* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium hydroxide In water at 20℃; for 16 h; Stage #2: With hydrogenchloride In water at 0℃; for 1 h;
In a 1 L round bottom flask, 55 g of sodium ethyloxalacetate (1.05 eq, 0.26 mol) and 26 g of formamidine acetate (1 eq, 0.25 mol) were added to a solution of sodium hydroxide (10 g) in 500 mL of water. The reaction mixture was stirred at room temperature for 16 hours.[00262] Concentrated HCl was added carefully to the mixture until pH = 1, a fine solid precipitated and the reaction mixture was stirred at 0°C for 1 hour. The solid was filtered then washed with water and ether. The white solid was then left in a vacuum oven heated at4O0C for 20 hours. Trituration in methanol gave the title compound in 25percent yield. 1H NMR(dβ-DMSO): 12.88 (IH, OH), 8.24 (s, IH), 6.83 (s, IH).
15%
With sodium hydroxide In water at 20℃; for 12 h;
To a solution of formamidine acetate (10 g, 96 mmol) in 200 mL of water was added diethyl oxalacetate sodium salt (21 g, 100 mmol) and sodium hydroxide (3.8 g, 96 mmol). The reaction mixture was stirred overnight at room temperature, before 6 N HCl was added carefully to adjust PH = 1. The mixture was allowed to stand overnight at 0 °C, and the resultant precipitate was filtered and dried in vacuum to give the desired product (2 g, 15percent) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.25 (s, 1H), 6.83 (s, 1H).
Reference：
[1] Patent: WO2010/20432, 2010, A2, . Location in patent: Page/Page column 91
[2] European Journal of Medicinal Chemistry, 2018, vol. 149, p. 30 - 44
[3] Patent: US2011/21500, 2011, A1, . Location in patent: Page/Page column 39
[4] Patent: US2011/59954, 2011, A1, . Location in patent: Page/Page column 71
[5] Patent: US2011/172218, 2011, A1, . Location in patent: Page/Page column 28
[6] Patent: US2011/195954, 2011, A1, . Location in patent: Page/Page column 79
3
[ 6313-33-3 ]
[ 40876-98-0 ]
[ 6299-87-2 ]
Yield
Reaction Conditions
Operation in experiment
37%
Stage #1: at 20℃; for 0.666667 h; Stage #2: With sodium hydroxide In water at 0℃;
Preparation of -hydroxypyrimidine-^carboxylic acid:; To a suspension of 2.52 g (12.0 mmol) of diethyloxaloacetate sodium salt in 8 mL of water was added 1.9 mL of 6.25 M NaOH(α? ), dropwise over 1 min. The mixture was stirred at ambient temperature for 40 min to give an orange solution. Next, 2.1 g (26 mmol) of formamidine hydrochloride in 2 mL of water was added. The reaction was cooled with an ice bath, and with the aid of a pH meter, the pH was maintained between 1 1 and 1 1.5, by the addition of 6.25 M NaOH as the reaction progressed over 40 min. The pH was then adjusted to 1 by the addition of 12 M HCl, giving a white precipitate. This was filtered, washed with 0.1 M HCl (2 x 5 mL), then dried on the filter to give 618 mg (37percent) of a light tan solid.
With acetic acid In ethanol at 20℃; for 7.5 h; Heating / reflux
(Reference Example 3) Synthesis of 3-ethoxycarhonyl-5-hydroxy-1-methylpyrazole 50.0 g (0.24 mole) of diethyl oxaloacetate sodium salt was suspended in 500 ml of ethanol. Thereto was added 25 ml of acetic acid. Thereto was dropwise added, at room temperature in 0.5 hour with stirring, 15 g (0.33 mole) of 97percent methylhydrazine. After the dropwise addition, the mixture was stirred at room temperature for 2 hours and successively at the refluxing temperature for 5 hours. After cooling, ethanol was distilled off under reduced pressure. To the residue were added 200 ml of ethyl acetate and 100 ml of water. After phase separation, the aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two ethyl acetate layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride 50 ml of a saturated aqueous sodium chloride solution in this order. The resulting ethyl acetate layer was dried over anhydrous sodium sulfate and subjected to vacuum distillation to remove the solvent. To the resulting crystals was added 100 ml of water.
53%
With sulfuric acid In methylated spirits 74OP at 25 - 60℃; for 5.25 h; Heating / reflux
Ester formationConcentrated sulphuric acid (13.5g:013 mol) was added dropwise over 5 min to stirred methylated spirits 74OP (100ml) and then cooled to <30C. Methyl hydrazine (11.51g; 0.25mol) was added dropwise over 10min at <60C and the mixture then cooled to 25C, followed by the addition diethyl oxalacetate sodium salt (60.84g; 0.275mol). After stirring for 2 hours the temperature was raised to reflux and maintained for 3 hours, cooled and then filtered. The filtrates evaporated and the resulting residue stirred with water. The product was filtered and washed with water before being recrystallised from water to give an off white solid (22.84g:53percent: mass spectrum (M-H) -ve 169)
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 4, p. 1228 - 1234
6
[ 141-78-6 ]
[ 95-92-1 ]
[ 40876-98-0 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1888, vol. 246, p. 324
[2] Gazzetta Chimica Italiana, 1887, vol. 17, p. 520[3] Gazzetta Chimica Italiana, 1890, vol. 20, p. 169,170
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 1, p. 218,597
[5] Justus Liebigs Annalen der Chemie, 1888, vol. 246, p. 324
[6] Gazzetta Chimica Italiana, 1887, vol. 17, p. 520[7] Gazzetta Chimica Italiana, 1890, vol. 20, p. 169,170
[8] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 1, p. 218,597
[9] Fortschr. Teerfarbenfabr. Verw. Industriezweige, 1, 218; 1, 597,
[10] Fortschr. Teerfarbenfabr. Verw. Industriezweige, 1, 218; 1, 597,
7
[ 40876-98-0 ]
[ 691-84-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 3, p. 601 - 605
8
[ 40876-98-0 ]
[ 85230-37-1 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With acetic acid In toluene at 20℃; for 0.5 h; Stage #2: With hydrazine hydrochloride In toluene at 100℃;
Acetic acid (150 mL) was added drop-wise to a solution of sodium 1 ,4-diethoxy- (0282) 1 ,4-dioxobut-2-en-2-olate (30.0 g, 0.143 mol) in toluene (150 mL), and the mixture was stirred at room temperature for 30 minutes, whereupon hydrazine monohydrochloride (85percent, 17 g, 0.29 mol) was added. The reaction mixture was stirred for an additional 30 minutes at room temperature and subsequently heated at 100 °C overnight. It was then concentrated in vacuo and extracted with ethyl acetate (500 mL); the organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product as a yellow solid. Yield: 17 g, 0.1 1 mol, 77percent. 1H NMR (400 MHz, DMSO-cf6) δ 12.75 (br s, 1 H), 5.91 (br s, 1 H), 4.24 (q, J=7 Hz, 2H), 1 .27 (t, J=7 Hz, 3H).
