Janagliflozin

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Janagliflozin

WeightAverage: 460.95
Monoisotopic: 460.1652664

Chemical FormulaC25H29ClO6

China 2024, approvals 2024, Jilin Huisheng Biopharmaceutical Co, sihuan, SGLT2 inhibitors, Huiyoujing

Janagliflozin is an SGLT2 inhibitor developed by Sihuan Pharmaceutical.[1][2][3][4][5][6] It is approved in China for the treatment of type 2 diabetes.[7]

PAPER

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0042-1751524

(71) (a) Wu, F. US9315438B2, 2016. (b) Wu, F. EP2891654A1, 2014.

Initially, the two advanced intermediates were synthesized and then coupled under cryogenic conditions using nBuLi. The construction of 242 commences with the reaction of 5-bromo-2-chlorobenzoic acid (26c) with oxalyl chloride and a catalytic amount of DMF in DCM, yielding the acid chloride derivative 26c′. This intermediate is then subjected to Friedel–Crafts acylation with anisole to produce 240 in
71% yield. Subsequent reduction of 240 was carried out using boron trifluoride–diethyl etherate and triethylsilane in a DCM/acetonitrile mixture, leading to the formation of 241 in an excellent yield. Demethylation of compound 241 is accomplished using boron tribromide at low temperature, resulting in 242 with a yield of 97%. On the other hand, the synthesis of 245 involves two steps starting from commercially available cyclopent-3-en-1-ol (243). The Simmons Smith cyclopropanation of 243 is performed using a mixture of trifluoroacetic acid, diiodomethane, and diethylzinc in DCM, providing 244 with a yield of 48%. Compound 244 is then further treated with methanesulfonyl chloride to give the mesylated compound 245 in a yield of 68%. Subse quently, 4-(5-bromo-2-chlorobenzyl)phenol (242) is allowed to react with 245 in the presence of NMP, cesium carbonate, and BTEAC (benzyltriethylammonium chloride) to give 246. The next step involves a lithium–halogen exchange on
246 using n-butyllithium, with addition to 22 at –78 °C affording the hydroxy intermediate. Methylation of this hydroxy intermediate using methanesulfonic acid and methanol provides 247 in 98% yield. Reduction of 247 using borontrifluoride–diethyl etherate and triethylsilane at –78 °C furnishes 248. To achieve the desired isomer, all of the hydroxy groups of compound 248 were protected using acetic anhydride, DMAP, and pyridine in DCM at 0 °C to give the O-acylated compound 249. In the final step, 249 is hydrolyzed us ing lithium hydroxide monohydrate in a mixed solvent consisting of methanol, THF, and water to provide the desired compound janagliflozin (14) in a yield of 91%. This truncated synthetic route is protection-group-free, and is well suited for scale-up. The drawback of the synthetic route is
the late-stage enrichment of the desired isomer in the final product via acylated derivative 249. The poor isolated yield of 249 is not commercially favored due to low throughput and an increase in raw material and production costs.

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00017

SYN

https://www.sciencedirect.com/science/article/abs/pii/S022352342400223X

PAT

US9315438,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US142552820&_cid=P11-MEPJES-88258-1

Example 1

Preparation of (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Formula II)

(1) Preparation of 5-bromo-2-chlorobenzoyl chloride

      
      5-bromo-2-chlorobenzoic acid (270 g, 1.15 mol) was suspended in methylene chloride (2700 mL). To the resulting mixture was added N,N-dimethylformamide (1 mL), and then added dropwise oxalyl chloride (288 mL, 3.46 mol) at 0° C. After the completion of dropwise addition, the mixture was warmed up to 20° C. and reacted for 3 h. The reaction mixture became clear, and TLC (Thin layer chromatography) indicated the completion of reaction. The reaction mixture was evaporated by rotation at 30-35° C. to produce a product, which was directly used in the next reaction.

