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Enavogliflozin, DWP-16001
Enavogliflozin, DWP-16001
(2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
CAS: 1415472-28-4
Chemical Formula: C24H27ClO6
Molecular Weight: 446.92
Elemental Analysis: C, 64.50; H, 6.09; Cl, 7.93; O, 21.48
Green Cross Corp INNOVATOR
Daewoong Pharmaceutical Co Ltd
Enavogliflozin is an antidiabetic (hypoglycemic).
Daewoong is investigating DWJ-304 , a sodium/glucose cotransporter 2 (SGLT-2) inhibitor, for treating type 2 diabetes. By February 2017, preclinical development was underway. Daewoong is developing DWP-16001 , presumed to be enavogliflozin, a SGLT-2 inhibitor, for treating type 2 diabetes. In September 2019, launch was expected in 2023.
PATENT
WO2012165914
DWP-16001 expire in EU states until June 2032 and US in November 2033.
PATENT
US 2014274918
PATENT
US2019169174
Paragraph 0305; 0340; 0347
H NMR (400 MHz, CD3OD) δ 7.02 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.59 (t, J=8.8 Hz, 2H), 4.11 (d, J=9.2 Hz, 1H), 3.96 (ABq, ΔvAB=19.0 Hz, JAB=15.2 Hz, 2H), 3.87-3.84 (m, 1H), 3.67-3.63 (m, 1H), 3.47-3.37 (m, 3H), 3.35-3.33 (m, 3H), 1.85-1.79 (m, 1H), 0.91-0.86 (m, 2H), 0.61-0.57 (m, 2H)
PATENT
WO2017217792 , claiming process for preparing diphenylmethane derivative.
1H NMR(400 MHz, CD 3OD) δ 7.02(d, J = 8.0 Hz, 2H), 6.92(d, J = 8.0 Hz, 2H), 6.81(s, 1H), 4.59(t, J = 8.8 Hz, 2H), 4.11(d, J = 9.2 Hz, 1H), 3.96(ABq, Δv AB = 19.0 Hz, J AB = 15.2 Hz, 2H), 3.87-3.84(m, 1H), 3.67-3.63(m, 1H), 3.47-3.37(m, 3H), 3.35-3.33(m, 3H), 1.85-1.79(m, 1H), 0.91-0.86(m, 2H), 0.61-0.57(m, 2H); [M+Na] + 469.
PATENT
WO-2020036382
The present invention relates to a method for producing an intermediate useful for the synthesis of a diphenylmethane derivative that can be used as a SGLT inhibitor. A method for synthesizing a compound of formula 7 according to the present invention has solved the problem of an existing synthesis process which requires an additional process due to the synthesis of Grignard reagent and the management of a related substance. In addition, the process can be simplified by minimizing the formation of the related substance and eliminating the need for reprocessing of reaction products, thereby becoming capable of maximizing a yield of a diphenylmethane derivative.
Process for preparing intermediates of SGLT inhibitor and their use for the synthesis of diphenyl-methane derivative, which can be used as SGLT inhibitors.

REFERENCES
1: Markiewicz M, Jungnickel C, Stolte S, Białk-Bielińska A, Kumirska J, Mrozik W. Ultimate biodegradability and ecotoxicity of orally administered antidiabetic drugs. J Hazard Mater. 2017 Jul 5;333:154-161. doi: 10.1016/j.jhazmat.2017.03.030. Epub 2017 Mar 16. PubMed PMID: 28349868.
2: Holt RI. Trials of new anti-diabetes agents. Diabet Med. 2017 Feb;34(2):147. doi: 10.1111/dme.13306. PubMed PMID: 28090726.
/////// DWJ-304, Daewoong Pharmaceutical, DWP-16001, SGLT-2 inhibitor, type 2 diabetes, KOREA, Enavogliflozin
ClC1=C2C(CCO2)=C([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)C=C1CC4=CC=C(C5CC5)C=C4
Tianagliflozin IND filed by Tianjin Institute of Pharmaceutical research
Tianagliflozin,
taigeliejing, 6-deoxydapagliflozin
Molecular Formula: | C21H25ClO5 |
---|---|
Molecular Weight: | 392.8732 g/mol |
IND Filing…Tianjin Institute of Pharmaceutical research
Tianjin Institute Of Pharmaceutical Research,
(3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methyloxane-3,4,5-triol
1–[4–Chloro–3–(4–ethoxybenzyl)phenyl]–1,6–dideoxy–β–d–glucopyranose
CAS N. 1461750-27-5
The structures of dapagliflozin and 6-deoxydapagliflozin (1)
,deletion of the 6-OH in the sugar moiety of dapagliflozin led to the discovery of a more potent SGLT2 inhibitor, 6-deoxydapagliflozin (1, ). In an in vitro assay, 1 was a more active SGLT2 inhibitor, with IC 50 = 0.67 nM against human SGLT2 (hSGLT2), as compared with 1.1 nM for dapagliflozin, leading to the identification of 1 as the most active SGLT2 inhibitor discovered so far in this field. Also in an in vivo assay, 1 also introduced more urinary glucose in a rat urinary glucose excretion test (UGE) and exhibited more potent blood glucose inhibitory activity in a rat oral glucose tolerance test (OGTT) than dapagliflozin.
