Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives

A technology for benzoic acid and derivatives, which is applied in the field of preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives, can solve problems such as not being significantly upgraded, and achieves easy access to , the effect of low cost

Pending Publication Date: 2019-12-24
IDORSIA PHARM LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The cesium and potassium salts were not significantly upgraded; however, the formation of the sodium salt in THF resulted in the removal of the undesired isomer at the expense of about 15% of the desired isomer as the solvent volume was adjusted"

Method used

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  • Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives
  • Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives
  • Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 11

[0238] Example 1.1: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt (5-methoxy-2-(2H-1,2,3 -triazol-2-yl)potassium benzoate)

[0239] 2-Bromo-5-methoxybenzoic acid (21.5g, 0.093mol, 1eq.), copper (I) iodide (0.886g, 0.05eq.) and K 2 CO 3 The powder (32.2 g, 2.5 eq.) was suspended in dioxane (600 mL) and water (8.4 mL). Add 1H-1,2,3-triazole (10.8mL, 2eq.) and trans-N,N-dimethylcyclohexane-1,2-diamine (1.32g, 0.1eq.) to the mixture . The mixture was heated at reflux for 3.5 h. IPC shows full conversion. The ratio of desired N(2) to regioisomeric N(1) isomer was 84:16. The mixture was cooled to 40°C and filtered. The filter cake was washed with dioxane (100 mL). The solid was dried to obtain 50.6 g of a blue solid. The ratio of N(2) to N(1) isomers was 98.6:1.4.

[0240] Table 1: Characterization data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 1

[0241] technology Data overview annot...

Embodiment 12

[0242]Example 1.2: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0243] The solid from Example 1.1 was dissolved in water (300 mL). TBME (200 mL) and 32% aqueous HCl (35 mL) were added. Separate the aquifer and discard it. The organic layer was washed with a mixture of 2N aqueous HCl (100 mL) and 32% aqueous HCl (20 mL). The organic layer was washed with 1N aqueous HCl (50 mL). The organic layer was extracted with 1N aqueous NaOH (200 mL). The aqueous layer was heated to 45 °C and traces of TBME were removed under reduced pressure. To the aqueous layer was added 32% aqueous HCl (20 mL) at 45 °C. At pH 6, seed crystals are optionally added. At 40°C, the resulting suspension was filtered. The filter cake was washed with water (30 mL). The product was dried at 60°C and 5 mbar. Yield: 12.4 g, 61%. Purity: 100% a / a,t R 0.63min. Seed crystals were obtained by careful crystallization according to the above procedure.

[0244] MP: 80°C (DSC).

[0245] 1...

Embodiment 13

[0248] Example 1.3: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

[0249] For example, 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (5g, 0.0228mol) obtained according to the steps of Reference Example 1 and KHCO 3 (1.61g, 0.7eq) was suspended in dioxane (100mL) and water (1mL). The mixture was heated at reflux for 40 min. The mixture was cooled to 20°C and filtered. Yield: 2.56 g, 44%. 1 H NMR (400MHz, D2O) δ: 3.80 (s, 3H), 7.04 (m, 2H), 7.46 (d, J = 8.7Hz, 1H), 7.82 (s, 2H). MP: 279.5°C (DSC additionally exhibited a broad endotherm at about 153°C to 203°C attributable to endothermic desolvation; melting was followed by exothermic decay).

[0250] Table 3: Characterization data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 2

[0251] technology Data overview annotation XRPD crystallization see image 3

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Abstract

The present invention relates to a process for the preparation of particular 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives of formula (I), to certain crystalline forms of potassium salts of said2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives of formula (IK), to certain crystalline forms of said 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives of formula (I), and to their use in the preparation of pharmaceuticals such as (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

Description

technical field [0001] The present invention relates to a process for the preparation of 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives, especially of formula (I), involving formula (I K Certain crystalline forms of the potassium salt of the 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives of ), relating to the 2-(2H-[1 ,2,3] Certain crystalline forms of triazol-2-yl)-benzoic acid derivatives and their use in the preparation of medicaments, in particular certain orexin receptor antagonists such as (S)- (2-(5-Chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)-(5-methoxy-2-(2H -1,2,3-triazol-2-yl)phenyl)methanone. Background technique [0002] Orexin receptor antagonists comprising a 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid moiety, for example from WO2008 / 020405, WO2008 / 038251, WO2008 / 081399, WO2008 / 139416, WO2008 / 150364、WO2011 / 050200、WO2012 / 148553、WO2013 / 068935、WO2013 / 169610、WO2013 / 182972、WO2014 / 057435、WO2104 / 141065、WO2015 / 083071、WO2015 / 083070、WO201...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/06
CPCC07D249/06B01J23/72C07B2200/13
Inventor 帕特里克·德尔韦希特冈泽尔·施密特
Owner IDORSIA PHARM LTD
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