126
Vol. 55, No. 1
(MꢃH)ꢃ. IR (KBr) cmꢁ1: 1794, 1768, 1732. 1H-NMR (CDCl3) d: 2.89 (4H,
s, Pyr), 7.50—7.53 (2H, m, Ar H-3, H-5), 7.66—7.69 (1H, m, Ar H-4),
8.13—8.15 (2H, m, Ar H-2, H-6). 13C-NMR (CDCl3) d: 25.7 (Pyr C-3, C-
4), 125.2 (Ar C-1), 128.8 (Ar C-3, C-5), 130.5 (Ar C-2, C-6), 134.9 (Ar C-
4), 161.9 (–COO), 169.1 (Pyr C-2, C-5). Anal. Calcd for C11H9NO4: C,
60.27; H, 4.14; N, 6.39. Found: C, 60.24; H, 4.24; N, 6.34.
Experimental
Melting points are uncorrected. IR spectra were measured by Shimadzu
FTIR-8100 spectrometer. 1H- and 13C-NMR spectra were obtained on a
JEOL JNM A-500 (500 MHz for H, 125 MHz for 13C) at 35 °C unless oth-
1
erwise noted. Chemical shifts are expressed as d ppm downfield from an in-
1
ternal tetramethylsilane (TMS). Signal assignments were confirmed by H--
1H correlation spectroscopy (COSY), 1H–13C heteronuclear multiple-quan-
Pyrrolidine-2,5-dion-1-yl 3,4-Dichlorophenylacetate (2f) FAB-MS
tum coherence (HMQC), or H–13C heteronuclear multiple-bond connectiv-
1
1
(positive) m/z: 302 (MꢃH)ꢃ. IR (KBr) cmꢁ1: 1821, 1784, 1730. H-NMR
ity (HMBC) spectra. FAB-MS were obtained by JEOL JMS-HX110 mass
spectrometer. The preparation of racemic b-aminoalanines (3a, b) as starting
materials has already been described in our previous paper.12) The following
abbreviations in brackets were used: cyclohexane ring (Cyhx), piperidine
ring (Ppd), pyrrolidine ring (Pyr), and benzotriazole group (Bt).
(CDCl3) d: 2.83 (4H, s, Pyr), 3.89 (2H, s, CH2Ph), 7.18—7.19 (1H, m, Ar
H-6), 7.43—7.46 (2H, m, Ar H-2, H-5). 13C-NMR (CDCl3) d: 25.6 (Pyr C-
3, C-4), 36.7 (CH2Ph), 128.6 (Ar C-6), 130.8 (Ar C-5), 131.3 (Ar C-2),
131.4 (Ar C-4), 132.3 (Ar C-3), 132.9 (Ar C-1), 165.9 (–COO), 168.7 (Pyr
C-2, C-5). Anal. Calcd for C12H9NO4Cl2: C, 47.71; H, 3.00; N, 4.64. Found:
C, 47.75; H, 3.10; N, 4.66.
Isolation of Activated Carboxylic Acid (2). General Procedure At
room temperature, 1-ethyl-3-(3ꢀ-dimethylaminopropyl)carbodiimide hydro-
chloride (WSCI) (5.5 mmol) was added to a solution of carboxylic acid (1)
(5.0 mmol) and 1-hydroxybenzotriazole monohydrate (HO-Bt) (5.5 mmol) or
1-hydroxysuccinimide (HO-Su) (5.5 mmol) in dichloromethane (CH2Cl2) or
dimethylformamide (DMF) and the resulting mixture was stirred until the
starting material disappeared. In case of entries 1, 4, and 6 (Table 1), the re-
action mixture was washed with water. After drying over Na2SO4, evapora-
tion of the solvent gave the desired products (2a,d, f) in almost quantitative
yields. In the case of entries 2, 3, and 5 (Table 1), after addition of water the
precipitates were collected by filtration or the resulting mixture was ex-
tracted with diethyl ether, washed with brine, and dried over Na2SO4. Evapo-
ration of the solvent afforded good purity of the compounds (2b, c, e). The
products could be used for the next stage without further purification.
