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An improved process for the preparation of (1aR,5S,8S,10R,22aR)-5-(1,1-dimethylethyl)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-14-methoxy-3,6-dioxo-8H-7,10-methanocyclopropa[18,19]-[1,10,3,6]dioxadiazacyclonon-adecino[11,12-b]quinoxaline-8-carboxylic acid.

IP.com Disclosure Number: IPCOM000246780D
Publication Date: 2016-Jun-30
Document File: 4 page(s) / 182K

Publishing Venue

The IP.com Prior Art Database

Abstract

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This is the abbreviated version, containing approximately 42% of the total text.

Page 01 of 4

An improved process for the preparation of (1aR,5S,8S,10R,22aR)-5-(1,1-

dimethylethyl)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-14-methoxy-

3,6-dioxo-8H-7,10-methanocyclopropa[18,19]-[1,10,3,6]dioxadiazacyclonon-

adecino[11,12-b]quinoxaline-8-carboxylic acid.

(1aR,5S,8S,10R,22aR)-5-(1,1-dimethylethyl)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a- tetradecahydro-14-methoxy-3,6-dioxo-8H-7,10-methanocyclopropa[18,19][1,10,3,6] dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylic acid is a key intermediate for the preparation of (1aR,5S,8S,10R,22aR)-N-[(1R,2S)-1- [(Cyclopropylsulfonamido)carbonyl]-2-ethenylcyclopropyl]-14-methoxy-5-(2- methylpropan-2-yl)-3,6-dioxo- 1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H- 7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-
b]quinoxaline-8-carboxamide and is prepared by the following process.

Step-1: Process for 2-benzyl 1-(tert-butyl) (2S,4R)-4-((3-chloro-7-methoxy-

quinoxalin-2-yl)oxy)-pyrrolidine-1,2-dicarboxylate

Method-1

Charged 2-benzyl 1-(tert-butyl) (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (0.0092-
0.015 mole) in suitable solvent such as NMP, DMAc, DMSO, acetonitrile and mixture thereof. Charged 2,3-dichloro-6-methoxy quinoxaline (0.0087 mole) and added suitable base such as DBU, DABCO, cesium carbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide and sodium hydride (1.1 to
1.5 mole eq.). The reaction mass was stirred at 40-50°C.After completion of reaction water and suitable solvent such as MDC, MTBE, ethyl acetate or toluene was added at ambient temperature. Organic layer was separated and washed with water followed by mixture of DMSO and water, water, 2N aq. HCl and water successively. The organic layer was evaporated to obtain oil which was used in next step without purification. Method-2

Charged (2S,4R)-1-(tert-butoxycarbonyl)-4-((3-chloro-7-methoxyquinoxalin-2-yl)oxy)- pyrrolidine-2-carboxylic acid (0.111 mole) in a suitable solvent such as ethanol, methanol or isopropyl alcohol. Water was added to the reaction mass and the pH was

1


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adjusted to 6 to 8 using an aqueous base such as cesium carbonate, potassium carbonate, sodium carbonate. The organic layer was evaporated under vacuum to obtain a solid. A suitable solvent such as DMF or DMSO was added followed by benzyl bromide (0.024 to 0.035 mole) and maintained at ambient temperature. After completion of reaction a suitable solvent such as MDC, ethyl acetate, MTBE, toluene and water was added at ambient temperature. Organic layer was separated and washed with water followed by aq. sodium bicarbonate at ambient temperature. Organic layer was evaporated to obtain an oil which was used in next step without purification.

Step-2:Process for (R)-2-((((1R,2S)-2-(5-(3-(((3R,5S)-5-((benzyloxy)carbonyl)-1-

(tert-butoxy-carbonyl)pyrrolidin-3-yl)oxy)-6-methoxyquinoxalin-2-yl)pent-4-yn-1-

yl)cyclo-propoxy)-carbonyl)amino)-3,3-dimethylbutanoic acid...