Journal of Medicinal Chemistry
ARTICLE
General Procedure for the Synthesis of the Triazine Monomers
3AꢀC(aꢀc). Procedure A. A solution containing the disubstituted
triazine 2AꢀC (1.0 mmol), the corresponding amine (3.0 mmol), and
DIPEA (3.0 mmol) in dioxane (10 mL) was stirred at 60ꢀ100 °C for
24 h in a sealed tube. After cooling to room temperature, volatiles were
evaporated and the residue was dissolved in ethyl acetate (20 mL) and
washed with a NH4Cl saturated solution (10 mL). The organic layer was
dried over anhydrous MgSO4, filtered, and evaporated. The residue was
then purified as indicated for each compound.
Procedure B. A microwave vial was loaded with disubstituted triazine
2AꢀC (1.0 mmol), the corresponding amine (3.0 mmol), DIPEA
(3.0 mmol), and 1,4-dioxane (10 mL). The reaction vessel was sealed
and heated in a microwave reactor at 100 °C for 1ꢀ2 h. After cooling,
volatiles were evaporated to dryness and the residue was dissolved in
ethyl acetate (20 mL) and washed with a NH4Cl saturated solution
(10 mL). The organic layer was dried over anhydrous MgSO4, filtered,
and evaporated. The residue was then purified as indicated for each
compound.
Compound 3Aa. According to procedure A for the synthesis of
triazine monomers, N-methylpiperazine (87 μL, 0.81 mmol) and DIPEA
(139 μL, 0.81 mmol) wereadded toa solution of2A(160 mg, 0.27 mmol)
in dioxane (5 mL), and the mixture was stirred at 60 °C for 24 h in a sealed
tube, affording a residue that was purified by column chromatography
(dichloromethane/methanol, 10:1) to yield 114 mg (80%) of a colorless
oil identified as 3Aa. MS (ES, positive mode): m/z 534 (M + H)+, 1H
NMR (CDCl3, 300 MHz) δ: 2.24 (s, 3H, CH3N), 2.32ꢀ2.35 (m, 4H,
CH2N), 3.12 (m, 4H, β-CH2Phe), 3.68 (s, 6H, CH3O), 3.77 (m, 4H,
CH2N), 4.70ꢀ4.89 (m, 2H, R-CHPhe), 5.15 (bs, 1H, NH), 5.35
(bs, 1H, NH), 7.02ꢀ7.22 (m, 10H, Ar). Anal. Calcd for C28H35N7O4:
C, 63.02; H, 6.61; N, 18.37. Found: C, 62.97; H, 6.63; N, 18.09.
Compound 3Ab. According to procedure B for the synthesis of
triazine monomers, a microwave vial was charged with 2A (300 mg,
0.61 mmol), benzylamine (200 μL, 1.85 mmol), and DIPEA (320 μL,
1.85 mmol) in dioxane (5 mL), and the mixture was heated at 100 °C for
2 h. The residue was purified by flash chromatography (hexane/ethyl
acetate 2:1); yield 214 mg (65%); mp 54ꢀ56 °C. MS (ES, positive
mode): m/z 541 (M + H)+. 1H NMR (DMSO-d6, 300 MHz) δ:
2.80ꢀ3.18 (m, 4H, β-CH2Phe), 3.62 (bs, 6H, CH3O), 4.31ꢀ4.73 (m,
4H, CH2N, R-CHPhe), 6.71ꢀ7.35 (m, 18H, NH, Ar). Anal. Calcd for
C30H32N6O4: C, 66.65; H, 5.97; N, 15.55. Found: C, 66.47; H, 6.33;
N, 15.69.
CH2N), 3.08ꢀ3.18 (m, 4H, β-CH2Trp), 3.71 (m, 4H, CH2N),
4.30ꢀ4.75 (m, 2H, R-CHTrp), 6.49 (bs, 1H, NH), 6.75 (bs, 1H,
NH), 6.89ꢀ7.59 (m, 10H, H-2i Trp, Ar), 10.81 (s, 2H, NH-1i
Trp), 12.30 (bs, 2H, COOH). Anal. Calcd for C30H33N9O4: C, 61.74;
H, 5.70; N, 21.60. Found: C, 61.42; H, 5.86; N, 21.73.
The synthesis, analytical, and spectroscopic data of all the other
triazine monomers 4AꢀC(aꢀc) is fully described in the Supporting
Information.
General Procedure for the Synthesis of the Triazine Dimers 5AꢀC-
(aꢀc). Procedure A. A mixture containing a disubstituted triazine
2AꢀC (1.0 mmol), the corresponding diamine (0.6 mmol), and DIPEA
(3.0 mmol) in dioxane (10 mL) was stirred at 100 °C for 48 h in a sealed
tube. After cooling to room temperature, volatiles were evaporated to
dryness in vacuo, and the residue was dissolved in ethyl acetate (20 mL)
and treated with a saturated solution of NH4Cl (10 mL). The organic
layer was dried over anhydrous MgSO4, filtered, and evaporated. The
residue was then purified as indicated for each compound.
Procedure B. A microwave vial was charged with the disubstituted
triazine 2AꢀC (1.0 mmol), the corresponding diamine (0.6 mmol),
DIPEA (3.0 mmol), and dioxane (10 mL). The reaction vessel was
sealed and heated in a microwave reactor at 100ꢀ120 °C for 2ꢀ3 h.
After cooling to room temperature, the volatiles were evaporated to
dryness in vacuo, and the residue was dissolved in ethyl acetate (20 mL)
and treated with a saturated solution of NH4Cl (10 mL). The organic
layer was dried over anhydrous MgSO4, filtered, and evaporated. The
residue was purified as indicated for each compound.
