Synthesis of 1-oxo-1-(3-pyridazinyl) derivatives - Potent inhibitors of Fatty Acid Amide Hydrolase (FAAH): An improved and optimized procedure

Article abstract of DOI:10.1055/s-2007-990774

A greatly improved procedure for the preparation of long-chain α-ketopyridazines, a class of potent inhibitors of fatty acid amide hydrolase (FAAH), is described. This optimization study shows a great dependence of the yields of desired products on the pyrididazinyl lithium/Weinreb amide ratio and offers a general approach to this kind of compound. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990774

PAPER
3051
Synthesis of 1-Oxo-1-(3-pyridazinyl) Derivatives – Potent Inhibitors of Fatty
Acid Amide Hydrolase (FAAH): An Improved and Optimized Procedure
a
b
a
a
a
I
G
mprove
d
Procedu
o
re for FAAH
f
Inhibito
f
rs redo Rosini,* Daniele G. Andreotti, Primiano D’Ambrosio, Emanuela Marotta, Alessandro Tinarelli,
a
Paolo Righi
a
Dipartimento di Chimica Organica ‘A. Mangini’ – Alma Mater Studiorum, Università di Bologna, Viale del Risorgimento 4,
0136 Bologna, Italy
4
Fax +39(051)2093654; E-mail: goffredo.rosini@unibo.it
GlaxoSmithKline, Medicine Research Centre, Via A. Fleming 4, 37135 Verona, Italy
b
Received 18 May 2007; revised 19 June 2007
oxo-1-(3-pyridazinyl)octadec-9-ene (1) was unusually
potent and was prepared in only 11% yield by addition of
pyridazinyllithium to the Weinreb amide of oleic acid 2
Abstract: A greatly improved procedure for the preparation of
long-chain a-ketopyridazines, a class of potent inhibitors of fatty
acid amide hydrolase (FAAH), is described. This optimization
study shows a great dependence of the yields of desired products on
(
Equation 1). Pyridazinyllithium was prepared according
4
the pyrididazinyl lithium/Weinreb amide ratio and offers a general to the procedure of Queguiner and co-workers reported in
approach to this kind of compound.
1995, when they accomplished the functionalization of di-
Key words: 3-acylpyridazines, regioselective acylations, FAAH azines – p-deficient heteroaromatic systems – without the
inhibitors, Weinreb amides, lithiation, drugs
assistance of any ortho-directing metalation group
(
DMG).5
Fatty acid amides (FAAs) represent a class of neuromod-
ulatory lipids that includes the endogenous sleep-inducing
substance oleamide and the endocannabinoid anandamide
H
N
O
1
2
. pyridazine
. Weinreb amide 2
N
+
n-BuLi
N
7
7
THF, –78 °C to r.t.
(
Figure 1). Fatty acid amide hydrolase (FAAH) is an in-
TMP
1
ternal membrane protein (IMP) that hydrolyzes bioactive
amides, therefore, the enzyme is responsible for the deg-
TMP/n-BuLi/pyridazine/2 = 4:4:1:1
1
radation of oleamide and anandamide.
Equation 1 Boger’s procedure for the preparation of compound 1
They found that the optimal procedure for the metalation
of pyridazine was to use a four-fold excess of lithium
2
,2,6,6-tetramethylpiperidine (LTMP) as the metalating
O
agent in THF at –75 °C. They also found that a very short
metalation reaction time (6 min) was required when alde-
hydes were used as electrophiles, affording ortho-mono-
substituted products obtained in 7–47% yield along with
varying amounts of disubstituted products (Scheme 1).
oleamide
NH2
O
HN
anandamide
OH
R
1
2
. LTMP, –75 °C,
THF, 6 min
. RCHO
R
N
N
OH
N
N
N
N
OH
HO
Figure 1 Endogenous fatty acid amides that serve as chemical mes-
+
7
–47 %
sengers
R
4
Scheme 1 Literature procedure for pyridazine alkylation
The inhibitors of FAAH may serve as useful tools to clar-
ify the role of these two endogenous amides and may
prove to be useful therapeutic agents for the treatment of
sleep disorders or pain.
