Process Development of a CRF1 Receptor Antagonist Based on the

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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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Organic Process Research & Development

Process Development of a CRF1 Receptor 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, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

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ABSTRACT: 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 1,3,5trichloro-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 and 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.

KEYWORDS: Selective chlorination, Chlorine migration, Benzimidazolone, Benzimidazole, CRF1 receptor antagonist


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INTRODUCTION Corticotropin-releasing factor (CRF) is believed to be the main regulator of the hypothalamus– pituitary–adrenocortical (HPA) axis via CRF1 receptors.1-4 Over the last two decades, a number of non-peptide, small-molecule CRF1 receptor antagonists have been investigated as a means for the treatment of stress-related disorders. Our discovery team revealed that 4-chloro-2-(2,4dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzo[d]imidazole (1) may serve as an effective CRF1 receptor antagonist (Figure 1).5

Figure 1. CRF1 receptor antagonist 1. Discovery synthesis of 1 started with 2-chloro-3-nitrobenzoic 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’-carbonylbis1H-imidazole (CDI). The ethyl groups of 7 were introduced by Grignard reaction with EtMgBr. An acid-catalyzed dehydration of 7 gave olefins, which were hydrogenated with a palladium catalyst to afford 7-alkyl-substituted benzimidazolone 8. Chlorination at the 4-position of 8 using N-chlorosuccinimide (NCS) and azobisisobutyronitrile (AIBN) and subsequent chlorination at the 2-position of 9 with POCl3 provided 2,4-dichlorobenzimidazole 10. Finally, replacement of


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the chlorine atom at the 2-position with phenol 11 produced the active pharmaceutical ingredient (API) 1, which was supplied for non-clinical studies in early development stages. Scheme 1. Discovery Synthesis of 1 HO

O

O

1) (COCl)2, DMF CH2Cl2 2) MeOH

Cl

H N

O H N

CDI THF

NH2

78%

5

O

O N H

1) HCl, H2O, EtOH 2) H2, Pd-C, EtOH

N

70%

6

N

OH

O

O N H

NCS AIBN CCl4

54%

N H 7

N

POCl3

N

O 68% Cl

99%

4

EtMgBr Et2O THF

N

H2, Pd-C MeOH

NO2

3

O

O

>99%

NO2

2

8

O MeNH2 THF

Cl

>99%

NO2

O

O

9

Cl

11

Cl 1

Cl 82%

N H

HO

K2CO3, DMF 64%

N Cl

10

From the view point of process research and development, selective synthesis of 4chlorobenzimidazolone was a primary issue to be addressed. Under the discovery synthesis conditions, the chlorination of 8 proceeded in a non-selective manner to give 9 with a contamination of regioisomers and dichloro species. As these by-products 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 4-chlorobenzimidazolone/4-


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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 4-position of 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 two-step sequence of dehydration-hydrogenation, and the costly end game process. Herein we report a novel regioselective chlorination of the 4-position of benzimidazolone 8 via a chlorine migration mechanism and an improved process for the production of CRF1 receptor antagonist 1. 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 7-position of benzimidazolone 12. Commercially available 7-bromoisatin 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 7position 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


6

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The initial approach to Route A was a Kumada coupling of 12 with 3-pentyl Grignard reagent (Scheme 3, equation 1). 7-Bromoisatin 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 iso-propyl 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(o-tol)3]2, Pd(dba)3 with 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (X-Phos), 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 7-metalated benzimidazolone to pentan-3-one (Scheme 3, equation 2). Halogen-metal exchange of 12 using n-BuLi proceeded at


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-78 oC to generate the 7-lithiated intermediate, which reacted with pentan-3-one 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 α-hydrogens of pentan-3-one. Although MgBr2 or ZnCl2 was added prior to the nucleophilic addition, as a means of metal exchange, the yield was not improved. 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). N-methylation of 14 using MeI quantitatively proceeded in the presence of K2CO3 and a catalytic amount of water in DMF. Nmethylated 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 Pd-C catalyst. When the reaction was carried out


8

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in EtOAc at room temperature, the reaction stalled half way. LC-MS analysis suggested that Nhydroxy 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 Pd-C 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 1,8-diazabicyclo[5.4.0]undec-7-ene (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% two-step yield and >99% purity. 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). LC-MS analysis suggested that the major by-products were ethyl aryl ketone 22 and its reductant 23. This indicated that the second alkylation did not proceed smoothly due to

β-hydride reduction of 22 occurring competitively. Reducing the amount of EtMgBr (4 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 work-up. 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


10

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(Isolated yield of 7) (equiv)

(equiv)

