NMR DATA.....LEARN FROM COCK

Cock says use the above scheme to understand from basics the 1H NMR, 13C NMR, IR ETC, the below data will help you to systematically understand the signals ...happy learning online

Starting material is shown/described below




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13 C NMR

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1H NMR




START THE EXERCISE OF LEARNING..............................

1-(4-Nitrophenyl)piperidin-2-one (11)^[ 7 ]

A solution of 5-chloropentanoyl chloride (12.9 mL, 15.50 g, 0.10 mol) in tetrahydrofuran (THF, 20 mL) was added below 5 °C to a solution of 4-nitroaniline (11.05 g, 0.08 mol) and triethylamine (22.5 mL, 0.16 mol) in THF (50 mL). The mixture was stirred at room temperature under N₂ for 5 h. Potassium tert-butoxide (24.70 g, 0.22 mol) was added to the reaction solution in batches below 5 °C during 30 min and then stirred at room temperature for 2 h. The suspension was concentrated to dryness and redissolved in ethyl acetate (100 mL) and water (100 mL) to separate the organic phase. The aqueous phase was extracted with ethyl acetate (2 × 80 mL) and washed with water (2 × 80 mL) and brine (80 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated completely to get a yellow solid. The recrystallization of the crude product from ethyl acetate afforded 11 as a pale yellow solid. Yield: 15.13 g, 86%;

 IGNORE ABOVE SYNTHETIC SCHEME AND TRY TO UNDERSTAND THE SIGNALS

mp 97–99 °C; 

IR (KBr, cm⁻¹): 3015 and 2958 (C-H aliphatic), 1656 (C˭O stretching), 1520 (aromatic C˭C), 1477, 1343 (N˭O stretching), 1308 and 1168 (C-N stretching), 860 and 698 (Ar-H aromatic bending); 

¹H NMR (500 MHz, CDCl₃, ppm),  
δ: 8.25 (d, J = 8.8 Hz, 2H), aromatic H ortho to nitro
7.50 (d, J = 8.8 Hz, 2H), 
3.73 (t, J = 5.8 Hz, 2H), 
2.62 (t, J = 6.5 Hz, 2H), 
1.96–2.01 (m, 4H); 

¹³C NMR (125 MHz, CDCl₃, ppm), δ: 170.3, 150.0, 145.2, 125.9 (2C), 124.3 (2C), 50.9, 33.1, 23.4, 21.2; 


MS/EI m/z = 220.1 (M⁺).

 COCK WILL TEACH YOU

3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (12)^[ 7 ]

Phosphorus pentachloride (18.7 g, 0.09 mol) was slowly added to a solution of 11 (6.6 g, 0.03 mol) in chloroform (40 mL) at room temperature. The resulting mixture was heated to reflux for 3 h, poured into ice water, and extracted with chloroform (3 × 30 mL). The combined organic phase was washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The residue was dissolved in morpholine (30 mL) and refluxed for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting solid was redissolved in water, and the precipitate was filtered. The recrystallization of the filter cake from ethyl acetate afforded 12 as a yellow solid. Yield: 7.08 g, 78%; 

mp 158–160 °C; 

IR (KBr, cm⁻¹): 2814 (C-H aliphatic), 1673 (C˭O stretching), 1626 (aliphatic C˭C), 1591 and 1510 (aromatic C˭C), 1487 (N˭O stretching), 1350 (C-N stretching), 1112 (C-O stretching), 835 and 783 (Ar-H aromatic bending);

 ¹H NMR (500 MHz, CDCl₃, ppm), δ: 8.25 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.9 Hz, 2H), 5.80 (t, J = 4.1 Hz, 1H), 3.84–4.01 (m, 6H), 2.83–2.96 (m, 4H), 2.54–2.68 (m, 2H);

 ¹³C NMR (125 MHz, CDCl₃, ppm), δ: 161.3, 148.4, 144.6, 143.5, 124.6 (2C), 124.1 (2C), 115.7, 66.7 (2C), 50.5 (2C), 48.3, 23.3; 

MS/EI m/z = 303.1 (M⁺).

