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Synthesis of N-Acylamino-ethoxyacetic Acid Derivatives.

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Synthesis of N- Acylamino-ethoxyaceticAcid Derivatives
Synthese von N-Acylamino-ethoxyesigsiure-Derivaten
Ervin KoroSec, Darja PoljSak, and UroS Urleb*
Department of Pharmacy, University of Ljubljana, ASkerceva 9,61000 Ljubljana, Slovenia
Received November 19,1991
In the course of our investigation towards the design and
synthesis of potential immunomodulators related to muramyldipeptide'), N-acylaminoethoxyacetic acid derivatives
were needed as valuable key intermediates for the synthesis
of some model compounds.
Such aliphatic amino acid compounds in which the carboxylic group and
an acylated amino group are separated by three or four units are useful in
treatment of convulsive disorders and also have anxiolytic and sedative
properties2).They are also suitable as ingredients in phosphate-free washing and cleaning agents3'.
Some syntheses on this type of compounds have been described24).
In this communication we report about a simple and quick
approach to the N-acylaminoethoxyacetic acid derivatives.
A common feature of all of these transformations is the
selective N-acylation of 2-(2-aminoethoxy)ethanol (1)followed by oxydation with Jones reagent5).
Three different types of acylating reagents were used. 2(2-aminoethoxy)ethanol (1)was transformed with N-carbethoxyphthalimide6) into N-(2-(2-hydroxyethoxy)-ethyl)
phthalimide (2a)(Scheme 1).
Treatment of 1 with the N-hydroxysuccinimide ester of
dodecanoic acid7) led selective N-acylation even in the
presence of an unprotected hydroxyl group and gave N-(2(2-hydroxyethoxy)ethyl) dodecanoylamide (2b). The third
type of acylating reagents were carboxylic acid chlorides
such as p-chlorobenzoyl chloride or 1-adamantmecarbony1
chloride which gave in reaction with 1 N-(2-(2-hydroxyethoxy)ethyl)4chlorbenmide (2c) and N-(2-(2-hydroxyethoxy)ethyl)-1-adamantane carboxamide (2d) (Scheme 1).
Under the described conditions 0-acylated products were
formed only in traces. The N-acylated aminoalcohols afforded upon oxidation with Jones reagent carboxylic acid
derivatives 3a-d (Scheme).
This work was supported by the Research Council of Slovenia.
Experimental Part
Melting points: Reichert hot stage microscope, uncorrected.- IR:PerkinElmer FlTR 1600.- 'H-NMR: 300 MHz, Varian VXR-300. Tetramethylsilane as internal standard.- Microanalyses: a Perkin-Elmer elemental analyzer 2400 CHN.
Generalprocedure for the acylation with N-hydroxysuccinimideesters or
with N-carbethoxyphthalimide
A solution of the acylating reagent (2 mmol) in anhydrous THF (7 ml)
was added dropwise to the stirred solution with ice-bath cooling of 1 (2
mmol) in anhydrous THF (10 ml). Temp. of the reaction mixture was then
left to reach room temp. and stirring was continued for 12 h, THF was
removed under reduced pressure and the residue purified using column
2a purified using gel filtration (Sephadex-Pharmacia, methano1:chloro-
form = 1:l) and recrystallization from ethylacetate,SO%, m.p. 63-64OC.- 'HNMR (CDCl3): 6 (ppm) = 3.40-4.0 (m; 8H, 4 CH,); 7.40-7.80 (m; 4H, phthaloyl).- IR (KBr): 3560, 2900, 1720: 1480: 1440; 1200, 1120 cm-'.C12H13N04 (235.2 ) Calc. C 61.3 H 5.57 N 5.95 Found C 61.4 H 5.76 N 6.0.
White , q s t a l s (si!ica gel, chlorofomxmethanol = 15:1), 87%, m.p. 6062°C.- 'H-NMR (CDCI,): 6 (ppm) = 0.88 (t; 3 H J = 6.7 Hz; CH3), 1.16-
Arch. Pharm. (Weinheim)325,251-252(1992)
OVCH VerlagsgesellschaftmbH, D-6940 Weinheim, 1992
2; 3 b
2; k
R = dodecanoyl
R = p-chlorophenyl
R = adamantyl
0365-6233/92/0404-0251 $3.50 -k .25/0
1.40 (m: 16 H; 8 CH2), 1.52-1.70 (m;2 H CH2). 2.18 (t; 2H, J = 7.7 Hz,
CHzO), 3.40-3.50 (m; 2H, NH-CHz), 3.52-3.63 (m; 4 H 2 CH2),3.71-3.80
(m: 2H, CftOH), 6.11 (br. s; lH, NH).- IR (KBr): 3300,2910 1650; 1550;
I130 1070 cm-'.- CI6H33NO3(287.4) Cak. C 66.9 H 11.57 N 4.9 Found C
66.9 H 11.67 N 5.0.
Generalprocedurefor the acylation with carboqlic acid chlorides
A solution of an acylating reagent (25 mmol) in anhydrous 1,Cdioxane
(30 ml) was added dropwise to the stirred solution of 1 (25 mmol) in 12.5
ml2M NaOH with ice-bath cooling. The temp. of the reaction mixture was
then allowed to reach rmm temp. and stimng was continued for 5 h. The
solvent was removed under reduced pressure, water (30 ml) was added and
the product was extracted with ethyl acetate (5 x 25 ml). After drying
(MgSO,), the solvent was removed i.vac. and the residue purified using
column chromatographyor recrystallization.
