Journal of Medicinal Chemistry
Article
Carbamate Formation. Procedure C. The diamine (1 equiv) was
dissolved in water (5 mL per 1 mmol), followed by the addition to the
solution of NaOH in pellets (1 equiv). The solution was cooled down
to 0 °C. 4-Bromophenyl chloroformate (1.2 equiv) was then added
dropwise, and after some minutes, a white precipitate started
appearing. After 3 h, the reaction was extracted with CH2Cl2 (3×),
and the organics were dried over Na2SO4, filtered, and evaporated
under reduced pressure. Unless otherwise indicated, the residue was
purified using a preparative RP-HPLC, and only fractions with a purity
>95% were lyophilized.
0.081 mmol, 15% yield). 1H NMR (CDCl3, 300 MHz): δ 10.81 (br s,
1H), 7.50 (br d, J = 10 Hz, 1H), 7.47−7.40 (m, 2H), 7.09−7.01 (m,
2H), 3.85 (qd, J1 = 10 Hz, J2 = 4 Hz, 1H), 3.65 (br d, J = 12 Hz, 1H),
3.48−3.32 (m, 1H), 3.28−2.85 (m, 3H), 2.69−2.52 (m, 1H), 2.42−
2.22 (m, 1H), 2.21−1.74 (m, 8H), 1.60−1.22 (m, 5H). 13C NMR
(CDCl3, 75 MHz): δ 154.6, 150.2, 132.1, 123.6, 118.2, 67.2, 52.5,
50.2, 46.4, 33.6, 24.3, 23.6, 22.8, 22.3, 22.5. MS (ESI+) m/z 381.4
([M + 1, Br79]+), 383.4 ([M + 1, Br81]+). HRMS (ESI+) calcd for
C18H26N2O2Br79, 381.1177 ([M + 1]+]) found 381.1190; mp (°C)
145−146.
Procedure D. To a solution of 4-bromophenylchloroformate
(1.2 equiv) in dry THF (10 mL per 1 mmol) cooled to 0 °C under
argon were added dropwise Et3N(2 equiv) and the diamine (1 equiv)
diluted in THF. The reaction mixture was then stirred for 2 h at room
temperature. The reaction was quenched with brine and extracted with
EtOAc (3×), and the organics layers were dried over Na2SO4, filtered,
and evaporated under reduced pressure. Unless otherwise indicated,
the residue was purified using a preparative RP-HPLC, and only
fractions with a purity >95% were lyophilized.
N-(((R)-1-(Pent-2-ynyl)pyrrolidin-2-yl)methyl)benzo[d]thiazole-6-
carboxamide, TFA Salt (8b). Using procedure A, this product was
obtained from amine 31 as a colorless oil (103 mg, 0.241 mmol, 27%
yield). 1H NMR (CDCl3, 300 MHz): δ 12.22 (br s, 1H), 9.14 (s, 1H),
8.90 (t, J = 6 Hz, 1H), 8.59 (s, 1H), 8.14 (d, J = 8 Hz, 1H), 8.07 (d, J =
8 Hz, 1H), 4.07−3.64 (m, 6H), 3.36−3.21 (m, 1H), 2.34−1.87 (m,
6H), 1.06 (t, J = 7 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 167.7 (C),
157.3 (CH), 154.8 (C), 133.8 (C), 130.2 (C), 125.4 (CH), 123.2
(CH), 121.8 (CH), 93.2 (C), 66.6 (C), 65.5 (CH), 53.5 (CH2), 43.9
(CH2), 39.7 (CH2), 27.8 (CH2), 23.2 (CH2), 12.9 (CH3), 12.1 (CH2).
MS (ESI+) m/z 328.1 ([M + 1]+). HRMS (ESI+) calcd for
C18H22N3OS, 328.1483 ([M + 1]+); found, 328.1485.