 COCK WILL TEACH YOU

1-(4-Aminophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one (13)

A solution of sodium sulfide nonahydrate (9.60 g, 0.04 mol) in water (20 mL) was added to a solution of 12 (6.07 g, 0.02 mol) in ethanol (60 mL). The mixture was heated to 50 °C and stirred for 4 h, cooled to room temperature, and concentrated in vacuo. The residue was added to ethyl acetate (60 mL), heated to boiling, and filtered. The filtrate was concentrated in vacuo to dryness to yield 13 as a pale yellow solid. Yield: 4.92 g, 90%; 

mp 180–182 °C; 

IR (KBr, cm⁻¹): 3428 and 3350 (N-H stretching), 2811 (C-H aliphatic), 1656 (C˭O stretching), 1610 (aliphatic C˭C), 1519 and 1444 (aromatic C˭C), 1260 (C-N stretching), 1131 and 1117 (C-O stretching), 765 and 748 (Ar-H aromatic bending);

 ¹H NMR (500 MHz, CDCl₃, ppm), δ: 7.09 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.52–5.70 (m, 1H), 3.75–3.90 (m, 4H), 3.53–3.71 (m, 4H), 2.83–3.10 (m, 4H), 2.42–2.59 (m, 2H);

¹³C NMR (125 MHz, DMSO-d ₆, ppm), δ: 160.6, 146.7, 143.1, 131.9, 126.4 (2C), 113.7, 113.5 (2C), 65.9 (2C), 49.9 (2C), 48.9, 22.9;

 MS/EI m/z = 273.2 (M⁺). HRMS/EI calcd. for C₁₅H₁₉N₃O₂: 273.1477; found: 273.1468.

COCK TEACHES

3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one (4)^[ 6 ]

A solution of 5-chloropentanoyl chloride (1.6 mL, 1.94 g, 12.5 mmol) in THF (10 mL) was added to a solution of 13 (2.73 g, 10 mmol) and triethylamine (2.8 mL, 20 mmol) in THF (75 mL) below 5 °C. The mixture was stirred at 50 °C under N₂ for 2 h. Potassium tert-butoxide (3.37 g, 30 mmol) was added to the reaction solution in batches below 5 °C during 30 min and then stirred at 50 °C for 8 h. The suspension was cooled to room temperature and concentrated in vacuo to dryness. The residue was dissolved in water, stirred, and then filtered. The filter cake was washed with water and dried to afford 4 as a white solid. Yield: 3.02 g, 85%; 

mp 204–206 °C;


IR (KBr, cm⁻¹): 2965, 2852 and 2803 (C-H aliphatic), 1646 (C˭O stretching), 1616 (aliphatic C˭C), 1514 and 1463 (aromatic C˭C), 1262 (C-N stretching), 1114, 1070 and 1050 (C-O stretching), 835 and 783 (Ar-H aromatic bending);


¹H NMR (500 MHz, CDCl₃, ppm), δ: 7.35 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.66 (t, J = 4.3 Hz, 1H), 3.78–3.86 (m, 6H), 3.60–3.65 (m, 2H), 2.82–2.90 (m, 4H), 2.43–2.59 (m, 2H), 2.24–2.41 (m, 2H), 1.93–2.01 (m, 4H);

¹³C NMR (125 MHz, CDCl_3, ppm), δ: 170.8, 162.1, 144.3, 141.7, 141.5, 127.3(2C), 126.4(2C), 115.1, 67.4(2C), 52.3, 51.1(2C), 49.2, 33.5, 24.2, 24.0, 22.1;

MS/EI m/z = 355.2 (M⁺). HRMS/EI calcd. for C₂₀H₂₅N₃O₃: 355.1896; found: 355.1906.





HE TAUGHT YOU STEPWISE

(Z)-Ethyl 2-Chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (3)^[ 4 , 11–13 ^]

Hydrochloric acid (35–36%, 6 mL, 60 mmol) was added to a solution of 4-methoxyaniline (2.46 g, 20 mmol) in water (12 mL) at −5 to 0°C. A solution of sodium nitrite (1.66 g, 24 mmol) in water (8 mL) was added to the mixture dropwise below 0 °C. Then, the reaction solution was stirred for 30 min at 0 °C, followed by the addition of sodium acetate (3.28 g, 40 mmol) until pH 5–6. After that, a solution of ethyl 2-chloroacetoacetate (2.8 mL, 3.28 g, 20 mol) in methanol (30 mL) was added dropwise to the reaction mixture at 0 to 5 °C. The resulting solution was stirred at room temperature for 4 h. The solution was removed from the mixture in vacuo, and the residue was dissolved in water (10 mL) and ethyl acetate (20 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic phase was washed with water (2 × 10 mL) and brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtrated, and concentrated thoroughly. The recrystallization of the crude product from ethyl acetate afforded 3 as a pale yellow solid. Yield: 3.94 g, 77%; 

mp 106-109 °C;

