Pyrazol-5-ol

Hydrazine hydrate (3.62 mL, 48.53 mmol) was added dropwise to a cooled (ice bath) solution of methyl propiolate (4.23 mL, 47.58 mmol) in methanol (40 mL). The reaction was allowed to stir for 30 min at room temperature. Brine (10 mL) was added and then the methanol was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (4.x.75 mL) and the combined organic layers were dried (MgSOTo a solution of methyl prop-2-ynoate (150 g, 1785.7 mmol) in MeOH (1500 mL) was added hydrazine hydrate (89.2 g, 1784.0 mmol) dropwise at 0° C. The reaction was stirred at r.t. for 30 min. Saturated aqueous sodium chloride (400 mL) was added, and then methanol was removed under vacuum. The aqueous layer was extracted with EtOAc (3×500 mL), and the combined organic layers were dried over NaThe compound of hydrazine monohydrate (85percent, 4.81g, 95.2mrnol) was added dropwise to a cooled (ice bath) solution of 92 (8g, 96.2mmol) in methanol (5OmL). The reaction was allowed to stir for 30 minutes at room temperature, then, the solvent was removed under vacuo. Theremaining aqueous layer was extracted with Et0Ac(5mL5) and the combined organic layerswere dried (MgSO4), filtered and concentrated in vacuo to yield the title product 93 (5g, yield:62?/o)1HNIS’iR (400 MHz, DMSO.-d6): ö5.40 (s, 2H), 7.32 (s, 2 H).(a) The process of Example II is followed except that 500 ml. of toluene solvent is included to the charge in step A. The resulting pyrazolone is obtained in about 60% yield.This reaction was repeated on larger scale (0.03 mole) with similar results (85% yield). The reduction step required 0.20 mole of ammonium formate with heating at 50 for 30 min. A solution of diester 4 (6.5 g, 0.02 mole) and p-nitrophenylisothiocyanate (4.3 g, 0.024 mole) in THF (60 ml) in a three-neck flask fitted with thermometer, nitrogen inlet, and magnetic stir bar was cooled to -50 with a dry ice/isopropanol bath. Potassium t-butoxide (2.6 g, 0.023 mole) was added to the mixture before allowing it to warm slowly to about 10. 'The deep red color initially present faded to a yellow-orange color as the reaction progressed. The course of the reaction could also be followed by TLC (silica gel) using 2:1 heptane:ethyl acetate (plus a little acetic acid to reduce streaking) as eluent. The thioamide product is yellow, is less mobile than either starting material, and couples slowly with Dox to give an orange[dye.] Ice (50 g), 1 N NaHCO3 (30 ml), water (100 ml), and heptane (150 ml) were then added to the mixture before stirring vigorously. The orange aqueous layer was separated and treated with 30 ml of 12 N HCl to precipitate the product as a gum which could be induced to crystallize by the addition of diethyl ether. A total of 8.2 g (81%) of adduct 5 was obtained. Subsequent experiments showed that this reaction proceeded equally well using DMF as solvent with molecular sieves present to absorb water at a preparatively more practical reaction temperature of 0. Bases such as sodium methoxide or potassium carbonate also worked but the reaction was generally slower. Trichlorophenylhydrazine (4.65 g, 0.022 mole) and adduct 5 (10.67 g, 0.021 mole) were combined in 100 ml of THF and cooled to 10 before adding dicyclohexylcarbodiimide (4.5 g, 0.022 mole), warming to room temperature, and stirring for 30 min. The hydrazone intermediate was converted to pyrazolone by addition of 1, 8-diazabicylo[5.4.0]undec-7-ene (DBU, 3.2 g, 0.021 mole) to the mixture and stirring for 10 min.EXAMPLE 3 Preparation of pyrazolone from N'-(3-dimethylaminopropyl)-sulfanilamide having the structure: STR14 A solution of 0.2 g mole (51.5 g) of the intermediate prepared as in in 215 mL water, is iced to 0 C., and stirred in an ice bath. Hydrochloric acid (95 mL, 37%) is added followed by a solution of 14 g of sodium nitrite. After stirring for ten minutes with a slight excess of nitrite present, the excess is removed with sulfamic acid. The diazonium salt solution is neutralized to pH 6 by sifting in 28 g of sodium bicarbonate at 0 C. During 15 minutes, 25.2 g of sodium sulfate is sifted in, and the pH rises to 9.4. To the bright orange colored solution, after 30 minutes and at <5 C., is added 22 g sodium bisulfite during 10 minutes. The solution is pale yellow and diazo nearly disappears. Colorless crystalline precipitate begins to form. The reaction is then stirred an additional two