6

7

22

23

%

1

EtMgBr (5)c

N/A

0

77

9

12

77

2

EtMgBr (4)d

N/A

0

74

8

15

74

3

EtMgCl (4)e

N/A

0

80

14

6

80 (76)

4

EtMgBr (4)d

TMEDA (4)

0

2

93

2

N/A

5

EtMgBr (4)d

LiCl (1)

9

64

14

11

72

6

EtMgBr (4)d

CeCl3 (1)

5

83

4

6

83

7

EtMgBr (4)d

LaCl3·2LiCl (0.3)

0

86

6

7

91 (76)

General procedure: Compound 6 was added to Grignard reagent at 10 oC and then the mixture was stirred at 60 oC for 1 hour. Additive was pre-mixed with the Grgnard reagent. Assay yield was determined by HPLC using an external standard. A typical isolation method was described in the experimental section. bHPLC peak area% detected by UV 277 nm c3 mol/L Et2O solution d 1 mol/L THF solution e2 mol/L THF solution a

The subsequent dehydration-hydrogenation sequence was improved to establish a one-pot and high-yielding 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/Z-mixture 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 one-pot 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 by-product 25. A screening of acids and solvents revealed that p-toluenesulfonic acid in AcOH can suppress the aromatic ring reduction (run 3). Lowering H2 pressure (from 0.5 to 0.2 MPa) further decreased the by-product formation without giving any influences on the dehydroxylation sequence to give 8 in 92% yield (run 4). Table 2. One-pot Dehydroxylation Sequence

Run

Acid

Solv.

(equiv)

H2

LCAPa

MPa

7

E-24

Z-24

8

25

%

Isolated yield of 8

1b

N/A

THF

0.3

0

23

0

75

0

75

2

conc. HCl (0.3)

AcOH

0.5

0

0

0

86

6

71


12

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3

TsOH·H2O (0.5)

AcOH

0.5

0

0

0

94

1

83

4

TsOH·H2O (0.5)

AcOH

0.2

0

0

0

97

0

92

a

HPLC peak area% detected by UV 230 nm bFirstly 7 was dehydrated in THF with TFA (22 vol) at 5 oC for 4 hours and then the resultant E/Z-mixture 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. 2-Chlorobenzimidazole 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. LC-MS 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). LC-MS 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, over-reaction also proceeded to yield a wide variety of dichlorinated by-products 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 3-6). 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, 1,3,5-trichloro-1,3,5-triazinane-2,4,6trione (TCCA), with NaH successfully increased the conversion of the main reaction but enhanced the over-reaction as well (run 8). A screening of bases revealed that relatively-strong inorganic bases, Cs2CO3 (run 9) and K3PO4 (run 10), remarkably increased the over-reaction. In sharp contrast, t-BuONa significantly decreased the over-reaction with lower conversion (run 11). LC-MS analysis on the chlorination reaction of 8 in the presence of t-BuONa 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 N-chloro compound 32 as depicted in Scheme 6, which is similar to a mechanism reported for chlorination of the 5-position of dihydroquinolin-2-one.13 As N-chloro 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


14

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conditions. The slower migration might result in the lower generation of dichloro species. Based on this idea, an increase of t-BuONa was attempted (run 12). However, an excess amount of tBuONa increased 31. Therefore, a split-addition of t-BuONa was attempted as follows; (1) tBuONa (1.0 equiv) and TCCA (0.35 equiv) were added to 8 in toluene, and (2) additional tBuONa (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 mono- and di-chlorination (sum of 9, 29, and 30 : 31 = 89 : 2). Table 3. Selective Chlorination of the 4-Position of Benzimidazolonea

Ru

Reagent

Temp. Time LCAPb

Additive

Assay

n

yield of 9 (equiv)

(equiv)

˚C

hrs

8

9

29

30

31c

%

1

NCS (1.05)

AIBN (0.1)

85

4

2

67

7

13

7

66

2

NCS (1.05)

NA

25

4

7

67

6

14

3

75

3

NCS (1.05)

ZrCl4 (0.05)

5

4

5

66

6

15

4

66

4

NCS (1.05)

AlCl3 (0.05)

5

4

9

50

17

14

7

54

5

NCS (1.05)

LiCl (0.1)

5

4

7

64

6

16

3

70


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6

NCS (1.05)

ZnCl2 (0.1)

5

4

6

61

8

17

6

65

7

NCS (1.05)

NaH (1.0)

25

8

24 74

0

2

0

64

8

TCCA

NaH (1.0)

25

2

6

80

1

3

9

81

Cs2CO3 (1.0)

25

8

6

56

0

3

31

63

K3PO4 (1.0)

25

8

4

60

3

1

30

65

t-BuONa (1.0)

