A Novel Synthesis of Ibutilide Fumarate
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
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1
1716 cm-1. H NMR(400 MHz, CDCl3): ꢀ = 3.64-3.41 (m,
was added into the solution, the mixture was stirred for 2 h at
room temperature. The solvent was removed under a reduced
pressure to get a residue and the residue was dissolved in
heated acetone (230mL), and the mixture was treated with
active carbon for 0.5 h, removed the active carbon by filter,
ether (150mL) was added into the solution, the mixture was
calmed down to 0-5 oC for 12 h, to crystal the solid. The
solid was recrystalized with acetone and ether (v/v = 2:3),
and dried in vaccum at 50-60 oC Then Ibutilide Fumarate(1,
25g, 72%) was obtained. m.p: 118-119 oC. IR: 3386 cm-1;
3100 cm-1;1973 cm-1.1H NMR(400 MHz, CDCl3): ꢀ = 7.28-
7.26(m, 2H, ArH), 7.19-7.18(m, 2H, ArH), 6.44(m, 1H,
C=CH-), 4.66(m, 1H, CHOH), 2.90(s, 3H, CH3S), 3.00-
2.81(m, 6H, NCH2), 1.78-1.25(m, 14H, CCH2C), 1.18-
1.19(m, 3H, NCH2CH3), 0.88-0.87 (m, 3H, CH3C6H12N).
13C NMR (100 MHz, CDCl3): ꢀ = 172.5 (COOH), 142.0
(CHOH), 136.1 (SO2NHC), 135.7 (CCHOH), 127.0 (m-Ar-
N), 121.7 (o-Ar-N), 72.8 (CH=CH), 53.0 (NCH2),
51.4(NCH2), 46.1(NCH2), 39.1, 37.2, 31.7, 28.9, 27.1, 23.8,
22.5, 22.0, 14.0, 9.0.
6H, NCH2), 1.41-1.22 (m, 14H, CCH2C), 0.99-1.00 (m, 3H,
NCH2CH3), 0.87-0.90 (m, 3H, NC6H12CH3).
N-[{4-(N-ethyl-N-heptylamino)butanoyl}phenyl]methane-
sulfonamides (3)
4-(N-ethyl-N-heptylamino)butanoic acid hydrochloride
(9, 37.0 g, 0.16mol), was suspended in CH2Cl2 (160mL),
SOCl2 (76.8 g, 0.64mol) was added dropwise dropped under
an ice bath. Then the reaction mixture was refluxed for 2 h.
When the reaction was finished, the dichloromethane and
thionyl dichloride were removed under a reduced pressure to
get a red-brown residue, 4-(N-ethyl-N-heptylamino)butanoyl
chloride hydrochloride(4, 33 g, 85%) was obtained, and this
residue was used in next reaction without any further
purification.
To the mixture of N-methylsulfonyl aniline (33.0 g,
0.13mol) in CS2 (120 mL), 4 was added dropwise. Then
anhydrous AlCl3 (31.4 g, 0.24mol) was added gradually at 0
oC. The reaction mixture was continually stirred for another
o
5 h at 0 C. After that, ice 5% NaOH (200mL) was added
ACKNOWLEDGEMENT
into the mixture, the mixture was extracted with CH2Cl2 (100
mL X 2), the organic phase was dried by anhydrous Na2SO4,
removed the solid by filter and the solvent under a reduced
pressure to get a light yellow oil, the oil was recrystallized
with EtOAc and hexane(v/v = 1:3) to get N-[{4-(N-ethyl-N-
heptylamino)butanoyl}phenyl]methanesulfonamides (3, 35.8
g, 72%) as a white solid. IR: 3327 cm-1;1681 cm-1;1600-1400
We appreciate the financial support from the Science
and Technology Research Project of Chongqing Education
Commission (No. KJ080314).
REFERENCES
1
cm-1. H NMR(400 MHz, CDCl3): ꢀ = 7.81-7.83 (m, 2H,
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N-[{4-(N-ethyl-N-heptylamino)-1-hydroxybutyl}phenyl]
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and the solvent under a reduced pressure to get a light yellow
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1
solid. IR: 3253 cm-1, 3131 cm-1, 1681 cm-1. H NMR (400
MHz, CDCl3): ꢀ = 7.35-7.37 (m, 2H, ArH), 7.15-7.17 (m,
2H, ArH), 4.60 (m, 1H, CHOH), 2.95(s, 3H, CH3S), 2.69-
2.41(m, 6H, NCH2), 1.70-1.24(m, 14H, CCH2C), 1.10-
1.11(m, 3H, NCH2CH3), 0.87-0.90 (m, 3H, CH3C6H12N).
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N-[(ꢁ-Amino-1-hydroxyalkyl)phenyl]methanesylfonamide deriva-
Ibutilide Fumarate (1)
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(a) Li, H.; Yue, C.; Sun, B., Fu ma suan yi bu li te de he cheng fang
fa (in Chinese), CN Patent, 200510050686, 2006. (b) Tian, R.; Li,
N-[{4-(N-ethyl-N-heptylamino)-1-hydroxybutyl}phenyl]
methanesulfonamide (2, 30.0 g, 0.078mol) was dissolved in
anhydrous ethanol (200mL), fumaric acid (4.14 g, 0.036mol)
[10]