Reference：
[1] Patent: WO2017/145013, 2017, A1, . Location in patent: Page/Page column 54
[2] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 4, p. 1228 - 1234
9
[ 40876-98-0 ]
[ 153597-59-2 ]
Reference：
[1] Patent: WO2017/145013, 2017, A1,
10
[ 57297-29-7 ]
[ 40876-98-0 ]
[ 858956-25-9 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: for 0.333333 h; Stage #2: at 70℃; Stage #3: With hydrogenchloride In water at 20℃;
A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 0C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). Characterising data for the compound are as follows: 1H nmr (400MHz, d6-DMSO) δH 13.30 (1H, br s), 12.97 (1H, br s), 6.59 (1H, s), 1.94 (1H, quintet), 1.04 (4H, m) ppm.
63%
Stage #1: With sodium hydroxide In water for 0.333333 h; Stage #2: at 70℃; Stage #3: With hydrogenchloride In water at 20℃;
A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 0C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). 1H nmr (400MHz, d6-DMSO) δH 13.30 (1 H, br s), 12.97 (1 H, br s), 6.59 (1 H, s), 1.94 (1 H, quintet), 1.04 (4H, m) ppm.
With sodium ethanolate; In diethyl ether; for 1h;Heating;
Sodium salt of dimethyl ester of oxaloacetic acid (DMOA, GS-170) and the sodium salt of diethyl ester of oxaloacetic acid (DEOA, GS-1 96) were obtained in the following way. A 250 ml flask was filled while stirring with 50 mmol of sodium methoxide or sodium ethoxide and a mixture of 100 ml of diethyl ether with 50 mmol of dimethyl oxalate or diethyl oxalate, correspondingly. Then 51 mmol of methyl acetate or ethyl acetate were added. Then the reaction mixture was boiled within 1 hour with back flow condenser. Afier cooling, white precipitate sedimented in the form of sodium salt of dimethyl ester of oxaloacetic acid or sodium salt of diethyl ester of oxaloacetic acid, correspondingly. The resulting salt was filtered, washed with diethyl ether and dried. The resultant sodium salt of dimethyl ester of oxaloacetic acid and sodium salt of diethyl ester of oxaloacetic acid have the following properties: 1) Properties of the resultant sodium salt of dim- ethyl ester of oxaloacetic acid. Product yield-6.83 g (75%). 1R-NMR (300 MHz, DMSO-d5), oe (ppm): 3.44 (s, 3R, CR3), 3.61 (s, 3R, CR3), 5.10 (s, 1R, CR). 13C-NMR (300 MRz, DMSO-d5), oe (ppm): 48.96 (CR3), 51.38 (CR3), 82.35 (CR), 167.77 (CO), 168.36 (CO), 169.96 (CO). 2) Properties of the resultant sodium salt of diethyl ester of oxaloacetic acid. Product yield-7.36 g (70%). mp=188-190 C. 1R-NMR (300 MRz, DMSO-d5), oe (ppm):1.13 (t, 3R, CR3, J3=7 Rz), 1.20 (t, 3R, CR3, J3=7 Rz), 3.92 (q, 2R, CR2, J3=7 Rz), 4.07 (q, 2R, CR2, J3=7 Rz), 5.09 (s, 1R, CR). 13C-NMR (300 MRz, DMSO-d5), oe (ppm): 13.92 (CR3), 14.62 (CR3), 56.71 (CR2), 59.97 (CR2), 82.76 (CR), 167.41 (CO), 168.59 (CO), 169.66 (CO).
With acetic acid; In water; toluene; at 20℃; for 5h;Heating / reflux;
To a mixture of diethyl oxalacetate sodium salt (10.5 g, 50 mmol), acetic acid (100 mL) and toluene (50 mL) was added an aqueous solution (50 mL) of (2-methylphenyl)hydrazine hydrochloride (7.93 g, 50 mmol) under stirring at room temperature, and the mixture was heated under reflux for 3 hr. After cooling, the reaction mixture was partitioned. The organic layer was washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give yellow crystals. This product was dissolved in acetic acid (36 mL), and the mixture was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and recrystallized from hexane-ethyl acetate to give the title compound (2.69 g, yield 22%) as colorless crystals. 1H NMR (CDCl3) delta: 1.30 (3H, t, J=7.2Hz), 2.02 (3H, s), 3.74(1H, s), 4.33(2H, q, J=7.2Hz), 5.94(1H, s), 7.13-7.36(4H, m).
Acetic acid (150 mL) was added drop-wise to a solution of sodium 1 ,4-diethoxy- (0282) 1 ,4-dioxobut-2-en-2-olate (30.0 g, 0.143 mol) in toluene (150 mL), and the mixture was stirred at room temperature for 30 minutes, whereupon hydrazine monohydrochloride (85%, 17 g, 0.29 mol) was added. The reaction mixture was stirred for an additional 30 minutes at room temperature and subsequently heated at 100 C overnight. It was then concentrated in vacuo and extracted with ethyl acetate (500 mL); the organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product as a yellow solid. Yield: 17 g, 0.1 1 mol, 77%. 1H NMR (400 MHz, DMSO-cf6) delta 12.75 (br s, 1 H), 5.91 (br s, 1 H), 4.24 (q, J=7 Hz, 2H), 1 .27 (t, J=7 Hz, 3H).
With acetic acid; In ethanol; at 20℃; for 7.5h;Heating / reflux;
(Reference Example 3) Synthesis of 3-ethoxycarhonyl-5-hydroxy-1-methylpyrazole 50.0 g (0.24 mole) of diethyl oxaloacetate sodium salt was suspended in 500 ml of ethanol. Thereto was added 25 ml of acetic acid. Thereto was dropwise added, at room temperature in 0.5 hour with stirring, 15 g (0.33 mole) of 97% methylhydrazine. After the dropwise addition, the mixture was stirred at room temperature for 2 hours and successively at the refluxing temperature for 5 hours. After cooling, ethanol was distilled off under reduced pressure. To the residue were added 200 ml of ethyl acetate and 100 ml of water. After phase separation, the aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two ethyl acetate layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride 50 ml of a saturated aqueous sodium chloride solution in this order. The resulting ethyl acetate layer was dried over anhydrous sodium sulfate and subjected to vacuum distillation to remove the solvent. To the resulting crystals was added 100 ml of water.
