GISADENAFIL AND INTERMEDIATES TEACHING US NMR

GISEDENAFIL

GISEDENAFIL BESYLATE

334826-98-1 free form
334827-98-4 (as besylate)

• UK 369003
• UK-369,003
• UK0369,003
• UNII-S6G4R7DI1C

THERAPEUTIC CLAIM Treatment of lower urinary tract
symptoms associated with BPH

READ AT'http://newdrugapprovals.org/2014/01/28/gisadenafil-for-erectile-dysfunction/

LEARN NMR STEP BY STEP

1..............

Ethyl 3-ethyl-1H-pyrazole-5-carboxylate 

1H NMR (300 MHz, CDCl3): 

δ=1.20 (3H, t), METHYL OF  -CH2-CH3

1.28 (3H, t),  METHYL OF  -C=O-O-CH2-CH3

 2.67 (2H, q), CH2 OF  OF  -CH2-CH3

4.29 (2H, q),  CH2  OF  -C=O-O-CH2-CH3

6.55 (1H, s), LONE PYRAZOLE PROTON ON RING

12.56 (1H, s). NH PROTON

LRMS m/z=167.1 [M-H]+, C8H12N2O2 requires 168.2.

2.......... Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid 

 δ (DMSOd6): 

1.13 (3H,t), METHYL OF  -CH2-CH3

2.56 (2H,q), CH2 OF-CH2-CH3

6.42 (1H,s).LONE PYRAZOLE PROTON ON RING

VERY EASY..FEELING HAPPY..1H NMR IS EASY

3...........

3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid

 δ (DMSOd6): 

1.18 (3H,t), METHYL OF  -CH2-CH3

2.84 (2H,m), CH2  OF  -CH2-CH3

13.72 (1 H,s). NH PROTON

ALERT..........LONE PYRAZOLE PROTON ON RING LOST DUE TO NITRO SUBSTITUTION

4...........

3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide

 δ (DMSOd6): 

1.17 (3H,t), METHYL OF  -CH2-CH3

2.87 (2H,m),CH2 OF  -CH2-CH3

7.40 (1H,s), 

7.60 (1H,s), 

7.90 (1H,s). 

ALL NH AND NH2 SIGNALS

DO IT YOURSELF.............NMR IS EASY

LRMS: m/z 185 (M+l)+.

5...........

5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide

m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4O4 requires C, 44.63; H, 5.79; N, 23.14%.

δ (CDCl3): 

1.18 (3H, t), METHYL OF  -CH2-CH3

2.98 (2H, q),CH2 OF  -CH2-CH3

 3.22 (3H, s), METHYL OF -OCH3

3.77 (2H, t), CH2 OF NCH2-CH2-O-CH3

4.28 (2H, q), CH2 OF NCH2 -CH2-O-CH3

6.03 (1H, s), NH2

7.36 (1H, s).NH2

LRMS: m/z=243 (M+1)+

6......

4-Amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide

 m.p.=131° C. Found: C, 50.75; H, 7.62; N, 26.38. C9H16N4O2 requires C, 50.94; H, 7.55; N, 26.42%.

 δ (CDCl3):

 1.20 (3H, t),

 2.63 (2H, q),

 3.32 (3H, s),

3.74 (2H, t), 

3.95 (2H, s), NH2 OF PYRAZOLE

4.15 (2H, t), 

5.27 (1H, s),C=0-NH2

 6.59 (1H, s).C=O-NH2

NITRO IS CONVERTED TO AMINO....DO IT YOURSELF

LRMS: m/z=213 (M+1)+

7.....................

N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide.

m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.

δ (CDCl3): 

1.04 (3H, t), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING

1.22 (3H, t), METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN

1.60 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING

2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING

2.54 (4H, m), 4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM

2.96 (2H, q), CH2 OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN

3.12 (4H, m), 4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP

3.36 (3H, s), METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN

3.81 (2H, t), CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.27 (2H, t), CH2 OF NCH2 -CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.80(2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING

5.35(1H, s), C=0--NH2

6.68 (1H, s), C=O-NH2

8.66 (1H, d) ,PYRIMIDINE AROM H .....AWAY/PARA TO C=O-NH -PYRAZOLE GP

 8.86 (1H, d), PYRIMIDINE AROM H .....CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift to delta 9.06 after cyclization in next step ie formation of GISADENAFIL

10.51 (1H, s). NH

LRMS: m/z=539 (M+1)+

FINAL

1-(6-Ethoxy-5-[3-ethyll-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine•ethyl acetate solvate.

 m.p.=157° C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5CO2CH3 requires C, 53.21; H, 6.49; N, 18.25%.

δ (CDCl3):
1.07 (3H, t), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING
1.42 (3H, t),  METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN
1.61 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING
2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING
2.57 (4H, m),4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM
3.08 (2H, q), CH2 OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN
3.15 (4H, m),4H OF -NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP
3.32 (3H, s),METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN
3.92 (2H, q),  CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.48 (2H, q), CH2 OF NCH2 -CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.77 (2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING
8.65 (1H, d), PYRIMIDINE AROM H .....AWAY/PARA TO C=O-NH -PYRAZOLE GP
9.06 (1H, d). PYRIMIDINE AROM H .....CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift from 8,86 delta to  9.06 after cyclization in this step ie formation of GISADENAFIL
The spectrum also has signals that correspond to a solvate with ethyl acetate.

LRMS: m/z=520 (M+1)+