Synthesis of Methyl 7,9-Dimethyl-5-oxo-2,3,4,5-tetrahydro-1 H -benzo[ b ]azepine-1-carboxylate and Its Analogues

Article abstract of DOI:10.1055/s-0034-1378279

A high-yielding five-step synthesis of the title compound, methyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate, starting from 2,4-dimethylaniline was developed. This synthesis involved N-alkylation of 2,4-dimethylaniline with ethyl 4-bromobutyrate to obtain ethyl 4-[(2,4-dimethylphenyl)amino]butanoate. Carbamoylation of the latter followed by hydrolysis of the resulting ester provided 4-[(2,4-dimethylphenyl) (methoxycarbonyl)amino]butanoic acid. Activation of the carboxylic acid using thionyl chloride followed by intramolecular cyclization via a Friedel-Crafts reaction using aluminum trichloride provided the title compound in good yield. Analogues of the title compound were also prepared similarly. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378279

PAPER
▌2463
pSaypenr thesis of Methyl 7,9-Dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-
1-carboxylate and Its Analogues
Large-Scale Synthesis of Benzazepinone Derivatives
Radhe K. Vaid,* Sathish K. Boini, Charles A. Alt, Jeremy T. Spitler, Chad E. Hadden, Scott A. Frank, Eric D. Moher
Small Molecule Design and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Fax +1(317)2764507; E-mail: vaid_radhe_k@lilly.com
Received: 06.03.2014; Accepted after revision: 20.05.2014
ous targets such as enzymes, ion channels, and G-protein
Abstract: A high-yielding five-step synthesis of the title com-
coupled receptors (GPCRs).3,4 As a part of an ongoing
pound, methyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-ben-
project on cholesteryl ester transfer protein (CETP) inhib-
zo[b]azepine-1-carboxylate, starting from 2,4-dimethylaniline was
developed. This synthesis involved N-alkylation of 2,4-dimethyl-
itor,5 Evacetrapib, multi-kilogram quantities of the title
aniline with ethyl 4-bromobutyrate to obtain ethyl 4-[(2,4-dimeth- compound 1 (Figure 1) were required for development.
ylphenyl)amino]butanoate. Carbamoylation of the latter followed
by hydrolysis of the resulting ester provided 4-[(2,4-dimethylphe-
nyl)(methoxycarbonyl)amino]butanoic acid. Activation of the car-
from 2,4-dimethylaniline (3),6 the poor isolated yield of 1
boxylic acid using thionyl chloride followed by intramolecular
cyclization via a Friedel–Crafts reaction using aluminum trichloride
Although, we had reported the synthesis of 1 and 7,9-di-
methyl-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (2)
(38–49%) necessitated the development of a practical pro-
cess to meet the multi-kilogram requirement of 1. Herein
we report the details of a high-yielding and practical syn-
thesis of 1.
provided the title compound in good yield. Analogues of the title
compound were also prepared similarly.
Key words: alkylation, carbamoylation, hydrolysis, Friedel–Crafts
reaction
O
O
Benzo-fused seven-membered nitrogen heterocyclic
rings, broadly termed as benzazepines, represent a partic-
ularly interesting class of heterocylces.1 The benzazepine
moiety constitutes the core structure of numerous pharma-
cologically important compounds.2 Several members of
this class have exhibited biological activity toward vari-
N
N
H
CO2Me
2
1
Figure 1 Structure of compounds 1 and 2
O
O
OEt
OEt
N
H
O
8
N
N
H
CO2Me
1
2
Br
O
7
OH
OEt
N
N
CO2Me
O
CO2Me
O
NH2
9
10
3
ClCO2Me
Br
11
4
+
OH
OH
H2N
N
H
NH
O
O
CO2Me
6
5
12
Scheme 1 Retrosynthetic pathways for 1
SYNTHESIS 2014, 46, 2463–2470
Advanced online publication: 24.06.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378279; Art ID: ss-2014-m0164-op
© Georg Thieme Verlag Stuttgart · New York

2464
R. K. Vaid et al.
PAPER
A retrosynthetic analysis of 1 revealed that its synthesis ation of 12 with 7 using powdered metal hydroxides or
might be achieved by intramolecular Friedel–Crafts reac- carbonates. Synthesis of 9 using metal hydroxides or pow-
tion of 6, 8, 9, or 10 (Scheme 1). Compound 6 might be dered sodium or potassium carbonate was unsuccessful.
obtained by direct metal-catalyzed coupling of 4 and 5. Synthesis of 9 was, however, successful using cesium car-
Compound 10 could be obtained either by carbomylation bonate in N,N-dimethylformamide under dilute condi-
of 6 or by hydrolysis of 9. Synthesis of 9 could be tions (20 volumes) in 60% yield (Scheme 3). Due to the
achieved by a) N-alkylation of 3 with 7 followed by car- environmental concern for the disposal of cesium waste
bamoylation of resulting product 8 or b) alkylation of 12 and large volumes of N,N-dimethylformamide required,
with 7.
we explored the synthesis of 9 from 8.
Following the literature precedent,7 the synthesis of 6 was Thus, the synthesis of 8 was explored by N-alkylation of
successfully achieved by coupling 4 with 5 using Pd(dba)2 3 with 7 (Scheme 4). The treatment of 3 with 7 in Hünig’s
and ligand 13 in 77% yield (Scheme 2). Compound 10 base (DIPEA) as solvent at 100 °C provided a mixture of
was obtained by treating 6 with methyl chloroformate and desired mono-N-alkylated product 8 along with bis-N-al-
potassium carbonate. We were unsuccessful in finding a kylated product 14. Significantly higher amounts of 14
commercially available ligand as a replacement for 13. were observed as the scale of reaction was increased.
Thus, due to limited large-scale availability of ligand 13 Therefore, the impact of other parameters such as type of
and its tedious synthesis,8 we explored other pathways for base, temperature, and solvent on the selectivity was ex-
the synthesis of 10 as shown in Scheme 1.
amined in the formation of 8. The reaction was performed
in triethylamine at 75 °C with slow addition of 7 over 24
hours in order to minimize the levels of 14. However,
these modifications resulted in an extended reaction time
of >70 hours. Even with an additional charge of 7, the lev-
el of 3 could not be driven to the desired target of <3%,
without a concomitant increase in levels of 14.