53%
With sulfuric acid; In methylated spirits 74OP; at 25 - 60℃; for 5.25h;Heating / reflux;
Ester formationConcentrated sulphuric acid (13.5g:013 mol) was added dropwise over 5 min to stirred methylated spirits 74OP (100ml) and then cooled to <30C. Methyl hydrazine (11.51g; 0.25mol) was added dropwise over 10min at <60C and the mixture then cooled to 25C, followed by the addition diethyl oxalacetate sodium salt (60.84g; 0.275mol). After stirring for 2 hours the temperature was raised to reflux and maintained for 3 hours, cooled and then filtered. The filtrates evaporated and the resulting residue stirred with water. The product was filtered and washed with water before being recrystallised from water to give an off white solid (22.84g:53%: mass spectrum (M-H) -ve 169)
With acetic acid; In toluene; at 100℃; for 8.5h;
5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester; [Show Image] (1) To a solution of diethyl oxalacetate sodium salt (30.0 g) in toluene (200 ml), acetic acid (200 ml) and methylhydrazine (15 ml) were added and stirred at 100C for 8.5 hours. The reaction mixture was concentrated, and the resulting residue was diluted with saturated aqueous sodium chloride and extracted with AcOEt. The resulting organic layer was dried over MgSO4, filtered and evaporated under reduced pressure to remove the solvent. The resulting solid was washed with Et2O/hexan (Et2O/hexane = 2/1) and dried to give the titled compound (18.8 g, brown powder). 1H NMR (600 MHz, DMSO-D6) delta ppm: 1.25 (t, J=7.1 Hz, 3 H), 3.59 (s, 3 H), 4.16-4.25 (m, 2 H), 5.77 (s, 1 H)
5-ethoxy-2H-pyrazole-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
With hydrazine dihydrochloride; In ethanol; water; at 20℃;Reflux;
This compound was prepared from the sodium salt of diethyloxalacetate (9k) as follow: diethyloxalacetate sodium salt (27.8 g, 0.132 mol; 95 % pure) was dissolved in ethanol (300 mL) and water (20 mL). To this was added hydrazine dihydrochloride (14.3 g, 0.136 mol) and the suspension was stirred overnight at room temperature before heating to reflux for an additional 12 hours. The solvent was removed under reduced pressure; the residue was dispersed in water and made basic with solid sodium hydrogencarbonate. The aqueous phase was extracted with ethyl acetate five times, dried over sodium sulfate and concentrated to dryness. The residue was further purified by a chromatography over silica gel (dichloromethane / ethanol 97-3) to yield compound 10k (2.19 g, 9 %) as a low melting solid. 1H (CDCl3): 1.41 (m, 6H); 4.26 (q, 2H, J = 7.0); 4.38 (q, 2H, J = 7.0); 6.22 (s, 1H); 10.6 (s (br), 1H). 13C (CDCl3): 14.2; 14.7; 61.4; 65.3; 93.2; 134.3; 159.6; 163.4.. HRMS: Calcd. for C8H12N2O+ H: 185.0926. Found: m/z, 185.0980.
Preparation of -hydroxypyrimidine-^carboxylic acid:; To a suspension of 2.52 g (12.0 mmol) of diethyloxaloacetate sodium salt in 8 mL of water was added 1.9 mL of 6.25 M NaOH(alpha? ), dropwise over 1 min. The mixture was stirred at ambient temperature for 40 min to give an orange solution. Next, 2.1 g (26 mmol) of formamidine hydrochloride in 2 mL of water was added. The reaction was cooled with an ice bath, and with the aid of a pH meter, the pH was maintained between 1 1 and 1 1.5, by the addition of 6.25 M NaOH as the reaction progressed over 40 min. The pH was then adjusted to 1 by the addition of 12 M HCl, giving a white precipitate. This was filtered, washed with 0.1 M HCl (2 x 5 mL), then dried on the filter to give 618 mg (37percent) of a light tan solid.
Preparation of 6-hydroxy-2-phenylpyrimidine-4-carboxylic acid:; Diethyl oxaloacetate sodium salt 4.84 g (23.0 mmol) was added to a solution of 16 mL of water and 4 mL of ethanol. The suspension was stirred for 5 min, then a solution of 3.6 mL (22.5 mmol) of 6.25 M NaOH(O(? ) was added. The mixture was stirred at ambient temperature for 15 minutes to give a tan solution. To this was added a solution of 3.01 g (19.2 mmol) of benzamidine hydrochloride in 15 mL of H2O, <n="68"/>giving a solution with pH=l 1. Next, 1 mL of 6.25 M NaOH was added, pH = 1 1 when done, then the reaction was stirred at 80 C for 2 h. Additional NaOH was added during the heating period to maintain the pH between 1 1 and 12. (A total of about 10 mmol additional NaOH was added.) The reaction was cooled to 5 C, then 12M HCl was added until pH = 1. The white precipitate was collected, washed with water, and dried on the filter to give 3.09 g (74%) of the product as a white solid.
In acetic acid; at 100℃; for 2h;Product distribution / selectivity;
Example 12: 4-((S)-4-Carboxy-2-[5-(1 -ethoxycarbonyl-cyclobutoxy)-1 -(3-methoxy-phenyl)- I H-pyrazole-S-carbonyO-aminoJ-butyryO-piperazine-i-carboxylic acid ethyl ester; (i) 5-Hydroxy-1 -(3-methoxy-phenyl)-1 H-pyrazole-3-carboxylic acid ethyl ester; To a solution of 1.2 g of 2-Oxo-succinic acid diethyl ester monosodium salt in 10 ml acetic acid, 900 mg of (3-Methoxy-phenyl)-hydrazine hydrochloride was added and the reaction mixture was heated to 1000C for 2h. Then, the reaction mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by <n="73"/>chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 300 mg. Example 16: 4-((S)-4-Carboxy-2-[5-ethoxycarbonylmethoxy-1-(3-methoxy-phenyl)-1 H- pyrazole-S-carbonyll-aminoJ-butyryO-piperazine-i-carboxylic acid ethyl ester; (i) 5-Hydroxy-1-(3-methoxy-phenyl)-1 H-pyrazole-3-carboxylic acid ethyl ester; To a solution of 1.2 g of 2-Oxo-succinic acid diethyl ester monosodium salt in 10 ml acetic acid, 900 mg of (3-Methoxy-phenyl)-hydrazine hydrochloride was added and the reaction mixture was heated to 1000C for 2h. Then, the reaction mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure.Yield: 300 mg.
Example 71 : 4-((S)-4-Carboxy-2-[5-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo- ethoxy]-1 -(3-fluoro-phenyl)-1 H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1 - carboxylic acid ethyl ester; (i) 4-((S)-4-tert-Butoxycarbonyl-2-[1 -(3-fluoro-phenyl)-5-hydroxy-1 H-pyrazole-3- carbonyl]-amino}-butyryl)-piperazine-1 -carboxylic acid ethyl ester; <n="104"/>To a solution of 2.500 g 1-(3-fluoro-phenyl)-5-hydroxy-1 H-pyrazole-3-carboxylic acid (prepared by Standard procedure using <strong>[2924-16-5]3-fluorophenylhydrazine hydrochloride</strong> and sodium diethyl-2-oxosuccinate followed by ester hydrolysis) and 3.864 g 4-((S)-2-amino-4-tert- butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF 1.723 g HOBt1 1.9 ml DIPEA and 2.157 g EDC were added and the reaction mixture was stirred for 16 h at RT. Then the reaction mixture was evaporated, diluted with ethyl acetate and subsequently extracted with aqueous LiCI (4 % w/w) and aqueous NaHCCb. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction. Yield: 7.2 g.; Example 77: 4-((S)-3-Carboxy-2-[5-[2-((S)-2-cyclopropylmethyl-carbamoyl-pyrrolidin-1 -yl)- 2-oxo-ethoxy]-1-(3-fluoro-phenyl)-1 H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1- carboxylic acid ethyl ester; (i) 4-((S)-3-tert-Butoxycarbonyl-2-[1 -(3-fluoro-phenyl)-5-hydroxy-1 H-pyrazole-3- carbonyl]-amino}-butyryl)-piperazine-1 -carboxylic acid ethyl ester; To a solution of 3.199 g 1-(3-fluoro-phenyl)-5-hydroxy-1 H-pyrazole-3-carboxylic acid(prepared by standard procedure using <strong>[2924-16-5]3-fluorophenylhydrazine hydrochloride</strong> and sodium diethyl-2-oxosuccinate followed by ester hydrolysis) and 4.743 g 4-((S)-2-amino-3-tert- butoxycarbonyl-propionyl)-piperazine-1 -carboxylic acid ethyl ester in 26 ml DMF 2.205 g HOBt, 2.5 ml DIPEA and 2.760 g EDC were added and the reaction mixture was stirred for 16 h at RT. Then the reaction mixture was evaporated, diluted with ethyl acetate and subsequently extracted with aqueous LiCI (4 % w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction. Yield: 7.2 g.
