Process Development of a CRF1 Receptor Antagonist Based on the Selective Chlorination of a Benzimidazolone via Chlorine Migration

Article abstract of DOI:10.1021/acs.oprd.6b00389

A practical synthesis of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzo[d]imidazole 1, a novel corticotropin-releasing factor 1 (CRF₁) receptor antagonist, has been developed. The key chemical transformations were (1) a novel regioselective chlorination at the 4-position of a benzimidazolone intermediate with 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione in the presence of sodium tertiary butoxide via a chlorine migration mechanism (N-3 to C-4) and (2) a one-pot, three-step dehydroxylation sequence (dehydration, isomerization, and hydrogenation) of a benzylic tertiary alcohol in the presence of p-toluenesulfonic acid and a Pd catalyst. The endgame was also optimized for quality and yield improvement. The chromatography-free six-step process starting from a commercially available material afforded 1 in 35% overall yield and greater than 99% purity.

Full text of DOI:10.1021/acs.oprd.6b00389

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Full Paper
1
Process Development of a CRF Receptor Antagonist Based on a Novel
Selective Chlorination of a Benzimidazolone via Chlorine Migration
Yasuhiro Sawai, Osamu Yabe, Keiichiro Nakaoka, and Tomomi Ikemoto
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00389 • Publication Date (Web): 12 Jan 2017
Downloaded from http://pubs.acs.org on January 18, 2017
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Process Development of a CRF1 Receptor
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Antagonist Based on a Novel Selective Chlorination
of a Benzimidazolone via Chlorine Migration
Yasuhiro Sawai,* Osamu Yabe, Keiichiro Nakaoka, Tomomi Ikemoto
Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 17ꢀ85,
Jusohonmachi 2ꢀchome, Yodogawaꢀku, Osaka 532ꢀ8686, Japan
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ABSTRACT: A practical synthesis of 4ꢀchloroꢀ2ꢀ(2, 4ꢀdichloroꢀ6ꢀmethylphenoxy)ꢀ1ꢀmethylꢀ7ꢀ
(pentanꢀ3ꢀyl)ꢀ1Hꢀbenzo[d]imidazole 1, a novel corticotropinꢀreleasing factor 1 (CRF1) receptor
antagonist, has been developed. The key chemical transformations were: (1) a novel
regioselective chlorination at the 4ꢀposition of a benzimidazolone intermediate with 1,3,5ꢀ
trichloroꢀ1,3,5ꢀtriazinaneꢀ2,4,6ꢀtrione in the presence of sodium tertiary butoxide via a chlorine
migration mechanism (Nꢀ3 to Cꢀ4), and (2) a oneꢀpot and threeꢀstep dehydroxylation sequence
(dehydration, isomerization, and hydrogenation) of a benzylic tertiary alcohol in the presence of
pꢀtoluenesulfonic acid and a Pd catalyst. The endgame was also optimized for quality and yield
improvement. The chromatographyꢀfree sixꢀstep process starting from a commercially available
material afforded 1 in 35 % overall yield and greater than 99% purity.
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KEYWORDS: Selective chlorination, Chlorine migration, Benzimidazolone, Benzimidazole,
CRF1 receptor antagonist
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INTRODUCTION
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Corticotropinꢀreleasing factor (CRF) is believed to be the main regulator of the hypothalamus–
pituitary–adrenocortical (HPA) axis via CRF1 receptors.1ꢀ4 Over the last two decades, a number
of nonꢀpeptide, smallꢀmolecule CRF1 receptor antagonists have been investigated as a means for
the treatment of stressꢀrelated disorders. Our discovery team revealed that 4ꢀchloroꢀ2ꢀ(2,4ꢀ
dichloroꢀ6ꢀmethylphenoxy)ꢀ1ꢀmethylꢀ7ꢀ(pentanꢀ3ꢀyl)ꢀ1Hꢀbenzo[d]imidazole (1) may serve as an
effective CRF1 receptor antagonist (Figure 1).5
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Figure 1. CRF1 receptor antagonist 1.
Discovery synthesis of 1 started with 2ꢀchloroꢀ3ꢀnitrobenzoic acid 2 (Scheme 1).5 The raw
material 2 was esterified to give methyl benzoate 3, followed by methylamination to yield 4.
Nitrobenzene 4 was hydrogenated using a palladium catalyst to generate diamine 5. A
benzimidazolone intermediate 6 was prepared by ring construction of 5 with 1, 1’ꢀcarbonylbisꢀ
1Hꢀimidazole (CDI). The ethyl groups of 7 were introduced by Grignard reaction with EtMgBr.
An acidꢀcatalyzed dehydration of 7 gave olefins, which were hydrogenated with a palladium
catalyst to afford 7ꢀalkylꢀsubstituted benzimidazolone 8. Chlorination at the 4ꢀposition of 8 using
Nꢀchlorosuccinimide (NCS) and azobisisobutyronitrile (AIBN) and subsequent chlorination at
the 2ꢀposition of 9 with POCl3 provided 2,4ꢀdichlorobenzimidazole 10. Finally, replacement of
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the chlorine atom at the 2ꢀposition with phenol 11 produced the active pharmaceutical ingredient
(API) 1, which was supplied for nonꢀclinical studies in early development stages.
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Scheme 1. Discovery Synthesis of 1
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HO
O
O
O
O
O
1) (COCl)2, DMF
CH2Cl2
2) MeOH
H
N
MeNH2
THF
H2, Pd-C
MeOH
Cl
Cl
>99%
>99%
99%
NO2
NO2
NO2
2
3
4
OH
O
O
O
CDI
THF
O
EtMgBr
Et2O
THF
H
N
1) HCl, H2O, EtOH
2) H2, Pd-C, EtOH
N
N
O
O
78%
70%
N
H
54%
N
NH2
H
5
6
7
HO
Cl
Cl
NCS
AIBN
CCl4
N
11
N
POCl3
82%
N
N
O
O
1
Cl
N
H
68%
K2CO3, DMF
64%
N
H
Cl
Cl
8
9
10
From the view point of process research and development, selective synthesis of 4ꢀ
chlorobenzimidazolone was a primary issue to be addressed. Under the discovery synthesis
conditions, the chlorination of 8 proceeded in a nonꢀselective manner to give 9 with a
contamination of regioisomers and dichloro species. As these byꢀproducts were difficult to
remove by common scalable purification such as crystallization in downstream processes, they
led to undesirable results that gave big impacts on not only overall yield but also API quality.