hours, heated to 75 C. and 70 g 37% hydrochloric acid is added. The temperature is increased to 90-95 C. and held for four hours with sulfur dioxide evolving. The solution is stirred and cooled overnight. Sodium hydroxide (55 g, 50%) is added to pH 6. Ethyl acetoacetate (26 g; 0.2 mole) is added at 35 C. Heating to the boiling point, and acidification with hydrochloric acid (20 mL) gives a yellow tarry precipitate.Synthesis of a Pyrazolone 10.0 Grams (67 mmols) of a 2, 3-dichloropropionic acid amide and 100 g of a tetrahydrofuran were fed into a 200-ml four neck flask, followed by the dropwise addition of 10.1 g (202mmols) of a hydrated hydrazine over a period of 20 minutes in a water bath maintained at 15 C. with stirring. The temperature was then raised to 50 C., and the reaction was finished after stirred for one hour. 100 Grams of the tetrahydrofuran was added-to the reaction product that was obtained by condensing and drying the reaction solution, and the mixture was stirred at room temperature. After insoluble matters were separated by filtration, the tetrahydrofuran solution of the product was analyzed by gas chromatography to find that a pyrazolone was contained in an amount of 5.3 g. The yield of the pyrazolone was 94 mol % on the basis of the 2, 3-dichloropropionic acid amide. The tetrahydrofuran solution of the above product was condensed and dried again, and was recrystallized with water to obtain white crystals of the pyrazolone, m.p. 162 to 164 C. (165 C. according to the literature).The following pyrazolone dyestuffs are obtained completely analogously:Step 2 Preparation of the pyrazolone of Formula I. 17 g Hydrazinoester of step 1, 8.1 g 4-aminoacetanilide and 10 ml glacial acetic acid were heated for 2.[. hours on a boiling water bath, the reaction mixture while hot stirred with 50 ml methanol and then cooled. The precipitated product was drawn off and washed with methanol. This represents pyrazolone in a relatively pure form. Yield: 16.3 g, i.e. 80% of the theoretical F. 149-153CExamples of such compounds are the following: ... 4-(2-chloro-phenylhydrazono)-1-phenyl-3-methyl-4, 5-dihydro-5-pyrazolone 4-phenylhydrazone-1-(4-sulfo-phenyl)-3-methyl-4, 5-dihydro-5-pyrazolone 4-(2-chloro-phenylhydrazono)-1-(2-chloro-phenyl)-3-methyl-4, 5-dihydro-5-pyrazolone 4-(2-sulfo-phenylhydrazono)-1-(2-chloro-phenyl)-3-methyl-4, 5-dihydro-5-pyrazolone -dihydro-5-pyrazolone 4-(2-hydroxy-4-nitro-5-methylsulfonyl-phenylhydrazono)-3-methyl-4, 5-dihydro-1-phenyl-5-pyrazolone 4-(2-hydroxy-3-nitro-5-tert-amyl-phenylhydrazono)-3 -methyl-1-phenyl-4, 5-dihydro-5-pyrazolone 4-(2-hydroxy-4-nitro-phenylhydrazono)-3-methyl-1-phenyl-4, 5-dihydro-5-pyrazolone.a. Preparation of 2-(4-chloro-2-fluorophenyl)-1, 4, 5, 6-tetrahydrocyclopentapyrazol-3(2H)-one 7.5 Parts of 4-chloro-2-fluorophenylhydrazine and 6.6 parts of methyl 2-oxocyclopentanecarboxylate (purchased from Aldrich Chemical Company) were dissolved in 200 parts toluene. The reactants were heated at reflux for 1-2 hours removing water that was formed. The reaction mixture was cooled to 100 C., and a solution of 5.0 parts of sodium methoxide dissolved in 25 parts methanol was added dropwise, removing methanol as its azeotrope with toluene. The reaction mixture was heated until the internal temperature reached 110. The reaction was then cooled and poured into 200 parts ice water. The organic layer was separated, and the aqueous layer was washed twice with diethyl ether. Cold, dilute hydrochloric acid was added, with stirring, to the aqueous layer until pH 2 was reached. The resulting oily product solidified and was filtered, dried and recrystallized from acetonitrile to yield 3.3 parts of tan crystalline material, m.p. 157-160. Alternatively, the above pyrazolone was prepared by the following procedure.EXAMPLE 4 Preparation of 3-bromo-2-(4-Chloro-2-fluorophenyl)-2, 4, 5, 6-tetrahydrocyclopentapyrazole 7.5 parts of 4-chloro-2-fluorophenylhydrazine and 6.6 parts of methyl 2-oxocyclopentanecarboxylate (purchased from Aldrich Chemical Company) were dissolved in 200 parts toluene. The reactants were heated at reflux for 1-2 hours. Water was removed as formed. The reaction mixture was cooled to 100, and a solution of 5.0 parts of sodium methoxide dissolved in 25 parts of methanol was added dropwise, removing methanol as its azeotrope with toluene. The reaction mixture was heated until the