Continuous flow synthesis of lorazepam
AssigneesPurdue Research Foundation, Continuity Pharma, LLC
InventorsDavid Thompson, Shruti Biyani, Michael McGuire, Seok-Hee Hyun
Life of this patent
Estimating the term…
Abstract
A method for synthesis of Lorazepam in a continuous flow using continuous flow reactor, in which method comprises five steps including N-acylation, diazepine ring closure, imine N-oxidation, Polonovski-type rearrangement, and ester hydrolysis; a green reagent comprising a peroxide reagent and rhenium oxide catalyst for N-oxidation of delorazepam; and an ammonium source combination for the synthesis of delorazepam.
Claims30
A method for synthesis of (7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one) lorazepam (1)
- in a continuous flow reactor which method comprises:
- (a) acylating 2-amino-2′,5-dichlorobenzophenone (2) by mixing a solution comprising (2)
- with a solution comprising an acylating agent, and a solution comprising an acid scavenger to yield 2-halo-N-(4-chloro-2-(2-chlorobenzoyl)phenyl)acetamide (halo intermediate, (3));
- wherein X is a halogen comprising Cl or Br;
- (b) cyclizing the halo intermediate (3) by mixing a solution comprising the halo intermediate (3) with a solution comprising an ammonium reagent to yield 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (delorazepam, (4));
- (c) oxidizing delorazepam (4) by mixing a solution comprising delorazepam (4) with a solution comprising a peroxide reagent and a solution comprising a rhenium oxide catalyst to yield 7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine 4-oxide (delorazepam N-oxide, (5));
- (d) mixing a solution comprising delorazepam N-oxide (5) with a solution comprising an acylating reagent for performing Polonovski-type rearrangement to yield 7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl acetate (lorazepam acetate, (6));
- and
- (e) hydrolyzing lorazepam acetate (6) by mixing a solution comprising lorazepam acetate (6) and a solution comprising a base and an additive to yield lorazepam (1).
(canceled)
(canceled)
(canceled)
(canceled)
(canceled)
(canceled)
(canceled)
(canceled)
A reagent for N-oxidation of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (delorazepam (4)) to yield delorazepam N-oxide (5) comprising a combination of a peroxide reagent and a rhenium oxide catalyst.
29-30. (canceled)
An ammonium reagent for cyclization of a 2-halo-N-(4-chloro-2-(2-chlorobenzoyl)phenyl)acetamide (halo intermediate (3)) to yield 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (delorazepam, (4)) comprising a mixture of ammonium bromide and ammonium hydroxide, or a mixture of ammonium iodide, ammonium acetate, and ammonium chloride.
Dependencies are inferred from the claim text.