1051375-19-9 Usage
Description
Dolutegravir sodium (Tivicay), developed and marketed by
GlaxoSmithKline, was approved by the FDA in August 2013 as a
novel integrase inhibitor for the treatment of HIV infection.
Dolutegravir was fast-tracked by the FDA in February 2012, and
joins an important class of drugs known as Integrase Strand
Transfer inhibitors (INSTi’s). INSTi’s are characterized by their
two-metal-chelating scaffolds, which are known to chelate Mg2+
cofactors in the enzyme active site, l interrupting function of
HIV-1 integrase, which is essential for replication of viral DNA into
host chromatin.Other drugs in this class, raltegravir and
elvitegravir, are known to require either high dosages or PK
boosting agents, respectively, with raltegravir also exhibiting
substantial loss of potency in several major HIV-1 integrase mutation
pathways. Dolutegravir was pursued with the goal of developing
a novel INSTi with a once-daily, low-dosage treatment with
improved resistance profile and without the need for the use of a
PK boosting agent. Dolutegravir sodium has been approved
for treating a broad population of HIV-infected patients, including
adults undergoing their first treatment as well as those who have
been treated with other integrase transfer strand inhibiting
agents.
Definition
ChEBI: An organic sodium salt that is the monosodium salt of dolutegravir. Used for treatment of HIV-1.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 1051375-19-9 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,5,1,3,7 and 5 respectively; the second part has 2 digits, 1 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 1051375-19:
(9*1)+(8*0)+(7*5)+(6*1)+(5*3)+(4*7)+(3*5)+(2*1)+(1*9)=119
119 % 10 = 9
So 1051375-19-9 is a valid CAS Registry Number.
1051375-19-9Relevant articles and documents
Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium
Dietz, Jule-Philipp,Lucas, Tobias,Gro?, Jonathan,Seitel, Sebastian,Brauer, Jan,Ferenc, Dorota,Gupton, B. Frank,Opatz, Till
, p. 1898 - 1910 (2021/08/01)
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.
Practical Synthetic Method for the Preparation of Pyrone Diesters: An Efficient Synthetic Route for the Synthesis of Dolutegravir Sodium
Yasukata, Tatsuro,Masui, Moriyasu,Ikarashi, Fumiya,Okamoto, Kazuya,Kurita, Takanori,Nagai, Masahiko,Sugata, Yoshihide,Miyake, Naoki,Hara, Shinichiro,Adachi, You,Sumino, Yukihito
, p. 565 - 570 (2019/03/26)
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.
CONTINUES FLOW PROCESS FOR THE PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS - POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES AND INTERMEDIATES THEREOF
-
, (2019/09/04)
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).