25

4

16 79

0

2

3

72

t-BuONa (1.1)

25

4

12 73

0

2

8

70

t-BuONa (1.0+0.5)

e

6

0

3

2

86

(0.35) TCCA

9

(0.35) 10

TCCA (0.35)

11

TCCA (0.35)

12

TCCA (0.35)

13d

TCCA

86

(0.35) a

General 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. bHPLC peak area% detected by UV 230 nm cMixture of three regioisomers of dichloro species dToluene 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 2-position without purification, except for a quench with aqueous Na2SO3 and a removal of the resultant 1,3,5-triazinane-2,4,6-trione 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% two-step 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 byproducts such as dichloride 33, trichloride 34, and monochloride 35 (Figure 2). Crystallization of 10 in a mixed solvent of toluene and n-heptane 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. By-products identified in the chlorination of the 2-position of benzimidazolone . The end game reaction was a nucleophilic addition of phenol 11 to 2,4-dichlorobenzimidazole 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 by-products 36 and 37 were generated in the reaction mixture (Figure 3). The aforementioned crystallization effectively decreased 36 to 99% purity (HPLC analysis detected by UV230 nm). Scheme 8. Endgame: Nucleophilic Addition of Phenol 11 to 2,4-Dihlorobenzimidazole 10


18

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Figure 3. By-products 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 t-BuONa, the reaction of benzimidazolone 8 with chlorinating reagent TCCA proceeded regioselectively to give the desired 4-chlorobenzimidazolone 9 with improved yield (68% to 86%). The selectivity was resulting from the chlorine migration mechanism, in which a chlorine atom migrated from the 3position of the N-chloro intermediate 32 to the 4-position of 9. The tedious two-step dehydrationhydrogenation of tertiary alcohol 7 was also improved to a simple and efficient one-pot operation. p-Toluenesulfonic 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 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 B-540 microscopic melting point apparatus. NMR spectra were taken on a Bruker DPX-300 (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. LC-MS analyses were conducted using a Thermo Finnigan TSQ 7000. All HPLC analyses were performed on a Shimadzu LC-2010CHT HPLC system equipped with a reversed-phase column (Inertsil ODS-3 (5 µm, 4.6 x 150 mm) or YMC-Pack ODS-A (5 µm, 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. 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 0-5 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 1H NMR (300 MHz, DMSO-d6) 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, DMSO-d6) 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 N-ethyldiisopropylamine (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, DMSO-d6) 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, DMSO-d6) 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. 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 63-64 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, DMSO-d6) δ 1.20, 1.43 (s, 9H), 3.00, 3.05 (s, 3H), 3.86, 3.87 (s, 3H), 7.68-7.72 (m, 1H), 8.12-8.14 (m, 1H), 8.19-8.21 (m, 1H); 13C NMR (126 MHz, DMSO-d6) 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. A mixture of 19 (10.0 g, 32.2 mmol), 5% Pd-C (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, DMSO-d6) δ 0.77 (t, J = 7.3 Hz, 6H), 1.77-1.94 (m, 4H), 3.68 (s, 3H), 4.98 (s, 1H), 6.81-6.94 (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. 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), p-toluenesulfonic acid monohydrate (0.81 g, 4.27 mmol), 5% Pd-C (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), 1.61-1.81 (m, 4H), 3.15-3.24 (m, 1H), 3.67 (s, 3H), 6.91-7.06 (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 n-hexane) 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), 1.66-1.85 (4H, m), 3.243.32 (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). Synthesis of 2,4-dichloro-1-methyl-7-(pentan-3-yl)-1H-benzo[d]imidazole (10). 1,3,5Trichloro-1,3,5-triazinane-2,4,6-trione (1.18 g, 5.08 mmol) was added to a mixture of 8 (3.00 g, 13.7 mmol), t-BuONa (1.32 g, 13.7 mmol), and toluene (60 mL) at room temperature. The mixture was allowed to warm to 35 oC. Then t-BuONa (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), 1.58-1.80 (m, 4H), 3.11-3.20 (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 n-heptane (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 n-heptane (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), 1.62-1.86 (m, 4H), 3.19-3.29 (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. Synthesis of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1Hbenzo[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), 1.65-1.83 (m, 4H), 2.30 (s, 3H), 3.18-3.27 (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, DMSO-d6) 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. ASSOCIATED CONTENT Supporting Information. The supporting information is available free of charge on the ACS Publications website at DOI: . LC-MS data of N-chloro intermediate 32 and 4-chloro intermediate 9 (PDF). AUTHOR INFORMATION Corresponding Author *[email protected] ORCID Yasuhiro Sawai: 0000-0002-6722-2068 Notes