Pd(dba)2, 13
KOH, t-BuOH
4
+
N
H
CO2H
90 °C, 18 h
77%
H2N
CO2H
6
5
ClCO2Me
K2CO3, THF
Several alternative bases including pyridine, N-methyl-
morpholine, and potassium carbonate were screened, but
alkylation results were poor. A more detailed comparison
study of triethylamine and Hünig’s base were undertaken.
The alkylation was much worse in Hünig’s base at both 75
and 100 °C. The reaction rate was slow and bis-alkylation
was three times higher as compared to the alkylation reac-
tion performed using base triethylamine. Consequently,
triethylamine was chosen for further process develop-
ment. In this study, the reaction temperature and stoichi-
ometries of triethylamine and 7 were studied (Table 1
entries 1–9). Low equivalents of both triethylamine and 7
at 85 °C did not lead to desired target level of 3 (<3%; en-
try 1). A combination of high equivalents of 7 and low
equivalent of triethylamine allowed the reaction to reach
completion within three hours (entry 2). However, as ex-
pected, the level of 14 quickly increased to unacceptably
high level. Use of 1.5 equivalents of 7 provided interme-
diate results in regard to conversion and levels of bis-al-
kylation. Doubling the charge of triethylamine (entry 5)
not only slowed the reaction rate, but also led to a reduc-
tion in 14. Use of high equivalence of triethylamine was
88%
Pt-Bu2
Oi-Pr
N
CO2H
CO2Me
ligand 13
10
Scheme 2 Synthesis of 10
A survey of the literature revealed that N-alkylation of un-
substituted or N-substituted carboxamides with alkyl ha-
lides under basic conditions can be accomplished in good
yield.9–12 Thus, the synthesis of 9 was attempted by alkyl-
Cs2CO3
DMF
OEt
N
NH
OEt
Br
CO2Me
O
CO2Me
9
12
O
7
Scheme 3 Synthesis of 9
NH2
OEt
Hünig’s base
N
3
toluene
O
+
OEt
+
N
100 °C
OEt
H
O
Br
O
8
O
OEt
7
14
Scheme 4 Synthesis of 8
Synthesis 2014, 46, 2463–2470
© Georg Thieme Verlag Stuttgart · New York

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Large-Scale Synthesis of Benzazepinone Derivatives
2465
excessive, thus co-solvents and addition rate of 7 were ex- by workup allowed the rejection of the bis-hydrolysis im-
amined. CPME (cyclopentyl methyl ether) and toluene purity originating from 14 to obtain 10 of high purity. The
were both tested as co-solvents in the synthesis of 8 (Table resulting solution of 10 in dichloromethane was used
2). As the yield and quality profile of 8 was observed to be without further purification for the formation of 15.
comparable, toluene was selected as co-solvent for further
exploration. Entries 7 and 8 in Table 2 compare the impact
of an up-front charge of 7 to the reaction versus a 16-hour
charge of 7. Both reactions gave similar conversions and
product profiles. Thus, we preferred the up-front charge of
7 in the reaction along with the use of toluene as a co-sol-
vent in the synthesis of 8. A toluene solution of product 8
containing 14 and unreacted 3 obtained after an aqueous
Synthesis of 2 via cyclization of 8 under acidic conditions
was unsuccessful as it resulted in the formation of unde-
sired impurities and 1-(2,4-dimethylphenyl)pyrrolidin-2-
one. Based upon the literature,13,14 attempts to cyclize 9 or
10 to 1 using trifluroacetic anhydride, methanesulfonic
anhydride, methanesulfonic acid, trifluoromethanesulfon-
ic acid, or polyphosphoric acid were also unsuccessful
and resulted in the formation of undesired impurities.
Thus, it was planned to carry out the synthesis of 1 via cy-
clization of an activated form of 10 such as acid chloride
work up was used as such without any purification for the
synthesis of 9.
15 using Lewis acids.
Table 1 N-Alkylation Data of Compound 8
Preparation of acid chloride 15 from 10 was accomplished
using either thionyl chloride or oxalyl chloride in the pres-
Entry Et3N Compound 7 Temp Time GC area%
(equiv) (equiv)
(°C)
(h)
ence of either N,N-dimethylformamide or 2,6-lutidine cat-
alyst and solvent dichloromethane or 1,2-dichloroethane
(DCE). Use of SOCl2 was preferred over oxalyl chloride
due to its lower cost. Among the commonly employed
Lewis acids such as BCl3, FeCl3, SnCl4, ZnCl2, TiCl4, and
aluminum trichloride for the Friedel–Crafts reaction,14
only aluminum trichloride successfully provided 1 from
15. As indicated by HPLC data, unreacted starting mate-
rial and a few impurities were observed with the use of
Lewis acids other than aluminum trichloride. Among the
solvents (CH2Cl2, DCE, heptanes, nitromethane, and sul-
folane) tested for conversion of 15 into 1 by aluminum
trichloride, the best result was obtained using dichloro-
methane.