Here, we present improvements to the synthesis of com-
pound 1 and some other significant representatives of the
same family of compounds on a gram scale. Weinreb
2
In 2000, Boger and co-workers reported the preparation
6,7
amides 2–6 of fatty acids were prepared by adding N,O-
3
of exceptionally potent a-keto heterocycle inhibitors of
dimethylhydroxylamine hydrochloride to the acyl chlo-
ride of fatty acids dissolved in dichloromethane in the
presence of pyridine at room temperature (Table 1).
fatty acid amide hydrolase (FAAH). Among them (Z)-1-
With these Weinreb amides in hand we first tried to repro-
duce the procedure developed by Boger and co-workers to
convert the amide 2 into the desired a-keto hetrocycle 1;
SYNTHESIS 2007, No. 19, pp 3051–3055
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.09.2007
DOI: 10.1055/s-2007-990774; Art ID: P05807SS
Georg Thieme Verlag Stuttgart · New York
©

3
052
G. Rosini et al.
PAPER
Table 1 Preparation of Weinreb Amidesa
(Z)-1-oxo-1-(3-pyridazinyl)octadec-9-ene (1) was isolat-
ed after flash chromatography in only 4% yield. In an ini-
tial attempt to maximize the yield of 1 the critical factor
was considered to be the relative amounts of the reagents
involved in the formation of the pyridazinyllithium spe-
cies: TMP, n-BuLi, and pyridazine. In the original proce-
dure (Equation 1) an excess of the lithiating agent, LTMP,
is used with respect to the pyridazine. This excess might
lead to double lithiation of pyridazine and formation of
disubstitued by-products.
O
O
Me
CH2Cl2, Py
r.t.
+
⋅HCl
OMe
HN
R
Cl
R
N
OMe
Me
Yield (%)b
Acyl chloride of Weinreb amides
Oleic acid
O
82
OMe
N
7
7
2
Me
We changed this ratio and used a stoichiometric ratio of
the lithiating agent to the pyridazine, while keeping the
excess of pyridazinyllithium with respect to the Weinreb
amide (TMP/n-BuLi/pyridazine/amide 2 = 4:4:4:1). This
lowered the chances for double lithiation of pyridazine
while keeping reaction times short. We also found that the
reported quench of the reaction mixture with 12 N HCl–
THF–EtOH (1:4.5:4.5) at low temperature followed by a
slow rise to room temperature and neutralization by satu-
Stearic acid
O
93
81
OMe
N
16
3
Me
Linolenic acid
O
OMe
N
4
7
4
Me
Elaidic acid
Erucic acid
O
86
84
OMe
rated NaHCO is deleterious, since significant amounts of
3
N
6
7
5
products are destroyed to give back oleic acid. Much bet-
ter results were obtained by quenching the reaction at low
temperature by the slow addition of aqueous saturated
Me
O
OMe
NH Cl.
N
4
7
11
6
Me
The changes described above allowed a dramatic im-
provement of the yield of 1, from the reported 11% to a
good 78% after isolation by column chromatography. The
reaction was completed in 30 minutes at –75 °C and a pro-
longed reaction time only allowed a slight improvement
a
All reactions were run on a 18.0–20.0 mmol scale in CH Cl (50 mL)
2
2
at r.t.
b
Isolated yield of pure product.
(
83% yield after 120 min).
