3-Bromopropylamine hydrobromide → tert-butyl 3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate

HRID 1269344Notes

Reaction equation

HRID 1269344 reaction equation
Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Br.BrCCCN.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.NCCC[N:38]1[CH2:43][CH:42]=[C:41]([C:44]2[CH:45]=[C:46]([NH:50][C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][CH:49]=2)[CH2:40][CH2:39]1.N1CC=C(C2C=C(NC(=O)C)C=CC=2)CC1>ClCCl.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[C:51]([NH:50][C:46]1[CH:45]=[C:44]([C:41]2[CH2:42][CH2:43][N:38]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:39][CH:40]=2)[CH:49]=[CH:48][CH:47]=1)(=[O:53])[CH3:52]

Participants

9

Reactant 5

HCID 787013-Bromopropylamine hydrobromideHCID 90495Di-tert-butyl dicarbonateHCID 4460490tert-butyl N-(3-bromopropyl)carbamate2×HCID 21957202N-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamideHCID 21957228N-(3-(1,2,3,6-Tetrahydropyridin-4-yl)phenyl)acetamide

Product 1

HCID 21957172tert-butyl 3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

The reaction of saturated of aqueous Na2CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakis-triphenylphosphine palladium (0) (1.15 g) in dimethoxy ethane (40 mL) at reflux temperature overnight gave tert-butyl 4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridine carboxylate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11–12) gave the desired product. TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE: was prepared from 3-bromopropylamine hydrobromide and BOC2O in the presence of base in dichloromethane. N-{3-[1-(3-AMINOPROPYL)-1,2,3,6-TETRAHYDRO-4-PYRIDINYL]PHENYL}ACETAMIDE: The reaction of tert-butyl N-(3-bromopropyl)carbamate and N-[3-(1,2,3,6-tetrahydro-4-pyridinyl) phenyl]acetamide in refluxing dioxane with catalytic Bu4NI and base to give tert-butyl 3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11–12) gave the desired product. METHYL (4S)-3-({[3-(4-[3-(ACETYLAMINO)PHENYL]-3,6-DIHYDRO-1(2H)-PYRIDINYL) PROPYL]AMINO}CARBONYL)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXY METHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: Prepared from the reaction of 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate (describe in PCT Publication No. WO 00/37026, published Jun. 29, 2000) and N-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide: 1H NMR δ 8.90 (t, 1H, J=3.6 Hz), 7.75 (s, 1H), 7.50–7.00 (m, 8H), 6.68 (s, 1H), 6.03 (br s, 1H), 4.67 (s, 2H), 3.71 (s, 3H), 3.47 (s, 3H), 3.38 (ABm, 2H), 3.16 (m, 2H), 2.71 (t, 2H, J=5.4 Hz), 2.56 (m, 4H), 2.35–1.90 (br, 2H), 2.17 (s, 3H), 1.82 (p, 2H, J=7.2 Hz); ESMS, 612.25 (M+H)+. TRITIATED METHYL (4S)-3-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE ([3H] COMPOUND A): This radiochemical synthesis was carried out by Amersham Pharmacia Biotech, Cardiff, Wales. A methanolic solution of methyl (4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propyl]amino}carbonyl)-4-(3,4-difluorophenyl)-6-(methoxy methyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate was exposed to tritium gas at 1 atmosphere pressure in the presence of 5% palladium on carbon with stirring overnight to give the tritiated methyl (4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxy methyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate ((+)-isomer). After purification by reverse phase HPLC (Hypersil ODS, 4.6×100 mm, methanol:H2O:Et3N 10:90:1 to 100:0:1 in 15 min at 1.0 mL/min, with radiochemical and UV detection), this product was used as a radioligand in the MCH1 binding assays. The same procedure was carried out with H2 gas in place of 3H2 to afford the non-radioactive version of Compound A.

Sources & evidence

ORD record
ord-bac0d587eddb48f589163a41a5e61512
Source dataset
uspto-grants-2007_04
Patent number
US07199135B2

Reaction notes

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