Morpholine-4-carboxamidine; hydrobromide[ No CAS ]
[ 40876-98-0 ]
[ 933686-76-1 ]
Yield
Reaction Conditions
Operation in experiment
Reference Example 10 -Chloro-l-morpholin^-vI-pyrimidine^-carboxylic acid methyl ester (Intermediate J)To a solution of diethyloxalacetate sodium salt (10 g) in ethanol (15 mL) and water (70 mL) was added an aqueous solution of sodium hydroxide (2.02 g in 10 mL) and the reaction was stirred at 30 C for 30 minutes. Then, morpholinoformamidine hydrogen bromide (8.09 g) was added and the pH adjusted to 11 with aqueous sodium hydroxide solution. The reaction was heated at 60 0C for 4 h and then cooled to room temperature. Hydrochloric acid was added until the pH reached 1.5. The solid was filtered, washed with water and air dried to give 6-hydroxy-2-morpholin-4-yl- pyrimidine-4-carboxylic acid as an off-white solid. To a suspension of 6-hydroxy-2-mophiholin-4-yl-pyrimidine-4-carboxylic acid(10 g) in methanol (20 mL) and toluene (80 mL) at 0C was added trimethylsilyl diazomethane (26.70 mL of a 2 M solution in ether) dropwise. After stirring at room temperature for 4 h the reaction was quenched with acetic acid (10 mL) and the solid was filtered and air dried to give 6-hydroxy-2-morpholin-4-yl-pyrimidine-4-carboxylic acid methyl ester.To a suspension of 6-hydroxy-2-morpholin-4-yl-pyrimidine-4-carboxylic acid methyl ester (10.175g) in phosphorus oxychloride (50 mL) was added N5N- dimethylaniline (1 mL) and the reaction was heated at reflux for 5 h. After cooling to room temperature the reaction was poured carefully onto ice-water. The mixture was basifed with sodium carbonate and then extracted into ethyl acetate. The organics were <n="70"/>washed with aqueous brine solution, dried (MgSO4) and reduced in vacuo to give the title compound.
A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 0C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). Characterising data for the compound are as follows: 1H nmr (400MHz, d6-DMSO) deltaH 13.30 (1H, br s), 12.97 (1H, br s), 6.59 (1H, s), 1.94 (1H, quintet), 1.04 (4H, m) ppm.
63%
A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 0C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). 1H nmr (400MHz, d6-DMSO) deltaH 13.30 (1 H, br s), 12.97 (1 H, br s), 6.59 (1 H, s), 1.94 (1 H, quintet), 1.04 (4H, m) ppm.
EXAMPLE 4 Preparation of 6-amirio-5-chloro-2- (4-chlorophenyl)-4-pyriinidirecarboxylic acid (Compound 65)' Step A: Preparation of 2- (4-chlorophenyl)-1, 6-dihydro-6-oxo-4-pyrimidinecarboxylic acid To a mixture of diethyl oxalacetate sodium salt (123.2 g, 586 mmol) in water (750 mL) was slowly added aqueous sodium hydroxide (50%, 47 g, 586 mmol). After 1 h the solids had dissolved. 4-Chlorobenzenecarboximidamide monohydrochloride (111.95 g, 586 mmol) was then added, and the mixture was heated at 70 C overnight. After cooling to room temperature concentrated hydrochloric acid was slowly added (causing foaming) until the pH was lowered to 1.5. The solid was isolated by filtration and washed with water and methanol. The solid was then triturated twice with hot methanol, washed repeatedly with 1 N hydrochloric acid, then once with methanol and dried to afford the title compound (66.07 g). 1H NMR (DMSO-d6) S 8. 23 (d, 2H), 7.65 (d, 2H), 6.90 (s, 1H).
2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 2 Preparation of 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (Compound 135) Step Al : Preparation of 2-cyclopropyl-1, 6-dihydro-6-oxo-4-pyrimidinecarboxylic acid To a mixture of diethyl oxalacetate sodium salt (150 g, 714 mmol) in methanol (300 mL) and water (150 mL) warmed to 30 °C was added 50percent aqueous sodium hydroxide (56 g, 700 mmol) in water (60 mL) over 30 minutes, over which time the temperature remained at 25-30 °C and the pH at 11-12. Then the stirred mixture was heated for an additional 30 min at 35 °C. To this mixture was added <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (64 g, 530 mol) in portions over 15 minutes. The orange solution was heated to 50 °C over 30 minutes and held at that temperature for 3 h. The reaction mixture was cooled to 35 °C, and concentrated hydrochloric acid (ca. 70 g, 0.7 mol) was added gradually (resulting in foaming) over 30 minutes at 30-40 °C until the pH was about 1.5- 2.5. The mixture was concentrated with a rotary evaporator at 35-40 °C to remove alcohols, stirred for 3-4 h at 25 °C to complete crystallization of the product. After the mixture was cooled to 0 °C the solid was collected by filtration. The solid was washed with water (2 x 60 mL), suction-dried, and then dried in a vacuum-oven at 60 °C to afford the title compound as a beige solid (ca. 60 g). 1H NMR (DMSO-d6) otilde; 6. 58 (s, 1H), 1.95 (m, 1H), 1.0 (m, 4H).; Step A2: Another preparation of 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidine- carboxylic acid To a mixture of diethyl oxalacetate sodium salt (210 g, 950 mmol) in methanol (500 mL) and water (400 mL) was added 50percent aqueous sodium hydroxide (80 g, 1.0 mol) in water (60 mL) over 30 minutes, over which time the temperature remained at 25-30 °C and the pH at 11-12. Then the stirred mixture was heated for an additional 30 min at 30 °C. To this mixture was added <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (110 g, 910 mol). The orange solution was heated to 50 °C over 30 minutes and held at that temperature for 5 h. The reaction mixture was cooled to 30 °C and concentrated to half volume at reduced pressure at 35-40 °C and concentrated hydrochloric acid (140 g, 1.4 mol) was added gradually (resulting in foaming) over 30 minutes at 25-30 °C until the pH was about 1-2. The mixture was stirred at 5 °C for 1 h to complete crystallization of the product. After the mixture was cooled to 0 °C the solid was collected by filtration. The solid was washed with water (3 x 60 mL), suction-dried, and then dried in a vacuum-oven at 70 °C to afford the title compound as a beige solid (100 g) ; m. p. 235-236 °C (dec. ). 1H NMR (DMSO-d6) 8 6.58 (s, 1H), 1.95 (m, 1H), 1.0 (m, 4H).