Although a variety of syntheses have been reported for the preparation of benzimidazolone
derivatives as well as the analogous benzimidazole derivatives,6 to the best of our knowledge, no
literature precedents have been reported for the preparation of 4ꢀchlorobenzimidazolone/4ꢀ
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chlorobenzimidazole except for the discovery synthesis. Thus, the process research was directed
to the development of a selective chlorination at the 4ꢀposition of
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9
benzimidazolone/benzimidazole derivatives, which could then be transformed to the final
intermediate 10. In addition, the following drawbacks of the discovery synthesis were addressed:
(1) use of commercially unavailable raw material 2, (2) insufficient yields of the Grignard
reaction, the twoꢀstep sequence of dehydrationꢀhydrogenation, and the costly end game process.
Herein we report a novel regioselective chlorination of the 4ꢀposition of benzimidazolone 8 via a
chlorine migration mechanism and an improved process for the production of CRF1 receptor
antagonist 1.
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RESULTS AND DISCUSSION
Two types of synthetic route to 8 were proposed (Scheme 2). Route A highlights reactions that
introduce the alkyl pendant directly to the 7ꢀposition of benzimidazolone 12. Commercially
available 7ꢀbromoisatin 13 appeared to be the best raw material for the preparation of 12. In
contrast, the alkyl moiety is constructed by a reaction of the carboxylate substituent at the 7ꢀ
position of 6 with nucleophilic alkylating reagents in Route B, which is the same pathway as the
discovery synthesis. Trisubstituted benzene 14 appeared to be the best raw material for Route B,
in view of commercial availability as well as chemical transformation to 6.
Scheme 2. Route Design of 1
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The initial approach to Route A was a Kumada coupling of 12 with 3ꢀpentyl Grignard reagent
(Scheme 3, equation 1). 7ꢀBromoisatin 13 was methylated with MeI to produce 15. A treatment
of 15 with aqueous NaOH and 30% aqueous H2O2 generated anthranilic acid 16. Subsequent
Curtius rearrangement using diphenylphosphoryl azide (DPPA) successfully transformed 16 to
12. Commercially available isoꢀpropyl Grignard reagent was used for investigating the Kumada
coupling reaction in a model case study. An appropriate protocol was made for preliminary
screening of Pd and Ni catalysts, including Pd(PPh3)4, PdCl2(dppf), PdCl2[P(oꢀtol)3]2, Pd(dba)3
with 2ꢀdicyclohexylphosphinoꢀ2’,4’,6’ꢀtriisopropylbiphenyl (XꢀPhos), or NiCl2(dppf). The case
study concluded that the method was inappropriate because of low conversion (unreacted 12
remained in 10 to 69% by HPLC peak area analysis detected by UV 277 nm, typically around
50%), low yield of 17 (4 to 20%, typically around 15%), and formation of hydrogenated
byproduct 18 (4 to 66%, typically around 30%). The results were thought to be attributable to an
acidic urea proton of 12, even though excess amounts of Grignard reagent were used.
The second approach to Route A was nucleophilic addition of a 7ꢀmetalated benzimidazolone to
pentanꢀ3ꢀone (Scheme 3, equation 2). Halogenꢀmetal exchange of 12 using nꢀBuLi proceeded at
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ꢀ78 oC to generate the 7ꢀlithiated intermediate, which reacted with pentanꢀ3ꢀone to give the target
product 7 in only 24% by HPLC peak area analysis detected by UV 277 nm, albeit with 18 in
72%, since the lithiated intermediate was protonated with αꢀhydrogens of pentanꢀ3ꢀone.
Although MgBr2 or ZnCl2 was added prior to the nucleophilic addition, as a means of metal
exchange, the yield was not improved.
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Scheme 3. Route A
The undesirable results on the trials for Route A directed our interest to Route B and chemical
transformations of 14 to 6 were firstly investigated (Scheme 4). Nꢀmethylation of 14 using MeI
quantitatively proceeded in the presence of K2CO3 and a catalytic amount of water in DMF. Nꢀ
methylated product 19 was isolated as crystals in 98% yield with >99% purity by simply adding
water to the reaction mixture. Subsequent catalytic reduction of the nitro substituent on 19 was
performed under H2 pressure (0.2 MPa) using PdꢀC catalyst. When the reaction was carried out
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in EtOAc at room temperature, the reaction stalled half way. LCꢀMS analysis suggested that Nꢀ
hydroxy intermediate 20 remained unreacted (19 : 20 : 21 = 0 : 94 : 6). However, switching the
solvent to a mixed solvent (EtOAc : MeOH = 1 : 1) achieved full conversion of 20 to 21 to
generate quantitative yields of 21 with 99% purity. Diamine 21 was processed to the following
step without any purification except for a removal of PdꢀC by filtration because the reaction
proceeded cleanly and crystallization of 21 caused a large mother liquor loss. As 21 has a Boc
group on its nitrogen atom, we envisaged that its carbonyl moiety could be utilized for the ring
closure reaction while the original synthesis of 6 employed CDI as a carbonyl source.5 Screening
studies on bases including K2CO3, sodium alkoxide, and 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene
(DBU) revealed that two equivalents of NaOMe effectively promoted the ring closure reaction to
generate good yields of 6 (21 :6 = 1 : 96). Benzimidazolone 6 was isolated as crystals, by adding
diluted hydrochloric acid directly to the reaction mixture, in 85% twoꢀstep yield and >99% purity.