Table 2 Influence of the Pirydazinyllithium/Weinreb Amide Ratio on the Yields of 1-Oxo-1-(3-pyridazinyl) Derivatives 1,7–10
O
O
1
2
. THF, –75 °C, 30 min
. aq NH4Cl
Li
N
N
OMe
N
R
N
R
N
+
Me
1, 7–10
2–6
Weinreb amide
1 equiv)
Pyridazinyl Li
(n equiv)
1-Oxo-1-(3-pyridazinyl) derivative
Yield (%)a,b
Mp (°C)
40–41
(
2
3
4
1.2
O
17
34
78
86
2
2
4
6
.0
.0
.0
(Lit. 40–42)
N
N
7
7
1
(
11)c
d
1.2
O
–
–
93–94
d
2
2
4
6
.0
.0
.0
(Lit. 83–85)
N
N
34
32
16
(
12)c
7
1.2
O
–d
oil
2
4
6
.0
.0
.0
42
67
88
N
N
7
7
8
Synthesis 2007, No. 19, 3051–3055 © Thieme Stuttgart · New York

PAPER
Improved Procedure for FAAH Inhibitors
3053
Table 2 Influence of the Pirydazinyllithium/Weinreb Amide Ratio on the Yields of 1-Oxo-1-(3-pyridazinyl) Derivatives 1,7–10
(
continued)
O
O
1
2
. THF, –75 °C, 30 min
. aq NH4Cl
Li
N
N
OMe
N
R
N
R
N
+
Me
1, 7–10
2–6
Weinreb amide
1 equiv)
Pyridazinyl Li
(n equiv)
1-Oxo-1-(3-pyridazinyl) derivative
Yield (%)a,b
Mp (°C)
63–65
(
5
1.2
O
42
62
83
77
2
2
4
6
.0
.0
.0
(Lit. 55–57)
N
N
6
7
9
42)c
(
6
1.2
O
– d
–
22
73
54–55
d
2
4
6
.0
.0
.0
N
N
7
11
10
a
b
c
d
All reactions were run on a 4.0–5.0 mmol scale in anhyd THF at –75 °C for 30 min.
Yield of isolated product after column chromatography.
The reported yields are given in parentheses.
2
No appreciable result.
In order to further optimize the process, the influence of solvent and excess reagent were removed under reduced pressure,
and the crude acid chloride was dried under vacuum. The crude
the pyridazinyllithium/Weinreb amide ratio was exam-
compound was dissolved in anhyd EtOH free CH Cl (40 mL), and
2
2
ined. Table 2 shows how increasing the amounts of reac-
tants with respect to the Weinreb amide 2 raises the
reaction yields. Therefore, the same protocol was applied
to the conversion of Weinreb amides 3–6 into the corre-
sponding 3-pyridazinyl derivatives 7–10 (Table 2).
N-methoxy-N-methylamine hydrochloride (1.9 g, 19.5 mmol) was
added. The mixture was cooled at 0 °C and pyridine (3.15 g, 38.95
mmol) was slowly added. The stirring was continued for 12 h at r.t.
The mixture was diluted with CH Cl (50 mL) and the organic layer
2
2
was washed with H O (5 × 30 mL) and then with aq sat. CuSO
2
4
(
2 × 30 mL). The organic layer was dried (MgSO ) and evaporated
4
In conclusion, an improved and optimized deprotonation
of pyridazine was achieved, maintaining regioselectivity
and greatly improving previously reported yields, and
at reduced pressure to give the amide (Table 1).
(
Z)-N-Methoxy-N-methyloctadec-9-enamide (2)
thereby allowing the preparation of a family of important Colorless oil; R = 0.39 (PE–EtOAc, 4:1); GC: t = 2.96 min.
f
R
FAAH inhibitors on a gram scale without the formation of
disubstituted derivatives.
IR (film): 3000, 2918, 2844, 1669, 1469, 1372 cm–1.
1
H NMR (CDCl ): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.21–1.41 (m, 20
3
H), 1.63 (m, 2 H), 1.96–2.07 (m, 4 H), 2.41 (t, J = 7.7 Hz, 2 H), 3.18
(
13
s, 3 H), 3.68 (s, 3 H), 5.28–5.41 (m, 2 H).
All chemicals were obtained from commercial suppliers and used
without further purification. Melting points are uncorrected. Flash
chromatography was carried out on 300–400 mesh silica gel. IR
spectra were recorded on a PerkinElmer Spectrum RX 1 FT-IR
C NMR (CDCl ): d = 13.99, 22.57, 24.33, 27.08, 27.12, 29.05,
3
2
1
9.21, 29.31, 29.42, 29.62, 29.66, 31.79, 31.81 (by DEPT), 61.05,
29.67, 129.82.
1
13
spectrometer. H and C NMR spectra were recorded on a Varian
Gemini 300 MHz instrument and chemical shifts were referenced to
TMS as internal standard. GC analyses were performed on a Agilent
Technologies 6850-series GC system with a flame ionization detec-
tor (320 °C) using a capillary column (Agilent HP-5, 5% phenyl
methyl siloxane, 30 m × 0.32 mm i.d. × 0.25 mm film). The column
temperature was programmed from 250 °C (held for 2 min) to
Anal. Calcd for C H NO : C, 73.79; H, 12.08; N, 4.30. Found: C,
2
0
39
2
7
3.83; H, 12.15; N, 4.24.