60 g
To a mixture of diethyl oxalacetate sodium salt (150 g, 714 mmol) in methanol (300 mL) and water (150 mL) warmed to 30° C. was added 50percent aqueous sodium hydroxide (56 g, 700 mmol) in water (60 mL) over 30 minutes, over which time the temperature remained at 25-30° C. and the pH at 11-12. Then the stirred mixture was heated for an additional 30 min at 35° C. To this mixture was added <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (64 g, 530 mol) in portions over 15 minutes. The orange solution was heated to 50° C. over 30 minutes and held at that temperature for 3 h. The reaction mixture was cooled to 35° C., and concentrated hydrochloric acid (ca. 70 g, 0.7 mol) was added gradually (resulting in foaming) over 30 minutes at 30-40° C. until the pH was about 1.5-2.5. The mixture was concentrated with a rotary evaporator at 35-40° C. to remove alcohols, stirred for 3-4 h at 25° C. to complete crystallization of the product. After the mixture was cooled to 0° C. the solid was collected by filtration. The solid was washed with water (2*60 mL), suction-dried, and then dried in a vacuum-oven at 60° C. to afford the title compound as a beige solid (ca. 60 g). 1H NMR (DMSO-d6) delta 6.58 (s, 1H), 1.95 (m, 1H), 1.0 (m, 4H).
In a 1 L round bottom flask, 55 g of sodium ethyloxalacetate (1.05 eq, 0.26 mol) and 26 g of formamidine acetate (1 eq, 0.25 mol) were added to a solution of sodium hydroxide (10 g) in 500 mL of water. The reaction mixture was stirred at room temperature for 16 hours.[00262] Concentrated HCl was added carefully to the mixture until pH = 1, a fine solid precipitated and the reaction mixture was stirred at 0°C for 1 hour. The solid was filtered then washed with water and ether. The white solid was then left in a vacuum oven heated at4O0C for 20 hours. Trituration in methanol gave the title compound in 25percent yield. 1H NMR(dbeta-DMSO): 12.88 (IH, OH), 8.24 (s, IH), 6.83 (s, IH).
15%
With sodium hydroxide; In water; at 20℃; for 12h;
To a solution of formamidine acetate (10?g, 96?mmol) in 200?mL of water was added diethyl oxalacetate sodium salt (21?g, 100?mmol) and sodium hydroxide (3.8?g, 96?mmol). The reaction mixture was stirred overnight at room temperature, before 6?N HCl was added carefully to adjust PH?=?1. The mixture was allowed to stand overnight at 0?°C, and the resultant precipitate was filtered and dried in vacuum to give the desired product (2?g, 15percent) as a red solid. 1H NMR (400?MHz, DMSO-d6) delta 12.90 (s, 1H), 8.25 (s, 1H), 6.83 (s, 1H).
Step 1: 6-Hydroxypyrimidine-4-carboxylic acid 63.5 g (0.3 mol) sodium diethyloxalacetate and 30.2 g (0.3 mol) formamidine acetate were added to 24.1 g (0.6 mol) NaOH in 3.6 L water. The mixture was stirred overnight at RT. Then activated charcoal was added and the mixture was refluxed for 1 h. It was filtered off while hot and after cooling acidified with a hydrochloric acid solution. The solution was concentrated to dryness by rotary evaporation. The residue contained the desired product and was used in the next step without any further purification. Yield: 83.0 g
Step 1:6-hydroxypyrimidine-4-carboxylic acid63.5 g (287 mmol) sodium diethyl-oxalacetate and 30.2 g (287 mmol) formamidine acetate were added to 24.1 g (597 mmol) NaOH in 3.6 L water.The mixture was stirred overnight at RT.Then activated charcoal was added and the mixture was refluxed for 1 h.It was filtered hot and after cooling acidified with aqueous HCl.The solution was concentrated to dryness by rotary evaporation.The residue contained the desired product and was used in the next step without further purification.Yield: 83.0 g
Step 1: 6-hydroxypyrimidine-4-carboxylic acid; 63.5 g (287 mmol) sodium diethyl-oxalacetate and 30.2 g (287 mmol) formamidine acetate were added to 24.1 g (0.597 mol) NaOH in 3.6 L water. The mixture was stirred overnight at RT. Then activated charcoal was added and the mixture was refluxed for 1 h. It was filtered while hot and after cooling acidified with aqueous HCl. The solution was concentrated to dryness by rotary evaporation. The residue contained the desired product and was used in the next step without any further purification.Yield: 83.0 g
Step 1:6-hydroxypyrimidine-4-carboxylic acid63.5 g (0.29 mol) sodium diethyloxalacetate and 30.2 g (0.29 mol) formamidine acetate were added to 24.1 g (0.6 mol) NaOH in 3.6 L water.The mixture was stirred overnight at RT.Then activated charcoal was added and the mixture was refluxed for 1 h.It was filtered off hot and after cooling acidified with aqueous hydrochloric acid.The solution was evaporated to dryness by rotary evaporation.The residue contained the desired product and was used in the next step without any further purification.Yield: 83.0 g
A solution of sodium hydroxide (2.17 g, 54 mmol) in water (4.5 ml) was added to a stirred suspension of diethyl oxaloacetate sodium salt (6.65 g, 31.7 mmol) in water (40 ml) and the mixture stirred for 20 minutes until all the solid dissolved. 2-Pyridineamidine (3.85 g, 31.8 mmol) was added and the reaction mixture stirred at 70 0C overnight, then allowed to cool. Concentrated hydrochloric acid was added to bring the mixture to pH 1 and the solid removed by filtration to give 4-hydroxy-2-pyridin-2-ylpyrimidine-6- carboxylic acid as an off-white solid (4.00 g, 58%). 1H nmr (400 MHz, d6-DMSO) deltaH 8.79 (1 H, m), 8.42 (1 H, d), 8.12 (1 H, t), 7.70 (1 H, m), 7.0 - 5.5 (2H, br s), 6.96 (1 H, s) ppm.
Sodium hydroxide (0.4 g, 10 mmol) was added to a stirred solution of <strong>[40876-98-0]diethyl oxaloacetate sodium salt</strong> (1.3 g, 6.2 mmol) in water (50 ml) and the mixture stirred for 30 minutes. 2-Thiopheneamidine (1.0 g, 7.9 mmol) was added to the solution and the mixture was heated at 70 0C overnight, then cooled to 0 0C, acidified to pH1 and allowed to stand for an hour. The precipitate was isolated by filtration, washed with water and cold ethyl acetate and dried to yield 4-hydroxy-2-thiophen-2-ylpyrimidine-6-carboxylic acid as a white solid (0.81 g, 60%).1H nmr (400 MHz, d6-DMSO) deltaH 8.1 (1H, m), 7.85 (1 H, m), 7.2 (1H, m), 6.7 (1 H1 s) ppm (exchangeable protons not observed).
Example 2; 6-Me-3,2-HOPO3-Hydroxy-6-methyl-2(lH)-pyridinone-4-carboxylic Acid (6-1).[0261] This compound was synthesized by adapting a previously reported procedure (ref Feist, D. Chem. Ber. 1902, 55, 1540.). Sodium diethyloxylacetate (42.1 g, 200 mmol) was dissolved in THF (500 mL) and then placed into a 1-L three-neck round bottom flask. Chloroacetone (16 mL, 200 mmol) was added to the mixture. After 10 min, NH3 gas was bubbled through the reaction mixture. Finally, A1C13 (2.67 g, 20 mmol) was slowly added. The reaction mixture was stirred under ambient conditions for 5 days. The resulting orange solid was filtered off and suspended in 1 M HCl (500 mL) so that the pH < 3. The resulting suspension was stirred for 30 min and the precipitate filtered off, washed with distilled water, and recrystallized from hot EtOH(approximately 1 L) to yield colorless crystals (yield: 15.7 g, 40%). Mp: 227- 229 0C.[0262] IH NMR (J6-DMSO, 300 MHz): delta 1.24 (t, 3H, CH3), 2.07 (s, 3H, CH3), 4.22 (q, 2H, CH2), 6.07 (s, IH, CH).[0263] Anal. Calcd (found) for C9Hl lO4N: C, 54.82 (55.06); H, 5.62 (5.53); N, 7.11 (7.07).[0264] EI-MS (+): mlz 198 [MH+].