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Scheme 4. Route B
Then, the Grignard reaction was optimized (Table 1). When 6 was reacted with 5 equivalents of
EtMgBr in Et2O according to the protocol reported,5 the target compound 7 was obtained in 77%
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assay yield (run 1). LCꢀMS analysis suggested that the major byꢀproducts were ethyl aryl ketone
5
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22 and its reductant 23. This indicated that the second alkylation did not proceed smoothly due to
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β
ꢀhydride reduction of 22 occurring competitively. Reducing the amount of EtMgBr (4
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equivalents) in THF gave similar results (run 2). EtMgCl in THF gave 7 in slightly improved
assay yield with a decreased amount of 23 and an increased amount of 22 (run 3). Interestingly,
the addition of N,N,N’,N’ꢀtetramethylenediamine (TMEDA) selectively produced 22 (run 4).
Lithium chloride affected the conversion to give lower assay yield (run 5).7 Lewis acids such as
CeCl3 (run 6) and LaCl3·2LiCl (run 7) successfully decreased both 22 and 23.8 In particular,
LaCl3·2LiCl demonstrated a full conversion to give 7 in high 91% assay yield. The product was
crystallized directly from the reaction mixture by simply adding hydrochloric acid without any
other workꢀup. Although run 7 gave the best assay yield, the lower concentration of commercial
THF solution of EtMgBr caused a larger mother liquor loss. Thus, run 3 was selected as the
optimum condition on the basis of the isolated yield. The isolated crystals of run 3 had 97%
purity with a contamination of 22 (2%) and 23 (1%), which were purged in the subsequent step
and gave no impacts on API quality.
Table 1. Grignard Reactiona
Run Grignard reagent
Additive
LCAPb
Assay yield
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(Isolated yield of 7)
5
6
7
(equiv)
(equiv)
%
6
7
22 23
8
9
1
2
3
4
5
6
7
EtMgBr (5)c
EtMgBr (4)d
EtMgCl (4)e
EtMgBr (4)d
EtMgBr (4)d
EtMgBr (4)d
EtMgBr (4)d
N/A
0 77
0 74
9
8
12 77
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N/A
15 74
N/A
0 80 14
6
2
80 (76)
N/A
TMEDA (4)
LiCl (1)
CeCl3 (1)
LaCl3·2LiCl (0.3)
0 2
93
9 64 14 11 72
5 83
0 86
4
6
6
7
83
91 (76)
aGeneral procedure: Compound 6 was added to Grignard reagent at 10 oC and then the mixture
o
was stirred at 60 C for 1 hour. Additive was preꢀmixed with the Grgnard reagent. Assay yield
was determined by HPLC using an external standard. A typical isolation method was described
in the experimental section. HPLC peak area% detected by UV 277 nm 3 mol/L Et2O solution
d1 mol/L THF solution e2 mol/L THF solution
b
c
The subsequent dehydrationꢀhydrogenation sequence was improved to establish a oneꢀpot and
highꢀyielding transformation. Firstly, dehydration of 7 was carried out with an excess amount of
TFA and then the resultant dehydrated intermediate 24 was reduced under palladium catalyzed
hydrogenation conditions after removal of TFA by aqueous washing (Table 2, run 1). Although
substrate 7 was quantitatively converted to an E/Zꢀmixture of 24, the reduction reaction stalled
halfway. Interestingly, 1H NMR analysis demonstrated that the remaining intermediate was E-24
and that no Z-24 remained. This indicated that overall conversion of 7 to 8 could be possible in
oneꢀpot with higher yield if in-situ isomerization of E-24 to Z-24 as well as dehydration of 7 is
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started with acid. Using a catalytic amount of conc. HCl in AcOH, not only 7 and Z-24 but also
E-24 were completely consumed at 100 oC for 3 hours to give 8 under catalytic hydrogenation
conditions (run 2). However, aromatic ring reduction also proceeded to generate byꢀproduct 25.
A screening of acids and solvents revealed that pꢀtoluenesulfonic acid in AcOH can suppress the
aromatic ring reduction (run 3). Lowering H2 pressure (from 0.5 to 0.2 MPa) further decreased
the byꢀproduct formation without giving any influences on the dehydroxylation sequence to give
8 in 92% yield (run 4).
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Table 2. One-pot Dehydroxylation Sequence
Run Acid
Solv.
THF
H2
LCAPa
Isolated yield of 8
(equiv)
MPa
0.3
%
7 E-24 Z-24
8
25
1b
2
N/A
0 23
0 0
0
0
75 0
86 6
75
71
conc. HCl (0.3)
AcOH 0.5
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TsOH·H2O (0.5)
TsOH·H2O (0.5)
AcOH 0.5
AcOH 0.2
0 0
0
0
94 1
97 0
83
92
0 0
7
8
9
b
aHPLC peak area% detected by UV 230 nm Firstly 7 was dehydrated in THF with TFA (22
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o
vol) at 5 C for 4 hours and then the resultant E/Zꢀmixture of 24 was reduced under catalytic
hydrogenation conditions at 65 oC for 3 hours without acid.
To begin an intensive study on the regioselective chlorination, an alternative substrate
benzimidazole 26 was firstly examined because the discovery synthesis exhibited limited
regioselectivity in the chlorination of benzimidazolone 8. 2ꢀChlorobenzimidazole 26 was readily
prepared from 8 using POCl3 (Scheme 5). The chlorination of 26 was carried out with NCS and
AIBN in chlorobenzene at 90 oC for 9 hours and resulted in giving a complex mixture with only
18% assay yield of 10. LCꢀMS analysis suggested that the mixture contained regioisomers 27
and trichloro species 28 (26 : 10 : 27 : 28 = 17 : 17 : 18 : 28).9 The large amount of 28 generated
and the low conversion of 26 indicated that the dichlorobenzimidazoles 10 and 27 were rather
easily further chlorinated.
