Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3935
Scheme 7. Synthesis of the Alkyl Halide Intermediate 26a
a Reagents and conditions: (i) BBr3, CH2Cl2; (xviii) 2-(benzyloxy)acetyl chloride, Et3N, CH2Cl2; (xix) Lawesson’s reagent, toluene, reflux.
concentrated under reduced pressure. The residue was puri-
fied over silica eluting with 5% EtOAc-hexane to obtain
the title compound 32 (2.20 g, 46%). LCMS (ESI) 311.04
[M þ H]þ, 84%.
(20 equiv) in water (25 mL) was added to a solution of the sub-
stituted 1,3-benzothiazol-2-amine in 2-methoxy-ethanol (25 mL),
and the reaction mixture was heated to reflux overnight. After
cooling at room temperature, the mixture was diluted with water
(200 mL), acidified with 5N HCl solution to pH 4, and extracted
with CH2Cl2 (3ꢀ150 mL). The combined organic extracts were
washed with brine (100 mL), dried (Na2SO4), and concentrated
under reduced pressure to dryness, to give crude substituted
2-aminobenzenethiol. A portion of this material (1.5 equiv) were
mixed with 19 (150 mg, 0.7 mmol), and the mixture was stirred at
120 °C, in a preheated oil bath, under N2, for 2 h. EtOH (2 mL)
was added and the reaction mixture was heated at 120 °C for a
further 2 h. The products either precipitated from the reaction
mixture on cooling or the reaction mixtures were evaporated
and the crude products purified by trituration of the residue. See
the Supporting Information for exact details of each example.
2-[(Benzyloxy)methyl]-6-chloropyrido[3,2-d][1,3]thiazole (33).
To a solution of 32 (2.20 g, 7.07 mmol) in toluene (50 mL) was
added Lawesson’s reagent (2.84 g, 7.07 mmol, 1 equiv), and the
resulting reaction mixture was refluxed for 4-5 h. The solvent
was evaporated and the residue was purified over silica eluting
with 3% EtOAc-hexane to obtain the title compound 33 (1.75 g,
85%). LCMS (ESI) 291.18 [M þ H]þ, 87.50%.
2-(Bromomethyl)-6-chloropyrido[3,2-d][1,3]thiazole (26, Scheme 7).
A solution of 33 (2 g, 6.87 mmol) in CH2Cl2 (100 mL) was cooled
to -78 °C followed by dropwise addition of BBr3 (3.30 mL,
34.39 mmol, 5 equiv). The mixture was stirred at room tem-
perature for 3 h then was cooled again to -78 °C and quenched
by dropwise addition of water followed by extraction with
EtOAc (3 ꢀ 100 mL). The combined organic extracts were
washed with saturated NaHCO3 solution, dried (Na2SO4), filte-
red, and concentrated under reduced pressure. The residue was
purified over silica eluting with 2% EtOAc-hexane to obtain
Acknowledgment. We thank S. Ruston for support and
D. Davies and various colleagues for assistance and advice.
This work was funded by investments from L. Clay and East
Hill Management (Boston, MA) and The Wellcome Trust
under the Seeding Drug Discovery Initiative.
1
the title compound 26 (1.50 g, 88%). H NMR (DMSO-d6): δ
5.16 (s, 2H), 8.67 (d, J=2.4 Hz, 1H), 8.73 (d, J= 2.4 Hz, 1H).
MS (ESI) m/z: 262.90 [M þ H]þ.
General Procedure for the Alkylation of 4 Using Alkyl or
Arylmethyl Halides. K2CO3 (1.5-3.5 equiv) and NaI (0.2 equiv)
were added to a solution of 4 in DMF (3-8 mL per mmol). The
resulting suspension was stirred for 5 min at room temperature
before the corresponding halide (1.0-1.1 equiv) was added. The
reaction mixture was stirred at 20-60 °C for 3-18 h, under N2
atmosphere. After cooling to room temperature, one of two
workup procedures was followed. In some cases, the reaction
mixture was poured into water (15 mL per mmol), and the
precipitant solid was filtered, washed with water, and dried to
give the crude product. In other cases, the reaction mixture was
partitioned between EtOAc (30 mL per mmol) and water (20 mL
per mmol), the organic phase was separated, washed with water
(2ꢀ15 mL), dried (MgSO4), filtered, and concentrated in vacuo
to give the crude solid.
Supporting Information Available: Synthetic schemes and
experimental details of the intermediates used to make the
compounds described herein. This material is available free of
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3-(Cyanomethoxy)-2,6-difluorobenzamide (19). Compound 19
was prepared from 4 (1 g, 5.8 mmol) and chloroacetonitrile
(0.40 mL, 6.4 mmol, 1.1 equiv) using 1.5 equiv K2CO3, according
to the general procedure (60 °C, overnight, EtOAc/H2O workup).
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filtered, and dried in vacuo to give 19 as a gray solid (1.06 g,
86%); mp 122-123 °C. 1H NMR (DMSO-d6): δ 5.26 (s, 2H), 7.18
(app dt, J = 9.0, 1.8 Hz, 1H), 7.40 (m, 1H), 7.86 (br s, 1H), 8.14
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General procedure for the synthesis of substituted benzothia-
zole derivatives from 3-cyanomethoxy-2,6-difluoro-benzamide
(19) and substituted 1,3-benzothiazol-2-amines. A solution of KOH