N-Methoxy-N-methylstearamide (3)
White solid; mp 34–38 °C; R = 0.38 (PE–EtOAc, 4:1); GC: t =
f
R
3
.22 min.
–
1
IR (KBr): 2910, 2853, 1665, 1468, 1322 cm–1.
2
75 °C (held for 4 min) at 15 °C min . Solvents and reagents were
obtained anhydrous according to the reported procedures: THF (dis-
tilled from Na-benzophenone immediately prior to use), pyridine
1
H NMR (CDCl ): d = 0.88 (t, J = 6.8 Hz, 3 H), 1.19–1.37 (m, 28
3
H), 1.63 (m, 2 H), 2.41 (t, J = 7.7 Hz, 2 H), 3.18 (s, 3 H), 3.68 (s, 3
H).
(
distilled from KH), CH Cl , 2,2,6,6-tetramethylpiperidine (TMP)
2 2
and pyridazine (refluxed over and distilled from CaH ). n-BuLi was
2
1
3
7
C NMR (CDCl ): d = 14.07, 22.65, 24.62, 29.32, 29.40, 29.42,
titrated immediately before use. Petroleum ether (PE) used refers
3
2
9.48, 29.60, 29.65, 31.89, 61.11.
to the fraction with boiling range 40–60 °C.
Anal. Calcd for C H NO : C, 73.34; H, 12.62; N, 4.28. Found: C,
2
0
41
2
N-Methoxy-N-methylamides (Weinreb Amides) 2–6 of Fatty
Acids; General Procedure
7
3.28; H, 12.67; N, 4.23.
To a mixture containing the fatty acid (18.0 mmol) and anhyd
(
9E,12E)-N-Methoxy-N-methyloctadeca-9,12-dienamide (4)
CH Cl (14 mL), cooled to 0 °C, was added SOCl (2 M in CH Cl ,
2
2
2
2
2
Pale yellow oil; R = 0.42 (PE–EtOAc, 4:1); GC: t = 3.08 min.
f
R
1
7.5 mL, 35 mmol). The mixture was stirred for 4 h at 50 °C. The
Synthesis 2007, No. 19, 3051–3055 © Thieme Stuttgart · New York

3
054
G. Rosini et al.
PAPER
–
1
13
IR (film): 3003, 2921, 2847, 1673, 1459, 1141 cm .
C NMR (CDCl ): d = 18.81, 22.38, 22.51, 26.88, 26.91, 28.85,
3
1
28.96, 29.01, 29.05, 29.22, 29.42, 29.47, 31.60, 37.88, 124.39,
H NMR (CDCl ): d = 0.89 (t, J = 6.8 Hz, 3 H), 1.25–1.42 (m, 14
H), 1.62 (m, 2 H), 1.99–2.11 (m, 4 H), 2.41 (t, J = 7.6 Hz, 2 H), 2.77
3
1
26.93, 129.47, 129.66, 152.94, 155.47, 200.42.
(
t, J = 6.0 Hz, 2 H), 3.18 (s, 3 H), 3.68 (s, 3 H), 5.27–5.44 (m, 4 H).
Anal. Calcd for C H N O: C, 76.69; H, 10.53; N, 8.13. Found: C,
2
2
36
2
1
3
76.59; H, 10.47; N, 8.07.
C NMR (CDCl ): d = 14.00, 22.50, 24.57, 25.55, 27.13, 27.15,
3
2
1
9.10, 29.27, 29.35, 29.57, 31.45, 31.84, 61.11, 127.89, 127.93,
30.02, 130.12.
1
-(Pyridazin-3-yl)octadecan-1-one (7)
2
White solid; mp 91–93 °C (Lit. mp 83–85 °C); R = 0.18 (PE–
f
Anal. Calcd for C H NO : C, 74.25; H, 11.53; N, 4.33. Found: C,
7
20
37
2
EtOAc, 4:1); GC: t = 5.08 min.
R
4.31; H, 11.55; N, 4.25.
