US 12,239,943 B2
Continuous production of active pharmaceutical ingredients
Kamalesh Sirkar, Bridgewater, NJ (US)
Assigned to New Jersey Institute of Technology, Newark, NJ (US)
Filed by New Jersey Institute of Technology, Newark, NJ (US)
Filed on Sep. 1, 2023, as Appl. No. 18/241,405.
Application 18/241,405 is a division of application No. 17/546,305, filed on Dec. 9, 2021, granted, now 11,779,859.
Claims priority of provisional application 63/123,172, filed on Dec. 9, 2020.
Prior Publication US 2023/0405488 A1, Dec. 21, 2023
Int. Cl. C07C 213/06 (2006.01); B01D 9/00 (2006.01); B01D 9/02 (2006.01); B01D 11/04 (2006.01); B01D 61/28 (2006.01); B01D 61/36 (2006.01); B01D 63/02 (2006.01); C07C 213/10 (2006.01); C07D 403/06 (2006.01)
CPC B01D 9/0059 (2013.01) [B01D 9/02 (2013.01); B01D 11/0492 (2013.01); B01D 61/28 (2013.01); B01D 61/362 (2013.01); B01D 63/02 (2013.01); C07C 213/06 (2013.01); C07C 213/10 (2013.01); C07D 403/06 (2013.01); B01D 2009/0086 (2013.01)] 15 Claims
OG exemplary drawing
 
1. A method for continuous manufacturing of prexasertib monolactate monohydrate, said method comprising the steps of:
(a) combining compound 7 with hydrazine in the presence of acetic acid in methanol and THF at the temperature of about 130° C. to produce compound 8:

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(b) combining compound 8 with compound 9 in the presence of N-ethylmorpholine in DMSO at the temperature of about 85° C. to produce compound 10:

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(c) deprotecting compound 10 by combining it with formic acid at the temperature of about 25° to produce compound 1:

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 and
(d) subjecting compound 1 to lactic acid distillation in THF/water to produce compound 12:

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wherein each of steps (a)-(d) is carried out in a series of units connected to each other to support continuous flow; and
wherein said series of units comprises at least one membrane-based unit, wherein after step (a), combining compound 8 with toluene and carrying out countercurrent solvent extraction using the membrane-based unit to yield compound 8 in a mixture of toluene, methanol, water and THF, wherein the membrane-based unit is a pervaporation membrane device.