N-((S)-1-(2-Methylcyclopentyl)pyrrolidin-3-yl)benzo[d]thiazole-6-
carboxamide, TFA Salt (9b). Using procedure A, this product was
obtained from amine (S)-43 as a yellow oil (48 mg, 0.112 mmol, 25%
yield). 1H NMR (CDCl3, 300 MHz) diastereomeric mixture (1.5:1): δ
11.94 (br s, 0.6H), 11.80 (br s, 0.4H), 9.20 (br d, J = 8 Hz, 0.6H), 9.11
(s, 1H), 9.04 (br d, J = 8 Hz, 0.4H), 8.65 (s, 0.6H), 8.58 (d, J = 1 Hz,
0.4H), 8.19−8.04 (m, 2H), 5.28−5.08 (m, 1H), 4.06−3.81 (m, 2H),
3.32−2.87 (m, 3H), 2.70−2.51 (m, 1H), 2.49−1.50 (m, 8H), 1.12 (d,
J = 7 Hz, 1.2H), 1.07 (d, J = 7 Hz, 1.8H). 13C NMR (CDCl3,
75 MHz): δ 166.7 (C), 166.4 (C), 156.8 (C), 155.1 (C), 133.9 (C),
130.5 (C), 125.7 (CH), 125.6 (CH), 123.3 (CH), 121.9 (CH), 71.5
(CH), 71.4 (CH), 60.6 (CH2), 59.6 (CH2), 54.5 (CH2), 52.9 (CH2),
47.9 (CH), 47.6 (CH), 35.0 (CH), 34.9 (CH), 31.3 (CH2), 31.2
(CH2), 30.9 (CH2), 30.7 (CH2), 25.5 (CH2), 25.4 (CH2), 19.8 (CH2),
19.5 (CH2), 14.0 (CH3), 13.6 (CH3). MS (ESI+) m/z 330.2
([M + 1]+). HRMS (ESI+) calcd for C18H24N3OS, 330.1640 ([M + 1]+);
found, 330.1631.
(4-Chlorophenyl)(4-isopropyl-1,4-diazocan-1-yl)methanone (5a).
Using procedure A, this product was obtained from amine 46. The
final compound slowly hydrolyzed in 0.1% TFA (HPLC conditions).
For that reason, purification was done by column chromatography
(neutral alumina, CH2Cl2/MeOH 0.5%) to give 5a as a yellow oil
1
(20 mg, 0.068 mmol, 53% yield). H NMR (CDCl3, 300 MHz): δ
7.33−7.26 (m, 2H), 7.25−7.18 (m, 2H), 3.86 (br s, 1H), 3.40 (br s,
2H), 2.83−2.00 (br m, 6H), 1.70 (br s, 4H), 1.10 (br s, 6H). 13C
NMR (CDCl3, 75 MHz): δ 170.5 (C), 135.8 (C), 135.0 (C), 128.6
(CH), 127.6 (CH), 54.8 (br CH2), 54.1 (CH), 50.1 (br CH2), 39.8
(br CH2), 23.4 (CH2), 20.9 (CH3). MS (ESI+) m/z 295.4 ([M + 1,
Cl35]+), 297.2 ([M + 1, Cl37]+). HRMS (ESI+) calcd for
C16H24Cl35N2O, 295.1572 ([M + 1]+); found, 295.1566.
(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)(4-isopropyl-1,4-diazocan-
1-yl)methanone (5c). Using procedure A, this product was obtained
from 1-isopropyl-1,4-diazocane 46, prepared by a literature proce-
dure.45 The final compound slowly hydrolyzed in 0.1% TFA (HPLC
conditions) For that reason, purification was done by column
chromatography (neutral alumina, CH2Cl2/MeOH 0.5%) to give 5c
as a yellow oil (15 mg, 0.047 mmol, 37% yield). 1H NMR (CDCl3, 300
MHz): δ 6.98−6.79 (m, 3H), 4.25 (s, 4H), 4.11 (br s, 1H), 3.44 (br t,
2H), 2.91−2.27 (br m, 6H), 1.75 (br s, 4H), 1.15 (br d, J = 6 Hz, 6H).
13C NMR (CDCl3, 75 MHz): δ 171.0 (C), 144.4 (C), 143.3 (C),
130.6 (C), 130.5 (C), 119.7 (CH), 117.2 (CH), 115.7 (CH), 64.4
(CH2), 64.3 (CH2), 54.9 (br CH2), 54.1 (CH), 50.0 (br CH2), 39.9
(br CH2), 23.4 (CH2), 21.0 (CH3). MS (ESI+) m/z 319.0 ([M + 1]+).
HRMS (ESI+) calcd for C18H27N2O3, 319.2016 ([M + 1]+); found,
319.2012.
4-Chloro-N-((hexahydro-1H-pyrrolizin-7a-yl)methyl)benzamide
(6a). Using procedure A, this product was obtained from amine 63.
Purification by column chromatography (neutral alumina, CH2Cl2/
MeOH 2%) gave 6a as a yellow solid (40 mg, 0.143 mmol, 40% yield).
1H NMR (CDCl3, 300 MHz): δ 8.12 (br s, 1H), 7.91 (d, J = 8 Hz,
2H), 7.40 (d, J = 8 Hz, 2H), 3.63 (d, J = 6 Hz, 2H), 3.44−3.27 (m,
2H), 2.89−2.73 (m, 2H), 2.11−1.70 (m, 8H). 13C NMR (CDCl3, 75
MHz): δ 166.6, 137.7, 132.0, 128.8, 128.7, 78.0, 55.4, 45.6, 35.7, 24.7.