31.2%
10Part of <strong>[40876-98-0]oxalacetic acid diethyl ester sodium</strong>salt, dissolved in 100mL of tetrahydrofuran,Then add 5 parts of chloroacetone, ammonia gas was introduced into the reaction 4h, and then slowly added 0.5 parts of aluminum chloride, the reaction at room temperature for 5d. Stop the reaction,Suction filtration, the filter cake was dissolved in 700mL HCl, the pH <3, stirred 0.5h, suction filtration, the filter cake was washed with water, the filter cake was collected, recrystallized with absolute ethanol, , Yield: 31.2%.
Stepl : Diethyl (2Z)-2-hydroxybut-2-enedioate Diethyl oxalacetate, sodium salt (12O g, 0.571 mol) was partitioned between aqueous HCl (1.5 L adjusted to pH ~3) and CH2CI2 (500 mL). The layers were stirred at room temperature for 2.5 hours until completely homogenous. The organic extract was separated and the aqueous layer was extracted twice more with CH2CI2 (2X250 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated under vacuum. The resultant yellow oil was used in the following step without further purification.; Step 2 : Ethyl 3 -hydroxy-2-methyl-^-oxo- 1 ,2-dihydropyridine-4-carboxyIate For 30 minutes ammonia gas was bubbled vigorously through a cold (30C5 ice bath) mixture of diethyl oxalacetate (50.0 g, 0.265 mol) and chloroacetone (29.5 g, 0319 mol) in anhydrous THF (1 L) stirred with a mechanical stirrer. The solution turned dark orange and the temperature increased to 120C and then dropped to 5C. Ammonium acetate (40.9 g, 0.531 mol) was added and the reaction mixture was heated at reflux for 3 hours. The resultant bright yellow product mixture was cooled to room temperature and then slowly cooled to 50C using an ice bath. The yellow precipitate was collected by vacuum filtration, washing with THF, and stirred in aqueous HCl (1 M, 300 mL) for 30 minutes. The solid was then collected by filtration and dried under vacuum over night with heating to provide the title product as an off white solid. 1 H NMR (400 MHz, CDCI3) 6 12.0 (br s, IH), 9.90 (br s, IH), 6.14 (s, IH), 4.30 (q, J- 7.1 Hz,2H), 2.14 (s, 3H), 1.31 (t, J= 7.1 Hz5 3H). ES MS M+l - 198.3.
General procedure: A mixture of compound 1 (1 equiv) and aldehyde (1 equiv) together with an equimolar amount of amine in ethanol was refluxed towards completion (0.5 - 2 hours). Iced-water was added to the mixture after cooling and HCl was then added dropwise to pH 1. Filter the solid while appear. Traces aldehyde in the crude product was washed with water and ether to give (4a-k). Ethyl 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (4a) White solid; 60%; m.p. 106-109oC. IR (ATR) n/cm-1: 3344 (OH), 2986 (NH, amide), 1782 (C=O, ester), 1687 (C=C), 1670 (-N-C=O, amide), 1302 (C-N); 1H-NMR (400 MHz, CDCl3): delta 4.91-4.85 (2H, s, CH2), 4.39-4.32 (2H, q, J= 7.2 Hz, CH2), 1.38-1.31 (3H, t, J= 7.1 Hz, CH3); 13C-NMR (100 MHz, CDCl3,): delta 166.54 (COH), 164.23 (C=O) 151.29 (C=O), 116.09 (quat. C), 66.26 (OCH2), 62.09 (CH2), 14.34 (CH3); Anal. Calcd. for C7H9NO4: C, 49.12; H, 5.30; N, 8.18; O, 37.39. Found: C, 49.30; H, 4.65; N, 7.04; O, 39.01; GCMS m/z(EI, + ve): found 172.00 ([M]+), C7H9NO4 calculated 172.06
A stirred solution of diethyl oxalacetate sodium salt (504 mg, 2.4 mmol) and l-tert-butyl-3- methyl pyrazol-5-ylamine (250 mg, 1.63 mmol) in a mixture of acetic acid / water (0.3 mL, 6 mL), was heated at 80 C for 4 h. The reaction mixture was cooled to room temperature and the solid precipitate was filtered off then washed with water (50 mL). The solid was dissolved in ethyl acetate (50 mL) and dried over sodium sulfate. The organic layer was evaporated in vacuo to afford the title compound as a pale yellow solid (240 mg, 53%). HPLC-MS (Method A): MH+ requires m/z=278; Found m/z=278, Rt 3.63 min (100%). 1H MR (300 MHz, CDC13) delta 9.46 (br, 1H), 6.78 (s, 1H), 4.47-4.40 (q, 2H), 2.49 (s, 3H), 1.72 (s, 9H) and 1.44- 1.40 (t, 3H).
Compound B-26[0984] Step 1 : Synthesis of ethyl 3-ethyl-6-hydroxy-lH-pyrazolo[3,4-b]pyridine-4- carboxylate[0985] A stirred solution of 5-ethyl-lH-pyrazol-3-amine (1 g, 9.00 mmol) in acetic acid (6.6 niL) and water (20 niL) was cooled to 0 C and diethyl oxaloacetate sodium salt (1.88 g, 9.00 mmol) was added to it. Resulting solution was heated at 100 C for overnight. After completion of the reaction, the solid was filtered and dried to obtain the desiredintermediate (0.52 g, 24.6%).
6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With acetic acid; In water; at 85℃; for 15h;
1.1: 6-Hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester To a solution of 3-aminopyrazole (224 g, 2.7 mol) in water (1 L) were added a solution of diethyl oxalacetate sodium salt (567 g, 2.7 mol) in water (1.3 L) and then acetic acid in 4 portions (0.8 L). The reaction mixture was heated at 85C for 15 hours then cooled to room temperature and filtered. The precipitate was washed with water and then dried to afford the title compound as an orange solid (159 g, 28%). 1 H NMR (250 MHz, DMSO): delta 1.35 (t, 3H), 4.36 (q, 2H,), 6.69 (s, 1H), 8.16 (s, 1H).
28%
With acetic acid; In water; at 85℃; for 15h;
1.1: 6-Hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester To a solution of 3-aminopyrazole (224 g, 2.7 mol) in water (1 L) were added a solution of diethyl oxalacetate sodium salt (567 g, 2.7 mol) in water (1.3 L) and then acetic acid in 4 portions (0.8 L). The reaction mixture was heated at 85 C. for 15 hours then cooled to room temperature and filtered. The precipitate was washed with water and then dried to afford the title compound as an orange solid (159 g, 28%). 1H NMR (250 MHz, DMSO): delta 1.35 (t, 3H), 4.36 (q, 2H), 6.69 (s, 1H), 8.16 (s, 1H).