3
8
14
5.0
1
2
3
4
5
6
7
8
9
3.4
3.4
6.8
3.4
6.8
3.4
3.4
3.4
3.4
1.25
1.75
1.25
1.50
1.50
1.50
1.75
1.50
1.75
85
85
85
85
85
75
75
65
65
3
3
5.5
0.3
1.4
3.2
2.1
2.1
5.0
4.9
9.8
87.5
85.5 12.5
13
3
87.7
88.6
90.1
89.0
89.1
88.7
83.9
8.9
6.0
3.5
7.6
5.9
6.4
6.3
7
7
5
7
7
Following the literature precedent for catalytic Friedel–
Crafts acylation reactions,15,16 the use of other catalysts
such as silica-bound aluminum trichloride or bromopenta-
carbonylrhenium or AlPW12O40 or Ga(ONf)3 was ex-
plored in the synthesis of 1 from 15 under various
Carbamoylation of 8 to give 9 was achieved in toluene us-
ing methyl chloroformate and sodium carbonate. Subse-
quently, hydrolysis of 9 using sodium hydroxide followed
Table 2 Impact of Cosolvent, Stoichiometry, and Addition Time of 7 on the Synthesis of 8
Entry
Et3N
(equiv)
Cosolvent
(vol, mL)
Compound 7
(equiv)
Compound 7
Reaction time GC area%
addition time (h) (h)a
3
8
14
1
2
3
4
5
6
7
8
9
3.4
3.4
5.8
5.8
5.8
5.8
5.8
5.8
5.8
CPME (6.0)
toluene (6.0)
CPME (3.3)
CPME (3.3)
toluene (3.3)
toluene (3.3)
toluene (3.3)
toluene (3.3)
CPME (3.3)
1.43
1.40
1.43
1.26
1.26
1.26
1.26
1.30
1.26
16
16
16
16
16
16
–
20
20
19
21
21
22
17
18
17
2.9
1.8
2.4
4.2
3.5
2.5
3.1
2.4
2.8
90.3
91.1
91.7
90.8
91.1
92.1
91.2
92.6
90.9
6.4
6.7
5.3
5.3
4.8
5.4
5.0
5.0
5.5
16
–
a The reactions were complete after 5 h, but were held at 100 °C for the indicated time to ensure product stability.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2463–2470

2466
R. K. Vaid et al.
PAPER
conditions. Synthesis of 1 from 15 under catalytic of 10. The formation of dimer 16 was also observed under
Friedel–Crafts reaction conditions was unsuccessful.
dilute reaction conditions. This impurity, shown in Figure
2, was isolated and identified by NMR spectroscopy.
As mentioned previously, the Friedel–Crafts cyclization
was successfully completed using 15 and aluminum tri-
chloride as the Lewis acid, thus efforts were focused to
optimize this approach. The use of 15 prepared using cat-
alyst 2,6-lutidine led to the formation of more impurities
in the synthesis of 1. Further, the isolated product quality
and yield were low. Therefore, we decided to use N,N-di-
methylformamide as a catalyst for acid chloride forma-
tion. Impacts of solvent 1,2-dichloroethane and
temperature were evaluated in the synthesis of 1 from 15
(Table 3, entries 1–4). In 1,2-dichloroethane, at high tem-
perature and under dilute conditions a low yield of 1 was
obtained and product quality was also poor. The conver-
sion of 15 into 1 in dichloromethane under reflux condi-
tions was better as compared to the reaction performed in
1,2-dichloroethane. Thus, we preferred dichloromethane
to 1,2-dichloroethane for the synthesis of 1 using alumi-
num trichloride. In the process optimization study, the im-
pact of reaction concentration and Lewis acid
stoichiometry were studied in dichloromethane (entries
5–13). As indicated from the data (entry 10), low yield of
1 was obtained under dilute reaction conditions with 1.5
equivalents of Lewis acid. Similarly, high reaction con-
centration and Lewis acid equivalents (entries 5 and 7)
also provided low yield. The best transformation was ob-
served under dilute reaction conditions with 3.22 equiva-
lents of aluminum trichloride (entries 12 and 13).
O
OMe
N
O
O
N
MeO
16
O
Figure 2 Structure of impurity 16
Finally, we were able to achieve the synthesis of 1 from 3
without the isolation of intermediates by developing a
streamlined process as shown in Scheme 5. This stream-
lined process involved i) preparation of a toluene solution
of 8, ii) carbamoylation of 8 followed by hydrolysis of 9
to obtain 10, and iii) activation of 10 using thionyl chlo-
ride followed by intramolecular Friedel–Crafts reaction
with aluminum trichloride, workup and crystallization
from ethanol–water to obtain 1 in 67% isolated yield start-
ing from 3.
In a similar manner, analogues 17–19 of 1 were prepared
successfully (Figure 3).
Table 3 Impact of Aluminum Trichloride Stoichiometery, Solvent
Concentration, and Temperature on the Synthesis of 1 from 15
O
O
O
Entry AlCl3 Solvent
(equiv) (vol, mL)
Temp
(°C)
Time Compound1formation
(h) by HPLC assay (%)
N
N
N
CO2Me
CO2Me
CO2Me
1
2
3.22
3.22
3.22
3.22
3.22
3.22
3.22
3.22
3.22
1.5
DCE (12)
DCE (12)
DCE (12)
DCE (7)
70–75
50–55
43–45
36–38
2
2
3
3
3
3
2
2
2
2
2
3
2
54.6
61.9
64.0
57.3
72.4
75.0
77.0
88.0
88.5
70.2
77.0
87.5
88.2
17
18
19
Figure 3 Synthesis of 17–19
3
However, attempted synthesis of 20–22 under the same
conditions was unsuccessful, potentially as a result of the
reduced electron density of the aromatic ring bearing flu-
4
5
CH2Cl2 (7) 35–40
CH2Cl2 (9) 35–40
CH2Cl2 (10) 35–40
CH2Cl2 (12) 35–40
CH2Cl2 (14) 35–40
CH2Cl2 (12) 35–40
CH2Cl2 (12) 35–40
CH2Cl2 (14) 35–40
CH2Cl2 (12) 35–40
6
O
O
7
F
Cl
8
9
N
N
CO2Me
CO2Me
10
11
12
13
20
21
2.5
O
O
3.22
3.22
MeO
N
N
Cl
CO2Me
22
CO2Me
An LCMS analysis of the Friedel–Crafts reaction per-
formed under concentrated conditions indicated the pres-
ence of multiple peaks due to dimer, trimer, and polymers
23
Figure 4 Attempted synthesis of 20–23
Synthesis 2014, 46, 2463–2470
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Large-Scale Synthesis of Benzazepinone Derivatives
2467
STEP 1
Et3N, toluene
95–100 °C
OEt
OEt
Br
+
N
H
NH2
90%
O
O
7
8
3
STEP 2
Na2CO3
ClCO2Me
toluene
98%
STEP 3
MeOH, NaOH, H2O
55–60 °C, 3 h
OH
OEt
N
N
workup, concd HCl
99%
CO2Me
O
CO2Me
O
10
9
SOCl2
DMF (cat.)
