ChemicalBook CAS DataBase List Dolutegravir sodium

Dolutegravir sodium synthesis

11synthesis methods

Product Name:Dolutegravir sodium
CAS Number:1051375-19-9
Molecular formula:C20H20F2N3NaO5
Molecular Weight:443.38

The most likely process-scale synthesis of dolutegravir sodium, began with benzyl protection and alkylation of pyrone 46 with benzaldehyde, yielding alcohol 47 in 74% over 2 steps. Alcohol mesylation and in situ elimination provided the styrenyl olefin 48 in 94% yield, which further underwent an oxidative cleavage of the olefin to generate 49 by sequential addition of RuCl3/NaIO4 and NaClO2 (56% overall yield). Treatment of pyranone 49 with 3-amino-propane-2-diol (50) in ethanol at elevated temperatures delivered the corresponding pyridinone in 83% yield, and this was followed by esterification and sodium periodate-mediated diol cleavage to furnish intermediate 51 in 71% overall yield across the two-step sequence. l Next, the key ring-forming step in the synthesis of dolutegravir sodium consisted of cyclization of 51 with (R)-3- amino-butan-1-ol, a process which relies on substrate control to provide the desired tricyclic carbamoylpyridone system 52 in high stereoselectivity (20/1 in favor of the desired isomer).51 Previously, cyclization of systems such as 51 with unsubstituted amino alcohols were found to yield a mixture of diastereomeric products, therefore indicating the pivotal role of the chiral amino alcohol in influencing stereochemical bias during the overall cyclization step. In practice, reaction of 51 with (R)-3-amino-butan-1-ol at 90 ℃ led to isolation of a single cyclization product 52, after recrystallization from EtOAc. From 52, N-bromosuccinimide (NBS) bromination and subsequent treatment with amine 53 under palladium-catalyzed amidocarbonylative conditions led to amide 54 in 75% yield over 2 steps. Finally, removal of the benzyl group and subsequent crystallization using sodium hydroxide in water and ethanol provided dolutegravir sodium (VII) in 99% yield.

1206102-11-5 Synthesis

(4R,12aS)-N-(2,4-difluorobenzyl)-7-benzylhydroxy-4-Methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxaMide

1206102-11-5
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1051375-19-9
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Yield:1051375-19-9 98.9%

Reaction Conditions:

Stage #1: (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2’:4,5]-pyrazino[2,1-b][1,3]oxazine-9-carboxamidewith propylene glycol;palladium 10% on activated carbon;hydrogen at 50;
Stage #2: with sodium t-butanolate at 30 - 70;Temperature;

Steps:

4b Example 4 (General Procedure) Examples 4a, 4b, 4d and 4e: 1 .00 g (1 .96 mmol)

General procedure: Example 4 (General Procedure) Examples 4a, 4b, 4d and 4e: 1 .00 g (1 .96 mmol) DTG-OBn was suspended in 10 mL racemic 1 ,2-PG and 5 mL of a co-solvent. The flask was flushed with argon and then charged with 42 mg of 10% palladium on activated charcoal (50% wet, 0.20 mmol, 0.01 eq.). The resulting mixture was heated to 50 °C and stirred under hydrogen atmosphere until completion. The flask was flushed with argon and the warm mixture was filtered over glass fiber filter. The filtrate was charged into a clean flask and heated to the desired temperature (see Table below). A solution of 192 mg (1 .96 mmol, 1 .0 eq.) sodium tert-butylate in 2 ml. racemic 1 ,2-PG was added to the mixture, under vigorous stirring. After completion of the addition, a clear yellow solution was obtained. A solid started to precipitate within 5 min. After stirring for 5-15 min, the heating of the oil bath was turned off and after 90 min (T (oil bath) = approx. 30°C), the oil bath was removed, the mixture was stirred for another 30 min at RT and then filtered. The isolated solid was washed with acetone and dried at 50°C under vacuum (10 mbar) for different times (see table) yielding Dolutegravir sodium salt (1 :1 ) 1 ,2-propylene glycol solvate as off-white solid.

References:

WO2017/46131,2017,A1 Location in patent:Page/Page column 30; 31

1335210-35-9 Synthesis