IR (KBr, cm⁻¹): 3465 and 3257 (N-H stretching), 2999 and 2933 (C-H aliphatic), 1709 (C˭O stretching), 1519 and 1498 (aromatic C˭C), 1298 and 1226 (C-N stretching), 1169 and 1083 (C-O stretching), 820 and 745 (Ar-H aromatic bending); 

¹H NMR (500 MHz, CDCl₃, ppm), δ: 8.27 (s, 1H), 7.17 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H);

 ¹³C NMR (125 MHz, CDCl₃, ppm), δ: 159.8, 155.9, 135.4, 115.8 (2C), 115.0, 114.8 (2C), 62.6, 55.6, 14.3;

 MS/EI m/z = 256.1(M⁺).

NMR IS EASY

Ethyl 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (2)^[ 7 ]

Compound 4 (1.42 g, 4.0 mmol), triethylamine (1.7 mL, 12 mmol), and potassium iodide (0.064 g, 0.4 mmol) ware added to a solution of 3 (1.13 g, 4.4 mmol) in ethyl acetate (40 mL) at room temperature. The mixture was stirred for 6 h under reflux and then cooled to 0 °C. The resulting mixture was added dropwise with 4.0 N hydrochloric acid (5 mL, 20 mmol) and stirred at room temperature for 2 h. Thereafter, water (10 mL) was added to the mixture to separate the organic layer. The aqueous layer was extrated with ethyl acetate (3 × 10 mL), and then the combined organic extracts were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. Recrystallization of the residue from ethyl acetate and drying in vacuo afforded 2 as a pale yellow solid. Yield: 1.46 g, 75%; 

mp 120–124 °C; 

IR (KBr, cm⁻¹): 2936 and 2873 (C-H aliphatic), 1711 (C˭N stretching), 1658 (C˭O stretching), 1609 (aliphatic C˭C), 1558, 1513, 1482 and 1460 (aromatic C˭C), 1325, 1302 and 1254 (C-N stretching), 1144, 1088 and 1027 (C-O stretching), 833, 802 and 765 (Ar-H aromatic bending); 

¹H NMR (500 MHz, CDCl₃, ppm), δ: 7.49 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.48 (q, J = 7.0 Hz, 2H), 4.15 (t, J = 3.2 Hz, 2H), 3.82 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 3.33 (t, J = 6.8 Hz, 2H), 2.57 (t,J = 5.6 Hz, 2H), 1.94–2.00 (m, 4H), 1.45 (t, J = 7.0 Hz, 3H); 

¹³C NMR (125 MHz, CDCl₃, ppm), δ: 170.8, 162.8, 160.5, 157.9, 142.1, 140.6, 139.7, 133.7, 133.2, 127.63 (2C), 127.56, 127.44 (2C), 126.9 (2C), 114.3 (2C), 61.9, 56.2, 52.3, 51.6, 33.5, 24.2, 22.2, 22.1, 15.1; 

MS/EI m/z = 488.2 (M⁺).

NMR IS EASY

1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1)^[ 7 ]

To the advanced intermediate 2 (2.44 g, 5.0 mmol) was added 25% ammonia water (1.5 mL, 20 mmol) in methanol (20 mL), and the mixture was heated to 65 °C for 5 h in an autoclave of 50 mL. The resulting mixture was cooled to room temperature, poured into water (30 mL), and crystalized below 0°C. The precipitate was filtrated and dried in vacuo at 50°C to afford the desired product 1 as a pale white solid. Yield: 2.09 g, 91%;

APIXABAN

mp 171–173 °C; 

IR (KBr, cm⁻¹): 3448 and 3298 (N-H stretching), 2940 (C-H aliphatic), 1669 (C˭N stretching), 1614 (C˭O stretching), 1544 (aliphatic C˭C), 1513, 1463 and 1441 (aromatic C˭C), 1334, 1300 and 1254 (C-N stretching), 1146, 1111, 1090 and 1024 (C-O stretching), 835, 816, 794 and 758 (Ar-H aromatic bending); 

¹H NMR (500 MHz, CDCl₃, ppm), δ: 7.48 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 5.66 (brs, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.84 (s, 3H), 3.55–3.65 (m, 2H), 3.39 (t, J = 5.6 Hz, 2H), 2.57 (t, J = 6.2 Hz, 2H), 1.91–2.01 (m, 4H); 

¹³C NMR (125 MHz, CDCl₃, ppm), δ: 170.9, 164.4, 160.5, 158.0, 142.1, 140.6 (2C), 134.0, 133.2, 127.4 (4C), 126.9 (2C), 126.5, 114.4 (2C), 56.2, 52.3, 51.8, 33.5, 24.2, 22.1, 21.9; 

MS/EI m/z = 459.2 (M⁺).