Scheme 5. Alternative Substrate for Chlorination
The undesirable result with the alternative substrate turned our attention back to the chlorination
of 8. Firstly, the chlorination was carried out with NCS in the presence of a catalytic amount of
AIBN in chlorobenzene at 85 oC for 4 hours (Table 3, run 1). LCꢀMS analysis demonstrated that
the reaction was almost completed to give the target compound 9 in 66% assay yield.
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Regioisomers 29 and 30 were generated with low regioselectivity (9 : 29 : 30 = 67 : 7 : 13). In
addition, overꢀreaction also proceeded to yield a wide variety of dichlorinated byꢀproducts 31, in
a total of 7% by HPLC analysis. When chlorination was attempted in the absence of AIBN, the
reaction proceeded even at room temperature to give the similar result (run 2). According to
literature precedents, combinations of NCS with ZrCl410 or other Lewis acids11 were attempted
(runs 3ꢀ6). But contrary to our expectation, the addition of Lewis acids did not give any
significant improvements.12 Then, basic additives were examined, and to our surprise the
reaction with NCS in the presence of NaH showed excellent regioselectivity (9 : 29 : 30 = 74 : 0 :
2) and no production of dichloro species 31, although conversion and yield were rather low (run
7). A combination of alternative chlorinating reagents, 1,3,5ꢀtrichloroꢀ1,3,5ꢀtriazinaneꢀ2,4,6ꢀ
trione (TCCA), with NaH successfully increased the conversion of the main reaction but
enhanced the overꢀreaction as well (run 8). A screening of bases revealed that relativelyꢀstrong
inorganic bases, Cs2CO3 (run 9) and K3PO4 (run 10), remarkably increased the overꢀreaction. In
sharp contrast, tꢀBuONa significantly decreased the overꢀreaction with lower conversion (run 11).
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LCꢀMS analysis on the chlorination reaction of 8 in the presence of tꢀBuONa showed the
following phenomena; (1) the peak of 32 (the same molecular weight as 9) appeared first, (2) the
peak of 9 increased over time, and (3) the peak of 32 decreased synchronously. When the
reaction mixture including 32 was treated with aqueous Na2SO3, 32 disappeared and 8 was
regenerated instead. These observations suggested that the chlorination of 8 proceeded via a
chlorine migration of Nꢀchloro compound 32 as depicted in Scheme 6, which is similar to a
mechanism reported for chlorination of the 5ꢀposition of dihydroquinolinꢀ2ꢀone.13 As Nꢀchloro
intermediate 32 was not detected under acidic reaction conditions by HPLC analysis, the
migration of the chlorine atom appears to have proceeded faster in acidic conditions than in basic
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conditions. The slower migration might result in the lower generation of dichloro species. Based
on this idea, an increase of tꢀBuONa was attempted (run 12). However, an excess amount of tꢀ
BuONa increased 31. Therefore, a splitꢀaddition of tꢀBuONa was attempted as follows; (1) tꢀ
BuONa (1.0 equiv) and TCCA (0.35 equiv) were added to 8 in toluene, and (2) additional tꢀ
BuONa (0.5 equiv) was added to the mixture (run 13). The protocol worked very well to achieve
the best yield of 9 while maintaining excellent regioselectivity (9 : 29 : 30 = 86 : 0 : 3) and
selectivity between monoꢀ and diꢀchlorination (sum of 9, 29, and 30 : 31 = 89 : 2).
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Table 3. Selective Chlorination of the 4-Position of Benzimidazolonea
Ru Reagent
n
Additive
(equiv)
Temp. Time LCAPb
Assay
yield of 9
(equiv)
˚C
85
25
5
hrs
4
31c
7
%
8
2
7
5
9
7
9
29 30
1
2
3
4
5
NCS (1.05) AIBN (0.1)
NCS (1.05) NA
67
67
66
7
6
6
13
14
15
66
75
66
54
70
4
3
NCS (1.05) ZrCl4 (0.05)
NCS (1.05) AlCl3 (0.05)
NCS (1.05) LiCl (0.1)
4
4
5
4
50 17 14
7
5
4
64
6
16
3
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NCS (1.05) ZnCl2 (0.1)
NCS (1.05) NaH (1.0)
5
4
8
2
6
61
8
0
1
17
2
6
0
9
65
64
81
25
25
24 74
TCCA
(0.35)
NaH (1.0)
6
6
4
80
56
60
3
10
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9
TCCA
(0.35)
Cs2CO3 (1.0)
K3PO4 (1.0)
25
25
25
8
8
4
4
0
3
0
0
0
3
1
2
2
3
31
30
3
63
65
72
70
86
10 TCCA
(0.35)
11 TCCA
(0.35)
tꢀBuONa (1.0)
tꢀBuONa (1.1)
tꢀBuONa (1.0+0.5)
16 79
12 73
12 TCCA
(0.35)
25
8
13d TCCA
(0.35)
6
86
2
e
aGeneral procedure: Chlorinating regaent was added to a mixture of 8 (0.1 g) and additive in
chlorobenzene and then the resultant mixture was stirred. Assay yield was determined by HPLC
using an external standard. HPLC peak area% detected by UV 230 nm Mixture of three
b
c
d
regioisomers of dichloro species Toluene was used instead of chlorobenzene. Reaction scale: 8
(3.00 g). e25 oC/2 hours then 80 oC/2 hours.
Scheme 6. Plausible Mechanism of the Selective Chlorination
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As a highly selective reaction condition was established, 9 was used for the subsequent
chlorination of the 2ꢀposition without purification, except for a quench with aqueous Na2SO3 and
a removal of the resultant 1,3,5ꢀtriazinaneꢀ2,4,6ꢀtrione by filtration. The chlorination of 9 was
carried out with 5.5 equivalents of POCl3 at 100 oC for 6 hours to provide 10 in 73% twoꢀstep
yield (Scheme 7).14 As the impurities, such as regioisomer 30, dichloride 31, and unreacted 8,
also possess the reactivity toward POCl3, the reaction generated a variety of chlorinated byꢀ
products such as dichloride 33, trichloride 34, and monochloride 35 (Figure 2). Crystallization of
10 in a mixed solvent of toluene and nꢀheptane effectively purged 33 but did not perfectly
remove 34 and 35, which remained in the isolated crystals of 10 at a level of 0.8% and 2%,
respectively (HPLC analysis detected by UV230 nm).
