1-ethyl-1H-pyrazol-5-ol synthesis

Yield:-

Reaction Conditions:

Stage #1: methyl (2E)-3-methoxy-2-propenoate;ethylhydrazinewith sodium hydroxide;water at 40; pH=9.0 - 9.5; for 4 h;
Stage #2: with hydrogenchloride in water at 5; pH=3 - 4;

Steps:

139.A; 140.A

Example 139; (S)- 1 -(5-(3-(I -Ethyl- 1 H-pyrazol-5-yloxy)5-(pyridin-2-ylthio)pyridin-2-ylaminoV- 12.A- thiadiazol-3-vl )ethane- 1.2-diol hydrochloride; Step A: In IL glass beaker, ethylhydrazine oxalate (51.4 g, 342 mmol) was combined with water (300 ml). To the resulting slurry was added a 50% w/v NaOH solution (75.5 g) to adjust the pH to 9.5 (by pH-meter). The mixture was heated to 40 °C and methyl trans-3- methoxyacrylate (24.5 ml, 228 mmol) was added dropwise over 1 hour. The pH was adjusted periodically to 9.0-9.5 range by addition of 50 % w/v NaOH solution. After the completion of addition, the mixture was agitated for additional 3 hours at 40 °C and the pH was adjusted occasionally to about 9.0-9.5. The mixture was cooled to 5 °C and filtered. The filtrate was evaporated to about 150 ml, cooled to 5 °C and filtered again. The filtrate was acidified to pH 3-4 with 6 M HCI (45 ml) and extracted 8 times with 3: 1 mixture of chloroform/isopropanol. The combined extracts were dried (MgSO₄), filtered and evaporated. The crude product was purified over silica gel (20 % MeOH/EtOAc) to afford 1 -ethyl- 1H- pyrazol-5-ot (18.3 g, 71 % yield) as a yellow solid.; Example 140; ( S)- 1 -(5-(3-11 -ethyl- 1 H-pyrazol-5-yloxy)-5-( pyridin-2-ylthiotoyridin-2-ylamino)- 1.2.4- thiadiazol-3-vh-2-methylpropane- 1.2-diol; Step A: In IL glass beaker, ethylhydrazine oxalate (51.4 g, 342 mmol) was combined with water (300 ml). To the resulting slurry, 50% w/v NaOH solution was added (75.5 g) to adjust the pH to 9.5 (by pH-meter). The mixture was heated to 40 °C and methyl trans-3- methoxyacrylate (24.5 ml, 228 mmol) was added dropwise over 1 hour. The pH was adjusted periodically to about 9.0-9.5 by the addition of a 50 % w/v NaOH solution. After the completion of addition, the mixture was agitated for additional 3 hours at 40 °C and the pH was adjusted occasionally to about 9.0-9.5. The mixture was cooled to 5 °C and filtered. The filtrate was evaporated to about 150 ml , cooled to 5 °C and filtered. The filtrate was acidified to pH 3-4 with 6M HCI (45 ml) and extracted 8 times with a 3: 1 mixture of chloroform/isopropanol. The combined extracts were dried (MgSO₄), filtered and concentrated. The crude product was purified over silica gel (20 % MeOH/EtOAc) to afford 1 -ethyl- 1 H-pyrazol-5-ol (18.3 g, 71 % yield) as a yellow solid.

References:

WO2009/42435,2009,A1 Location in patent:Page/Page column 90-91; 94