(2) Preparation of (5-bromo-2-chlorophenyl)(4-methoxyphenyl)methanone

    
      Anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in methylene chloride (2050 mL) under a nitrogen protection. To the resulting mixture was added anisole (125 mL, 1.15 mol) in one batch at −5° C. After stirring for 20 mins, to the mixture was added dropwise a solution of 5-bromo-2-chlorobenzoyl chloride in methylene chloride (300 mL). The resulting mixture was reacted at −5° C. for 3 h. TLC indicated the completion of reaction. To the reaction mixture was poured 2N hydrochloric acid. The resulting mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce a solid. To the solid was added ethanol (150 mL), and the resulting mixture was washed and starched for 30 mins and filtered. The filter cake was oven dried to produce 265 g of a product in a yield of 71%.

(3) Preparation of 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene

      (5-bromo-2-chlorophenyl)(4-methoxyphenyl)methanone (265 g, 0.81 mol) was dissolved in methylene chloride (515 mL) and acetonitrile (1030 mL). To the resulting mixture was added triethyl silane (352 mL, 2.22 mol). Then to the resulting mixture was added dropwise boron trifluoride-diethyl etherate (273 mL, 2.22 mol) at 0° C. under a nitrogen protection. After the completion of dropwise addition, the resulting mixture was stirred for 20 min, warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture were added methyl tert-butyl ether (1.5 L) and a saturated sodium bicarbonate solution (1.5 L). The mixture was stirred for 30 mins. The organic phase was separated off, washed with a saturated sodium bicarbonate solution for four times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce an oily substance. To the oily substance was added ethanol. The resulting mixture was stirred at room temperature for 30 mins and in an ice bath for 30 mins. A great quantity of solid was separated out and filtered. The filter cake was dried to produce 226 g of a product in a yield of 89%.

(4) Preparation of 4-(5-bromo-2-chlorobenzyl)phenol

      4-bromo-1-chloro-2-(4-methoxybenzyl)benzene (226 g, 0.73 mol) was dissolved in methylene chloride (2240 mL) under a nitrogen protection and in a protection from light. To the resulting mixture was slowly added dropwise a solution of boron tribromide (357 g, 1.42 mol) in methylene chloride (1416 mL) at −78° C. After the completion of dropwise addition, the reaction mixture was warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture was slowly added dropwise water in an ice-water bath. The methylene chloride phase was collected. The residual aqueous phase was extracted with methylene chloride (1 L) for two times. The organic phases were combined, washed with water for two times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 210 g of a product in a yield of 97%.

(5) Preparation of (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol

      
      Diethyl zinc (7.16 L, 7.14 mol) was added dropwise to methylene chloride (9 L) at 0° C. When the white fume disappeared after the completion of dropwise addition, to the resulting mixture was slowly added dropwise a solution of trifluoroacetic acid (816 g, 7.16 mol) in methylene chloride (1 L). After the completion of dropwise addition, the resulting mixture was stirred for 30 mins. To the mixture was added dropwise a solution of methylene iodide (1918 g, 7.14 mol) in methylene chloride (1 L). After the completion of dropwise addition, the resulting mixture was stirred for 30 mins. To the mixture was added dropwise a solution of cyclopent-3-en-1-ol (200 g, 2.38 mol) in methylene chloride (800 mL). After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and reacted for 30 mins. TLC indicated the completion of reaction. The reaction mixture was poured into a saturated ammonium chloride. After stirring for 10 mins, the mixture was separated into an organic phase and an aqueous phase. The aqueous phase was extracted with methylene chloride (2 L) for one time. The organic phase was washed with a saturated sodium sulphite, with a saturated sodium bicarbonate, and with a saturated sodium chloride, and dried over anhydrous sodium sulphate. The residue is purified with a column chromatography to produce 112 g of a product in a yield of 48%.