Compound 5Aa. According to procedure A for the synthesis of
triazine dimers, reaction of 2A (128 mg, 0.25 mmol) with piperazine
(70 mg, 0.15 mmol) in the presence of DIPEA (131 μL, 0.75 mmol) in
dioxane (8 mL) afforded a residue that was purified by column
chromatography (hexane/ethyl acetate, 2:1); yield 197 mg (83%); mp
138ꢀ139 °C. MS (ES, positive mode): m/z 477 (M + 2H)2+, 953 (M +
H)+. 1H NMR (CDCl3, 300 MHz) δ: 3.05 (m, 8H, β-CH2Phe), 3.60 (m,
20H, CH3O, CH2N), 4.76 (m, 4H, R-CHPhe), 5.60ꢀ5.95 (bs, 4H,
NH), 7.02ꢀ7.21 (m, 20H, Ar). Anal. Calcd for C50H56N12O8: C, 63.01;
H, 5.92; N, 17.64. Found: C, 62.74; H, 6.28; N, 17.66.
Compound 5Ab. Following procedure B for the synthesis of triazine
dimers, a microwave vial was charged with 2A (386 mg, 0.80 mmol), 1,3-
xylylenediamine (66 μL, 0.48 mmol), DIPEA (360 μL, 2.04 mmol), and
dioxane (10 mL), and the mixture was irradiated at 100 °C for 2 h,
affording a residue that was purified by flash chromatography (hexane/
ethyl acetate, 1:1 to 1:2); yield 179 mg (58%); mp 102ꢀ104 °C. MS
(ES, positive mode): m/z 502 (M + 2H)2+, 1003 (M + H)+. 1H NMR
(CDCl3, 300 MHz) δ: 3.20 (m, 8H, β-CH2Phe), 3.33ꢀ3.64 (m, 12H,
CH3O), 4.52ꢀ4.59 (m, 8H, R-CHPhe, CH2N), 5.30ꢀ6.34 (m, 2H,
NH), 7.02ꢀ7.48 (m, 24H, NH, Ar). Anal. Calcd for C54H58N12O8: C,
64.66; H, 5.83; N, 16.76. Found: C, 64.79; H, 5.68; N, 16.98.
The synthesis, analytical, and spectroscopic data of all the other
triazine monomers 3AꢀC(aꢀc) is fully described in the Supporting
Information.
General Procedure for the Deprotection of the Methyl Esters. To a
solution containing the methyl ester derivative (1.0 mmol) in THF
(10 mL), a solution of LiOH H2O (2 equiv for each methyl ester group)
3
in water (10 mL) was added, and the mixture was stirred at room
temperature for 8 h. Then formic acid was added to reach pH = 2, and
volatiles were evaporated to dryness. The residue was dissolved in 2 mL of
dioxane/water (9:1) and was gently stirred with the resin Amberlite IRA400
(HCOOꢀ) for monomers and dimers, or Dowex 1 ꢁ 2 (HCOOꢀ) for
trimers through orbital stirring overnight. Then, the resin was washed with 4
volumes of dioxane/water (9:1). Cleavage of the product from the resin was
performed by treatment with formic acid/water (9:1) for 1 h with orbital
stirring, followed by washing with 4 volumes of formic acid/water (9:1).
The filtrate was evaporated to dryness in vacuo and lyophilized.
The synthesis, analytical and spectroscopic data of all the other triazine
dimers 5AꢀC(aꢀc) is fully described in the Supporting Information.
Compound 6Aa. Following the general procedure for the deprotec-
tion of methyl esters, compound 5Aa (100 mg, 0.10 mmol) in THF
(1 mL) was treated with LiOH H2O (36 mg, 0.84 mmol) in water
3
(1 mL). The residue was purified with Amberlite IRA400 (HCOOꢀ)
resin to yield 42 mg (47%) of 6Aa as a white solid; mp > 165 °C,
decompose; .MS (ES, positive mode): m/z 449 (M + 2H)2+, 897 (M +
H)+. 1H NMR (DMSO-d6, 300 MHz) δ: 3.19 (m, 8H, β-CH2Phe), 3.46
(m, 8H, CH2N), 4.40 (m, 4H, R-CHPhe), 6.68ꢀ6.93 (m, 4H, NH),
7.12ꢀ7.21 (m, 20H, Ar), 12.30 (s, 4H, COOH). HRMS (ES, negative
mode) Calcd for C46H48N12O8: 896.3718. Found: 896.3710. HPLC:
(system A) 6.5 min (98%); (system B) 3.7 min (99%).
Compound 4Ca. According to the general procedure for the
deprotection of methyl esters, compound 3Ca (100 mg, 0.16 mmol)
in THF (1 mL) was treated with LiOH H2O (28 mg, 0.64 mmol) in
3
water (1 mL). The residue was purified with Amberlite IRA400
(HCOOꢀ) resin to yield 65 mg (43%) of 4Ca as a white solid; mp >
250 °C, decompose. MS (ES, positive mode): m/z 584 (M + H)+.
1H NMR (DMSO-d6, 300 MHz) δ: 2.18 (s, 3H, CH3N), 2.34 (m, 4H,
Compound 6Ab. Following the general procedure for the deprotec-
tion of methyl esters, compound 5Ab (120 mg, 0.12 mmol) in THF
(1.5 mL) was treated with LiOH H2O (41 mg, 0.95 mmol) in water
3
(1.5 mL). The residue was purified with Amberlite IRA400 (HCOOꢀ)
5345
dx.doi.org/10.1021/jm200560r |J. Med. Chem. 2011, 54, 5335–5348