BULLETIN OF THE
Article
Formal Synthesis of Fesoterodine
KOREAN CHEMICAL SOCIETY
ꢀ
−
10 C. 3-[3-(N,N-Diisopropylamino)-1-phenylpropyl]-4-
concentrated in vacuo to give a white solid of (R)-2-[3-
(N,N-diisopropylamino)-1-phenylpropyl]-4-(hydroxymeth-yl)
hydroxy-benzaldehyde (6, 1.0 g, 2.9 mmol) in ethanol
10 mL) was then added to the suspension at −10 C and the
mixture was warmed to room temperature and stirred for
h. The mixture was neutralized by the addition of 1N HCl.
Solvent was evaporated and the residue was washed with sat-
urated aqueous NaHCO , extracted with dichloromethane,
dried over anhydrous MgSO , and concentrated in vacuo.
Purification was carried out by flash column chromatography
ꢀ
(
phenol (7b). Yield: 85%; 99% ee; Gummy solid; R = 0.23
f
1
(CHCl : MeOH = 5:1, v/v); H NMR (400 MHz, CDCl ): δ
3
3
3
7.32–7.29 (m, 4H), 7.23 (m, 1H), 7.04 (dd, J = 8.0, 2.0 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 4.50
(dd, J = 12.0, 4.0 Hz, 1H), 4.41 (s, 2H), 3.24 (septet, J = 6.8
Hz, 2H), 2.73 (m, 1H), 2.43–2.29 (m, 2H), 2.10 (m, 1H),
3
4
13
1.13 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H).
C
(
silica gel, CHCl / MeOH, 5:1, v/v) to afford compound to
NMR (100 MHz, CDCl ): δ 155.5, 144.5, 132.8, 132.6,
3
3
give compound 7. Yield: 0.92 g, 92%; Gummy solid; R =
0
δ 7.35–7.31 (m, 4H), 7.25–7.20 (m, 1H), 7.06 (dd, J = 8.2, 2.4
Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 4.51
128.5, 128.4, 127.5, 126.6, 126.3, 118.6, 65.4, 48.1, 42.1,
f
1
ꢀ
21
.23 (CHCl : MeOH = 5:1, v/v); H NMR (400 MHz, CDCl ):
39.5, 33.2, 19.9, 19.5. [α] +36 (at 20 C, c = 0.2, CHCl ),
3
3
D
3
lit:
ꢀ
½
αꢁD + 21:3 (at 22 C, c = 1.0, EtOH).
(
2
1
dd, J = 11.2, 3.6 Hz, 1H), 4.43(s, 2H), 3.25 (septet, J = 6.8 Hz,
Conclusion
H), 2.74 (m, 1H), 2.45–2.30 (m, 2H), 2.15–2.07 (m, 1H),
13
.12 (d, J = 6.8 Hz, 6H), 1.09 (d, J = 6.8 Hz, 6H);
C
In conclusion, formal synthesis of the enantiopure fesotero-
dine intermediate 7b was achieved through a simple but effi-
cient key step such as Friedel–Craft alkylation. The synthesis
was accomplished in seven steps with an overall higher yield
of 19% as compared to the previous reports. It can also be
extended to the synthesis of fesoterodine by acylation of com-
NMR (100 MHz, CDCl ): δ 155.5, 144.5, 132.8, 132.6,
3
1
3
28.5, 128.4, 127.5, 126.6, 126.3, 118.6, 65.4, 48.1, 42.1,
9.5, 33.2, 19.9, 19.5.
(
R)-2-[3-(N,N-Diisopropylamino)-1-phenylpropyl]-4-
hydroxymethyl)phenol(R)-(−)-O-acetylmandelic acid
salt (9): 2-[3-(N,N-Diisopropylamino)-1-phenylpropyl]-4-
(
10
10
pound 7b.
(
hyd-roxylmethyl)phenol (7, 0.7 g, 2.0 mmol) was dissolved
ꢀ
in tert-amyl alcohol and heated to 70 C, followed by the addi-
tion of (R)-(−)-O-acetylmandelic acid (0.2 g, 1.03 mmol). The
reaction temperature was lowered to 60 C and then stirred for
Acknowledgments. Y. Lee, Y. Jeong, and J. Ban acknowl-
edge financial support from the Korean Ministry of Education
through BK21-Plus Project for the Hanyang University Grad-
uate Program.
ꢀ
2
h. Afterward, the mixture was cooled to room temperature
and allowed to stand for 3 h. The mixture was then stirred at
ꢀ
2
5 C for 12 h followed by sufficient washing with tert-amyl
ꢀ
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
alcohol. The resulting product was dried for 12 h at 40 C in a
vacuum drying oven to obtain the salt 9. HPLC was performed
at Daicel Chiralcel OD-H 250 mm × 4.6 mm, 5 μm, 96:4 hex-
ane/ethanol (v/v) + 0.1% diethylamine, flow rate 1.0 mL/min
anddetectionat210nm. Yield:0.4g, 40%;Whitesolid;HPLC
Rt (min): 13.90 (R-form) and 14.68 (S-form) for the racemic
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6
7
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2
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1
7
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6
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(
added to 1.5 mL toluene to make a slurry after which the tem-
ꢀ
perature was increased to 50 Cfollowed by the addition of1.5
mL of 10% wt/vol potassium carbonate aqueous solution at
ꢀ
5
0 C. Next, the mixture was stirred vigorously for
h. After the reaction was completed, the organic layer was
6
washed with water, extracted, dried over MgSO , and
4
Bull. Korean Chem. Soc. 2015, Vol. 36, 2885–2889
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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