Scheme 7. Selective Chlorination Reactions of the 4- and 2-Position of Benzimidazolone
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Figure 2. Byꢀproducts identified in the chlorination of the 2ꢀposition of benzimidazolone .
The end game reaction was a nucleophilic addition of phenol 11 to 2,4ꢀdichlorobenzimidazole 10
(Scheme 8). The discovery synthesis used several portions of 11 (5.6 equivalents in total) and
K2CO3 (6.0 equivalents in total) in DMF at 100 oC for 34 hours to give 1 in 64% yield. The
insufficient yield using the large excess amounts of 11 and K2CO3 was attributed to the low
stability of 11 in the basic and heated reaction conditions. A screening of bases and solvents
revealed that the reaction proceeded faster with K3PO4 in DMSO, especially in concentrated
conditions. When the reaction was carried out with 1.2 equivalents of 11 and 2 equivalents of
K3PO4 in DMSO (3 volume) at 105 oC for 12 hours, the yield was remarkably increased to 89%.
The isolation procedure was also improved; the addition of aqueous acetone to the reaction
mixture successfully afforded crystals crude-1 without any tedious purifications, such as
extraction, aqueous washing, evaporation, and chromatography. Finally, API 1 was prepared by
recrystallization of crude-1 in aqueous acetone with 92% recovery. As the final intermediate 10
contained impurities 34 and 35, the corresponding byꢀproducts 36 and 37 were generated in the
reaction mixture (Figure 3). The aforementioned crystallization effectively decreased 36 to
<0.5% and completely purged 37, resulting in obtaining API 1 with high >99% purity (HPLC
analysis detected by UV230 nm).
Scheme 8. Endgame: Nucleophilic Addition of Phenol 11 to 2,4-Dihlorobenzimidazole 10
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Figure 3. Byꢀproducts identified in the endgame reaction.
CONCLUSION
We have reached to the API 1 from commercially available raw material 14 via a practical
synthetic pathway. Our study revealed that in the presence of tꢀBuONa, the reaction of
benzimidazolone 8 with chlorinating reagent TCCA proceeded regioselectively to give the
desired 4ꢀchlorobenzimidazolone 9 with improved yield (68% to 86%). The selectivity was
resulting from the chlorine migration mechanism, in which a chlorine atom migrated from the 3ꢀ
position of the Nꢀchloro intermediate 32 to the 4ꢀposition of 9. The tedious twoꢀstep dehydrationꢀ
hydrogenation of tertiary alcohol 7 was also improved to a simple and efficient oneꢀpot operation.
pꢀToluenesulfonic acid was found to be the best acid to catalyze not only dehydration of 7 but
also isomerization of the resultant olefins E-24 to Z-24, which was prone to hydrogenation. The
novel selective chlorination combined with the other process improvements allowed the
manufacturing process to produce quality API 1 with high >99% purity in 35 % yield over 6
steps, compared to 10% yield in the literature.
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EXPERIMENTAL SECTION
5
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8
9
General. All chemicals were purchased from commercial suppliers and used without further
purification. Activated carbon (Shirasagi A) was purchased from Osaka Gas Chemicals Co. Ltd.
Melting points were measured on a Büchi Bꢀ540 microscopic melting point apparatus. NMR
spectra were taken on a Bruker DPXꢀ300 (300 MHz) or a Bruker AVANCE 500 (500 MHz)
NMR spectrometer with TMS as the internal standard. Mass spectral analyses and microanalyses
were carried out at Takeda Analytical Research Laboratories, Ltd. LCꢀMS analyses were
conducted using a Thermo Finnigan TSQ 7000. All HPLC analyses were performed on a
Shimadzu LCꢀ2010CHT HPLC system equipped with a reversedꢀphase column (Inertsil ODSꢀ3
(5 ꢁm, 4.6 x 150 mm) or YMCꢀPack ODSꢀA (5 ꢁm, 4.6 x 150 mm)) with a detection by UV 254
nm unless otherwise indicated. Purity was determined by HPLC and presented as an area
percentage of the compound peak relative to the total area of all the peaks integrated.
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Synthesis of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (12). A solution of MeI (13.1
g, 92.3 mmol) in DMF (38 mL) was added to a mixture of 13 (19.0 g, 84.1 mmol), K2CO3 (17.4
g, 125.9 mmol), DMF (95 mL), and water (1.9 mL) at room temperature. The mixture was stirred
at room temperature for 1.5 hours. Upon completion of the reaction, water (190 mL) was added
and the mixture was stirred at 0ꢀ5 oC for 1 hour. The resultant precipitate was collected by
filtration, washed with water (150 mL) and dried in vacuo at 50 oC to give 15 (16.9 g, 70.4 mmol,
84% yield) as a brown solid. NMRs were consistent with those reported in the literature.15 1
H
NMR (300 MHz, DMSOꢀd6) δ 3.47 (s, 3H), 7.05 (t, J = 7.3 Hz, 1H), 7.55 (dd, J = 1.2 Hz, J = 7.3
Hz, 1H), 7.81 (dd, J = 1.2 Hz, J = 7.3 Hz, 1H); 13C NMR (75 MHz, DMSOꢀd6) δ 29.4, 103.5,
121.2, 123.9, 125.0, 142.9, 148.1, 159.1, 182.4; MS (ESI) m/z 257 (MNH4)+; Anal. Calcd for
C9H6NO2Br: C, 45.03; H, 2.52; N, 5.83; Br, 33.29. Found: C, 45.06; H, 2.45; N, 5.89; Br, 33.32.