(6) Preparation of (1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl methanesulfonate

      
      (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol (112 g, 1.14 mol) was dissolved in methylene chloride (1250 mL) in an ice-water bath. To the resulting mixture was added triethylamine (174 g, 1.69 mol), and then slowly added dropwise methylsulfonyl chloride (197 g, 1.72 mol). After the completion of dropwise addition, the resulting mixture was reacted for 30 mins at 0° C. TLC indicated the completion of reaction. The reaction mixture was poured into water and separated into an organic phase and an aqueous phase. The organic phase was washed with a diluted hydrochloric acid for one time, with water for two times, and then with a saturated sodium chloride, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 138 g of a product in a yield of 68%.

(7) Preparation of (1R,3s,5S)-3-(4-(5-bromo-2-chlorobenzyl)phenyloxy)bicyclo[3.1.0]hexane

  
      (1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl methanesulfonate (138 g, 0.78 mol) was dissolved in N-methylpyrrolidone (2.1 L). To the resulting mixture was added 4-(5-bromo-2-chlorobenzyl)phenol (210 g, 0.71 mol), cesium carbonate (462 g, 1.42 mol) and benzyltriethylammonium chloride (5.46 g, 24 mmol). Then the resulting mixture was stirred for 10 mins at room temperature, warmed up to 50° C., and reacted overnight. TLC indicated the completion of reaction. To the reaction mixture was added water. Then the resulting mixture was extracted with a mixed solution of petroleum ether and methyl tert-butyl ether (petroleum ether:methyl tert-butyl ether=1:1) for two times. The organic phases were combined, washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride for two times, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was purified with a column chromatography (petroleum ether:ethyl acetate=50:1) to produce 135 g of the product in a yield of 50%.
      Formula: C 19H 18BrClO; Mw: 377.71
       1H-NMR (400 MHz, CDCl 3) δ: 7.28-7.21 (m, 3H), 7.07-7.05 (d, 2H), 6.82-6.78 (m, 2H), 4.42-4.35 (m, 1H), 3.98 (s, 2H), 2.36-2.31 (m, 2H), 1.96-1.90 (m, 2H), 1.40-1.33 (m, 2H), 0.47-0.44 (m, 1H), 0.07-0.02 (m, 1H).

(8) Preparation of (3R,4S,5R,6R)-3,4,5-tri((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one

      (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (85 g, 0.47 mol) was suspended in THF (tetrahydrofuran) (932 mL). To the resulting mixture was added N-methylmorpholine (405 mL, 4.78 mol). Then the resulting mixture was cooled to −5° C. under a nitrogen protection, and TMSCI (trimethylsilane chloride) (360 mL, 4.78 mol) was added dropwise thereto. After the completion of dropwise addition, the resulting mixture was stirred at room temperature for 1 h and at 35° C. for 5 hr. Then the mixture was stirred overnight while the temperature was maintained at 25° C. TLC indicated the completion of reaction. To the reaction mixture was added toluene (200 mL) and added dropwise water (1 L) in an ice-water bath. The organic phase was collected, washed with sodium dihydrogen phosphate for one time, with water for one time, and with a saturated sodium chloride solution for one time, dried and concentrated to produce 218 g of a product in a yield of 100%.

(9) Preparation of (3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol

      
      (1R,3s,5S)-3-(4-(5-bromo-2-chlorobenzyl)phenyloxy)bicyclo[3.1.0]hexane (135 g, 0.358 mol) was dissolved in tetrahydrofuran (813 mL) and toluene (813 mL) under a nitrogen protection. The resulting mixture was cooled to −78° C., and n-butyl lithium (194 mL, 0.465 mol) was added dropwise thereto. After the completion of dropwise addition, the reaction mixture was stirred for 2 hr, sucked out with an injector, and then injected to a solution of (3R,4S,5R,6R)-3,4,5-tri((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (218 g, 0.47 mol) in toluene (950 mL). The resulting mixture was stirred for 1 hr, and a solution of methylsulfonic acid (44.9 mL, 2.15 mol) in methanol (1.2 L) was added thereto. The mixture was stirred at −78° C. for 1 hr, warmed up to room temperature, and reacted overnight. TLC indicated the completion of reaction. The reaction mixture was quenched with a saturated sodium bicarbonate solution, and extracted with ethyl acetate (2 L). The organic phase was washed with water and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 173 g of a product in a yield of 98%.