internal temperature attained 110. After cooling, the product was poured into 200 parts of ice water. The organic layer was separated, and the aqueous layer was wished twice with diethyl ether. Cold, dilute hydrochloric acid was added, with stirring to the aqueous layer until pH was attained. The resulting oily product solidified and was filtered, dried and recrystallized from acetonitrile to yield 3.3 parts of tan crystalline material, m.p. 157-160. Alternatively, the above pyrazolone was prepared by the following procedure.EXAMPLE I A diazonium salt solution was made by adding 31 g. of ice to a mixture of 46.9 g. (39.6 ml) of 32% HCl and 30 ml glacial HAc and dissolving 16.1 g. orthoaminobenzotrifluoride in the iced mixture; thereafter 25 ml 4N NaNO2 solution was added while holding the temperature below 0 C. and the diazonium salt solution was stirred for 45 minutes after the last addition of sodium nitrite before coupling with the pyrazolone prepared as follows: 40 grams Na2 CO3 was dissolved in 200 ml water, and 23.2 g. of 1-(phenyl-3-carbethoxy-5-pyrazolone was added.To a solution of l/7-pyrazol-3(2/ )-one (20.0 g, 238 mmol) in DCM (300 mL) was added triethylamine (37 mL, 267 mmol) at 0C. After 10 minutes, Boc20 (57.11 g, 262 mmol) in DCM (100 mL) was added drop-wise. After addition, the reaction was warmed to room temperature and was allowed to stir for 16 hours. The reaction was concentrated under reduced pressure and the crude residue was dissolved in water (100 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give /c/Z-butyl 3 -hydroxy- 1 //-pyrazole- 1 -carboxylate (2.8 g, yield: 6%) as a yellow solid. 1H NMR (400 MHz, DMSO-i): d = 10.92 (s, 1H), 7.97 (d, j= 3.2 Hz, 1H), 5.89 (d, j= 2.8 Hz, 1H), 1.53 (s, 9H).Step 1 : lH-pyrazol-3(2H)-one (1 g, 11.8 mmol) was dissolved in DMF (10 mL) and cesium carbonate (4.20 g, 12.9 mmol) was added. The reaction mixture was heated to 50 C. After 5 minutes, 2-bromo-l-(2-chlorophenyl)ethanone (2.35 g, 10.1 mmol) in DMF (12 mL) was slowly added over 10 min. The reaction mixture was stirred for 1 hour at 50 C. After cooling to RT, the mixture was partitioned between EtOAc (50mL) and saturated NaHCO-, (20 mL). The aqueous layer was washed with EtOAc and the combined organics were washed with water, washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-40% EtOAc) to give 2-(( l//-pyrazol-5-yl)oxy)- l -(2-chl orophenyl)ethanone (1.08 g, 4.57 mmol) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) d ppm 5.25 (s, 2 H) 5.66 (t, J=2.20 Hz, 1 H) 7.43 - 7.48 (m, 1 H) 7.49 (t, J=l .95 Hz, 1 H) 7.51 - 7.57 (m, 2 H) 7.72 (d, J=8.06 Hz, 1 H) 11.88 (br s, 1 H).Under the ice bath, Hydrazine hydrate in a 100 mL single-mouth bottle(0.75 mL, 15 mmol) A solution of ethyl propiolate (1.5 mL, 15 mmol) in methanol (15 mL).TLC detection, the raw material reaction is complete, spin dry methanol, A yellow viscous liquid was obtained and the next step was taken directly.1, 2-Dihydro-pyrazol-3-one (2.0 g, 23.8 mmol) and K£03 (11.5 g, 83.3 mmol) wereheated to 120 C in D:NIF (60 mL). 1, 3-Dibromo-butane (6.2 g, 28.6 mmol) was added and themixture was heated for 16 hrs. The solvent was removed in vacuo. The residue was partitionedbetween EA/H20 (50 mL /80 mL) and the layers were separated. The aqueous layer wasextracted with EA (50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The residue was purified by silica gel column (PE;EA = 5/1to 1/l) to give 7-methyl-6, 7-dihydro-5H-pyrazolo[5, 1-b][1, 3]oxazine (13 g, yield: 40%) as ayellow oil and 5-methyl-6, 7-dihydro-5H-pyrazolo[5, 1-b][1, 3]oxazine (500 mg, yield: 15%) as ayellow solid.[00565] 7-methyl-6, 7-dihydro-5H-pyrazolo[5, 1-b][l, 3]oxazine: 1HNJ'v1R (400 J.'ffiz, CDCb): 8= 7.32 (d, J = 2.0 Hz, lH), 5.45 (d, J = 1.6 Hz, lH), 4.36-4.31 (m, 2H), 4.24-4.18 (m, lH), 2.34-2.27 (m, 1H), 2.02-1.94 (m, 1H), 1.59 (d, J= 6.0 Hz, 3H).[00566] 5-methyl-6, 7-dihydro-5H-pyrazolo[5, 1-b][1, 3]oxazine: 1HN1VIR ( 400 J'VIHz, CDCb): 8= 7.30 (d, J = 1.6 Hz, lH), 5.45 (d, J = 2.0 Hz, 1H), 4.38-4.30 (m, 1H), 4.25-4.20 (m, 1H), 4.15-4.08 (m, lH), 2. 19-2.03 (m, 2H), 1.46 ( d, J = 6.4 Hz, 3H).

Molecular Weight:84.08
XLogP3:-0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Exact Mass:84.032362755
Monoisotopic Mass:84.032362755
Topological Polar Surface Area:41.1
Heavy Atom Count:6
Complexity:97
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes