Synthesis and application of 1-bromo-8-chloronaphthalene

Brief description

CAS: 20816-79-9

Molecular formula: C₁₀H₆BrCl

Molecular weight: 241.51

Color: White solid

Melting point: 87-88 °C

Boiling point: 150-160 °C (Press: 5-6 Torr)

Storage condition: Sealed in dry, Room Temperature

Density: 1.592±0.06 g/cm³ (Predicted)

Fig. 1 The structure of 1-bromo-8-chloronaphthalene

Synthetic routes:

Fig. 2 The synthetic scheme 1 of 1-bromo-8-chloronaphthalene.

To a solution of 8-chloronaphthalen-1-amine (57 g, 320 mmol, 1 eq) and TsOH•H₂O (219 g, 1.16 mol, 3.6 eq) in MeCN (1000 mL) was added a solution of NaNO₂ (39.8 g, 577 mmol, 1.8 eq) and CuBr (138 g, 963 mmol, 29.3 mL, 3 eq) in H2O (120 mL) at -5 °C, then the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was added saturated Na₂SO₃ solution (100 mL), stirred for 15 mins, and then extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether) to give 1-bromo-8-chloronaphthalene (56 g, 229 mmol, 72% yield, 99% purity). White solid; ¹H NMR (400 MHz, chloroform-d): δ 7.93 (dd, J = 1.2, 7.6 Hz, 1H), 7.82 (dd, J = 1.2, 8.4, 1H), 7.79 (dd, J = 1.2, 8.4, 1H),7.67 (dd, J = 1.2, 7.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.28 (t, J= 8.0 Hz, 1H) [1].

Fig. 3 The synthetic scheme 2 of 1-bromo-8-chloronaphthalene.

To a solution of 8-chloronaphthalen-1-amine (20.2 g, 114 mmol, 1 equiv) and TsOH•H20 (77.9 g, 409 mmol, 3.6 equiv) in MeCN (360 mL) at -5 °C was added NaNO₂ (14.12 g, 205 mmol, 1.8 equiv) followed by a solution of CuBr (10.4 mL, 341 mmol, 3 equiv) in H₂O (48 mL). The reaction mixture was warmed to room temperature. After 12 h sat. aq. Na₂SO₃ (200 mL) was added. After 30 min of stirring the reaction mixture was concentrated under reduced pressure to remove organic solvents. The aqueous phase was extracted into EtOAc (3 x 80 mL), then the combined organic phase was washed with sat. aq. NaCl (80 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (3→5% EtOAc/petroleum ether) to afford 1-bromo-8-chloronaphthalene (17.2 g, 63% yield) as white solid. ¹H NMR (400 MHz, CDCh) δ 7.93 (dd, J = 7.46, 1.22 Hz, 1H), 7.80 (ddd, J= 12.35, 8.19, 0.98 Hz, 2H), 7.67 (dd, J= 7.52, 1.28 Hz, 1H), 7.38 (t, J= 7.83 Hz, 1 H), 7.25-7.32 (m, 1H) [2].

Application

1-Bromo-8-Chloronaphthalene is primarily used as an intermediate in the preparation of a series of quinazoline compounds, and biologicalinhibitors and drug compositions of KRas G12C and KRas G12D that regulate biological processes [3, 4]. These inhibitors have played a significant role in the treatment of central nervous system diseases and other diseases [5].

References

[1] 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidines as KRas G12D inhibitors and their preparation. Wang, Xiaolun; Burns, Aaron Craig; Christensen, James Gail; Ketcham, John Michael; Lawson, John David; Marx, Matthew Arnold; Smith, Christopher Ronald; Allen, Shelley; Blake, James Francis; Chicarelli, Mark Joseph et al. From PCT Int. Appl. (2021), WO 2021041671 A1 Mar 04, 2021.

[2] Preparation of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine and quinazolin-4-amine derivatives as covalent Ras inhibitors and uses thereof. Pitzen, Jennifer; Aggen, James; Burnett, G. Leslie; Gill, Adrian L.; Semko, Christopher; Edwards, Anne V.; Gliedt, Micah James; Kiss, Gert; Jogalekar, Ashutosh; Knox, John E.; Buckl, Andreas; Koltun, Elena S. Assignee Revolution Medicines, Inc., USA. 2021.

[3] Quinazoline derivatives as KRAS G12D inhibitors and their preparation. Han, Huifeng; Gao, Panliang; Zhang, Wenlong; Ma, Cunbo; Wang, Peng; Liu, Dan; Zhang, Hao; Long, Wei Assignee: Jacobio Pharmaceuticals Co., Ltd., Peop. Rep. China.

[4] Preparation of substituted pyrido[4,3-d]pyrimidin-4-amines as KRas G12D inhibitors. Wang, Xiaolun; Lawson, John David; Marx, Matthew Arnold; Allen, Shelley; Barbour, Patrick Michael; Blake, James Francis; Dahlke, Joshua Ryan; Dai, Donghua; Fell, Jay Bradford; Fischer, John Peter; et al. From PCT Int. Appl. (2022).

[5] Quinazoline compounds, preparation methods and uses thereof as inhibitors of KRAS G12D. Dai, Xing; Wang, Yaolin; Jiang, Yueheng; Niu, Haotao; Liu, Yanqin; Yang, Hong; Han, Zixing; Wang, Zhenwu; Tao, Liangshan; Zhang, Qiang; et al. From PCT Int. Appl. (2022).

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