IR (KBr): 3047, 2920, 2849, 1699, 1572, 1469, 1259, 1017, 891
–
1
cm .
(
E)-N-Methoxy-N-methyloctadec-9-enamide (5)
1
Pale yellow oil; R = 0.39 (PE–EtOAc, 4:1); GC: t = 3.17 min.
H NMR (CDCl ): d = 0.88 (t, J = 6.8 Hz, 3 H), 1.21–1.46 (m, 28
f
R
–
3
1
H), 1.79 (quint, J = 7.5 Hz, 2 H), 3.40 (t, J = 7.5 Hz, 2 H), 7.66 (dd,
J = 4.9 Hz, J = 8.4 Hz, 1 H), 8.14 (dd, J = 8.4 Hz, J = 1.9 Hz, 1
IR (film): 2919, 2845, 1669, 1458, 1378, 1175 cm .
1
o
o
o
m
H NMR (CDCl ): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.20–1.40 (m, 20
3
H), 9.33 (dd, J = 5.0 Hz, J = 1.9 Hz, 1 H).
o m
H), 1.62 (m, 2 H), 1.91–2.01 (m, 4 H), 2.41 (t, J = 7.6 Hz, 2 H), 3.18
(
1
3
C NMR (CDCl ): d = 13.79, 22.36, 23.52, 28.97, 29.04, 29.13,
3
s, 3 H), 3.68 (s, 3 H), 5.30–5.41 (m, 2 H).
3
2
9.19, 29.31, 29.34, 29.38, 31.61, 37.87, 124.37, 126.92, 152,91,
1
C NMR (CDCl ): d = 14.02, 22.60, 24.57, 28.93, 29.10, 29.23,
3
155.46, 200.42.
2
1
9.34, 29.41, 29.52, 29.57, 31.45, 31.82, 32.53, 61.76, 130.17,
30.32.
Anal. Calcd for C H N O: C, 76.25; H, 11.05; N, 8.08. Found: C,
2
2
38
2
7
6.16; H, 11.04; N, 8.15.
Anal. Calcd for C H NO : C, 73.79; H, 12.08; N, 4.30. Found: C,
20
39
2
7
3.85; H, 12.15; N, 4.28.
(
9E,12E)-1-(Pyridazin-3-yl)octadeca-9,12-dien-1-one (8)
Yellow oil; R = 0.26 (PE–EtOAc, 4:1); GC: t = 4.88 min.
f
R
(
E)-N-Methoxy-N-methyldocos-13-enamide (6)
–
1
IR (KBr): 2926, 2856, 1701, 1457, 1380 cm .
1H NMR (CDCl
): d = 0.88 (t, J = 6.7 Hz, 3 H), 1.20–1.48 (m, 14
Pale yellow oil; R = 0.46 (PE–EtOAc, 4:1); GC: t = 5.23 min.
f
R
–
1
3
IR (film): 3049, 2920, 2848, 2295, 1652, 1421, 1261, 1176 cm .
H), 1.79 (quint, J = 7.0 Hz, 2 H), 1.99–2.12 (m, 4 H), 2.78 (t, J = 5.7
Hz, 2 H), 3.41 (t, J = 7.6 Hz, 2 H), 5.28–5.44 (m, 4 H), 7.66 (dd,
J = 4.9 Hz, J = 8.4 Hz, 1 H), 8.15 (dd, J = 8.4 Hz, J = 1.8 Hz, 1
1
H NMR (CDCl ): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.20–1.40 (m, 28
3
H), 1.62 (m, 2 H), 1.95–2.06 (m, 4 H), 2.41 (t, J = 7.7 Hz, 2 H), 3.18
o
o
o
m
(
1
s, 3 H), 3.68 (s, 3 H), 5.29–5.39 (m, 2 H).
H), 9.33 (dd, J = 5.0 Hz, J = 1.7 Hz, 1 H).
o
m
3
C NMR (CDCl ): d = 14.05, 22.62, 24.61, 27.15, 29.26, 29.33,
13
3
C NMR (CDCl ): d = 13.83, 22.32, 23.57, 25.58, 26.95, 26.97,
3
2
9.41, 29.47, 29.50, 29.57, 29.72, 31.85, 61.11, 129.81, 130.32.
