Chemical synthesis of morpholine derivatives
A morpholine and compound technology, applied in the field of morpholine derivatives, can solve problems such as inconvenient operation, and achieve the effects of shortening the reaction period, avoiding high-temperature cyclization reaction, and increasing the operating concentration
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
Embodiment 1
[0083] 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-( Preparation of 3-(5-oxo-1H,4H-1,2,4-triazolyl)methyl)morpholine
[0084] A solution of 3-chloromethyl-1,2,4-triazolin-5-one (3.18 g) in DMF (30 ml) was added to 2-( R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine (R)-camphor A slurry of sulfonate (15 g) and potassium carbonate (7.71 g). The reaction mixture was left at 22°C for 20 minutes, then water (400ml) was added over 30 minutes. The crystallized mixture was cooled in an ice bath, allowed to stand for 30 minutes and the product was collected by filtration. The solid title compound was washed with water (400ml), air dried and vacuum dried at 45-50°C. Yield = 11.4 g; 98.1% HPLC w / w analysis: 93.2% analysis Yield: (97.1A% HPLC profile).
Embodiment 2
[0086] Step (i) and (ii) Preparation of 3-benzyloxymethyl-1,2,4-triazolin-5-one
[0087] Sodium hydroxide pellets (10.83g) were added to a cooled (0°C), vigorously stirred solution of semicarbazide hydrochloride (15.1g) in water (10ml) / THF (50ml) under a nitrogen atmosphere. A solution of benzyloxyacetyl chloride (25 g) in THF (100 ml) was added over 5 minutes and the mixture was left at 0° C. for 2 hours (reaction completion monitored by HPLC).
[0088] The THF was removed under reduced pressure, 2M sodium hydroxide (60ml) was added and the solution was heated at reflux temperature for 5 hours. The reaction mixture was cooled to room temperature and left for 18 hours. The solution was neutralized with 6M hydrochloric acid and the slurry was cooled in an ice bath for 1 hour. The product was collected by filtration, washed with cold water (10ml) and dried in vacuo. 3-Benzyloxymethyl-1,2,4-triazolin-5-one (16.7 g) was obtained in 60% yield. It is a white crystalline solid, m...
Embodiment 33
[0091] The preparation of embodiment 33-chloromethyl-1,2,4-triazolin-5-one
[0092] To a slurry of 3-hydroxymethyl-1,2,4-triazolin-5-one (17 g) in acetonitrile (170 ml) was added thionyl chloride ( 19.9g). The reaction mixture was left at 20°C for 18 hours [Note: after 30 minutes all starting material had dissolved. 1 hour product started to crystallize]. TLC analysis (silica; ethyl acetate / methanol (9 / 1); iodine) showed the reaction was complete. Hexane (510 mL) was added in one portion, the reaction mixture was cooled in an ice bath for 1 hour and the product was collected by filtration. The solid was washed with hexane (100ml) and dried in vacuo. 3-Chloromethyl-1,2,4-triazolin-5-one (17.2 g) was obtained as a white solid in 87.4% yield. Melting point 197-199°C;
[0093] 1 H NMR in d; DMSO δ=4.43 (2H, s, CH 2 ), 11.48 (1H, s, NH) and 11.64 (1H, s, NH) ppm and 13 C NMR in d 6 DMSO, δ=37.0 (ClCH 2 ), 144.4 (CH 2 C=N) and 156.8 (NHCONH) pp...
PUM
| Property | Measurement | Unit |
|---|---|---|
| melting point | aaaaa | aaaaa |
| melting point | aaaaa | aaaaa |
Abstract
Description
Claims
Application Information
Login to View More