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30% Aqueous H2O2 (11.3 mL, 100.0 mmol) was added dropwise to a mixture of 15 (12.0 g, 50.0
mmol) and 1.0 mol/L aqueous NaOH (96 mL) below 15 oC. The mixture was stirred at 10 oC for
1 hour. After pH was adjusted to 4.0 with hydrochloric acid, the mixture was stirred at the same
temperature for 1 hour. The mixture was then extracted with EtOAc (60 mL) three times. The
combined organic layer was concentrated in vacuo to give a brownish white solid (11.2 g). A
part of the solid (2.13 g) and Nꢀethyldiisopropylamine (1.79 g, 13.9 mmol) were dissolved in
DMF (10.6 mL). DPPA (3.82 g, 13.9 mmol) was added dropwise to the solution at 75 oC. The
mixture was stirred at the same temperature for 1 hour. Water (10.6 mL) was added at room
temperature and then the mixture was stirred at 5 oC for 1 hour. The resultant precipitate was
collected by filtration, washed with water (10.6 mL) and diisopropylether (5.3 mL), and dried in
vacuo at 50 oC to give 12 (1.31 g, 5.77 mmol, 61% yield) as a grayish white solid. NMRs
consistent with those reported in the literature.16 1H NMR (300 MHz, DMSOꢀd6) δ 3.56 (s, 3H),
6.91 (t, J = 7.8 Hz, 1H), 6.98(dd, J = 1.1 Hz, J = 7.8 Hz, 1H), 7.14 (dd, J = 1.1 Hz, J = 7.8 Hz,
1H), 11.2 (s, 1H); 13C NMR (75 MHz, DMSOꢀd6) δ 29.4, 101.0, 108.8, 122.9, 125.6, 128.5,
130.9, 154.9; MS (ESI) m/z 225 (MH)+; Anal. Calcd for C8H7N2OBr: C, 42.32; H, 3.11; N,
12.34; Br, 35.19. Found: C, 42.30; H, 3.07; N, 12.36; Br, 35.15.
10
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59
60
Synthesis of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (6). A
solution of MeI (26.3 g, 186 mmol) in DMF (100 mL) was added to a mixture of 14 (50 g, 169
mmol), K2CO3 (35.0 g, 253 mmol), and DMF (150 mL) at room temperature. After the addition
of water (12.5 mL), the mixture was stirred at 35 oC for 7 hours. Upon completion of the reaction,
water (500 mL) was added to the reaction mixture at 5 oC and the resultant mixture was stirred at
the same temperature for 1 hour. The resultant precipitate was collected by filtration, washed
with water (250 mL), and dried in vacuo at 50 oC to give 19 (51.2 g, 365 mmol, 98% yield) as a
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pale yellow solid. Mp 63ꢀ64 oC; MS (ESI) m/z 310 (M)+; Anal. Calcd for C14H18N2O6: C, 54.19;
H, 5.85; N, 9.03. Found: C, 54.22; H, 5.81; N 9.21. Compound 19 was analyzed as a 1:4 mixture
of two isomers by NMRs. 1H NMR (500 MHz, DMSOꢀd6) δ 1.20, 1.43 (s, 9H), 3.00, 3.05 (s, 3H),
3.86, 3.87 (s, 3H), 7.68ꢀ7.72 (m, 1H), 8.12ꢀ8.14 (m, 1H), 8.19ꢀ8.21 (m, 1H); 13C NMR (126
MHz, DMSOꢀd6) δ 27.9, 28.3, 37.1, 38.2, 53.4, 80.5, 81.1, 128.3, 128.6, 129.3, 129.4, 131.3,
131.7, 135.0, 135.2, 135.5, 136.1, 148.7, 149.0, 152.9, 154.3, 165.0, 165.1.
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A mixture of 19 (10.0 g, 32.2 mmol), 5% PdꢀC (1.0 g, 55% wet, NE Chemcat, type STD),
EtOAc (25 mL), and MeOH (25 mL) was stirred under H2 pressure (0.2 MPa) at 50 oC for 3
hours. Upon completion of the reaction, the mixture was cooled to room temperature. Insoluble
matters were removed by filtration with activated carbon (1.0 g) and rinsed with EtOAc (20 mL).
The combined filtrate was concentrated in vacuo with the addition of toluene (50 mL) to give a
colorless oil. A solution of the oil in DMF (13.5 mL) was added to a mixture of NaOMe (3.48 g,
64.5 mmol) and DMF (36 mL) at 0 oC. The mixture was stirred at room temperature for 2.5
hours. Upon completion of the reaction, 1 mol/L HCl (90 mL) was added to neutralize the
mixture at 0 oC, and the mixture was stirred at the same temperature for 1 hour. The resultant
precipitate was collected by filtration, washed with water, and dried in vacuo at 50 oC to give 6
(5.66 g, 27.4 mmol, 85% yield) as a white solid. NMRs were consistent with those reported in
the literature.5 1H NMR (300 MHz, CDCl3) δ 3.59 (s, 3H), 3.95 (s, 3H), 7.08 (t, J = 7.9 Hz, 1H),
7.28 (dd, J = 1.2 Hz, J = 7.9 Hz, 1H), 7.52 (dd, J = 1.2 Hz, J = 7.9 Hz, 1H), 10.82 (brs, 1H); MS
(ESI) m/z 206 (M)+; Anal. Calcd for C10H10N2O3: C, 58.25; H, 4.89; N, 13.59. Found: C, 58.21;
H, 4.83; N, 13.64.
Synthesis of 7-(3-hydroxypentan-3-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (7).
