Improved synthetic process for preparing (2H-1, 2, 3-triazol-2-yl) phenyl compounds as orexin receptor modulators

A -2H-1, phenyl technology, applied in the preparation of hydrazone, drug combination, organic chemistry and other directions, can solve problems such as low yield

Pending Publication Date: 2022-05-27
JANSSEN PHARMA NV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

) but in all cases the cyclization to 2-aryltriazole derivatives via intermediates has low yields when the 4- and 5-positions of the triazole ring are unsubstituted

Method used

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  • Improved synthetic process for preparing (2H-1, 2, 3-triazol-2-yl) phenyl compounds as orexin receptor modulators
  • Improved synthetic process for preparing (2H-1, 2, 3-triazol-2-yl) phenyl compounds as orexin receptor modulators
  • Improved synthetic process for preparing (2H-1, 2, 3-triazol-2-yl) phenyl compounds as orexin receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Example 1: Synthesis of hydrazide acetaldehyde of formula IV

Embodiment 1a

[0142] Example 1a: Synthesis of (E)-2-(2-(3-fluorophenyl)hydrazono)acetaldehyde.

[0143]

[0144] A 40 w / w% solution of glyoxal in water (613 g, 4.22 mol) was added to a suspension of 177 g (1.06 mol) (3-fluorophenyl)hydrazine (hydrochloride) in 1.24 L of water, followed by 2 hours A solution of 129.9 g (1.58 mol) of sodium acetate in 708 mL of water was added. After stirring at room temperature for several hours, the suspension was filtered and the filter cake was washed with 0.89 L of water and dried in vacuo to afford 172.8 g (95% yield) of the title compound as a yellow solid.

[0145] mp 118°C-119°C.

[0146] 1 H NMR (DMSO-d 6)δ: 11.80(br s, 1H), 9.49(d, J=7.7Hz, 1H), 7.36(d, J=7.9Hz, 1H), 7.32-7.39(m, 1H), 6.96-7.03(m, 2H), 6.75-6.83 (m, 1H). 13 C NMR (DMSO-d 6 )δ: 190.4, 163.0 (br d, J=242.7Hz), 144.7 (br d, J=10.8Hz), 136.3, 131.2 (d, J=10.0Hz), 110.0 (d, J=2.3Hz), 108.5 (d, J=21.6 Hz), 100.6 (d, J=27.0 Hz). 19 F NMR (DMSO-d 6 )δ: -111.72.

[0147] HRMS...

Embodiment 1b

[0148] Example 1b: Synthesis of (E)-methyl 2-fluoro-6-(2-(2-oxoethylidene)hydrazino)benzoate

[0149]

[0150] A solution of methyl 2-fluoro-6-hydrazinobenzoate (17.65g, 0.08mol) in methanol-water (90ml+180ml) was added to 40w% aqueous glyoxal ( 58.04g, 0.8mol), water (100ml) and sodium acetate (9.85g, 0.12mol). The mixture was then stirred for about 1.5 hours and then filtered. The filter cake was washed with water (2 x 50 mL) and dried in vacuo. The dry solid (16.12g) was redissolved in ethyl acetate (50ml) at 50°C, then crystallized by slow addition of heptane (200ml) and cooling to 5°C. The resulting solid was filtered, rinsed with heptane (2 x 15ml) and dried in vacuo. The desired product was obtained as a yellow solid (13.33 g, 74% yield). mp 110.8°C.

[0151] 1 H NMR (DMSO-d 6 )δ: 11.74(s, 1H), 9.41(d, 1H), 7.49(m, 2H), 7.19(d, 1H), 6.92(m, 1H), 3.84(s, 3H).

[0152] MS(ESI-TOF) m / z: 225.1 ([M+H] + ).

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Abstract

The present invention describes a process for the preparation of (((3aR, 6aS)-5-(4, 6-dimethylpyrimidin-2-yl) hexahydropyrrolo [3, 4-c] pyrrol-2 (1H)-yl) (2-fluoro-6-(2H-1, 2, 3-triazol-2-yl) phenyl) methanone, which can be used in commercial manufacturing. The compounds are orexin receptor modulators and are useful in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by orexin activity, such as insomnia and depression.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of US Provisional Patent Application 62 / 883,857, filed August 7, 2019, and US Provisional Patent Application 62 / 971,265, filed February 7, 2020, which are incorporated herein by reference in their entirety. technical field [0003] The present invention relates to the preparation of (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2 - A method for the synthesis of fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Seltorexant), which can be used to modulate orexin receptors and used in Treatment of disease states, disorders and conditions mediated by orexin receptor activity. Background technique [0004] Orexin (or hypocretin) signaling is mediated by two receptors and two peptide agonists. Two orexin peptides (orexin A and orexin B), hereinafter referred to as orexin, bind to two high-affinity receptors called orexin-1 and orexin-2 receptors. The ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C249/16C07C251/76C07D295/30C07D249/06C07C311/49
CPCC07D487/04C07C249/16C07C251/76C07D295/30C07D249/06C07C311/49C07C251/78A61K31/506A61P25/20A61P25/24
Inventor D·P·M·德普雷K·马查F·D·梅迪娜P·韦斯特杜安C·Y·陈
Owner JANSSEN PHARMA NV
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