White crystals (diethylether), 77%. m.p. 8344°C.- 'H-NMR (CDC13): 6
(ppm) = 2.57 (s; IH, OH), 3.48-3.90 (m; 8H, 4 CH3.6.93 (br. s; lH, NH),
7.38 (d;2H, J = 9 Hz, 2-H, 6-H), 7.79 (d; 2H, 3-H, 5-H).- IR (KBr): 3350
2980; 2900; 1645; 1600; 1550 1125 cm-'.- Cl1Hl4C1NO3(243.7) Calc. C
54.2 H 5.79 N 5.8 Found C 54.3 H 5.98 N 5.6.
White crystals (acetone), 86%. m.p. 72-73°C.- 'H-NMR (CDCL,): 6
(pprn) = 1.71-2.1 (3 m: 15 H, adamantyl), 2.58 (br.; lH, OH), 3.42-3.50 (m;
2H. NHCH-J, 3.54-3.62 (m; 4H, 2 CHd, 3.74 (t; 2H, J = 4.6 Hz,CH2). 6.15
(s; lH, NH).- IR (KBr): 3346; 2903; 1633; 1531; 1452; 1285; 1133; 1070;
889 cm-'.- C15H25N03(267.4) Calc. C 67.4 H 9.42 N 5.2 Found C 67.2 N
9.55 N 5.1.
KoroSec, Poljk&, and Urleb
(s; 4H, phthaloyl).- IR (KBr): 3220; 1765; 1695; 1400; 1190; 1130; 1045;
1o00, 730 cm-'.- CI2HllNO5(249.2) Calc. C 57.8 H 4.45 N 5.6 Found C
57.8 H 4.51 N 5.7.
white crystals (acetone), 55%, m.p. 69-73°C (lit.'? m.p. 76"C).- 'HNMR (DMSO-d6): 6 (ppm) = 0.84 (t; 3H, J = 6.7 Hz, CH3), 1.16-1.30 (m;
16 H, 8 CH2). 1.38-1.52 (m;2H. CftCH2CO-), 2.03 (t; 2H, J = 7.4 Hz,
CbCO-), 3.15-3.25 (dt; 2H, NHCH2-), 3.44 (ti 2H, J = 5.9 Hz, C&O-),
3.97 (s; 2H, CH&DOH), 7.81 and 8.09 (2t; lH, J = 4.7Hz; NH), 12.6 (br.;
IH, COOH).- C16H31N04(301.4) Calc. C 63.7 H 10.37 N 4.6 Found C
63.3 H 10.41 N 4.8.
White crystals (ethyl acetate), 71%. m.p. 127-130°C.- 'H-NMR (DMSOd6): 6 (ppm) = 3.13-3.73 (m; 4H, NHCftCm, 4.1 (s; 2H, CH2COOH),
7.55 (d; 2H, J = 9 Hz; 2'-H, 6'-H), 7.9 (d; 2H, 3'-H, 5'-H).- IR (KBr):
3350; 2910; 1730; 1630; 1570; 1200, 1145; 1015 cm-'.- CllH14C1N03
White crystals (acetone), 86%, m.p. 120-124OC.- 'H-NMR (DMSO-d6):
6 (pprn) = 1.62-2.14 (m; 15 H, adamantyl); 3.4-3.53 (m; 2H, NHCHz), 3.65
(t; 2H, J = 4.7 Hz; CH~CHZO),
4.14 (s; 2H, CH2). 6.36 and 6.71 (2t; lH, J
= 4.6 Hz; CONHCHz), 7.93 (br.; lH, COOH).- IR (KBr): 3374; 2906,
1728; 1607; 1545; 1453; 1219; 1142.- C15H23NO4 (279.3) Calc. C 64.0 H
8.26 N 5.0 Found C 64.1 H 8.01 N 5.4.
S. Pecar, M. Sollner, U. Urleb et al., Eur. Pat. Appl. 91 116 356.6
I. Fish, N.J. Tenafly, AS. Schwartz, and S.Samuels, U.S. Pat.
To a stirred solution of 2a-d (5 mmol) in acetone (30 ml) CrO3 (12
4,372,974 (Jun. 1981) and U.S.Pat. 4,322,440 (Jun. 1980); C.A. 99,
mmol) in 35% H$04 (25 ml) was added dropwise at 0-3°C. The temp. of
P47926r (1983).
J.H. Krause and E. Schmadel, Ger. Offen. 26,44,498 (Apr. 1980); C.A.
the reaction mixture was then allowed to reach room temp. and stimng was
89,7790n (1978).
continued for 3 h. The mixture was poured into water (300 ml) and the
I. Danklmaier and H. Hoenig,Liebigs Ann. Chem. 1990,145.
product was extracted with ethyl acetate (5 x 50 ml). After drying
K. Bowden, LM. Heilbron, E.R.H. Jones, and B.C.L. Weedon, J.
(NazSOd), the solvent was removed i.vac.
Chem. SOC.1946,39.
P.M. Worster, C.C. Leznoff, and C.R. McArthur, J. Org. Chem. 45,
acid (3a)
174 (1980).
A. Paquet, Can. J. Chem. 57,2775 (1979).
White crystals (acetone), 80%. m.p. 127-129°C.- 'H-NMR (DMSO-d6):
6 (ppm) = 3.69-3.77(m;4H,NCH2CH20),3.99(s;2H,OCftCOOH),7.85
Generalprocedurefor the oxidation of N-acylatedderivatives of
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acid, synthesis, ethoxyacetic, acylamino, derivatives
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