(10) Preparation of (3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

      
      (3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (173 g, 0.352 mol) and triethyl silane (180 mL, 1.05 mol) were dissolved in methylene chloride (2 L) at −78° C. in a nitrogen protection. To the resulting mixture was slowly added dropwise boron trifluoride-diethyl etherate (134 mL, 1.05 mol). After the completion of dropwise addition, the mixture was reacted at −78° C. for 1 hr. The reaction mixture was slowly warmed up to room temperature and reacted for 1 hr. HPLC indicated the completion of reaction. To the reaction mixture was added dropwise a saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (1 L). The organic phase was washed with water and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 143 g of a product in a yield of 88%.

(11) Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

      (3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (143 g, 0.311 mol) was dissolved in methylene chloride (720 mL). To the resulting mixture were added pyridine (252 mL, 3.11 mol) and DMAP (4-dimethylaminopyridine) (1.9 g, 15.6 mmol), and then added dropwise acetic anhydride (292 mL, 3.11 mol) in an ice-water bath. The reaction mixture was stirred at room temperature for 3 hr, quenched with water, and extracted with ethyl acetate (1.5 L). The organic layer was washed with a diluted hydrochloric acid for three times, with a saturated sodium bicarbonate for one time, with water, and with a saturated sodium chloride, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was recrystallized with ethanol to produce 81 g of a product in a yield of 42%.

(12) Preparation of (2S,3R,4R,5 S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

      
      (2R,3R,4R /5 S, 6S)-2-(acetoxymethyl)-6-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (81 g, 0.129 mol) was dissolved in a mixed solvent of tetrahydrofuran (313 mL), methanol (470 mL) and water (156 mL). To the resulting mixture was added lithium hydroxide monohydrate (6.32 g, 150 mmol). The mixture was stirred at room temperature overnight. TLC indicated the completion of reaction. The solvent was removed from the reaction mixture by rotary evaporation. The residual reaction mixture was dissolved with ethyl acetate (400 mL). The organic phase was washed with an aqueous saturated sodium chloride solution, with an aqueous KHSO 4 solution, and with water twice, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was purified with C18 reverse phase preparative chromatography to produce 54.2 g of a final product in a yield of 91%.
      Formula: C 25H 29ClO 6 Mw: 460.95 LC-MS (m/z): 478.3 [M+NH 4] +
       1H-NMR (400 MHz, MeOD) δ: 7.35-7.26 (m, 3H), 7.08-7.06 (d, 2H), 6.76-6.74 (d, 2H), 4.45-4.41 (m, 1H), 4.10-4.00 (m, 3H), 3.89-3.88 (d, 1H), 3.71-3.69 (m, 1H), 3.45-3.38 (m, 3H), 3.31-3.26 (m, 1H), 2.34-2.29 (m, 2H), 1.87-1.81 (m, 2H), 1.37-1.33 (m, 2H), 0.43-0.42 (m, 1H), 0.11-0.10 (m, 1H).

PAT

EP2891654

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP142501978&_cid=P20-MEQIAN-96633-1

[0027]  The compound represented by formula (II) as defined hereinbefore, lab-made, its chemical name and preparation process are described in the following Example 1.

Reference compound 1: Compound 4 as described in the PCT application WO2013/000275A1, lab-made (with reference to the PCT application WO2013/000275A1), its structure is as follows:


Compound 4, i.e. the compound represented by formula (I).

Reference compound 2: Compound 22 as described in the PCT application WO2013/000275A1, lab-made (with reference to the PCT application WO2013/000275A1), its structure is as follows:


Compound 22.

