Synthesis, Skin Permeation, and PLS-Analysis of Naproxen Derivatives
601
Synthesis of Naproxen Derivatives 02–15
1505 cm−1. MS 299 (8,M), 212 (2), 185(100). Anal.
(C18H21NO3) C,H,N.
N-[2-(6-Methoxy-2-naphthyl)propionyl]-L-serine (02)
Aminocarbonylmethyl-2-(6-methoxy-2-naphthyl)propionate
(07)
L-Serine (1.05 g; 0.01 mol) was dissolved in 20 ml of
water containing 1.2 g (0.03 mol) NaOH. After addition of 50
ml water and 50 ml acetone, a solution of the acid chloride of
naproxen (7) (2.49 g; 0.01 mol) in a minimum amount of
acetone was added dropwise and the solution was stirred for
6 h at 20°C. After evaporation to half of the volume, 50 ml
water and sufficient dilute HCl was added to acidify the so-
lution. Extraction with ethyl acetate after drying with magne-
sium sulphate, filtration, and evaporation gave 1.77 g (56%)
of a white, crystalline powder, mp. 182°C (from ethanol/
diethyl ether). 1H-NMR ␦ 1.40 (d,3H), 3.35 (s,OH), 3.67
(t,2H), 3.86 (s,3H), 3.90 (q,1H), 4.30 (dt,1H), 7.1-7.8 (m,6H),
8.15 (d,NH), 12.51 (s,COOH). IR (KBr) 3554, 3322, 2982,
2940, 2902, 1741, 1715, 1636, 1605, 1551 cm−1. MS 317 (11,M),
299 (3), 255 (1), 230 (3), 185(100). Anal. (C17H19NO5) C,H,N.
Naproxen (2.30 g, 0.01 mol), 1.10 g (0.011 mol) triethyl-
amine, 1.03 g (0.011 mol) 2-chloroacetamide and 0.15 g (0.001
mol) sodium iodide were mixed in 10 ml DMF and stirred for
2 h at 90°C. After cooling, 50 ml water was added to the
mixture and it was extracted three times with 50 ml ethyl
acetate. The combined organic phase was washed successively
with sodium thiosulphate (2%) and sodium bicarbonate
(2%). After drying (MgSO4) and filtration, the residue of the
evaporated organic phase gave 2.13 g (74%) white crystals,
mp. 145°C (from ethanol). 1H-NMR ␦ 1.50 (d,3H); 3.87
(s,3H), 4.04 (q,1H), 4.35 (d,1H) 4.48 (d,1H), 7.1-7.8 (m,6H).
IR (KBr) 3488, 3062, 2997, 2982, 2963, 1723, 1693, 1678, 1603,
1505 cm−1. MS 287 (15,M), 269 (1), 229 (1), 212 (28), 185
(100). Anal. (C16H17NO4) C,H,N.
N-[2-(6-Methoxy-2-naphthyl)propionyl]-L-threonine (03)
N,N-Diethylcarbonylmethyl-2-(6-methoxy-2-
naphthyl)propionate (08)
This compound was prepared as described for 02 from
naproxen acid chloride (7) and L-threonine to give 2.85 g
(86%) of 03 as a white cystalline powder, mp. 179°C (from
acetone/hexane). 1H-NMR ␦ 1.07 (d,3H), 1.42 (d,3H), 3.86
(s,3H), 4.01 (q,1H), 4.24 (dd,1H), 7.1-7.8 (m,6H), 7.91 (d,NH).
IR (KBr) 3546, 3314, 3056, 2982, 2938, 1734, 1710, 1635, 1606,
1557, 1501 cm−1. MS 331 (6,M), 313 (2),287 (1), 269 (2), 185
(100), 170 (12), 141 (19), 115 (13). Anal. (C18H21NO5) C,H,N.
This compound was prepared according to the procedure
described for 07 with 1.64 g (0.011 mol) N,N-
diethylchloroacetamide (Lancaster) and gave 3.16g (92%)
white crystals, mp. 93°C (from ethanol) [lit.(13) mp. 89-
1
89,5°C, no spectroscopic data given]. H-NMR ␦ 0.99 (t,3H),
1.07 (t,3H), 1.51 (d,3H), 3.1-3.3 (m,4H), 3.87 (s,3H), 4.00
(s,1H), 4.75 (dd,2H), 7.1-7.8 (m,6H). IR (KBr) 3048, 2978,
2940, 2873, 1745, 1661, 1605, 1505 cm−1. MS 343 (4,M), 271
(1), 230 (1), 212 (100), 185 (56). Anal. (C20H25NO4) C,H,N.