MS (ESI+) m/z 279.2 ([M + 1, Cl35]+), 2281.2 ([M + 1, Cl37]+).
HRMS (ESI+) calcd for C15H20Cl35N2O, 279.1264 ([M + 1]+); found,
279.1260; mp (°C) 158−163.
N-((Hexahydro-1H-pyrrolizin-7a-yl)methyl)benzamide, TFA Salt
(6f). Using procedure A, the compound was obtained from amine 63
as a colorless oil (22.7 mg, 0.06 mmol, 30% yield). 1H NMR (MeOD,
300 MHz): δ 7.90 (dd, J1 = 3 Hz, J2 = 9 Hz, 2H), 763−7.58 (m, 1H),
7.54−7.48 (m, 2H), 3.74 (s, 2H), 3.69−3.61 (m, 2H), 3.28−3.22 (m,
2H), 2.27−2.24 (m, 8H). 13C NMR (MeOD, 75 MHz): δ 173.4,
133.9, 133.8, 130.0, 128.8, 84.5, 56.7, 47.6, 35.9, 25.5. MS (ESI+) m/z
245.1 ([M + 1]+). HRMS (ESI+) calcd for C15H21N2O, 245.1648
([M + 1]+); found, 245.1654.
((3S,9aR)-Hexahydro-3-methyl-1H-pyrido[1,2-a]pyrazin-2(6H)-
yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone, TFA Salt (10c).
Using procedure A, this product was obtained from amine 48 as a
1
colorless oil (22 mg, 0.053 mmol, 41% yield). H NMR (D2O, 400
MHz at 353 K): δ 7.63−7.45 (m, 3H), 5.29 (br s, 1H), 4.89 (s, 2H),
4.88 (s, 2H), 4.63−4.38 (m, 2H), 4.29−3.80 (m, 4H), 3.69−3.55 (m,
1H), 2.59−1.93 (m, 9H). 13C NMR (D2O, 100 MHz at 353 K): δ
120.9 (CH), 118.3 (CH), 116.4 (CH), 65.4 (CH2), 65.2 (CH2), 57.4
(CH), 54.0 (CH2), 47.8 (CH2), 46.2 (br CH), 42.7 (br CH2), 21.7
(CH2), 21.3 (CH2), 17.4 (CH2), 15.3 (CH3). MS (ESI+) m/z 317.4
([M + 1]+). HRMS (ESI+) calcd for C18H25N2O3, 317.1865 ([M +
1]+); found, 317.1860.
(S)-4-Bromophenyl Hexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-
2(3H)-carboxylate, TFA Salt [(S)-11e]. Using procedure C, this
product was obtained from amine 51 as a colorless oil (26 mg, 0.059
1
mmol, 8% yield). H NMR (D2O, 400 MHz): δ 7.66 (d, J = 9 Hz,
2H), 7.14 (d, J = 7 Hz, 2H), 4.40−3.56 (m, 7H), 3.47−3.20 (m, 2H),
2.54−1.85 (m, 6H). 13C NMR (D2O, 75 MHz): mixture of four
isomers δ 155.8, 155.6, 155.3, 155.0, 149.8, 149.7, 149.6, 132.6, 123.7,
118.8, 118.7, 118.7, 67.0, 66.9, 66.2, 65.5, 57.2, 57.1, 56.9, 56.8, 53.7,
53.6, 51.4, 51.3, 47.3, 47.0, 46.9, 46.8, 46.2, 43.9, 43.7, 28.1, 28.0, 27.7,
27.6, 26.2, 26.0, 25.2, 25.0, 23.3, 21.7, 21.6. MS (ESI+): m/z 339.2 ([M
+ 1, Br79]+), 341.2 ([M + 1, Br81]+). HRMS (ESI+) calcd for
C15H20Br79N2O2, 339.0708 ([M + 1]+); found, 339.0698.
N-(1-Aza-bicyclo[2.2.2]oct-2-ylmethyl)-4-fluorobenzamide, TFA
Salt (rac-12k). Compound 26k (79 mg, 0.30 mmol) and Pd/C
(40 mg) were diluted in dry MeOH (6 mL), and the solution was
stirred for 4 h under an hydrogen atmosphere. The reaction mixture
was then filtered over Celite and washed with MeOH. The filtrate was
concentrated under vacuum to afford a yellow oil, which was purified
by preparative HPLC to give the desired compound as a colorless oil
4-bromophenyl-2-(piperidin-1-yl)cyclohexylcarbamate, TFA salt (7e).
Using procedure C, this product was obtained from the corresponding
amine which was prepared according ref 40 as a white solid (39 mg,
4615
dx.doi.org/10.1021/jm300030r | J. Med. Chem. 2012, 55, 4605−4618