28%
With acetic acid; In water; at 85℃; for 15h;
1 .1 : 6-Hydroxy-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl esterTo a solution of 3-aminopyrazole (224 g, 2.7 mol) in water (1 L) were added a solution of diethyl oxalacetate sodium salt (567 g, 2.7 mol) in water (1 .3 L) and then acetic acid in 4 portions (0.8 L). The reaction mixture was heated at 85C for 15 hours then cooled to room temperature and filtered. The precipitate was washed with water and then dried to afford the title compound as an orange solid (159 g, 28%).1 H NMR (250 MHz, DMSO): ? 1 .35 (t, 3H), 4.36 (q, 2H,), 6.69 (s, 1 H), 8.16 (s, 1 H).
22%
With acetic acid; In water; at 0 - 100℃;
[0713] Step 2: Synthesis of ethyl 6-hydroxy-lH-pyrazolo[3,4-b]pyridine-4-carboxylate [0714] A stirred solution of lH-pyrazol-3 -amine (45 g, 542 mmol) in acetic acid (297 mL) and water (900 mL) was cooled to 0 C and <strong>[40876-98-0]diethyl oxaloacetate sodium salt</strong> (1 13.85 g:542.16 mmol) was added to it. Resulting solution was heated at 100 C for overnight. After completion of reaction, solid was filtered and dried to obtain the desired intermediate (25 g, 22%).
22%
In water; acetic acid; at 100℃; for 16h;
A stirred solution of lH-pyrazol-3-amine (45 g, 542.16 mmol) in acetic acid (297 mL) and water (900 mL) was cooled to 0 C and <strong>[40876-98-0]diethyl oxaloacetate sodium salt</strong> (113.85 g, 542.16 mmol) was added. The resulting solution was heated at 100 C for 16 h. After which time the solids were filtered and dried to obtain the title compound (22% yield).
With hydrogenchloride; acetic acid; In water; at 80℃; for 17h;Reflux;
A mixture of 3-amino-5-methylpyrazole (50.0 g), diethyl oxalate sodium salt (127.3 g) and acetic acid (113 mL) in 1N aqueous hydrochloric acid (625 mL) was stirred at 80 C. for 14 h, then refluxed for 3 h, cooled to r.t., and the precipitate formed was filtered by suction filtration and dried in vacuo at 60 C. The crude product was stirred in 500 mL ethyl acetate at r.t. and the solid was filtered off and dried in air. 40.2 g (35%) of the title compound were obtained as pale yellow solid. 1H-NMR (500 MHz, d6-DMSO): 1.33 (t, 3H), 2.45 (s, 3H), 4.34 (q, 2H), 6.44 (s, 1H), 11.90 (br s, 1H), 13.05 (br s, 1H). LC/MS (Method LC1): Rt=0.91 min; m/z=222.1 [M+H]+.
21.9%
With acetic acid; In water; at 0 - 100℃;
Synthesis of Compound B-13: N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3- yl)methyl)-l-isopropyl-3-methyl-6-(2,2,6,6-tetramethyl- 1 ,2,3, 6-tetrahydropyridin-4-yl)-lH- pyrazolo [3 ,4-b]pyridine-4-carboxamideCompound B- 13[0884] Step 1 : ethyl 6-hydroxy-3 -methyl- lH-pyrazolo [3, 4-b]pyridine-4-carboxylate[0885] A stirred solution of 5 -methyl- lH-pyrazol-3 -amine (5 g, 51.48 mmol) in acetic acid (33 mL) and water (100 mL) was cooled to 0 C and <strong>[40876-98-0]diethyl oxaloacetate sodium salt</strong> (10.81 g, 51.48 mmol) was added to it. Resulting solution was heated at 100 C for overnight. After completion of reaction the solid was filtered and dried to obtain the desired intermediate (2.5 g, 21.9%).
With sodium hydroxide; In water; at 20℃; for 22h;pH 10 - 11;
Step 1) Synthesis of 2-butyl-6-hydroxypyrimidine-4-carboxylic acid :<strong>[40876-98-0]diethyl oxaloacetate sodium salt</strong> was added 80 mL of water. To the stirred suspension was added 16 mL (100 mmol) of 6.25 M NaOH(aq.) over 1 min at ambient temperature. The mixture was stirred for 10 min, until only traces of undissolved oxaloacetate ester remained, giving an orange solution. To this was added a solution of 13.9 g (100 mmol) of n-pentanamidine hydrochloride in 20 mL of water. The reaction was monitored with a pH meter, and additional 6.25M NaOH was added as necessary to keep the pH between 10 and 11. After stirring at ambient temperature for 22 h, the mixture was cooled with an ice bath, then 12M HCl was added until pH=2, giving a white precipitate. This was filtered, washed with 50 mL of water, then dried on the filter for 1 h. The white solid was suspended in 50 mL of heptanes and distilled at 1 bar with a Dean-Stark trap until no more water collected in the trap. The suspension was cooled, filtered, and dried on the filter to give 8.13 g (41%) of 2-butyl-6-hydroxypyrimidine-4-carboxylic acid. MS (ESI) calcd for C9H12N2O3: 196. found: 197 [M+H].
With acetic acid; In water; toluene; at 80 - 130℃; for 10h;
Reference Example 36 tert-Butyl[(1-benzyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl]methylcarbamate Step (i) [0471] To a solution of Compound (Ib) (1.32 g, 6.3 mmol) in a mixture of acetic acid (13 mL) and toluene (6.3 mL) was added a solution of Compound (IIb) (1.00 g, 6.3 mmol) in water (6.3 mL). The reaction mixture was stirred at 80 C. for 4 hours, at 120 C. for 3 hours, and then at 130 C. for 3 hours. The solvent was evaporated under reduced pressure and water (3 mL) was added to the concentrated residue. The resulting solid was collected by filtration and toluene (5 mL) was added thereto. The mixture was heated under reflux for 1 hour, slowly cooled to 0 C., and stirred at 0 C. for 1 hour. The solid was collected by filtration and dried under reduced pressure to give Compound (IIIb) (919 mg, 59%).
6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With hydrogenchloride; acetic acid; In water; at 80℃; for 14h;
5-Aminopyrazole (25 g) and diethyl oxalacetate sodium salt (74.4 g) were dissolved under cooling in 1 N hydrochloric acid. 68.75 ml_ of glacial acetic acid were added and the mixture was stirred at 80C for 14 h. The mixture was cooled to room temperature and the formed precipite was filtered off and titurated in ethyl acetate to give 16.06 g (26%) of the desired product.LC/MS (Method LC1 ): Rt = 0.86 min; m/z = 208.07 [M+H]+.
26%
With hydrogenchloride; acetic acid; In water; at 80℃; for 14h;
(a) 6-Hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester 5-Aminopyrazole (25 g) and diethyl oxalacetate sodium salt (74.4 g) were dissolved under cooling in 1N hydrochloric acid. 68.75 mL of glacial acetic acid were added and the mixture was stirred at 80 C. for 14 h. The mixture was cooled to room temperature and the formed precipite was filtered off and titurated in ethyl acetate to give 16.06 g (26%) of the desired product. LC/MS (Method LC1): Rt=0.86 min: m/z=208.07 [M+H]+.