Tianjin Institute Of Pharmaceutical Research,天津药物研究院
SPECTRAL DATA of Tianagliflozin
1 as a white solid (3.65 g, 93 %). R f = 0.35 (EtOAc);
m.p.: 148–149 °C;
1H NMR (400 MHz, DMSO-d 6): δ = 7.35 (d, 1H, J = 8.4 Hz), 7.25 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.4 Hz), 4.95 (d, 1H, J = 5.2 Hz, OH), 4.90 (d, 1H, J = 4.4 Hz, OH), 4.79 (d, 1H, J = 5.6 Hz, OH), 3.92–4.01 (m, 5H), 3.24–3.29 (m, 1H), 3.18–3.22 (m, 1H), 3.09–3.15 (m, 1H), 2.89–2.95 (m, 1H), 1.29 (t, 3H, J = 7.0 Hz, CH2 CH 3 ), 1.15 (d, 3H, J = 6.0 Hz, CHCH 3 ) ppm;
13C NMR (100 MHz, DMSO-d 6): δ = 156.85, 139.65, 137.82, 131.83, 131.16, 130.58, 129.52, 128.65, 127.14, 114.26, 80.71, 77.98, 75.77, 75.51, 74.81, 62.84, 37.55, 18.19, 14.62 ppm;
IR (KBr): v¯¯¯ = 3,564 (w), 3,385 (s), 2,981 (s), 2,899 (s), 2,861 (s), 1,613 (m), 1,512 (s), 1,477 (m), 1,247 (s), 1,102 (s), 1,045 (s), 1,012 (s) cm−1;
HR–MS: calcd for C21H29ClNO5 ([M + NH4]+) 410.1729, found 410.1724.
PATENT
CN 103864737
http://www.google.com/patents/CN103864737A?cl=en
PATENT
WO 2014094544
http://www.google.com/patents/WO2014094544A1?cl=en
-27-
1 D1 -6 Optionally, the step (7 ‘) is the step (7’) in place:
LS l- [4 – D (I- Dl- 6)
A.
(DMSO-d 6, 400 MHz), δ 7.35 (d, 1H, J = 8.0 Hz), 7.28 (d, 1H, J ‘. 2.0 Hz), 7.17 (dd, IH, / = 2.0 Hz and 8.4 Hz), 7.05 (d, 2H, J: 8.8 Hz), 6.79 (d, 2H, 8.8 Hz): 4.924,95 (m, 2H), 4,81 (d, IH, 6,0 Hz), 3.93- 3.99 (m, 5H), 3,85 (d, 1H, J = 10,4 Hz), 3,66 (dd, IH, 5,2 Hz and 11,6 Hz), 3.17-3,28 (m, 3H), 3.02-3.08 (m: IH), 1.28 (t, 3H, J = 7,0 Hz), 0,80 (s, 9H), -0.05 (s, 3H), -0.09 (s, 3H) .
PATENT
[0066] The added 100mL dried over anhydrous methanol 0. 5g of sodium metal, nitrogen at room temperature with stirring, until the sodium metal disappeared. Followed by addition of 5. 2g (10mmol) of compound 6, stirring was continued at room temperature for 3 hours. To the reaction system was added 5g strong acid cation exchange resin, stirred at room temperature overnight, the reaction mixture until pH = 7. The resin was removed by suction, and the filtrate evaporated to dryness on a rotary evaporator, the residue was further dried on a vacuum pump to give the product I-D1-6, as a white foamy solid.
PATENT
WO 2014139447
PATENT related
http://www.google.com/patents/WO2013044608A1?cl=en
http://link.springer.com/article/10.1007%2Fs40242-014-4043-9#/page-1
Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.
Abstract
A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.
http://www.ncbi.nlm.nih.gov/pubmed/25557661
Paper

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes
http://www.ingentaconnect.com/content/ben/mc/2014/00000010/00000003/art00009?crawler=true
CLIP
A facile synthesis of 6-deoxydapagliflozin
The synthetic route to the target compound 1 is shown in Scheme 3. The starting material methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-α–d-glucopyranoside (3) was prepared from commercially available methyl α–d-glucopyranoside (2) according to a known method [5, 6].
Iodide 3 was reductively deiodinated to give 4 in 91 % yield under hydrogenolytic conditions using 10 % Pd/C as catalyst in the presence of Et3N as base in THF/MeOH at room temperature.
when the iodide 3 was treated with Barton–McCombie reagent (n-Bu3SnH/AIBN) [7] in toluene at room temperature no reaction occurred; however, when the reaction was carried out at elevated temperatures, such as reflux, a complex mixture formed with only a trace amount (3 %, entry 1) of the desired product 4.
When the iodide 3 was treated with LiAlH4 in THF at 0 °C to room temperature, another complex mixture was produced with only a trace amount (2 %, entry 2) of 4.
When Pd(OH)2 was used as the hydrogenolysis catalyst instead of 10 % Pd/C, the desired 4 was indeed formed (14 %, entry 4), but most of the starting material was converted to a few more polar byproducts, which were believed to result from the cleavage of at least one of the benzyl groups.
pdf available
Monatshefte für Chemie – Chemical Monthly
December 2013, Volume 144, Issue 12, pp 1903-1910
////////IND Filing, SGLT-2 inhibitor, type 2 diabetes, Tianagliflozin, taigeliejing, 6-deoxydapagliflozin, 1461750-27-5
Clc1c(cc(cc1)C2[C@@H]([C@H]([C@@H]([C@H](O2)C)O)O)O)Cc3ccc(cc3)OCC