1051375-19-9

Basic information

• Product Name: GSK1349572 sodiuM salt
• Synonyms: GSK1349572 sodiuM salt;DOLUTEGRAVIR SODIUM;GSK 1349572A;Dolutegravir sodiuM salt;Dolutegravir SodiuM ( API);Sodium (4R,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate;Dolutegravir sodium(GSK1349572);(4R,12aS)-N-[(2,4-Difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide sodium salt (1:1)
• CAS NO: 1051375-19-9
• Molecular Formula: C20H18F2N3NaO5
• Molecular Weight: 441.3605964
• EINECS: 812-620-6
• Product Categories: HIV-1 integrase inhibitor;Inhibitors
• Mol File: 1051375-19-9.mol

Chemical Properties

• Appearance: /
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly, Heated)
• Stability: Hygroscopic
• CAS DataBase Reference: GSK1349572 sodiuM salt(CAS DataBase Reference)
• NIST Chemistry Reference: GSK1349572 sodiuM salt(1051375-19-9)
• EPA Substance Registry System: GSK1349572 sodiuM salt(1051375-19-9)

Safety Data

• Hazardous Substances Data: 1051375-19-9(Hazardous Substances Data)

Usage

Synthesis

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.

in vitro

gsk1349572 is a two-metal-binding hiv integrase strand transfer inhibitor whose mechanism of action was established through resistance passage experiments, integrase enzyme assays, mechanistic cellular assays and activity against viral strains resistant to other classes of anti-hiv agents. in a variety of cellular antiviral assays, gsk1349572 inhibited hiv replication with subnanomolar or low-nanomolar potency and with a selectivity index of 9,400. the protein-adjusted half-maximal effective concentration extrapolated to 100% human serum was 38 nm [1].

references

[1] kobayashi m, yoshinaga t, seki t, wakasa-morimoto c, brown kw, ferris r, foster sa, hazen rj, miki s, suyama-kagitani a, kawauchi-miki s, taishi t, kawasuji t, johns ba, underwood mr, garvey ep, sato a, fujiwara t. in vitro antiretroviral properties of s/gsk1349572, a next-generation hiv integrase inhibitor. antimicrob agents chemother. 2011 feb;55(2):813-21. [2] van lunzen j, maggiolo f, arribas jr, rakhmanova a, yeni p, young b, rockstroh jk, almond s, song i, brothers c, min s. once daily dolutegravir (s/gsk1349572) in combination therapy in antiretroviral-naive adults with hiv: planned interim 48 week results from spring-1, a dose-ranging, randomised, phase 2b trial. lancet infect dis. 2012 feb;12(2):111-8.

Upstream product

• 1335210-34-8 (4R,12aS)-7-methoxy-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-carboxylic acid 
• 1335210-35-9 (4R,12aS)-N-(2,4-difluorobenzyl)-7-methyloxy-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 
• 1206102-04-6 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one 
• 1229006-11-4 C₂₀H₁₆O₃ 
• 119736-16-2 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester 
• 1206102-06-8 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 
• 1206102-07-9 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid methyl ester 
• 1206102-08-0 methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 
• 1206102-09-1 (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2’:4,5] pyrazino[2,1-b][1,3]oxazine-6,8-dione 
• 1206102-10-4 (4R,12aS)-7-(benzyloxy)-9-bromo-4-methyl-3,4,12,12atetrahydro-2H-pyrido [1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione 
• 1206102-11-5 (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-carboxamide 
• 118-71-8 Maltol 
• 500371-01-7 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde 
• 1246616-65-8 methyl 4-benzyloxy-2-((dimethylamino)methylene)acetoacetate 

Relevant articles and documents

Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium

A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was developed. The convergent strategy starts from (R)-3-amino-1-butanol and establishes the BC ring system in a 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2E/Z)-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr2·OEt2-mediated regioselective cyclization. Amide formation with 2,4-difluorobenzylamine was either performed from the free carboxylic acid or through aminolysis of the corresponding ethyl ester. Final salt formation afforded dolutegravir sodium in a 48-51% isolated yield (HPLC purity of 99.7-99.9%) over six linear steps.

NOVEL CRYSTALLINE POLYMORPHS OF SODIUM (4R,12AS)-9-{[(2,4-DIFLUOROPHENYL) METHYL]CARBAMOYL}-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO [1',2':4,5]PYRAZINO[2,1-B][1,3]OXAZIN-7-OLATE AND PROCESS FOR PREPARATION THEREOF

The present invention relates to novel crystalline polymorphs of sodium (4R,12aS)-9-{[(2,4-difluorophenyl) methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5] pyrazino[2,1-b] [1,3] oxazin-7-olate represented by the following structural formula-1a and process for their preparation. The present invention further relates to novel solvated forms of sodium (4R,12aS)-9-{[(2,4-difluoro phenyl) methyl] carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5] pyrazino[2,1-b][1,3] oxazin-7-olate compound of formula-1a and process for their preparation.

Practical Synthetic Method for the Preparation of Pyrone Diesters: An Efficient Synthetic Route for the Synthesis of Dolutegravir Sodium

A highly efficient and practical synthetic method for the preparation of pyrone diesters was established. The pyrone diester 3c can be prepared from readily available starting materials on a multihundred gram scale. The pyrone diester 3c can easily be converted to dolutegravir sodium (1). The synthetic route demonstrated herein provides an efficient and atom-economical synthetic method for preparing this potent anti-HIV agent.

Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis

A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladium-catalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity.

CONTINUES FLOW PROCESS FOR THE PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS - POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES AND INTERMEDIATES THEREOF

The present invention discloses continues flow process for the preparation of polycyclic carbamoyl pyridone derivatives and intermediates thereof. In particular, the present invention discloses a process for the preparation of intermediate. Formule (V).

NEW POLYMORPHS OF DOLUTEGRAVIR SODIUM

The present invention relates to new polymorphs of dolutegravir sodium and processes for the preparation of the new polymorphs of dolutegravir sodium. The present invention also provides pharmaceutical compositions comprising these new polymorphs, and medical uses of the polymorphs.

PROCESSES FOR PREPARING SOLID STATE FORMS OF DOLUTEGRAVIR SODIUM

Disclosed are processes for preparing solvate forms of Dolutegravir sodium.

NOVEL POLYMORPHS OF DOLUTEGRAVIR AND SALTS THEREOF

The present invention relates to novel crystalline forms of dolutegravir, process for its preparation and pharmaceutical composition comprising them.

Intermediate of these pyridonecarboxylic carbamoylalkanoic and HIV integrase inhibitor

A synthesis approach providing an early ring attachment via a bromination to compound I-I yielding compound II-II: whereby a final product such as AA: can be synthesized. In particular, the 2,4-difluorophenyl-containing sidechain is attached before creation of the additional ring Q.

PROCESS FOR THE PREPARATION OF DOLUTEGRAVIR

Processes for the preparation of dolutegravir and pharmaceutically acceptable salts utilizing alkenylamine are disclosed. Intermediates in those synthetic schemes are also disclosed.