EDOXABAN

 

Edoxaban, DU-176b

SYN..........http://newdrugapprovals.org/2015/01/13/daiichi-sankyo-receives-fda-approval-for-anti-clotting-drug-savaysa-edoxaban/

1H NMR PREDICTION

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13 C NMR

http://www.google.com/patents/EP2589590A1?cl=en

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(Reference Example 6) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (production method described in the pamphlet of International Publication No. WO 2007/032498)

• 
• Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2,S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (5) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyrzdine-2-carboxylic acid hydrochloride (8) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (X) (103.2 g). 
• 
  
• 1H-NMR (CDCl3) δ : 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J = 15.4 Hz), 3.75 (1H, d, J = 15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J = 8.8, 0.6 Hz), 7. 68 (1H, dd, J = 8.8, 2.4 Hz), 8.03 (1H, d, J = 7.8 Hz), 8.16 (1H, dd, J = 8.8, 0.6 Hz), 8.30 (1H, dd, J = 2. 4, 0.6 Hz), 9.72 (1H, s). 
• 
  
• MS (ESI) m/z: 548 (M+H)+.

Molecular Formula		C24H30ClN7O4S.C7H7HSO3
Molecular Weight		720.26
CAS Registry Number		480449-71-6 (912273-65-5)

TOSYLATE

(Reference Example 7) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono-p-toluenesulfonate monohydrate (X-a) (production method described in the pamphlet of International Publication No. WO 2007/032498)

• 
• N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (6.2 g) was dissolved in methylene chloride (120 ml). To the solution, a 1 mol/L solution of p-toluenesulfonic acid in ethanol (11.28 ml) was added, and the solvent was distilled off. To the residue, 15% hydrous ethanol (95 ml) was added, and the mixture was dissolved by stirring at 60°C. Then, the mixture was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain the title compound (X-a) (7.4 g).
  
  
• 
  
• 1H-NMR (DMSO-d6) δ : 1. 45-1. 54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J = 7.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 1.8 Hz), 8.46 (1H, t, J = 1.8 Hz), 8.75 (1H, d, J = 6.9 Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s).
  MS (ESI) m/z: 548 (M+H)+.
  Anal.: C24H30ClN7O4S·C7H8O3S·H2O
  Theoretical: C; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69.
  Found: C; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79. mp (dec.): 245-248°C.

1H NMR PREDICTION
CAS NO. 1229194-11-9, N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate H-NMR spectral analysis

13 CNMR PREDICTION
CAS NO. 1229194-11-9, N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide,4-methylbenzenesulfonic acid,hydrate C-NMR spectral analysis

SYN..........http://newdrugapprovals.org/2015/01/13/daiichi-sankyo-receives-fda-approval-for-anti-clotting-drug-savaysa-edoxaban/

..................

WO2015125710

　(Example 11)　N ¹ - (5-Chloro-2-yl) -N ² - [(1S, 2R, 4S)-4-(dimethylcarbamoyl) -2 - {[(5-methyl-4,5 , 6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl] Etanjiamido (X) [Production method via Compound (1-p2)]

[0137]

　In 10 mL test tube, compound (5-ms) (the compound of Reference Example 8) (100 mg, 0.216 mmol), Compound (1-p2) (81.4 mg, 0.216 mmol), K ₃ PO ₄ (91.7 mg, 0.432 mmol) and DMF (1 mL) was added, and the mixture was stirred at room temperature conditions for 3 hours. H To the reaction mixture ₂ O (2 mL) was added and the resulting slurry was stirred at room temperature overnight, the solid was filtered. The resulting solid H ₂ was washed with O (1 mL), was obtained by drying under reduced pressure the title compound (110.0 mg, 92.9%) as a solid.

[0138]

¹ H-NMR (500 Hz, CDCl ₃ ) delta: 9.72 (s, 1H), 8.30 (dd, 1H, J = 2.5, 0.5 Hz), 8.17 (dd, 1H, J = 9.0, 0.5 Hz), 8.03 (D , 1H, J = 8.5 Hz), 7.68 (dd, 1H, J = 9.0, 2.5 Hz), 7.39 (d, 1H, J = 8.5 Hz), 4.70-4.67 (m, 1H), 4.13-4.09 (m, 1H), 3.73 (d, 1H, J = 16.0 Hz), 3.70 (d, 1H, J = 16.0 Hz), 3.06 (s, 3H), 2.96-2.93 (m, 2H), 2.95 (s, 3H), 2.89-2.79 (m, 3H), 2.52 (s, 3H), 2.14-2.06 (m, 3H), 1.96-1.90 (m, 1H), 1.84-1.78 (m, 1H), 1.69-1.62 (m, 1H ).

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Location of Khajuraho Group of Monuments in India.

Location in Madhya Pradesh

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