CH2Cl2, 0–5 °C
STEP 4
STEP 5
O
AlCl3, CH2Cl2
35 °C
Cl
workup
crystallization
N
N
CO2Me
O
CO2Me
15
77%
1
Scheme 5 Synthesis of 1
lution was used as such in the next step; yield: 173.1 g (89%). A
pure sample of 8 was obtained by purification by column chroma-
tography using a mixture of EtOAc and hexane as eluent (70:30);
off-white solid; mp 202–213 °C.
orine or chlorine relative to methyl substituted substrates
(Figure 4). Attempted synthesis of 23 via an intramolecu-
lar Friedel–Crafts reaction resulted in a complex mixture.
An analysis of this reaction mixture by LCMS indicated
the presence of 23 to be less than 3%.
IR (KBr): 3412 (sharp), 1720 (sharp), 1618 cm–1 (sharp).
1H NMR (DMSO-d6): δ = 1.17 (t, J = 5.50 Hz, 3 H), 1.81 (m, 2 H),
2.02 (s, 3 H), 2.12 (s, 3 H), 2.36 (d, J = 4.30 Hz, 2 H), 3.05 (m, 2 H),
4.06 (q, J = 4.50 Hz, 2 H), 4.59 (br, 1 H), 6.42 (d, J = 3.80 Hz, 1 H),
6.75 (m, 2 H).
In conclusion, we have developed a high-yielding and
practical synthesis of benzazepinone 1 starting from 2,4-
dimethylaniline (3).
13C NMR (DMSO-d6): δ = 173.5, 144.6, 131.0, 127.4, 124.3,
122.30, 109.6, 60.2, 42.9, 31.8, 24.4, 20.5, 18.1, 14.6.
HRMS: m/z [M]+ calcd for C14H21NO2: 235.1572; found: 235.1575.
1H NMR and 13C NMR spectra were recorded using a Bruker
Avance 400, 500, and 600 MHz spectrometers. Chemical shifts (δ)
are expressed in ppm and coupling constants (J) are given in Hz.
Standard abbreviations are used to describe the signal patterns.
HRMS recordings were obtained using a Waters GCT Premier TOF
mass spectrometer with EI source. Column chromatography (CC)
was performed on silica gel (Fluka, silica gel 60, particle size
0.035–0.070 mm).
Step 2: Ethyl 4-[(2,4-Dimethylphenyl)(methoxycarbonyl)]ami-
nobutanoate (9)
To the above prepared toluene solution containing 8 (173.1 g, 735.6
mmol) was added toluene (540 mL) under N2. Na2CO3 (78.5 g,
740.6 mmol) was added and the reaction contents were cooled to 0–
10 °C. Methyl chloroformate (97.9 g, 1036 mmol) was charged to
the reaction mixture dropwise below 10 °C. The contents were
warmed to 10–20 °C and stirred for 1 h. The reaction progress was
monitored by HPLC (8 = not detected; 9 = 87.3%). H2O (540 mL)
was added to the mixture at 15–25 °C and the organic layer was sep-
arated. H2O (200 mL) was added to the mixture at 15–25 °C and the
contents were stirred for 30 min. The organic layer was separated
and analyzed by HPLC for 9. A toluene solution containing 776 g
of 9 (87.7% purity and 27.3% assay) was obtained. This solution
was used as such in the next step; yield 211.8 g (98%). A sample
was concentrated and purified by column chromatography; viscous
oil.
Methyl 7,9-Dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pine-1-carboxylate (1) (Scheme 5)
Step 1: Ethyl 4-[(2,4-Dimethylphenyl)amino]butanoate (8)
To a 3-necked round-bottomed flask equipped with a mechanical
stirrer, thermocouple, reflux condenser, and N2 purge was charged
2,4-dimethylaniline (3; 100.6 g, 830.2 mmol), toluene (330 mL, 3.3
vol), and Et3N (485 g, 4793 mmol). The reaction contents were
heated to 95–100 °C. Ethyl 4-bromobutyrate (7; 209.7 g, 1075.1
mmol) was added dropwise to the reaction mixture over 1 h. The re-
action contents were stirred at 95–100 °C for 6 h. The reaction prog-
ress was monitored by HPLC (3 = 3.0%, 8 = 90.3%; 14 = 5.1%).
The reaction contents were cooled to 15–25 °C. H2O (400 mL) was
added by maintaining a reaction temperature of 15–25 °C. The re-
action contents were stirred at 15–25 °C for 30–40 min. The organic
layer was separated and washed with H2O (300 mL). The organic
layer was concentrated to 200–300 mL at a temperature below
50 °C under vacuum (25–30 Torr). Thus, 261.9 g toluene solution
of 8 (89.3% purity and 66.1% potency assay) was obtained. This so-
1H NMR (CDCl3): δ = 1.22 (t, J = 5.50 Hz, 3 H), 1.85 (m, 2 H), 2.15
(s, 3 H), 2.31 (s, 3 H), 2.32 (m, 2 H), 3.37 (m, 1 H), 3.62 (s, 3 H),
3.78 (m, 1 H), 4.09 (q, J = 4.50 Hz, 2 H), 6.95 (m, 2 H), 7.26 (s, 1 H).
13C NMR (CDCl3): δ = 172.9, 156.4, 137.6, 137.4, 135.5, 131.7,
128.0, 127.4, 60.4, 52.9, 49.6, 31.6, 23.5, 21.0, 17.5, 14.2.
HRMS: m/z [M]+ calcd for C16H23NO4: 293.1627; found: 293.1629.
© Georg Thieme Verlag Stuttgart · New York
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R. K. Vaid et al.
