2014
DOI: 10.1021/op400289z
|View full text |Cite
|
Sign up to set email alerts
|

Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin

Abstract: The development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, ertugliflozin, for the treatment of type-2 diabetes is described. Highlights of the chemistry are a concise, four-step synthesis of a structurally complex API from known intermediate 4 via persilylation–selective monodesilylation, primary alcohol oxidation, aldol-crossed-Cannizzaro reaction, and solid-phase acid-catalyzed bicyclic ketal formation. The final API was isolated as the l-pyroglutamic acid… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
2
1
1
1

Citation Types

0
26
0

Year Published

2015
2015
2021
2021

Publication Types

Select...
5
3
1

Relationship

0
9

Authors

Journals

citations
Cited by 41 publications
(27 citation statements)
references
References 15 publications
0
26
0
Order By: Relevance
“… , This general strategy involved the preparation of Weinreb amide 19 , which was synthesized in 10 steps from d -glucose (Scheme ). ,, In their synthesis, allyl-protected intermediate 88 was prepared through a four-step process . These steps included condensation of d -glucose with allyl alcohol followed by the protection of the remaining free hydroxy groups using trityl and benzyl chloride and subsequent removal of the O -trityl group in an acidic medium. Other strategies based on allylation of the polyacetylated d -glucose catalyst with ZnCl 2 followed by protection and deprotection were also employed. , Thus, Swern oxidation of primary alcohol 88 generated the aldehyde precursor, which simultaneously underwent aldol condensation and Canizzaro reduction with formaldehyde to give tetrasubstituted intermediate 89 . , Lactol 92 was then prepared by protection of 89 with p -methoxybenzyl bromide (PMBBr) in the presence of NaH in DMF followed by removal of the allyl moiety by PdCl 2 .…”
Section: Synthesis Of Gliflozinsmentioning
confidence: 99%
See 1 more Smart Citation
“… , This general strategy involved the preparation of Weinreb amide 19 , which was synthesized in 10 steps from d -glucose (Scheme ). ,, In their synthesis, allyl-protected intermediate 88 was prepared through a four-step process . These steps included condensation of d -glucose with allyl alcohol followed by the protection of the remaining free hydroxy groups using trityl and benzyl chloride and subsequent removal of the O -trityl group in an acidic medium. Other strategies based on allylation of the polyacetylated d -glucose catalyst with ZnCl 2 followed by protection and deprotection were also employed. , Thus, Swern oxidation of primary alcohol 88 generated the aldehyde precursor, which simultaneously underwent aldol condensation and Canizzaro reduction with formaldehyde to give tetrasubstituted intermediate 89 . , Lactol 92 was then prepared by protection of 89 with p -methoxybenzyl bromide (PMBBr) in the presence of NaH in DMF followed by removal of the allyl moiety by PdCl 2 .…”
Section: Synthesis Of Gliflozinsmentioning
confidence: 99%
“…To overcome this problem, the same group of authors developed an alternative approach for the synthesis of 9 and its cocrystalline complex 118 (Scheme ). The new strategy was based on the stereoselective arylation of 12 described for other SGLT2 inhibitors. , The five-step process afforded the final product in 26% overall yield. As a first step, intermediate 114 was prepared through arylation of 12 with 84 followed by removal of the silyl ether protecting group using methanesulfonic acid (MsOH), affording 114 in 71% yield with >98% chemical purity.…”
Section: Synthesis Of Gliflozinsmentioning
confidence: 99%
“…Some other promising cocrystals that are under late-stage development are: a drug-drug cocrystal containing a non-steroidal anti-inflammatory drug, celcoxib, and an opiod drug, tramadol, which has superior analgesic efficacy compared to comparable doses of tramadol, 57 and a cocrystal of an anti-diabetic drug ertugliflozin with 5-oxo-proline. 58 …”
Section: Marketability Of Cocrystalsmentioning
confidence: 99%
“…Further, 39 is utilized to produce diol, 40 using TBAF, further substitution at C-5 of the glycoside moiety was incorporated using formaldehyde and K 2 CO 3 , to give 41. In the next step, formation of the oxetane take place, which on further treatment afforded the desired product (57). SAR study of the molecule disclosed the role of 8membered ring system in the glycoside moiety, which improves the metabolic stability.…”
Section: Ertugliflozinmentioning
confidence: 99%