Chiral 3, 3-difluoro-4-aminopyrrolidine derivative and preparation method thereof
A technology of aminopyrrolidine and amino derivatives, which is applied in the field of chirality, can solve the problems of difficult preparation and production of pyrrolidine derivatives, and achieve the effect of low cost and easy operation
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[0059] The embodiment of the present invention provides a preparation method of chiral 3,3-difluoro-4-aminopyrrolidine derivatives. In the embodiment of the present invention, a chiral 3,3-difluoro-4-aminopyrrolidine derivative is prepared by a kinetic resolution method, and the specific steps include:
[0060] S100. Using raw materials including racemic 3,3-difluoro-4-aminopyrrolidine derivatives and chiral tartaric acid to prepare a salt mixture;
[0061] S200. Use the first solvent to separate the salt mixture obtained through S100 by recrystallization to obtain a salt of a chiral 3,3-difluoro-4-amino derivative;
[0062] S300. In an alkaline solution, dissociate the salt of the chiral 3,3-difluoro-4-amino derivative obtained in S200 to obtain a chiral 3,3-difluoro-4-aminopyrrolidine derivative.
[0063] In S100, the chiral 3,3-difluoro-4-aminopyrrolidine derivative is (S)-3,3-difluoro-4-aminopyrrolidine derivative (i.e. structure i below) or (R) - 3,3-difluoro-4-aminopyr...
Embodiment 1
[0112] The preparation method that present embodiment provides, its reaction formula is as follows:
[0113]
[0114] Among them, the specific preparation method of the above product is: the raw material N-benzyl-3,3-difluoro-4-aminopyrrolidine (1000g, 4.74mol, 1.00eq) is dissolved in 5.0L (5.0v / v) ethanol, heated A pale yellow clear solution was obtained at 70°C. D-Tartaric acid (711 g, 4.74 mol, 1.00 eq) was added in portions and reflux was continued for 2 hours to give a clear solution. Subsequently, the temperature of the reaction system was slowly cooled to 0° C. at a rate of 10° C. / h under stirring and maintained for 2 hours. During the process, an obvious white solid was precipitated. The precipitated solid was collected by filtration (721 g, 1.99 mol, yield 42%).
Embodiment 2
[0116] The preparation method that present embodiment provides, its reaction formula is as follows:
[0117]
[0118] Wherein, the specific preparation method of the above-mentioned product is: the raw material (S)-N-benzyl-3,3-difluoro-4-carboxypyrrolidine·D-tartrate (700g, 1.93mol) is placed in 3.50L water, and divided Add 4M sodium hydroxide solution in batches to adjust the pH of the aqueous phase to 11. Ethyl acetate was added for extraction (2Lx3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. (S)-N-Benzyl-3,3-difluoro-4-carboxypyrrolidine was obtained as a pale yellow oil (388.7 g, yield 95%, ee value 91%). 1 H NMR (400MHz, CDCl 3 ), δ(ppm): 7.34~7.26(m, 5H), 3.63(q, J=12.8Hz, 1H), 3.48(sext, J=6.8Hz, 1H), 3.14-3.05(m, 2H), 2.86 -2.76 (m, 1H), 2.35 (t, J=8.0Hz, 1H). MS-ESI: theoretical value (M): 212.1; actual value: 213.1 (M+H + ). Specific rotation:
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