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Step 3: 4-[(2,4-Dimethylphenyl)(methoxycarbonyl)amino]buta-
noic Acid (10)
The i-PrOAc layer was separated and treated with activated carbon
(40 g) for 2 h at 15–25 °C. The contents were filtered via diatomite
(20 g) and the cake was washed with i-PrOAc (400 mL). The filtrate
was transferred to a flask and concentrated to 1–1.5 volume. EtOH
(400 mL) was added and the reaction mixture was concentrated to
1–2 volume. EtOH (352 mL) was added and the contents were con-
centrated to 2.5–2.8 volume. The contents were heated to 45–50 °C
to obtain a clear solution. H2O (392 mL) was added dropwise to the
solution at 45–50 °C over 30 min. A sample was drawn to determine
the ratio of EtOH–H2O (H2O–EtOH, 1.38). H2O (23 g) was charged
to the flask and the contents were cooled to 35 °C slowly. After
seeding the contents with solid 1 (2.0 g) at 35 °C, the contents were
stirred for 2 h at 35 °C. The mixture was cooled to 10 °C and stirred
for 2 h. The slurry was cooled to 0 °C and stirred for 16 h. Filtration
and washing of the cake with EtOH–H2O (1:2; 200 mL) provided an
off-white to a white solid. The product was dried under vacuum at
45–50 °C; yield: 138 g (76%); purity 99.3%; mp 79–81 °C.
1H NMR (DMSO-d6): δ = 1.51 and 1.67 (m, 1 H), 1.97 and 2.09 (m,
1 H), 2.10 and 2.17 (m, 3 H), 2.33 and 2.35 (s, 3 H), 2.15 and 2.10
(m, 3 H), 2.34 and 2.28 (m, 1 H), 2.38 (br s, 1 H), 2.53 and 2.67 (m,
1 H), 3.16 and 3.19 (m, 1 H), 3.51 and 3.70 (m, 3 H), 4.16 and 4.24
(m, 1 H), 7.22–7.26 (s, 1 H), 7.34 and 7.30 (s, 1 H).
13C NMR (DMSO-d6): δ = 202.4, 155.0, 136.8, 136.7, 135.7, 134.7,
125.8, 52.2, 45.0, 20.9, 19.9, 19.8, 16.0.
To a 3-necked round-bottomed flask equipped with a mechanical
stirrer, thermocouple, N2 purge was charged the toluene solution
prepared above containing 9 (211.8 g, 0.722 mol) and MeOH (300
mL). A solution of NaOH (59.2 g, 1.48 mol) in H2O (450 mL) was
added dropwise to the reaction mixture below 60 °C. The contents
were heated to 55–60 °C and this temperature was maintained for 3
h. The reaction progress was monitored by HPLC (9 = not detected;
10 = 89.9%). The reaction contents were cooled to 15–25 °C and
stirred for 20–30 min. The contents were allowed to stand for 30–
35 min. The aqueous layer was separated and washed with toluene
(175 mL). The aqueous layer was concentrated to 2–3 volumes on
a rotary evaporator at reduced pressure (27.4 Torr) at a maximum
temperature of ≤45 °C. After the addition of CH2Cl2 (475 mL), the
pH of the contents was adjusted to 1–2 with concd HCl (148 g) be-
low 5 °C. The contents were warmed to 15–25 °C and stirred for 30
min. The organic layer was separated, mixed with aq 5% HCl (320
mL), and the contents were stirred for 30 min at 15–25 °C. The or-
ganic layer was separated and concentrated at atmospheric pressure
at a maximum pot temperature of 58–60 °C to obtain an oil (348.3
g). HPLC data indicated 97.6% purity of 10 with 55.0% potency as-
say; yield 191.5 g (quant.). A sample (10 mL) was further concen-
trated to obtain a viscous oil. n-Heptane (20 mL) was added slowly
over 1 h to obtain a slurry. The solid was filtered to obtain the pure
compound 10; white solid; mp 60–61 °C.
HRMS: m/z [M]+ calcd for C14H17NO3: 247.1208; found: 247.1211.
1H NMR (CDCl3): δ = 1.86 (t, J = 5.50 Hz, 3 H), 2.15 (s, 3 H), 2.32
(s, 3 H), 2.40 (m, 2 H), 3.40 (m, 1 H), 3.62 (s, 3 H), 3.82 (m, 4 H),
6.97 (m, 2 H), 7.06 (s, 1 H), 10.96 (br, 1 H).
13C NMR (CDCl3): δ = 178.5, 156.7, 137.6, 137.4, 135.5, 131.8,
128.0, 127.5, 53.1, 49.4, 31.9, 23.3, 21.0, 17.5.
Dimethyl 14,16,74,76-Tetramethyl-6,12-dioxo-2,8-diaza-1,7(1,3)-
dibenzenacyclododecaphane-2,8-dicarboxylate (16)
Compound 1 (13 g) enriched with 16 was treated with MeOH (50
mL) at r.t. to obtain a slurry. The insoluble solids were collected by
filtration and washed with MeOH (25 mL). The pale yellow solid
was dried in vacuum oven at 40 °C to give 0.2 g of 16; mp 297–
302 °C.
HRMS: m/z [M]+ calcd for C14H19NO4: 265.1314; found: 265.1317.
Step 4: Methyl (4-Chloro-4-oxobutyl)(2,4-dimethylphenyl)car-
bamate (15)
1H NMR (CDCl3): δ = 1.81 (d, J = 5.50 Hz, 2 H), 1.91(d, J = 6.11
Hz, 2 H), 2.01 (s, 4 H), 2.02–2.04 (m, 2 H), 2.04 (s, 4 H), 2.12 (br s,
1 H), 2.24 (s, 5 H), 2.35 (s, 3 H), 2.63–2.68 (m, 1 H), 2.81 (br s, 2
H), 2.85 (d, J = 5.99 Hz, 2 H), 3.09 (dd, J =15.53, 5.62 Hz, 2 H),
3.14 (br s, 1 H), 3.40 (s, 3 H), 3.48 (br s, 3 H), 4.13 (d, J = 6.24 Hz,
1 H), 4.15 (d, J = 4.89 Hz, 1 H), 6.94 (s, 2 H), 7.02 (s, 1 H), 7.36 (s,
1 H), 7.44 (br s, 1 H).
13C NMR (CDCl3): δ = 202.5, 202.1, 157.3, 157.0, 140.8, 139.8,
139.6, 139.3, 139.1, 138.9, 138.7, 138.6, 136.3, 135.3, 130.9, 130.8,
54.2, 54.0, 50.5, 50.3, 39.5, 39.2, 26.2, 25.5, 24.7, 22.1, 18.6.
