62937-45-5 D-Prolinamide 447554, acatalyst-ligand compound, is more and more widely used in various fields.
With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.62937-45-5,D-Prolinamide,as a common compound, the synthetic route is as follows.
62937-45-5, In these Reference Examples the following method was used, with volumes and amounts as outlined in Table 1.The racemic mandelic acid derivative 3-chloro,5-difluoro-methoxy mandelic acid and (D)- proline amide were added to ethyl acetate saturated in water (8.1% water in ethyl acetate). The mixture was heated to reflux and stirred for 10 minutes at reflux. The thin suspension was cooled to 23C over 13 hours followed by further cooling to 180C over 40 minutes. The suspension was filtered and washed with ethyl acetate (3 x 30 ml) to give the salt. A sample was dissolved in a 1 : 1 mixture of 1 M HCl and ethyl acetate. The organic layer was separated, concentrated to dryness and analysed by chiral HPLC (for suitable methodology, see Reference Example 1 IA). This showed a high degree of purity of the “correct” enantiomer (see Table 1), (R)- 3-chloro,5-difluoro-methoxy mandelic acid.Table 1MA= racemic mandelic acid derivative, 3-chloro,5-difluoro-methoxy mandelic acid.PA= (D)-proline amide.Eq. PA= Amount of equivalents of (D)-proline amide compared to racemic mandelic acid derivative.EtOAc= ethyl acetate, as solution saturated in water.Water/EtOAc (%) = concentration of water in ethyl acetate. mmol MA/ ml water-EtOAc= concentration range of racemic mandelic acid derivative per ml of ethyl acetate and water. EPO e.e. (%) = enantiomeric excess defined as the % mole fraction denoting the enantiomers in a mixture.1) Corrected for purity, i.e. initially 86% pure racemic mandelic acid derivative.; In these Reference Examples the following method was used, with volumes and amounts as outlined in Table 2.The racemic mandelic acid derivative 3-chloro,5-difluoro-methoxy mandelic acid and (D)- proline amide were added to ethyl acetate and the mixture heated to reflux. At reflux, water was added and the mixture was stirred for another 10 minutes at reflux. The thin suspension was allowed to cool to 18C over 3 hours (in Reference Examples 4-8; 4 hours in Reference Example 9). The suspension was filtered and washed with ethyl acetate (3 x 30 ml) to give the salt. The salt was dissolved in a 1 : 1 mixture of 1 M HCl and ethyl acetate. The organic layer was separated, concentrated to dryness and analysed by chiral HPLC (for suitable methodology, see Reference Example 1 IA). This showed a high degree of purity of the “correct” enantiomer (see Table 2), (R)- 3-chloro,5-difluoro-methoxy mandelic acid.To exemplify in more detail, the following scheme was used in Reference Example 6: The racemic mandelic acid derivative 3-chloro,5-difluoro-methoxy mandelic acid (26.18 g, 93.3 mmol, 1 eq, 90% pure according to HPLC) and (D)-proline amide (4.80 g, 42 mmol, 0.45 eq) were added to ethyl acetate (54.5 ml) and the mixture heated to reflux. At reflux, 5.5 ml of water was added and the mixture stirred for another 10 minutes at reflux. The thin suspension was allowed to cool to 18C over 3 hours. The suspension was filtered and washed with ethyl acetate (3 x 30 ml) to give 8.6 g of the salt. A sample was dissolved in a 1:1 mixture of 1 M HCl and ethyl acetate. The organic layer was separated, concentrated to dryness and analysed by chiral HPLC. This showed 98.2% of the “correct” (i?)-enantiomer. From the mother liquor more material crystallised, which was filtered, washed and dried. This gave another 1.6 g of the salt. The free (i?)-mandelic acid was analysed by HPLC (for suitable methodology, see Reference Example HA) and contained 99.0% of the “correct” enantiomer. EPO Table 2MA = racemic mandelic acid derivative 3-chloro,5-difluoro-methoxy mandelic acid.PA = (D)-proline amide.Eq. PA = Amount of equivalents of proline amide compared to racemic mandelic acid derivativeEtOAc = ethyl acetate in ml.Water/EtOAc (%) = concentration of water in ethyl acetate. mmol MA/ ml water-EtOAc = concentration range of racemic mandelic acid derivative per ml of ethyl acetate and water. e.e. (%) = enantiomeric excess defined as the % mole fraction denoting the enantiomers in a mixture.1) Corrected for purity, i.e. initially 85-90% pure racemic mandelic acid derivative.2) The suspension was allowed to cool to 180C over 4 hours.; A solution of the racemic mandelic acid (obtained after the first racemisation) in ethyl o acetate (1.433 kg of a 29.9% (w/w) solution, 0.429 kg racemic mandelic acid, 1.698 mol, 1.00 eq) was filtered and added within 30 minutes to a stirred solution of D-prolinamide (0.095 kg, 0.853 mol, 0.49 eq) in ethyl acetate (0.407 kg, 0.452 L) as well as water (0.153 kg) at 72-75C. After the addition was completed a clear solution was obtained. The mixture was cooled to 58C within 45 min. No crystallisation was observed. The mixture s was cooled further to 0-20C within 2.5 hours. The salt started to precipitate at approximately 55C. After stirring for a further hour at 0-20C, the solid was filtered off and washed twice with a pre-cooled (0-50C) mixture of ethyl acetate/ water = 9:1 (w/w, 2 x EPO 0.20 kg). A wet,…
62937-45-5 D-Prolinamide 447554, acatalyst-ligand compound, is more and more widely used in various fields.
Reference£º
Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2006/125964; (2006); A1;,
Metal catalyst and ligand design
Ligand Template Strategies for Catalyst Encapsulation – NCBI