ChemicalBook CAS DataBase List Raltegravir

Raltegravir synthesis

7synthesis methods

Product Name:Raltegravir
CAS Number:518048-05-0
Molecular formula:C20H21FN6O5
Molecular Weight:444.42

The synthesis of raltegravir begins with the treatment of acetone cyanohydrin with liquid ammonia in a pressure vessel. The resulting aminonitrile is protected as the benzyl carbamate before reaction of the nitrile moiety with hydroxylamine to afford the amidoxime. The pyrimidone ring is then constructed by condensation with dimethyl acetylenedicarboxylate and subsequent cyclization in hot xylene. Methylation of the pyrimidone is performed next with iodomethane and magnesium methoxide in dimethylsulfoxide followed by conversion of the methyl ester to an amide with 4-fluorobenzylamine. The amine, liberated from hydrogenolytic removal of the carbobenzyloxy-protecting group, is acylated with oxadiazolecarbonyl chloride, prepared in three steps from 5-methyltetrazole, to afford raltegravir.

889131-28-6 Synthesis

5-Methyl-1,3,4-oxadiazole-2-carbonyl chloride

889131-28-6
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518048-05-0
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Yield:518048-05-0 95%

Reaction Conditions:

Stage #1:2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-6-oxo-4-pyrimidinecarboxamide with 4-methyl-morpholine in tetrahydrofuran at 0 - 5; for 0.166667 h;
Stage #2:5-methyl-1,3,4-oxadiazole-2-carboxylic acid chloride in tetrahydrofuran at 0 - 5; for 1.83333 h;

Steps:

1.8.B
To a 2 L round bottom flask free amine h (30 g) was added followed by THF (821 mL). The resulting slurry was cooled down to 0-5⁰C, after which NMM (21.56 g) was added and the slurry so obtained was stirred for 10 minutes at the cold temperature. The previously prepared acyl chloride- containing slurry was added slowly to the free amine slurry over the course of 20 minutes such that the temperature did not exceed 5 ⁰C. The slurry was then aged for 1.5 hours at 0-5⁰C. At this time HPLC showed no more amine h (<0.5 % LCAP, 100% conversion). The reaction mixture was then quenched with KQH (17 % in water) (150 mL) which was added over the course of 10 minutes. The resulting yellow slurry was then stirred for an additional hour at temperatures less than 1O⁰C. The yellow slurry was then acidified to pH 3-4 with HCl (2N) (300 mL). To the resulting red wine colored solution, IPA (450 mL) was added. The low boiling point organic solvents were then evaporated under reduced pressure (40 torr) at room temperature to a final solution volume of 650 mL, at which volume crystalline Compound A began to precipitate. Water (350 mL) was then added to this new slurry over the course of 1 hour. The slurry was then cooled to 0-10⁰C and aged for 2 hours. The aged slurry was filtered and the solid obtained was washed twice with water (100 mL each).. The solid so obtained was dried overnight under vacuum and nitrogen stream to give 38.3 g of Compound A (95% yield).

References:

MERCK & CO., INC. WO2007/87188, 2007, A2 Location in patent:Page/Page column 38-39

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889131-28-6 Synthesis

889131-28-6
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518048-03-8 Synthesis