To a 3-necked round-bottomed flask equipped with a mechanical
stirrer, thermocouple, and N2 purge was charged 10 (191.5 g, 722
mmol) and anhydrous CH2Cl2 (820 mL). DMF (2.163 g, 29.59
mmol) was added and the reaction contents were cooled to 0–5 °C.
SOCl2 (96.72 g, 813 mmol) was added dropwise to the solution
keeping the temperature below 5 °C. After the addition of SOCl2,
the reaction temperature was adjusted to 10–20 °C. The reaction
contents were stirred for 1–2 h. A sample was drawn and quenched
with MeOH for HPLC analysis. The reaction mixture was concen-
trated to an oil under vacuum at 25–35 °C. Anhydrous CH2Cl2 (500
mL) was added to dissolve the oil. The solution of 15 thus obtained
was used as such in the synthesis of 1.
HRMS: m/z [M]+ calcd for C28H34N2O6: 494.2417; found:
494.2422.
Alternate Procedure for the Synthesis of 4-[(2,4-Dimethylphe-
nyl)(methoxycarbonyl)amino]butanoic Acid (10) Starting from
4 (Scheme 2)
Cyclization of 15 to Methyl 7,9-Dimethyl-5-oxo-2,3,4,5-tetra-
hydro-1H-benzo[b]azepine-1-carboxylate (1)
To a 3-necked round-bottomed flask equipped with a mechanical
stirrer, thermocouple, reflux condenser and N2 purge was added an-
hydrous CH2Cl2 (1.96 L). AlCl3 (319 g, 2.36 mol) was added and
the contents were heated to 35–40 °C. The CH2Cl2 solution of 15
prepared above was added dropwise into the mixture at 35–40 °C
over 3 h. The reaction contents were stirred for 2–3 h at 35–40 °C.
A sample was drawn and quenched with aq 5% HCl for HPLC anal-
ysis. The reaction contents were cooled to 10–20 °C and added with
stirring to a precooled aq 5% HCl (805 mL) by maintaining a tem-
perature of 0–10 °C. The reaction contents were allowed to stand
for 30 min. The organic layer was separated and washed with aq 5%
HCl (445 mL) and the mixture was allowed to settle for 35 min. The
organic layer was separated and concentrated to 2–3 volumes under
reduced pressure. i-PrOAc (1.56 L) was added to the reaction flask
and the contents were concentrated to ~8 volumes on a rotary evap-
orator at reduced pressure (27.4 Torr) at a temperature below 30 °C.
i-PrOAc layer was washed with aq 0.5 M NaOH (980 mL) at 15–
25 °C and separated. The i-PrOAc layer was washed again with aq
0.5 M NaOH (490 mL) at 15–25 °C and then with H2O (490 mL).
Ethyl 4-[(2,4-Dimethylphenyl)(methoxycarbonyl)]aminobutano-
ate (9)
To a dried 3-necked round-bottomed flask equipped with a con-
denser, thermometer, and N2 purge was added Pd(dba)2 (3.80 g,
6.61 mmol), KOH (37.5 g, 568.12 mmol), and 4-aminobutanoic
acid (5; 23.0 g, 223 mmol), and the ligand di-tert-butyl(2′-isopro-
poxy-1,1′-binaphthyl-2-yl)phosphine (13; 3.25 g, 6.41 mmol). The
mixture was degassed with N2. Compound 4 (40.0 g, 216.14 mmol)
and t-BuOH (1.50 L) were added to the brown mixture. The mixture
was degassed with N2 and heated to 90 °C for 18 h. The reaction
progress was monitored by LCMS. After the completion of the re-
action, majority of t-BuOH was removed under vacuum. A brown
residue was obtained. H2O (100 mL) and CH2Cl2 (500 ml) were
added to the reaction mixture. The pH of the aqueous layer was ad-
justed to 3–4 by aq 4 M HCl. The contents were filtered through a
pad of Celite and the organic layer was separated. The aqueous lay-
er was extracted with CH2Cl2 (500 mL). The organic phase was
dried (MgSO4), filtered, and concentrated to half of the volume and
Synthesis 2014, 46, 2463–2470
© Georg Thieme Verlag Stuttgart · New York

PAPER
Large-Scale Synthesis of Benzazepinone Derivatives
2469
petroleum ether (bp 40–60 °C) (200 mL) was added. The brown so-
lution was cooled to 5–10 °C for 2 h to obtain a slurry, which upon
filtration and drying provided a brownish solid; yield: 36 g (78%);
purity: 96.5%; mp 107–114 °C.
1H NMR (DMSO6): δ = 1.77 (m, 2 H), 2.0 (s, 3 H), 2.13 (s, 3 H),
2.33 (m, 2 H), 3.02 (m, 2 H), 6.42 (d, J = 4.4 Hz, 1 H), 6.7 (m, 2 H),
11.97 (br, 1 H).
Acknowledgment
We are thankful to PharmExplorer and WuXi Pharmatech scientists
for providing the data. Professors M. Miller and W. Roush, Dr. Rick
Berglund, and Dr. T. Zhang are acknowledged for thoughtful
discussions and valuable suggestions. Prof. Z. Zhang is acknow-
ledged for providing compound 13 required in the synthesis of com-
pound 6. We are also thankful to Lisa Zollars for providing NMR
data of various compounds.
13C NMR (CDCl3): δ = 175.1, 144.9, 131.0, 127.4, 124.2, 122.3,
108.6, 43.1, 31.9, 24.5, 20.6, 18.1;
HRMS: m/z [M]+ calcd C12H17NO2: 207.1259; found: 207.1256.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
Conversion of 6 into 10
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
To a dried 1 L round-bottomed flask was added 6 (35.0 g, 168.9
mmol), THF (300 mL), K2CO3 (50.0 g, 361.8 mmol), and methyl
chloroformate (20 mL, 1.59 equiv). The brown heterogeneous mix-
ture was stirred at 25–30 °C for 14 h. LCMS data indicated the for-
mation of the desired product 10. The reaction mixture was filtered
and the cake was washed with CH2Cl2 (200 mL). The product was
extracted into aqueous phase by treating the CH2Cl2 layer with 2 M
NaOH (200 mL). The aqueous layer was extracted by CH2Cl2 (50
mL) and the combined organic phases were discarded. The pH of
the aqueous layer was adjusted to 1–2 by aq 6 M HCl. The product
was extracted with CH2Cl2 (2 × 100 mL). The brownish organic lay-
er was separated, dried (MgSO4), and concentrated to give a brown
viscous oil; yield: 40 g (88%); purity: 95.7%.