 

SO EASY

This is picked up from

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

Volume 43, Issue 1, 2013

DOI:10.1080/00397911.2011.591956, http://www.tandfonline.com/doi/full/10.1080/00397911.2011.591956#CIT0006

Jian'an Jiang^a & Yafei Ji^a*

pages 72-79

REFERENCES

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• 2. Schumacher , W. A. ; Bostwick , J. S. ; Stewart , A. B. ; Steinbacher , T. E. ; Xin , B. M. ; Wong , P. C. Effect of the direct factor Xa inhibitor apixaban in rat models of thrombosis and hemostasis . J. Cardiovasc. Pharm. 2010 , 55 , 609 – 616 .[CrossRef], [PubMed], [Web of Science ®]
• 3. Buller , H. ; Deitchman , D. ; Prins , M. ; Segers , A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis: The Botticelli DVT dose-ranging study . J. Thromb. Haemost. 2008 , 6 , 1313 – 1318 .[CrossRef], [PubMed], [Web of Science ®]
• 4. Becker , R. C. ; Alexander , J. H. ; Newby , L. K. ; Yang , H. Q. ; Barrett , Y. C. ; Mohan , P. ; Wang , J. ; Harrington , R. A. ; Wallentin , L. C. Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome . Thromb. Haemost. 2010 , 104 , 976 – 983 . [CrossRef], [PubMed], [Web of Science ®]
• 5. Turpie , A. G. G. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases . Arterioscler. Thromb. Vasc. Biol. 2007 , 27 , 1238 – 1247 . [CrossRef], [PubMed], [Web of Science ®]
• 6. Zhou , J. C. ; Oh , L. M. ; Ma , P. ; Li , H. Y. Synthesis of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO Patent 2003/0 49681, June 19 , 2003 .
• 7. Pinto , D. J. P. ; Orwat , M. J. ; Koch , S. ; Rossi , K. A. ; Alexander , R. S. ; Smallwood , A. ; Wong , P. C. ; Rendina , A. R. ; Luettgen , J. M. ; Knabb , R. M. ; He , K. ; Xin , B. M. ; Wexler , R. R. ; Lam , P. Y. S. Discovery of 1-(4-methoxypheny)-7-oxo-6-(-4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa .J. Med. Chem. 2007 , 50 , 5339 – 5356 . [CrossRef], [PubMed], [Web of Science ®]
• 8. Gant , T. G. ; Shahbaz , M. Pyrazole carboxamide inhibitors of factor Xa. WO Patent 2010/030983, March 18 , 2010 .
• 9. Yadav , G. D. ; Lande , S. V. Liquid–liquid–liquid phase-transfer catalysis: A novel and green concept for selective reduction of substituted nitroaromatics . Adv. Synth. Catal. 2005 , 347 , 1235 – 1241 . [CrossRef], [Web of Science ®]
• 10. Salan , Ü. ; Altındal , A. ; Bulut , M. ; Bekaroğlu , Ö. Synthesis and characterization of a new trans-2,2-azoquinoxaline bridged bisphthalocyanine . Tetrahedron Lett. 2005 , 46 , 6057 – 6061 . [CrossRef], [Web of Science ®]
• 11. Matiichuk , V. S. ; Potopnyk , M. A. ; Obushak , N. D. Molecular design of pyrazolo[3,4-d]pyridazines . Russ. J. Org. Chem.2008 , 44 , 1352 – 1361 . [CrossRef], [Web of Science ®]
• 12. Bianca , F. B. ; Mauro , C. F. ; Denis , G. ; Locatelli , E. ; Ricci , A. 1,3-Dipolar cycloaddition of nitrile imines with functionalized acetylenes: Regiocontrolled Sc(OTf)₃-catalyzed synthesis of 4- and 5-substituted pyrazoles . Synlett 2009 , 14 , 2328 – 2332
• 13. Anderson , W. K. ; Jones , A. N. Synthesis and evaluation of furan, thiophene, and azole bis[(carbamoyloxy)methyl] derivatives as potential antineoplastic agents . J. Med. Chem. 1984 , 27 , 1559 – 1565 . [CrossRef], [PubMed], [Web of Science ®]

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