2
1
8.91, 29.00, 29.10, 29.38, 31.27, 37.93, 124.46, 126.99, 127.68,
27.77, 129.83, 129.94, 153.00, 155.52, 200.50.
Anal. Calcd for C H NO : C, 75.53; H, 12.41; N, 3.67. Found: C,
24
47
2
7
5.61; H, 12.47; N, 3.61.
Anal. Calcd for C H N O: C, 77.14; H, 10.01; N, 8.18. Found: C,
2
2
34
2
7
7.34; H, 10.08; N, 8.11.
Pyridazines 1, 7–10; General Procedure
,2,6,6-Tetramethylpiperidine (2.07 mL, 12.3 mmol, 4.0 equiv) was
dissolved in anhyd THF (70.0 mL) and cooled to –30 °C. n-BuLi
1.5 M in hexane, 8.2 mL, 12.3 mmol, 4 equiv) was added dropwise,
2
(
E)-1-(Pyridazin-3-yl)octadec-9-en-1-one (9)
2
White solid; mp 63–64 °C (Lit. mp 55–57 °C); R = 0.16 (PE–
f
(
EtOAc, 4:1); GC: t = 4.92 min.
R
keeping the temperature below –25 °C. After the addition of n-BuLi
was complete, the mixture was warmed to 0 °C with an ice bath and
stirred at this temperature for 45 min. The mixture was then cooled
to –70 °C (internal) and a solution of pyridazine (0.89 mL, 12.3
mmol, 4 equiv) in anhyd THF (10 mL) was added dropwise. The
color of the mixture turned to red brown. Then a solution of Wein-
reb amide 2–6 (3.07 mmol) in THF (5 mL) was added, maintaining
the temperature as close as possible to –70 °C. The mixture was
stirred for 30 min. The workup of the mixture was performed by
–
1
IR (KBr): 2905, 2843, 1695, 1467, 1399, 958, 808, 714 cm .
1
H NMR (CDCl ): d = 0.87 (t, J = 6.7 Hz, 3 H), 1.28–1.54 (m, 20
H), 1.85 (quint, J = 7.4 Hz, 2 H), 2.01–2.10 (m, 4 H), 3.47 (t, J = 7.4
Hz, 2 H), 5.42–5.48 (m, 2 H), 7.75 (dd, J = 5.2 Hz, J = 8.5 Hz, 1
3
o
o
H), 8.22 (dd, J = 8.3 Hz, J = 1.8 Hz, 1 H), 9.42 (dd, J = 5.0 Hz,
o
m
o
Jm = 1.9 Hz, 1 H).
13
C NMR (CDCl ): d = 14.00, 22.57, 23.75, 28.89, 29.08, 29.14,
9.21, 29.39, 29.48, 29.55, 31.79, 32.47, 32.50, 38.07, 124.71,
27.22, 130.13, 130.33, 153,04, 155.66, 200.55.
3
2
1
adding aq sat. NH Cl (40 mL, initially dropwise) while allowing the
4
temperature to rise to r.t. The mixture was extracted with Et O
2
Anal. Calcd for C H N O: C, 76.69; H, 10.53; N, 8.13. Found: C,
(
3 × 40 mL). The ethereal solution was dried (MgSO ), filtered, and
22 36
2
4
7
6.81; H, 10.58; N, 8.09.
evaporated under reduced pressure to give the crude product that
was purified by flash column chromatography (Table 2).
(
Z)-1-(Pyridazin-3-yl)docos-13-en-1-one (10)
White solid; mp 54.0–55.5 °C; R = 0.16 (PE–EtOAc, 4:1); GC:
tR = 8.93 min.
(
Z)-1-(Pyridazin-3-yl)octadec-9-en-1-one (1)
f
2
White solid; mp 40–41 °C (Lit. mp 40–42 °C); R = 0.24 (PE–
EtOAc, 4:1); GC: t = 2.96 min.
f
IR (KBr): 2926, 2833, 1721, 1596, 1498, 1249, 864, 810 cm–1.
R
–
1
IR (KBr): 3052, 3009, 1700, 1567, 1465, 1267 cm .