1H-Benzotriazol-1-yl trans-2-Benzoylcyclohexanecarboxylate (2a)
FAB-MS (positive) m/z: 350 (MꢃH)ꢃ. IR (KBr) cmꢁ1: 1802, 1678. 1H-
NMR (CDCl3) d: 1.56—1.60 (3H, m, Cyhx H-3, H-4, H-5), 1.78—1.84
(1H, m, Cyhx H-6), 1.94—1.99 (1H, m, Cyhx H-4), 2.08—2.14 (1H, m,
Cyhx H-5), 2.19—2.25 (1H, m, Cyhx H-3), 2.37—2.44 (1H, m, Cyhx H-6),
3.26 (1H, dd, Jꢂ11.0, 4.5 Hz, Cyhx H-1), 3.94—3.98 (1H, m, Cyhx H-2),
7.26—7.41 (1H, m, Bt Ar-H), 7.47—7.60 (4H, m, Bt Ar-Hꢄ2 and m-Ar-H),
7.85 (1H, d, Jꢂ8.0 Hz, p-Ar-H), 7.93 (2H, dd, Jꢂ8.5, 1.0 Hz, o-Ar-H), 8.02
(1H, d, Jꢂ8.0 Hz, Bt Ar-H). 13C-NMR (CDCl3) d: 25.3, 25.5 (Cyhx C-4, C-
5), 29.1 (Cyhx C-6), 30.0 (Cyhx C-3), 42.4 (Cyhx C-1), 47.9 (Cyhx C-2),
108.8 (Bt Ar-C), 120.2 (Bt Ar-C), 124.7 (Bt Ar-C), 128.4, 128.6, 128.7 (o,
m-Ar-C and Bt Ar-C), 133.4 (p-Ar-C), 135.5 (Bt Ar-C), 135.7 (Ar C-1),
143.4 (Bt Ar-C), 171.7 (–COO), 202.1 (COPh). Anal. Calcd for C20H19N3O3:
C, 68.75; H, 5.48; N, 12.03. Found: C, 68.72; H, 5.53; N, 12.03.
1H-Benzotriazol-1-yl 4-(1-Piperidinyl)-3-fluorobenzoate (2b) FAB-
MS (positive) m/z: 341 (MꢃH)ꢃ. IR (KBr) cmꢁ1: 1782, 1611. 1H-NMR
(CDCl3) d: 1.66—1.69 (2H, m, Ppd H-4), 1.73—1.78 (4H, m, Ppd H-3, H-
5), 3.30—3.33 (4H, m, Ppd H-2, H-6), 7.00 (1H, t, Jꢂ8.5 Hz, Ar H-2),
7.27—7.45 (2H, m, Bt Ar-H), 7.52—7.55 (1H, m, Bt Ar-H), 7.84 (1H, dd,
Jꢂ4.0, 2.0 Hz, Ar H-5), 7.94—7.97 (1H, m, Ar H-6), 8.08 (1H, d, Jꢂ8.0 Hz,
Bt Ar-H). 13C-NMR (CDCl3) d: 24.2 (Ppd C-4), 25.8 (Ppd C-3, C-5), 50.9
(Ppd C-2 , C-6), 108.4 (Bt Ar-C), 114.8 (Ar C-1), 117.9 (Ar C-2, Jꢂ4.0 Hz),
118.4 (Ar C-5, Jꢂ24.0 Hz), 120.5 (Bt Ar-C), 124.7 (Bt Ar-C), 128.2 (Ar C-
6), 128.6 (Bt Ar-C), 129.0 (Bt Ar-C), 143.6 (Bt Ar-C), 146.9 (Ar C-4,
Jꢂ7.0 Hz), 153.6 (Ar C-3, Jꢂ247.0 Hz), 161.9 (CO). Anal. Calcd for
C18H17N4O2F: C, 63.52; H, 5.03; N, 16.46. Found: C, 63.64; H, 5.16; N,
16.34.