Compound 6 (35.0 g, 170 mmol) was added dropwise to 2.0 mol/L EtMgCl solution in THF (339
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mL, 678 mmol) below 30 oC. The mixture was stirred at 60 oC for 1 hour and then cooled to
room temperature. The mixture was added to 2 mol/L HCl (525 mL) below 25 oC. Water (175
mL) was added and then the mixture was stirred at 0oC for 1 hour. The resultant precipitate was
collected by filtration, washed with water (175 mL), and dried in vacuo at 50 oC to give 7 (30.1 g,
128 mmol, 76% yield) as a white solid.5 1H NMR (300 MHz, DMSOꢀd6) δ 0.77 (t, J = 7.3 Hz,
6H), 1.77ꢀ1.94 (m, 4H), 3.68 (s, 3H), 4.98 (s, 1H), 6.81ꢀ6.94 (m, 3H), 10.89 (brs, 1H); MS (ESI)
m/z 234 (M)+; Anal. Calcd for C13H18N2O2: C, 66.64; H, 7.74; N, 11.96. Found: C, 66.64; H,
7.74; N, 12.05.
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Synthesis of 1-methyl-7-(pentan-3-yl)-1H-benzo[d]imidazol-2(3H)-one (8). A mixture of 7
(2.00 g, 8.54 mmol), pꢀtoluenesulfonic acid monohydrate (0.81 g, 4.27 mmol), 5% PdꢀC (400 mg,
55% wet, NE Chemcat, type STD), and AcOH (10 mL) was stirred under H2 pressure (0.2 MPa)
at 95 oC for 5 hours. Upon completion of the reaction, the mixture was cooled to room
temperature and then filtered with AcOH (4 mL) to remove insoluble matters. Water (14 mL)
was added to the combined filtrate at 25 oC and then the mixture was stirred at 5 oC for 1 hour.
The resultant precipitate was collected by filtration, washed with water (10 mL), and dried in
vacuo at 50 oC to give 8 (1.70 g, 7.79 mmol, 92% yield) as a white solid. NMRs were consistent
with those reported in the literature.5 1H NMR (300 MHz, CDCl3) δ 0.82 (t, J = 7.4 Hz, 6H),
1.61ꢀ1.81 (m, 4H), 3.15ꢀ3.24 (m, 1H), 3.67 (s, 3H), 6.91ꢀ7.06 (m, 3H), 10.45 (brs, 1H); MS
(ESI) m/z 218 (M)+; Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C, 71.49;
H, 8.27; N, 12.90.
Synthesis of 2-chloro-1-methyl-7-(pentan-3-yl)-1H-benzo[d]imidazole (26). A mixture of 8
(4.00 g, 18.3 mmol) and POCl3 (20 mL, 215 mmol) was stirred at 110 oC for 2 hours. Upon
completion of the reaction, the mixture was concentrated in vacuo. The residue was diluted with
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EtOAc (100 mL) and then poured into cold saturated aqueous NaHCO3 (100 mL). The layers
were stirred for 15 minutes and then separated. The organic layer was washed with 10% aqueous
NaCl and then concentrated in vacuo. The residue was purified by silica gel chromatography
(eluent: 1:3 mixture of EtOAc and nꢀhexane) to give 26 (3.85 g, 16.3 mmol, 89% yield) as a
white solid.16 1H NMR (300 MHz, CDCl3) δ 0.82 (6H, t, J = 7.4 Hz), 1.66ꢀ1.85 (4H, m), 3.24ꢀ
3.32 (1H, m), 4.02 (3H, s), 7.07 (1H, dd, J = 0.9 Hz, J = 7.7 Hz), 7.19 (1H, t, J = 7.7 Hz), 7.54
(1H, dd, J = 0.9 Hz, J = 7.7 Hz).
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Synthesis of 2,4-dichloro-1-methyl-7-(pentan-3-yl)-1H-benzo[d]imidazole (10). 1,3,5ꢀ
Trichloroꢀ1,3,5ꢀtriazinaneꢀ2,4,6ꢀtrione (1.18 g, 5.08 mmol) was added to a mixture of 8 (3.00 g,
13.7 mmol), tꢀBuONa (1.32 g, 13.7 mmol), and toluene (60 mL) at room temperature. The
mixture was allowed to warm to 35 oC. Then tꢀBuONa (0.66 g, 6.87 mmol) was added at the
same temperature. The mixture was stirred at room temperature for 2 hours and at 80 oC for 2
hours. Upon completion of the reaction, toluene (60 mL) and aqueous solution (30 mL) of
Na2SO3 (693 mg, 5.50 mmol) were added below 10 oC. After the adjustment of pH to 1 with
conc. HCl (3 mL), the layers were stirred at room temperature for 0.5 hours. Insoluble matters
were removed by filtration and the filtered layers were separated. The obtained organic layer was
washed with water (30 mL), 5% aqueous NaHCO3 (30 mL), and water (30 mL). The resultant
organic layer was concentrated in vacuo to give 9 as a white solid, which was telescoped to a
downstream processing without further purification. NMRs were consistent with those reported
in the literature.5 1H NMR (300 MHz, CDCl3) δ 0.81 (t, J = 7.4 Hz, 6H), 1.58ꢀ1.80 (m, 4H),
3.11ꢀ3.20 (m, 1H), 3.66 (s, 3H), 6.87 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 9.86 (brs, 1H).
