'. Two crystallizations from ethyl acetate-hexane gave analytically pure material of mp 127-128'. (1) Melting points were determined on a calibrated Fisher-Johns apparatus. Elemental analyses were determined b y Drs. IYeiler and Strauss, Oxford, England.
