Monohydrate solvates of loracarbef
A technology of solvate and monohydrate, applied in the field of preparation of solvate of loracarb and pharmaceutical composition of crystalline monohydrate, can solve the problems of difficulty in batch preparation of loracarb monohydrate and the like
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Embodiment 1
[0063] Preparation of mono-N,N-dimethylacetamide solvate of Loracarbi
[0064] Step A: Preparation of N-Methylmorpholine Salt
[0065] At 20-25°C, in a mixture of N,N-dimethylacetamide (60ml) and N-methylmorpholine (3.0g), add p-nitrobenzyl 7β-amino-3-chloro-hydrochloride in portions 1-carba (1-dethia)-3-cephem-4-carboxylic acid (10.0 g) to form the free amine. The reaction mixture was stirred for 30 minutes, then cooled to -5 to -10°C.
[0066] Step B: Preparation of Mixed Anhydride
[0067] 9.3 g of the Na / K Dane salt of phenylglycine (prepared according to Dane et al., Angew.Chem, Vol. 74, p. 873, 1962) were suspended in N,N-dimethylacetamide (150 ml), and Stir for 30-40 minutes. The reaction mixture was cooled to -20 to -15°C, and methanesulfonic acid (0.12 g) and N-methylmorpholine (0.06 g) were added thereto. Ethyl chloroformate (3.3 g) was added in one portion and stirring was continued at -10 to -15°C for 90 minutes.
[0068] Step C: Condensation
[0069] Slowly...
Embodiment 2
[0076] Preparation of crystalline monohydrate of loracarb from mono-N,N-DMAc monohydrate solvate
[0077] Loracabie's mono-N,N-dimethylacetamide monohydrate solvate (10.0 g) was suspended in water (80 ml). 12N hydrochloric acid (1.0 ml) was added to obtain a clear solution. Activated carbon (1.0 g) was added and the reaction mixture was stirred for 30-40 minutes. The suspension was then filtered and washed with water (30ml). Raise the temperature of the filtrate to 50-55°C and wash with 8% NH 3 The pH of the solution was slowly adjusted to 1.8-1.9. The reaction mixture was stirred at 50-55°C for 30 minutes. Stirring was continued for another 30 minutes, then slowly cooled to 20-25°C. The slurry was washed with water. The filter cake was dried in an air oven at 40-45°C to give crystalline loracarbene monohydrate (5.0 g) with a bulk density greater than 0.6 g / ml. The IR, NMR and X-ray diffraction patterns of the crystalline loracarbene monohydrate were consistent with aut...
Embodiment 3
[0079] Preparation of Mono-N-Methylpyrrolidone Monohydrate Solvate of Loracarbi
[0080] Step A: Preparation of N-methylmorpholine salt:
[0081] Add p-nitrobenzyl 7βamino-3-chloro-hydrochloride to a mixture of N-methylpyrrolidone (60ml) and N-methylmorpholine (3.0g) within 15-20 minutes at -20 to -15°C 1-carba (1-dethia)-3-cephem-4-carboxylic acid (10.0 g). The reaction mixture was stirred for 60 minutes.
[0082] Step B: Preparation of Mixed Anhydride
[0083] 9.5 g of Na / K Dane's salt (prepared according to Dane et al., Angew. Chem., Vol. 74, p. 873, 1962) were suspended in N-methylpyrrolidone (120 ml) and stirred for 30-35 minutes. The reaction mixture was cooled to -20 to -15°C, and methanesulfonic acid (0.15 g) and N-methylmorpholine (0.08 g) were added thereto. Ethyl chloroformate (3.3 g) was added in one portion and stirring was continued at -10 to -15°C for 60-90 minutes.
[0084] Step C: Condensation
[0085] Slowly add the N-methylmorpholine hydrochloride soluti...
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