References
(1) (a) So, M.; Kotake, T.; Matsurra, K.; Kamimura, A. J. Org.
Chem. 2012, 77, 4017. (b) Hoyt, S. B.; London, C.; Park, M.
Tetrahedron Lett. 2009, 50, 1911. (c) Qadir, M.; Cobb, J.;
Sheldrake, P. W.; Whittall, N.; White, J. P.; Hii, K. K.;
Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70,
1545.
(2) (a) Moni, L.; Banfi, L.; Basso, A.; Galatini, A.; Spallarossa,
M.; Riva, R. J. Org. Chem. 2014, 79, 339. (b) Gilchrist, T. L.
Heterocyclic Chemistry, 3rd ed.; Addison Wesley: Essex,
1997, 414.
Compounds 17–19
Compounds 17–19 were synthesized following procedure described
for compound 1 starting from the corresponding aniline (85 mmol).
(3) (a) Kametani, T.; Fukumoto, K. Heterocycles 1975, 3, 931.
(b) Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org. Chem.
2001, 5, 519. (c) Meigh, J-P. K. In Science of Synthesis; Vol.
17; Weinreb, S. M.; Schaumann, E., Eds.; Thieme: Stuttgart,
2004, 825–927.
Compound 17
Yield: 5 g (62%); viscous oil.
1H NMR (DMSO-d6): δ = 7.49–7.48 (m, 1 H), 7.38–7.29 (m, 1 H),
7.30–7.28 (m, 1 H), 3.70 (t, J = 6.5 Hz, 2 H), 3.64 (s, 3 H), 2.61–
2.48 (m, 2 H), 2.33 (s, 3 H), 1.98–1.94 (m, 2 H).
13C NMR (CDCl3): δ = 200.6, 154.7, 139.1, 135.8, 133.4, 133.0,
128.0, 127.9, 52.4, 52.4, 47.5, 22.6, 19.9.
HRMS: m/z [M + Na]+ calcd for C13H15NO3 + Na: 256.0941; found:
256.0944.
(4) (a) Albright, J. D.; Reich, M. F.; Delos Santos, E. G.; Dusza,
J. P.; Sum, F. W.; Venkatesan, A. M.; Coupet, J.; Chan, P.
S.; Ru, X.; Mazandarani, H.; Bailey, T. J. Med. Chem. 1998,
41, 2442. (b) Kondo, K.; Ogawa, H.; Shinohara, T.;
Kurimura, M.; Tanada, Y.; Kan, K.; Yamashita, H.;
Nakamura, S.; Hirano, T.; Yamamura, Y.; Mori, T.;
Tominaga, M.; Itai, A. J. Med. Chem. 2000, 43, 4388.
(c) Wyatt, P. G.; Allen, M. J.; Chilcott, J.; Hickin, G.; Miller,
N. D.; Woollard, P. M. Bioorg. Med. Chem. Lett. 2001, 11,
1301. (d) Kondo, K.; Kan, K.; Tanada, Y.; Bando, M.;
Shinohara, T.; Kurimura, M.; Ogawa, H.; Nakamura, S.;
Hirano, T.; Yamamura, Y.; Kido, M.; Mori, T.; Tominaga,
M. J. Med. Chem. 2002, 45, 3805. (e) Pitt, G. R. W.; Batt, A.
R.; Haigh, R. M.; Penson, A. M.; Robson, P. A.; Rooker, D.
P.; Tartar, A. L.; Trim, J. E.; Yea, C. M.; Roe, M. B. Bioorg.
Med. Chem. Lett. 2004, 14, 4585. (f) Failli, A. A.; Shumsky,
J. S.; Steffan, R. J.; Caggiano, T. J.; Williams, D. K.;
Trybulski, E. J.; Ning, X.; Lock, Y.; Tanikella, T.;
Hartmann, D.; Chan, P. S.; Park, C. H. Bioorg. Med. Chem.
Lett. 2006, 16, 954.
Compound 18
Yield: 4 g (60%); mp 79–81 °C; purity: 96.2%.
1H NMR (DMSO-d6): δ = 7.51 (d, J = 7.5 Hz, 1 H), 7.47–7.38 (m,
1 H), 7.38–7.28 (m, 1 H), 4.24 (ddd, J = 6.6, 10.1, 13.2 Hz, 1 H),
3.51 (s, 2 H), 3.19 (ddd, J = 2.9, 6.8, 13.2 Hz, 1 H), 2.68–2.55 (m,
1 H), 2.46–2.29 (m, 1 H), 2.21–2.12 (m, 3 H), 2.03 (br s, 1 H), 2.11–
1.95 (m, 1 H), 1.74–1.45 (m, 1 H).
13C NMR (CDCl3): δ = 203.8, 155.8, 137.8, 136.8, 136.7, 135.2,
128.5, 126.6, 53.4, 53.4, 45.6, 21.7, 17.1.
HRMS: m/z [M + Na]+ calcd for C13H15NO3 + Na: 256.0941; found:
256.0946.
(5) Nicholls, S. J.; Brewer, H. B.; John, J. P.; Kastelein, J. J. P.;
Krueger, K. A.; Wang, M-D.; Shao, M.; Hu, B.; McErlean,
E.; Nissen, S. E. JAMA 2011, 306, 2099; and references cited
therein.
(6) Chen, X.; Frank, S. A.; Remick, D. M.; Pedersen, S. W. US
Patent 331309 A1, 2010; Chem. Abstr. 2011, 154, 118675.
