Improved method for preparing 4,4 - difluoro - proline
A proline and acid catalyst technology, applied in 4 fields, can solve the problems of high toxicity, 4,4-difluoro-L-proline large-scale commercial preparation limitation, high price and other problems
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[0019] The method for preparing 4,4-difluoro-L-proline ester of the present invention comprises the following steps:
[0020] (1) Place trans-4-hydroxy-L-proline in C 1 ~C 6 In the monohydric alcohol, in the presence of an acid catalyst, reflux for 5 to 7 hours (esterification reaction) to obtain an esterification product; the esterification product is placed in an aprotic solvent together with the compound (A), and in the presence of a base Reflux for 3 to 5 hours to obtain compound (I);
[0021] Wherein: said acid catalyst is SOCl 2 , HCl, H 2 SO 4 , PCl 3 , PCl 5 or POCl 3 , the more preferred alcohol is C 1 ~C 4 monohydric alcohols; the recommended aprotic solvents are benzene, toluene, methylene chloride, tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO), and the bases are KOH, NaOH, Ba(OH) 2 , Ca(OH) 2 、Na 2 CO 3 、K 2 CO 3 , NaHCO 3 、KHCO 3 , triethylamine or dimethylamine.
[0022] (2) Place compound (I) in an aprotic solution, add an oxidizing agent ...
Embodiment 1
[0029] (1) trans-4-hydroxy-L-proline ethyl ester hydrochloride:
[0030] In a 500ml three-necked flask, dissolve trans-4-hydroxy-proline (20.0g, 0.15mol) in EtOH (200ml) to form a suspension, lower the reaction temperature to 0°C, add thionyl chloride (20.2g , 0.17mol). After 2 hours of dropwise addition, the temperature was raised to reflux, and a clear solution was formed under vigorous stirring. Stir for 6h. Naturally cooled at room temperature, crystals were precipitated. Add 30ml of methyl tert-butyl ether for dilution, and filter with suction. The filter cake was washed with 30 ml of methyl tert-butyl ether, and dried to obtain 26.86 g of white needle-like crystals, yield: 90.4%. mp 152.2-152.3°C, [α] 20 D -73°.
[0031] (2) N-tert-butoxycarbonyl-trans-4-hydroxy-L-proline ethyl ester:
[0032] In a 500ml three-necked flask, trans-4-hydroxyl-proline ethyl ester hydrochloride (29.4g) was dissolved in dioxane and water mixed (250ml) solution, and triethylamine was a...
Embodiment 2
[0044] (1) trans-4-hydroxy-L-proline ethyl ester hydrochloride:
[0045] In a 500ml three-necked flask, dissolve trans-4-hydroxy-proline (20.0g, 0.15mol) in ethanol (200ml) to form a suspension, lower the reaction temperature to 0°C, and inject HCl gas (0.4mol) . Warm to reflux, forming a clear solution with vigorous stirring. Stir for 6h. Naturally cooled at room temperature, crystals were precipitated. Add 30ml of methyl tert-butyl ether for dilution, and filter with suction. The filter cake was washed with 30 ml of methyl tert-butyl ether, and dried to obtain 27.86 g of white needle-like crystals, yield: 93.8%. mp 152.2-152.3°C, [α] 20 D -73°.
[0046] (2) N-tert-butoxycarbonyl-trans-4-hydroxy-L-proline ethyl ester:
[0047] In a 500ml three-necked flask, dissolve trans-4-hydroxy-proline ethyl ester hydrochloride (29.4g) in dichloromethane (250ml) solution, add triethylamine, tert-butoxy CH of carbonyl chloride (43.6g) 2 Cl 2 (50ml) solution. The temperature was...
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