1
H NMR (CDCl ): d = 0.88 (t, J = 6.7 Hz, 3 H), 1.14–1.46 (m, 28
3
1
H), 1.79 (quint, J = 7.5 Hz, 2 H), 1.98–2.05 (m, 4 H), 3.04 (t, J = 7.4
H NMR (CDCl ): d = 0.85 (t, J = 6.8 Hz, 3 H), 1.20–1.48 (m, 20
3
Hz, 2 H), 5.42–5.48 (m, 2 H), 7.66 (dd, J = 5.2 Hz, J = 8.5 Hz, 1
H), 1.79 (quint, J = 7.2 Hz, 2 H), 1.96–2.08 (m, 4 H), 3.41 (t, J = 7.5
Hz, 2 H), 5.29–5.41 (m, 2 H), 7.67 (dd, J = 5.1 Hz, J = 8.5 Hz, 1
o
o
H), 8.14 (dd, J = 8.3 Hz, J = 1.6 Hz, 1 H), 9.34 (dd, J = 5.0 Hz,
o
m
o
o
o
Jm = 1.5 Hz, 1 H).
H), 7.84 (dd, J = 8.3Hz, J = 1.7 Hz, 1 H), 9.34 (dd, J = 5.0 Hz,
o
m
o
Jm = 1.5 Hz, 1 H).
Synthesis 2007, No. 19, 3051–3055 © Thieme Stuttgart · New York

PAPER
Improved Procedure for FAAH Inhibitors
3055
1
3
C NMR (CDCl ): d = 13.74, 22.38, 23.48, 26.85, 28.93, 28.96,
Patricelli, M. P.; Cravatt, B. F. Proc. Natl. Acad. Sci. U.S.A.
2000, 97, 5044. (b) Boger, D. L. (The Scripps Research
Institute) US Patent 6462054 B1, 2002; Chem. Abstr. 2002,
3
2
1
9.09, 29.16, 29.19, 29.26, 29.41, 31.54, 37.06, 37.82, 124.34,
26.88, 129.51, 152.86, 155.41, 200.55.
1
37, 279215.
Anal. Calcd for C H N O: C, 77.94; H, 11.07; N, 6.99. Found: C,
26
44
2
(
3) The use of a-keto heterocycles as inhibitors was first
disclosed by Edwards et al. in 1992: Edwards, P. D.; Meyer,
E. F. Jr.; Vijayalakshimi, J.; Tuthill, P. A.; Andisik, D. A.;
Gomes, B.; Strimpler, A. J. Am. Chem. Soc. 1992, 114, 1854.
4) Plé, N.; Turck, A.; Couture, K.; Quéguiner, G. J. Org. Chem.
7
7.85; H, 11.09; N, 6.94.
Acknowledgment
(
(
This research was supported in part by Alma Mater Studiorum –
Università di Bologna and MiUR, Italy (PRIN 2005: ‘Stereoselezi-
one in Sintesi Organica. Metodologie ed Applicazioni’).
1995, 60, 3781.
5) (a) More recently, a new strategy for deprotonative func-
tionalization of aromatics with excellent chemoselectivity
and unique regioselectivity using t-Bu-P4 base in the
presence of ZnI has appeared in the literature: Imahori, T.;
2
References
Kondo, Y. J. Am. Chem. Soc. 2003, 125, 8082. (b) Using
this approach, pyridazine was treated with diphenyl ketone
and gave a 4-substituted 1,2-adduct in 91% yield.
(
1) (a) Cravatt, B. F.; Giang, D. K.; Mayfield, S. P.; Boger, D.
L.; Lerner, R. A.; Gilula, N. B. Nature (London) 1996, 384,
(
(
6) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
83. (b) McKinney, M. K.; Cravatt, B. F. Ann. Rev. Biochem.
3815. (b) Ballini, R.; Marcantoni, E.; Torreggiani, E. J. Nat.
2
005, 74, 411.
Prod. 1997, 60, 505.
(
2) (a) Boger, D. L.; Sato, H.; Lerner, A. E.; Hedrick, M. P.;
Fecik, R. A.; Miyauchi, H.; Wilkie, G. D.; Austin, B. J.;
7) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41,
1879.
Synthesis 2007, No. 19, 3051–3055 © Thieme Stuttgart · New York