N,N-Diethyl-2-(6-methoxy-2-naphthyl)propionamide (04)
Naproxen acid chloride (7) (2.49 g, 0.01 mol) was dis-
solved in 50 ml chloroform and 1.4 g (0,02 mol) diethylamine
was added. After 10 h of stirring at 20°C the organic phase
was washed successively with dilute HCl, NaOH, and water,
dried with magnesium sulphate and evaporated. The residue
was recrystallized from diethyl ether to yield 2.45 g (86%) of
N,N-Diethanolaminocarbonylmethyl-2-(6-methoxy-2-
naphthyl)propionate (09)
The corresponding chloroacetamide was not commer-
cially available. It was prepared from ethyl-chloroacetate and
diethanolamine at 0°C. The complete reaction to the amide
was detected by IR-spectroscopy (strong absoption band at
1644 cm−1 instead of the ester band at 1738 cm−1). Following
the procedure for 07 compound 09 was obtained as 1.61 g
(43%) of a white powder, mp. 117°C (from ethyl acetate/
diethyl ether) [lit.(14) mp. 113–114°C, no spectroscopic data
given]. 1H-NMR ␦ 1.50 (d,3H), 3.3-3.5 (m,8H), 3.86 (s,3H),
3.99 (q,1H), 4.69 (t,OH), 4.86 (t,OH), 4.86 (dd,2H), 7.1-7.8
(m,6H). IR (KBr) 3362, 3058, 2991, 2963, 2940, 1737, 1632,
1604, 1504 cm−1. MS 375 (3,M), 358 (2), 344 (5), 328 (1) 286
(2), 271 (1), 230 (3), 212 (50), 185 (100). Anal. (C20H25NO6)
C,H,N.
1
a white powder, mp. 79°C (lit.12 no data given). H-NMR ␦
0.92 (t,3H), 1.01 (t,3H), 1.37 (d,3H), 3.1-3.5 (m,4H), 3.88
(s,3H), 4.12 (q,1H), 7.1-7.8 (m,6H). IR (KBr) 3058, 3027,
3005, 2976, 2961, 2951, 1636, 1602, 1505 cm−1. MS 285 (5,M)
256 (1), 212 (1), 185 (94), 100 (100). Anal. (C18H23NO2),
C,H,N.
N,N-Bis-(2-hydroxyethyl)-2-(6-methoxy-2-
naphthyl)propionamide (05)
This compound was prepared as described for 04 with
diethanolamine and obtained as 1.27 g (40%) of white crys-
1
tals, mp. 97°C (from ethyl acetate/diethyl ether). H-NMR ␦
1.34 (d,3H), 3.1-3.6 (m,8H), 3.86 (s,3H), 4.27 (q,1H), 4.64
(OH), 4.86 (t,OH), 7.1-7.8 (m,6H). IR (KBr) 3362, 3057, 2968,
2929, 2870, 1606, 1505 cm−1. MS 317 (8,M), 286(1), 272 (1),
228 (1), 212 (2), 185 (100). Anal. C18H23NO4) C,H,N.
Morpholinocarbonylmethyl-2-(6-methoxy-2-
naphthyl)propionate (10)
The ester 10 was prepared as described for 07. The chlo-
roacetylamide was synthesized from chloroacetyl chloride
and morpholine (1:2). 10 was isolated as 3.11 g (87%) of white
4-[2-(6-Methoxy-2-naphthyl)propionyl]-morpholine (06)
This compound was prepared as described for 04 with crystals, mp. 123°C (from ethyl acetate/diethyl ether). 1H-
morpholine and was isolated as 2.84 g (95%) of white crystals, NMR ␦ 1.51 (d,3H), 3.3-3.5 (m,8H), 3.87 (s,3H), 4.01 (q,1H),
mp. 112°C (from ethyl acetate/diethyl ether). 1H-NMR ␦ 1.37 4.88 (dd,2H), 7.1-7.8 (m,6H). IR (KBr) 3049, 2967, 2933, 2906,
(d,3H), 3.1-3.6 (m,8H), 3.88 (s,3H), 4.23 (q,1H), 7.1-7.8 1742, 1657, 1605, 1505 cm−1. MS 357 (7,M), 270 (1), 228 (1),
(m,6H), IR (KBr) 3055, 3007, 2962, 2925, 2899, 1632, 1604, 212 (100), 185 (72). Anal. (C20H23NO5) C,H,N.