(12) Preparation of

[0057]  (2 S,3 R,4 R,5 S,6 R)-2-(3-(4-(((1 R,3 s,5 S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorophenyl)-6-(hydr oxymethyl)tetrahydro-2 H-pyran-3,4,5-triol

[0058]  (2 R,3 R,4 R,5 S,6 S)-2-(acetoxymethyl)-6-(3-(4-(((1 R,3 s,5 S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlo rophenyl)tetrahydro-2 H-pyran-3,4,5-triyl triacetate (81g, 0.129mol) was dissolved in a mixed solvent of tetrahydrofuran (313mL), methanol (470mL) and water (156mL). To the resulting mixture was added lithium hydroxide monohydrate (6.32g, 150mmol). The mixture was stirred at room temperature overnight. TLC indicated the completion of reaction. The solvent was removed from the reaction mixture by rotary evaporation. The residual reaction mixture was dissolved with ethyl acetate (400mL). The organic phase was washed with an aqueous saturated sodium chloride solution, with an aqueous KHSO 4 solution, and with water twice, dried over anhydrous sodium sulphate, and evaporated by rotation. The residue was purified with C18 reverse phase preparative chromatography to produce 54.2g of a final product in a yield of 91%.
Formula: C 25H 29ClO 6 Mw: 460.95 LC-MS( m/ z): 478.3 [M+NH 4] +
1H-NMR (400MHz, MeOD) δ: 7.35-7.26 (m, 3H), 7.08-7.06 (d, 2H), 6.76-6.74 (d, 2H), 4.45-4.41 (m, 1H), 4.10-4.00 (m, 3H), 3.89-3.88 (d, 1H), 3.71-3.69 (m, 1H), 3.45-3.38 (m, 3H), 3.31-3.26 (m, 1H), 2.34-2.29 (m, 2H), 1.87-1.81 (m, 2H), 1.37-1.33 (m, 2H), 0.43-0.42 (m, 1H), 0.11-0.10 (m, 1H).

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Janagliflozin, engineered by Jilin Huisheng Biopharmaceutical Co., Ltd., a subsidiary under the umbrella of Sihuan Pharmaceutical Holdings Group, falls within the category of oral sodium-glucose co-transporter 2(SGLT2) inhibitors. This agent has been specifically designed with the aim of optimizing glycemic regulation in the adult population grappling with type 2 diabetes mellitus (T2DM) [54]. It is marketed under the brand name Huiyoujing. In 2024, the NMPA gave its approval for Janagliflozin, indicated for adult patients with T2DM, where it can be employed either as a standalone treatment (monotherapy) or in combination with metformin to optimize blood glucose regulation [55]. The clinical effectiveness of Janagliflozin was substantiated through a Phase III clinical trial (NCT03811548). This trial specifically assessed its application as a monotherapy in Chinese patients suffering from T2DM
whose blood glucose was not well – managed via diet and exercise alone. The findings of the study indicated notable decreases in glycated hemoglobin levels. Concurrently, improvements were observed in both body weight and blood pressure. Collectively, these outcomes serve as evidence of the drug’s ability to enhance glycemic regulation [56]. Regarding safety, Janagliflozin was generally well-tolerated. In line with the well-established safety characteristics of SGLT2 inhibitors, the frequently encountered adverse events associated with this treatment were urinary tract infections and genital mycotic infections. No serious adverse events were reported during the trial [57].
The synthesis of Janagliflozin, depicted in Scheme 13, commences with the acylation of 5-bromo-2-chlorobenzoic acid (Jana-001) using oxalyl chloride, yielding the acyl chloride intermediate Jana-002 [58]. Friedel-Crafts acylation of Jana-002 with anisole (Jana-003) affords ketone Jana-004. Subsequent reduction of the carbonyl group in Jana-004 produces Jana-005. Demethylation of Jana-005 with BBr3
generates phenol Jana-006, which undergoes substitution with intermediate Jana-007 to form ether Jana-008. Addition of gluconolactone (Jana-009) to Jana-008 affords Jana-010, where concurrent TMS
deprotection during etherification yields Jana-011. Reduction of Jana-011 using Et3SiH/BF3.ET2Oproduces Jana-012which is sequentially esterified with Ac2O , and hydrolyzed under LiOH conditions, ultimately yielding Janagliflozin