(7) Ma, F.; Xie, X.; Ding, L.; Gao, J.; Zhang, Z. Tetrahedron
2011, 67, 9405; and references cited therein.
(8) Xie, X.; Zhang, T. Y.; Zhang, Z. J. Org. Chem. 2006, 71,
6522.
(9) Gajda, T.; Zwierzak, A. Synthesis 1981, 1005.
(10) Brehme, R. Synthesis 1976, 113.
Compound 19
Yield: 7 g (65%); mp 123–125 °C.
1H NMR (DMSO-d6): δ = 7.05 (s, 1 H), 6.91 (s, 1 H), 3.65 (br s, 2
H), 3.56 (s, 3 H), 2.55–2.43 (m, 3 H), 2.29 (s, 3 H), 2.23 (s, 3 H),
1.87–1.71 (m, 2 H).
13C NMR (CDCl3): δ = 205.9, 155.4, 140.6, 138.1, 136.3, 133.8,
130.7, 126.3, 52.6, 46.9, 40.7, 22.5, 20.6, 19.0.
HRMS: m/z [M + H]+ calcd for C14H17NO3: 248.1208; found:
248.1206.
(11) Koziara, A.; Zawadzki, S.; Zwierzak, A. Synthesis 1979,
527.
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Synthesis 2014, 46, 2463–2470

2470
R. K. Vaid et al.
PAPER
(12) Chen, X.; Cioffi, C. L.; Dinn, S. R.; Escribano, A. M.;
Fernandez, M. C.; Fields, T.; Herr, R. J.; Mantlo, N. B.;
Delanava, E. M. M.; Mateo-Herranz, A. I.; Parthasarathy, S.;
Wang, X. US Patent 2342 A1, 2006; Chem. Abstr. 2006,
144, 108328.
(13) (a) Firouzabadi, H.; Iranpoor, N.; Amani, K. Green Chem.
2001, 3, 131. (b) Firouzabadi, H.; Iranpoor, N.; Amani, K.
Synthesis 2002, 59. (c) Firouzabadi, H.; Iranpoor, N.;
Amani, K.; Nowrouzi, F. J. Chem. Soc., Perkin Trans. 1
2002, 2601. (d) Firouzabadi, H.; Iranpoor, N.; Amani, K.
J. Mol. Catal. A 2003, 195, 289. (e) Firouzabadi, H.;
Iranpoor, N.; Amani, K. Synthesis 2003, 408.
T.; Ohno, T.; Nishimura, T.; Suda, S.; Kobayashi, S. Chem.
Lett. 1991, 1059. (i) Harada, T.; Ohno, T.; Kobayashi, S.;
Mukaiyama, T. Synthesis 1991, 1216. (j) Mukaiyama, T.;
Suzuki, K.; Han, J. S.; Kobayashi, S. Chem. Lett. 1992, 435.
(k) Suzuki, K.; Kitagawa, H.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1993, 66, 3729. (l) Pivsa-Art, S.; Okuro, K.; Miura,
M.; Murata, S.; Nomura, M. J. Chem. Soc., Perkin Trans. 1
1994, 1703. (m) Izumi, J.; Mukaiyama, T. Chem. Lett. 1996,
739. (n) Effenberger, F.; Eberhard, J. K.; Maier, A. H. J. Am.
Chem. Soc. 1996, 118, 12572. (o) Desmurs, J. R..
Labrouillère M.; Roux, C. L.; Gaspard, H.; Laporterie, A.;
Dubac, J. Tetrahedron Lett. 1997, 38, 8871. (p) Répichet, S.;
Roux, C. L.; Dubac, J.; Desmurs, J. R. Eur. J. Org. Chem.
1998, 2743.
(f) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F.; Amani, K.
Chem. Commun. 2003, 764.
(14) (a) Friedel–Crafts and Related Reactions; Vol. I–IV; Olah,
G. A., Ed.; New York, 1963. (b) Olah, G. A. Friedel–Crafts
Chemistry; Wiley-Interscience: New York, 1973.
(c) Heaney, H. In Comprehensive Organic Synthesis; Vol. 2;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991, 733.
(15) (a) Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533.
(b) Effenberger, F.; Epple, G. Angew. Chem., Int. Ed. Engl.
1972, 11, 300. (c) Roberts, R. M. G.; Sadri, A. R.
(16) (a) Kawada, A.; Mitamura, S.; Kobayashi, S. J. Chem. Soc.,
Chem. Commun. 1993, 1157. (b) Kawada, A.; Mitamura, S.;
Kobayashi, S. Synlett 1994, 545. (c) Kawada, A.; Mitamura,
S.; Kobayashi, S. Chem. Commun. 1996, 183. (d) Kusama,
H.; Koichi, N. Bull. Chem. Soc. Jpn. 1995, 68, 2379.
(e) Mikami, K.; Kotera, O.; Motoyama, Y.; Sakaguchi, H.;
Maruta, M. Synlett 1996, 171. (f) Nishikido, J.; Nakajima,
H.; Saeki, T.; Ishii, A.; Mikami, K. Synlett 1998, 1347.
(g) Matsuo, J.; Odashima, K.; Kobayashi, S. Synlett 2000,
403. (h) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F.
Tetrahedron Lett. 2003, 44, 5343. (i) Firouzabadi, H.;
Iranpoor, N.; Nowrouzi, F. Tetrahedron 2004, 60, 10843.
(j) Boroujeni, K. P. Chin. Chem. Lett. 2010, 21, 1395; Chem.
Abstr. 2011, 154, 45712.
Tetrahedron 1983, 39, 137. (d) Effenberger, F.; Sohn, E.;
Epple, G. Chem. Ber. 1983, 116, 1195. (e) Mukaiyama, T.;
Nagaoka, H.; Ohshima, M.; Murakami, M. Chem. Lett.
1986, 165. (f) Effenberger, F.; Steegmuller, D. Chem. Ber.
1988, 121, 117. (g) Effenberger, F.; Steegmuller, D.; Null,
V.; Ziegler, T. Chem. Ber. 1988, 121, 125. (h) Mukaiyama,
Synthesis 2014, 46, 2463–2470
© Georg Thieme Verlag Stuttgart · New York