Preparation of 2-[(2-Benzoylcyclohexane)carboxamido]-3-(piperidin-
1-yl)propanoic Acid (4a) A solution of b-aminoalanine dihydrochloride
(3a) (0.35 g, 1.43 mmol) in potassium bicarbonate (K2CO3) (0.99 g,
7.17 mmol) in H2O (ca. 8 ml) was added to a solution of activated carboxylic
acid (2a) (0.5 g, 1.43 mmol) in CH2Cl2, then EtOH (10 ml) was added to this
solution. After stirring for 5 h at room temperature, the reaction mixture was
concentrated under reduced pressure and the residue triturated with EtOH to
give a solid material. After separation of this product by filtration, the filtrate
was concentrated, and purification of the product by silica gel column with
ethanol as solvent afford 4a (0.49 g, 89%). FAB-MS (positive) m/z: 387
(MꢃH)ꢃ. IR (KBr) cmꢁ1: 3363, 3262, 1665, 1640, 1607. 1H-NMR (CDCl3)
d: 1.25—2.12 (14H, m, Ppd H-3, H-4, H-5 and Cyhx H-3, H-4, H-5, H-6),
2.72—2.87 (1H, m, Cyhx H-1), 2.92—3.35 (6H, m, Ppd H2, H-6 and CH2-
1-piperidinyl), 3.62—3.67 (1H, m, Cyhx H-6), 4.26—4.30 (1H, m, NHCH-
COOH), 5.0—7.0 (1H, br, COOH), 7.47 (1H, dd, Jꢂ15.0, 7.5 Hz, CONH),
7.50—7.56 (3H, m, m, and p-Ar-H), 7.96—7.98 (2H, m, o-Ar-H). 13C-NMR
(CDCl3) d: 22.1, 22.2, 22.8, 25.5, 25.6, 29.8, 30.0 (Cyhx C-3—C-6 and Ppd
C-3—C-5), 46.2 (Cyhx C-1), 46.9 (Cyhx C-2), 49.2 (CONHCHCOOH),
53.9 (ꢄ2) (Ppd C-2, C-6), 56.9 (CH2-1-piperidinyl), 128.5 (ꢄ3), 128.6 (Ar
C-2, C-3, C-5, C-6), 132.7 (Ar C-4), 136.5 (Ar C-1), 172.3 (COOH), 175.4
(CONH), 203.2 (COPh). Anal. Calcd for C22H30N2O4·H2O: C, 65.32; H,
7.97; N, 6.93. Found: C, 65.25; H, 8.00; N, 6.92.
Preparation of 2-[3-Fluoro-4-(piperidin-1-yl)benzamido]-3-(pi-
peridin-1-yl)propanoic Acid (4b) A solution of b-aminoalanine dihydro-
chloride (3a) (0.43 g, 1.76 mmol) and K2CO3 (1.21 g, 8.76 mmol) in H2O
(ca. 10 ml) was added to a solution of activated carboxylic acid (2b) (0.6 g,
1.76 mmol) in acetonitrile (CH3CN), and the mixture was stirred for 0.5 h.
After concentration under reduced pressure, 1 N-hydrochloric acid (1 N-HCl)
was added to make the solution pH ca. 5. Evaporation of the solvent gave a
viscous residue, and then trituration of this product with EtOH afforded
solid material. After separation of this material by filtration, the filtrate was
concentrated and purified through a silica gel column (ethanol→ethanol/am-
monia as solvent) to give 4b (0.52 g, 78%). FAB-MS (positive) m/z: 378
(MꢃH)ꢃ. IR (KBr) cmꢁ1: 3390, 3260, 1650, 1617. 1H-NMR (DMSO-d6) d:
1.43—1.46 (2H, m, Ppd H-4), 155—1.67 [10H, m, (Ppd H-3ꢄ2, H-5ꢄ2 and
H-4)ꢄ2], 2.69—2.94 [10H, m, (Ppd H-2ꢄ2, H-6ꢄ2)ꢄ2 and CH2-1-
piperidinyl], 4.50—4.51 (1H, m, NHCHCOOH), 4.65 (1H, br, COOH), 7.05
(1H, t, Jꢂ8.5 Hz, Ar H-2), 7.58—7.63 (2H, m, Ar H-5, H-6), 8.24 (1H, d,
Jꢂ7.0 Hz, NH). 13C-NMR (DMSO-d6) d: 22.7, 23.6 (Ppd C-4), 24.5 (ꢄ2),
25.4 (ꢄ2) (Ppd C-3, C-5), 48.6 (CHCOOH), 51.8 (ꢄ4) (Ppd C-2, C-6), 64.8
(CH2-1-piperidinyl), 114.8, (Ar C-5), 118.3 (Ar C-2), 124.0 (Ar C-6), 126.7
(Ar C-1), 143.0 (Ar C-4), 153.7 (d, Jꢂ244.1 Hz, Ar C-3), 164.5 (CONH),
172.4 (COOH). Anal. Calcd for C20H28N3O3F·0.3H2O: C, 62.74; H, 7.53; N,
10.98. Found: C, 62.73; H, 7.70; N, 10.75.
1H-Benzotriazol-1-yl
4-Amino-5-chloro-2-methoxybenzoate
(2c)
FAB-MS (positive) m/z: 319 (MꢃH)ꢃ. IR (KBr) cmꢁ1: 3422, 3322, 1786,
1636. 1H-NMR (DMSO-d6) d: 3.83 (3H, s, OCH3), 6.46 (1H, s, Ar H-3),
6.58 (2H, br s, NH2), 7.51, 7.64 (each 1H, dd, Jꢂ7.0, 1.0 Hz, Bt Ar-H), 7.78
(1H, d, Jꢂ8.0 Hz, Bt Ar-H), 8.03 (1H, s, Ar H-6), 8.14 (1H, d, Jꢂ8.0 Hz, Bt
Ar-H). 13C-NMR (DMSO-d6) d: 55.9 (OCH3), 97.1 (Ar C-3), 99.0 (Ar C-1),
108.8 (Ar C-5), 109.8 (Bt Ar-C), 119.7 (Bt Ar-C), 125.0 (Bt Ar-C), 127.7
(Bt Ar-C), 128.6 (Bt Ar-C), 132.6 (Ar C-6), 142.7 (Bt Ar-C), 152.6 (Ar C-
4), 159.4 (Ar C-2), 161.6 (–COO). Anal. Calcd for C14H11N4O3Cl: C, 52.76;
H, 3.48; N, 17.58. Found: C, 52.80; H, 3.60; N, 17.63.
Preparation of 2-(4-Amino-5-chloro-2-methoxy)benzamido-3-(piperi-
din-1-yl)propanoic Acid (4c) Reaction of activated carboxylic acid (2c)
(0.5 g, 1.57 mmol) with b-aminoalanine dihydrochloride (3a) (0.39 g,
1.59 mmol) was carried out in the same manner described above in the
preparation of 4b. The isolated crude product was purified by column chro-
matography (SiO2/ethanol) to give (4c) (0.48 g, 86%). FAB-MS (positive)
m/z: 356 (MꢃH)ꢃ. IR (KBr) cmꢁ1: 3460, 3368, 3206, 1680, 1624, 1590. 1H-
NMR (DMSO-d6) d: 1.48 (2H, t, Jꢂ5.5 Hz, Ppd H-4), 1.62—1.63 (4H, m,
H-3, Ppd H-5), 2.80—2.84 (3H, m, Ppd H-2, H-6 and CHAHB-1-
piperidinyl), 2.91—2.94 (2H, m, Ppd H-2, H-6), 3.15 (1H, dd, Jꢂ12.0,
6.0 Hz, CHAHB-1-piperidinyl), 3.86 (3H, s, OCH3), 4.0—5.6 (1H, br,
COOH), 4.30—4.32 (1H, m, NHCHCOOH), 5.97 (2H, s, NH2), 6.52 (1H, s,
Ar H-3), 7.73 (1H, s, Ar H-6), 8.58 (1H, d, Jꢂ5.0 Hz, NH). 13C-NMR
(DMSO-d6) d: 22.3 (Ppd C-4), 24.2 (Ppd C-3, C-5), 48.7 (NHCHCOOH),
52.6 (Ppd C-2, C-6), 56.0 (OCH3), 57.3 (CH2-1-piperidinyl), 97.6 (Ar C-3),
109.0 (Ar C-1), 109.6 (Ar C-5), 131.5 (Ar C-6), 148.7 (Ar C-4), 157.7 (Ar
1H-Benzotriazol-1-yl Benzoate (2d) FAB-MS (positive) m/z: 239
(MꢃH)ꢃ. IR (KBr) cmꢁ1: 1809, 1781. 1H-NMR (CDCl3) d: 726—7.28 (2H,
m, Bt Ar H), 7.53—7.57 (1H, m, Bt Ar H), 7.59—7.63 (2H, m, Ar H-3, H-
5), 7.76—7.79 (1H, m, Ar H-4), 8.09—8.11 (1H, m, Bt Ar), 8.27—8.30
(2H, m, Ar H-2, H-6). 13C-NMR (CDCl3) d: 108.3 (Bt Ar-C), 120.6 (Bt Ar-
C), 124.8 (Bt Ar-C), 124.9 (Ar C-1), 128.7 (Bt Ar-C), 128.9 (Bt Ar-C),
129.2 (Ar C-3, C-5), 130.7 (Ar C-2, C-6), 135.5 (Ar C-4), 143.6 (Bt Ar-C),
162.8 (–COO). Anal. Calcd for C13H9N3O2: C, 65.27; H, 3.79; N, 17.56.
Found: C, 65.47; H, 3.98; N, 17.64.
Pyrrolidine-2,5-dion-1-yl Benzoate (2e) FAB-MS (positive) m/z: 220