A mixture of 9, POCl3 (7.0 mL, 75.1 mmol), and toluene (3.5 mL) was stirred at 100 oC for 6
hours. Upon completion of the reaction, the mixture was cooled to room temperature and then
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concentrated in vacuo. Toluene (35 mL) and water (28 mL) were added to the residue. After the
adjustment of pH to 11 with 8 mol/L aqueous NaOH (8.0 mL), the layers were separated and
then the organic layer was washed with water (35 mL). Activated carbon (0.75 g) was added to
the organic layer. Insoluble matters were removed by filtration and rinsed with toluene. The
combined filtrate was concentrated in vacuo and then toluene (3.5 mL) was added. After the
addition of nꢀheptane (14 mL) to the slurry at room temperature, the mixture was stirred at 5 oC
for 1 hour. The resultant precipitate was collected by filtration, washed with a cold 1:4 mixture
of toluene and nꢀheptane (7.0 mL), and dried in vacuo at 50 oC to give 10 (2.70 g, 9.96 mmol,
73% yield) as a white solid. NMRs consistent with those reported in the literature.5 1H NMR
(300 MHz, CDCl3) δ 0.81 (t, J = 7.4 Hz, 6H), 1.62ꢀ1.86 (m, 4H), 3.19ꢀ3.29 (m, 1H), 4.01 (s, 3H),
7.04 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H); MS (ESI) m/z 270 (M)+; Anal. Calcd for
C13H16N2Cl2: C, 57.58; H, 5.95; N, 10.33; Cl, 26.15. Found: C, 57.53; H, 5.91; N, 10.36; Cl,
26.03.
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Synthesis of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-
benzo[d]imidazole (1). A mixture of 10 (5.00 g, 18.4 mmol), 11 (3.92 g, 22.1 mmol), K3PO4
(7.83 g, 36.9 mmol), and DMSO (15 mL) was stirred at 105 oC for 12 hours. Upon completion of
the reaction, acetone (15 mL) and water (15 mL) were successively added at 30 oC and the
mixture was stirred at the same temperature for 1 hour. The resultant precipitate was collected by
filtration, washed with 50% aqueous acetone (10 mL) and water (20 mL), and dried in vacuo at
50 oC to give crude 1 (6.72 g, 16.3 mmol, 89% yield) as a reddish white solid. A mixture of
crude 1 (6.00 g, 14.6 mmol) and acetone (36 mL) was heated to 40 oC to give a clear solution.
Activated carbon (0.30 g) was added to the solution and then insoluble matters were removed by
filtration and rinsed with acetone (9 mL). Water (18 mL) was added dropwise to the combined
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filtrate and the mixture was stirred at room temperature for 1 hour. The resultant precipitate was
collected by filtration, washed with 50% aqueous acetone (12 mL), and dried in vacuo at 50 oC
to give 1 (5.57 g, 13.5 mmol, 92% yield, 99.5% purity by HPLC analysis detected by UV 230
nm) as white crystals. NMRs were consistent with those reported in the literature.5 1H NMR (300
MHz, CDCl3) δ 0.85 (t, J = 7.4 Hz, 6H), 1.65ꢀ1.83 (m, 4H), 2.30 (s, 3H), 3.18ꢀ3.27 (m, 1H), 3.98
(s, 3H), 6.93 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.31 (d, J =
2.4 Hz, 1H); 13C NMR (75 MHz, DMSOꢀd6) δ 12.1, 17.0, 29.1, 32.3, 41.1, 120.1, 120.5, 122.2,
127.7, 127.8, 128.1, 129.9, 131.5, 133.8, 134.7, 137.6, 146.8, 154.9; MS (ESI) m/z 411 (M)+;
Anal. Calcd for C20H21N2OCl3: C, 58.34; H, 5.14; N, 6.80; Cl, 25.83. Found: C, 58.32; H, 5.13;
N, 6.79; Cl, 25.84.
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ASSOCIATED CONTENT
Supporting Information.
The supporting information is available free of charge on the ACS Publications website at DOI: .
LCꢀMS data of Nꢀchloro intermediate 32 and 4ꢀchloro intermediate 9 (PDF).
AUTHOR INFORMATION
Corresponding Author
*yasuhiro.sawai@takeda.com
ORCID
Yasuhiro Sawai: 0000ꢀ0002ꢀ6722ꢀ2068
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We thank Mr. Yoichiro Ishimaru for helpful discussions, Dr. David Cork for his advice on the
manuscript, Mr. Kenichi Oka for LCꢀMS analysis and Miss. Mika Murabayashi for NMR
analysis.
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(9) HPLC peak area analysis detected by UV230 nm. HPLC data are available for other reaction
conditions; in the absence of AIBN at 70 oC for 8 hours, the reaction resulted in low conversion
(26 : 10 : 27 : 28 = 81 : 4 : 4 : 6, assay yield 3%). Applying the combination of NCS and ZrCl4 at
50 oC for 9 hours, the conversion was improved (26 : 10 : 27 : 28 = 9 : 33 : 19 : 35, assay yield
40%). The combination of NCS/TCCA with tꢀBuONa was not attempted because of the lack of a
urea proton.
(10) Zhang, Y.; Shibatomi, K.; Yamamoto H. Synlett. 2005, 18, 2837ꢀ2842.
(11) For a combination of NCS with FeCl3, see: Tanemura, K.; Suzuki, T.; Nishida, Y.;
Satsumabayashi, K.; Horaguchi, T. Chem. Lett. 2003, 32, 932ꢀ933. HPLC data are available for
the chlorination of 8 using NCS with FeCl3 in acetonitrile (8 : 9 : 29 : 30 : 31 = 43 : 17 : 15 : 17 :
3).
(12) For a combination of Nꢀiodosuccinimide with Brønsted acid CF3SO3H, see: Olah, G. A.;
Wang, G.;Sandford, G.; Prakash, G. K. S. J. Org. Chem. 1993, 58, 3194ꢀ3195. HPLC data are
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available for the chlorination of 8 with NCS in CF3SO3H (8 : 9 : 29 : 30 : 31 = 1 : 36 : 7 : 37 : 17,
assay yield 36%), in CH3SO3H (8 : 9 : 29 : 30 : 31 = 7 : 25 : 10 : 32 : 25, assay yield 27%), and
in CH3CO2H (8 : 9 : 29 : 30 : 31 = 66 : 9 : 8 : 16 : 1, assay yield 4%).
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A.; Larhed, M. Org. Process Res. Dev. 2014, 18, 1582ꢀ1588.
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C.; Cho, S.; Pratt, S.; Siedem, C.; Aso, K. Gyoten, M. PCT Int. Appl. WO2006/116412(A2),
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