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The authors declare no competing financial interest. ACKNOWLEDGMENTS We thank Mr. Yoichiro Ishimaru for helpful discussions, Dr. David Cork for his advice on the manuscript, Mr. Kenichi Oka for LC-MS analysis and Miss. Mika Murabayashi for NMR analysis. REFERENCES (1) Gilligan, P. J. Expert Opin. Ther. Pat. 2006, 16, 913-924. (2) Williams, J. P. Expert Opin. Ther. Pat. 2013, 23, 1057-1068. (3) Dzierba, D. C.; Hartz, A. R.; Bronson, J. J. Annu. Rep. Med. Chem. 2008, 43, 3-23. (4) Owen, M. J.; Nemeroff C. B. Pharmacol. Rev. 1991, 43, 425-473. (5) Mochizuki, M.; Kojima, T.; Kobayashi, K.; Kotani, E.; Ishichi, Y.; Kanzaki, N.; Nakagawa, H.; Okuda, T.; Kosugi, Y.; Yano, T.; Sako, Y.; Tanaka, M; Aso, K. Bioorg. Med. Chem 2016, doi: http://dx.doi.org/10.1016/j.bmc.2016.11.011. (6) For resent progresses in practical synthesis of benzimidazole derivatives, see: (a) Yang, F.; Wu, C.; Li, Z.; Tian, G.; Wu, J.; Zhu, F.; Zhang, J.; He, Y. Shen, J. Org. Process Res. Dev. 2016, 20, 1576−1580. (b) Kuroda, K.; Tsuyumine, S.; Kodama, T. Org. Process Res. Dev. 2016, 20, 1053−1058. (c) Funel, J.-A.; Brodbeck, S.; Guggisberg, Y.; Litjens, R.; Seidel, T.; Struijk, M.; Abele, S. Org. Process Res. Dev. 2014, 18, 1674−1685. (d) Chen, J.; Przyuski, K.; Roemmele, R.; Bakale, R. P. Org. Process Res. Dev. 2014, 18, 1427−1433. (e) Betti, M.; Genesio, E.; Marconi, G.; Coccone, S. S.; Wiedenau P. Org. Process Res. Dev. 2014, 18, 699−708. (f) Oda,


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S.; Shimizu, H.; Aoyama, Y.; Ueki, T.; Shimizu, S.; Osato, H.; Takeuchi, Y. Org. Process Res. Dev. 2012, 16, 96−101. (g) Webel, M; Palmer, A. M.; Scheufler, C.; Haag, D.; Müller, B Org. Process Res. Dev. 2010, 14, 142−151. (h) Barkalow, J. H.; Breting, J.; Gaede, B. J.; Haight, A. R.; Henry, R.; Kotecki, B.; Mei, J.; Pearl, K. B.; Tedrow, J. S.; Viswanath S. K. Org. Process Res. Dev. 2007, 11, 693−698. (7) For LiCl-mediated reaction of Grignard reagent, see: Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333-3336. (8) Krasovskiy, A.; Kopp, K.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 497-500. (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 t-BuONa was not attempted because of the lack of a urea proton. (10) Zhang, Y.; Shibatomi, K.; Yamamoto H. Synlett. 2005, 18, 2837-2842. (11) For a combination of NCS with FeCl3, see: Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Chem. Lett. 2003, 32, 932-933. 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 N-iodosuccinimide with Brønsted acid CF3SO3H, see: Olah, G. A.; Wang, G.;Sandford, G.; Prakash, G. K. S. J. Org. Chem. 1993, 58, 3194-3195. 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%). (13) Winter, D. K.; Drouin, A.; Lessard, J.; Spino, C. J. Org. Chem. 2010, 75, 2610-2618. (14) Murase, N.; Murata, Y.; Numata, T.; Satake, K. Synth. Commun. 2008, 38, 1478-1484. (15) Engen, K.; Sävmarker, J.; Rosenström, U.; Wannberg, J.; Lundbäck, T.; Jenmalm-Jensen, A.; Larhed, M. Org. Process Res. Dev. 2014, 18, 1582-1588. (16) (a) Aso, K.; Mochizuki, M.; Kojima, T.; Kobayashi, K.; Pratt, S. A.; Gyorkos, A. C.; Corrette, C. P.; Cho, S. Y. PCT Int. Appl. WO2008/051533(A2), 2008. (b) Gyorkos, A; Corrette, C.; Cho, S.; Pratt, S.; Siedem, C.; Aso, K. Gyoten, M. PCT Int. Appl. WO2006/116412(A2), 2006.


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Process Development of a CRF1 Receptor Antagonist Based on the

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