[54] L. Gao, Z. Cheng, B. Su, X. Su, W. Song, Y. Guo, L. Liao, X. Chen, J. Li, X. Tan, F. Xu,
S. Pang, K. Wang, J. Ye, Y. Wang, L. Chen, J. Sun, L. Ji, Efficacy and safety of
janagliflozin as add-on therapy to metformin in Chinese patients with type 2
diabetes inadequately controlled with metformin alone: a multicentre,
randomized, double-blind, placebo-controlled, phase 3 trial, Diabetes Obes Metab
25 (2023) 785–795.
[55] L. Ji, X. Jiang, Q. Hao, Z. Cheng, K. Wang, S. Pang, M. Liu, Y. Guo, X. Chen, X. Su,
T. Ning, J. Liu, F. Bian, Y. Li, Z. Zhang, W. Song, J. Sun, Efficacy and safety of
janagliflozin monotherapy in Chinese patients with type 2 diabetes mellitus
inadequately controlled on diet and exercise: a multicentre, randomized, double-
blind, placebo-controlled, phase 3 trial, Diabetes Obes Metab 25 (2023)
1229–1240.
[56] L. Song, X. Wang, J. Sun, X. Hu, H. Li, P. Hu, D. Liu, A model-informed approach to
accelerate the clinical development of janagliflozin, an innovative SGLT2 inhibitor,
Clin. Pharmacokinet. 62 (2023) 505–518.
[57] Canagliflozin, Drugs and Lactation Database (Lactmed®), National Institute of
Child Health and Human Development, Bethesda (MD), 2006.
[58] F. Wu, Optically Pure benzyl-4-chlorophenyl-C-glucoside Derivatives as SGLT
Inhibitors (Diabetes Mellitus), 2015. EP2891654.

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References

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  3.  Zhao, Hengli; Wei, Yilin; He, Kun; Zhao, Xiaoyu; Mu, Hongli; Wen, Qing (December 2022). “Prediction of janagliflozin pharmacokinetics in type 2 diabetes mellitus patients with liver cirrhosis or renal impairment using a physiologically based pharmacokinetic model”. European Journal of Pharmaceutical Sciences. 179: 106298. doi:10.1016/j.ejps.2022.106298. PMID 36162752. S2CID 252505056.
  4.  Zhao, Hengli; Zhao, Zhirui; He, Kun; Mi, Nianrong; Lou, Kai; Dong, Xiaolin; Zhang, Wenyu; Sun, Jingfang; Hu, Xinyu; Pang, Shuguang; Cheng, Hong; Wen, Qing (August 2023). “Pharmacokinetics, Pharmacodynamics and Safety of Janagliflozin in Chinese Type 2 Diabetes Mellitus Patients with Renal Impairment”. Clinical Pharmacokinetics. 62 (8): 1093–1103. doi:10.1007/s40262-023-01256-0. PMID 37284974. S2CID 259097798.
  5.  Gao, Leili; Cheng, Zhifeng; Su, Benli; Su, Xiuhai; Song, Weihong; Guo, Yushan; Liao, Lin; Chen, Xiaowen; Li, Jiarui; Tan, Xingrong; Xu, Fangjiang; Pang, Shuguang; Wang, Kun; Ye, Jun; Wang, Yuan; Chen, Lili; Sun, Jingfang; Ji, Linong (March 2023). “Efficacy and safety of janagliflozin as add‐on therapy to metformin in Chinese patients with type 2 diabetes inadequately controlled with metformin alone: A multicentre, randomized, double‐blind, placebo‐controlled, phase 3 trial”. Diabetes, Obesity and Metabolism. 25 (3): 785–795. doi:10.1111/dom.14926. PMID 36433709. S2CID 253967474.
  6.  Ji, Linong; Jiang, Xiaozhen; Hao, Qingshun; Cheng, Zhifeng; Wang, Kun; Pang, Shuguang; Liu, Meiying; Guo, Yushan; Chen, Xiaowen; Su, Xiuhai; Ning, Tao; Liu, Jie; Bian, Fang; Li, Yulan; Zhang, Zhinong; Song, Weihong; Sun, Jingfang (May 2023). “Efficacy and safety of janagliflozin monotherapy in Chinese patients with type 2 diabetes mellitus inadequately controlled on diet and exercise: A multicentre, randomized, double‐blind, placebo‐controlled, Phase 3 trial”. Diabetes, Obesity and Metabolism. 25 (5): 1229–1240. doi:10.1111/dom.14971. PMID 36594724. S2CID 255474211.
  7.  “NMPA approves China’s second homegrown SGLT2 inhibitor janagliflozin”. bioworld.com. January 23, 2024.
Legal status
Legal statusRx in China; investigational elsewhere
Identifiers
IUPAC name
CAS Number1800115-22-3
PubChem CID91820686
DrugBankDB16209
UNIIWK4RT85HCA
Chemical and physical data
FormulaC25H29ClO6
Molar mass460.95 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

///////////Janagliflozin, china 2024, approvals 2024, Jilin Huisheng Biopharmaceutical Co, sihuan, SGLT2 inhibitors, Huiyoujing, WK4RT85HCA, XZP 5695, UNII-WK4RT85HCA, 1800115-22-3

SYN

SYNTHESIS 2024, 56, 906–943

synthesis of janagliflozin (14) was achieved through an eleven-step process in an overall yield of 3% (Scheme 45).71 Initially, the two advanced intermediates were synthesized and then coupled under cryogenic conditions using nBuLi. The construction of 242 commences with the reaction of 5-bromo-2-chlorobenzoic acid (26c) with oxalyl chloride and a catalytic amount of DMF in DCM, yielding the acid
chloride derivative 26c′. This intermediate is then subjected to Friedel–Crafts acylation with anisole to produce 240 in 71% yield. Subsequent reduction of 240 was carried out using boron trifluoride–diethyl etherate and triethylsilane in a DCM/acetonitrile mixture, leading to the formation of 241 in an excellent yield. Demethylation of compound 241 is accomplished using boron tribromide at low temperature, re
sulting in 242 with a yield of 97%. On the other hand, the synthesis of 245 involves two steps starting from commercially available cyclopent-3-en-1-ol (243). The Simmons Smith cyclopropanation of 243 is performed using a mixture of trifluoroacetic acid, diiodomethane, and diethylzinc in DCM, providing 244 with a yield of 48%. Compound 244 is then further treated with methanesulfonyl chloride to
give the mesylated compound 245 in a yield of 68%. Subsequently, 4-(5-bromo-2-chlorobenzyl)phenol (242) is allowed to react with 245 in the presence of NMP, cesium carbonate, and BTEAC (benzyltriethylammonium chloride) to give 246. The next step involves a lithium–halogen exchange on
246 using n-butyllithium, with addition to 22 at –78 °C affording the hydroxy intermediate. Methylation of this hydroxy intermediate using methanesulfonic acid and methanol provides 247 in 98% yield. Reduction of 247 using boron trifluoride–diethyl etherate and triethylsilane at –78 °C furnishes 248. To achieve the desired isomer, all of the hydroxy groups of compound 248 were protected using acetic anhydride, DMAP, and pyridine in DCM at 0 °C to give the O-acylated compound 249. In the final step, 249 is hydrolyzed us ing lithium hydroxide monohydrate in a mixed solvent consisting of methanol, THF, and water to provide the desired compound janagliflozin (14) in a yield of 91%. This truncated synthetic route is protection-group-free, and is well suited for scale-up. The drawback of the synthetic route is
the late-stage enrichment of the desired isomer in the final product via acylated derivative 249. The poor isolated yield of 249 is not commercially favored due to low throughput and an increase in raw material and production costs

(71) (a) Wu, F. US9315438B2, 2016. (b) Wu, F. EP2891654A1, 2014.

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