General procedure: A suspension of sodium diethyl oxalacetate (3) (1 equiv), methylamine(2) (1 equiv), and aldehyde (1) (1 equiv) in ethanol was heated atreflux till completion (TLC).After cooling, the mixture was added on ice-water and then acidified with HCluntil pH 4. The precipitate was filtered, washed with water and petroleum etherin order to remove traces of aldehyde. After drying under reduced pressure the2,3-dioxopyrrolidines 4a-c wereobtained with sufficient purity as white solids
General procedure: A suspension of sodium diethyl oxalacetate (3) (1 equiv), methylamine(2) (1 equiv), and aldehyde (1) (1 equiv) in ethanol was heated atreflux till completion (TLC).After cooling, the mixture was added on ice-water and then acidified with HCluntil pH 4. The precipitate was filtered, washed with water and petroleum etherin order to remove traces of aldehyde. After drying under reduced pressure the2,3-dioxopyrrolidines 4a-c wereobtained with sufficient purity as white solids
General procedure: A suspension of sodium diethyl oxalacetate (3) (1 equiv), methylamine(2) (1 equiv), and aldehyde (1) (1 equiv) in ethanol was heated atreflux till completion (TLC).After cooling, the mixture was added on ice-water and then acidified with HCluntil pH 4. The precipitate was filtered, washed with water and petroleum etherin order to remove traces of aldehyde. After drying under reduced pressure the2,3-dioxopyrrolidines 4a-c wereobtained with sufficient purity as white solids
Acetic acid 2-methylene-3-oxo-1-p-tolyl-butyl ester[ No CAS ]
[ 40876-98-0 ]
C19H20O6[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
In N,N-dimethyl-formamide; at 120℃; for 1h;
General procedure: A mixture of 1a (109 mg, 0.5 mmol) and 2a (116 mg, 0.55 mmol) in DMF (1.0 mL) was stirred at 120 C for 1 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 4:1), compound 4a was obtained as pale yellow oil, 123 mg (75%). Other compounds were synthesized similarly, and the spectroscopic data of 4a fare as follows.
Acetic acid 1-(4-chloro-phenyl)-2-methylene-3-oxo-butyl ester[ No CAS ]
[ 40876-98-0 ]
[ 1510830-61-1 ]
Yield
Reaction Conditions
Operation in experiment
79%
In N,N-dimethyl-formamide; at 120℃; for 1h;
General procedure: A mixture of 1a (109 mg, 0.5 mmol) and 2a (116 mg, 0.55 mmol) in DMF (1.0 mL) was stirred at 120 C for 1 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 4:1), compound 4a was obtained as pale yellow oil, 123 mg (75%). Other compounds were synthesized similarly, and the spectroscopic data of 4a fare as follows.
General procedure: A mixture of 1a (218 mg, 1.0 mmol) and 2a (231 mg, 1.1 mmol) in DMF (1.5 mL) was stirred at room temperature for 12 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/CH2Cl2/EtOAc, 10:1:1), compound 3a was obtained as colorless oil, 183 mg (53%) along with 5a (43 mg, 17%). Other compounds were synthesized similarly, and the spectroscopic data of 3a, 5a, 6a, 3d,3f and 3h are as follows.
General procedure: A mixture of 1a (109 mg, 0.5 mmol) and 2a (116 mg, 0.55 mmol) in DMF (1.0 mL) was stirred at 120 C for 1 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 4:1), compound 4a was obtained as pale yellow oil, 123 mg (75%). Other compounds were synthesized similarly, and the spectroscopic data of 4a fare as follows.
General procedure: A mixture of 1a (109 mg, 0.5 mmol) and 2a (116 mg, 0.55 mmol) in DMF (1.0 mL) was stirred at 120 C for 1 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 4:1), compound 4a was obtained as pale yellow oil, 123 mg (75%). Other compounds were synthesized similarly, and the spectroscopic data of 4a fare as follows.
Acetic acid 2-methylene-3-oxo-1-phenyl-pentyl ester[ No CAS ]
[ 40876-98-0 ]
[ 1510830-69-9 ]
Yield
Reaction Conditions
Operation in experiment
56%
In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: A mixture of 1a (218 mg, 1.0 mmol) and 2a (231 mg, 1.1 mmol) in DMF (1.5 mL) was stirred at room temperature for 12 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/CH2Cl2/EtOAc, 10:1:1), compound 3a was obtained as colorless oil, 183 mg (53%) along with 5a (43 mg, 17%). Other compounds were synthesized similarly, and the spectroscopic data of 3a, 5a, 6a, 3d,3f and 3h are as follows.
Acetic acid 2-methylene-3-oxo-1-phenyl-pentyl ester[ No CAS ]
[ 40876-98-0 ]
[ 1510830-64-4 ]
Yield
Reaction Conditions
Operation in experiment
74%
In N,N-dimethyl-formamide; at 120℃; for 1h;
General procedure: A mixture of 1a (109 mg, 0.5 mmol) and 2a (116 mg, 0.55 mmol) in DMF (1.0 mL) was stirred at 120 C for 1 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 4:1), compound 4a was obtained as pale yellow oil, 123 mg (75%). Other compounds were synthesized similarly, and the spectroscopic data of 4a fare as follows.
General procedure: A mixture of 1a (218 mg, 1.0 mmol) and 2a (231 mg, 1.1 mmol) in DMF (1.5 mL) was stirred at room temperature for 12 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/CH2Cl2/EtOAc, 10:1:1), compound 3a was obtained as colorless oil, 183 mg (53%) along with 5a (43 mg, 17%). Other compounds were synthesized similarly, and the spectroscopic data of 3a, 5a, 6a, 3d,3f and 3h are as follows.
A mixture of 1a (109 mg, 0.5 mmol) and 2a (116 mg, 0.55 mmol) in DMF (1.0 mL) was stirred at 120 C for 1 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 4:1), compound 4a was obtained as pale yellow oil, 123 mg (75%). Other compounds were synthesized similarly, and the spectroscopic data of 4a fare as follows.
EXAMPLE 15: Et02C-Pz Coupling Moiety [00450] An ethyl ester-pyrazalinone (Et02C-Pz) electrophilic trap coupling moiety was synthesized according to Scheme 15 below. I l l [00451] Ethyl l-methyl-5-oxo-4,5-dihydro-lH-pyrazole-3-carboxylate (Gl) - A solution of 165 methylhydrazine, 660mg sodium diethyl oxaloacetate, 179 acetic acid and 6 mL ethanol were heated at 50C for 20h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography using 3% methanol:DCM to yield 120mg of the desired product. [00452] 1H NMR (400MHz, CDC13) 5.97 (s, 1H), 4.34 (q, J= 7.2Hz, 2H), 3.72 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H). LRMS (ESI) calcd for C7Hi0N2O3 [M+H]+: 171; found 171.
N'-((1R,3R,5S)-9-((1R,6S,8S)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)benzene-1,2-diamine[ No CAS ]
[ 40876-98-0 ]
ethyl 2-(4-((1R,3R)-9-(bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With acetic acid; In toluene; at 100℃; for 7h;Inert atmosphere;
ethyl 2-(4-((1R,3R)-9-(bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)acetate (d10) To a solution of c14 (1.0 g, 2.72 mmol) in toluene (20 mL) were added <strong>[40876-98-0]<strong>[40876-98-0]oxalacetic acid diethyl ester sodium</strong> salt</strong> (1.14 g, 5.44 mmol) and acetic acid (0.545 mL, 9.52 mmol) at a temperature of about 25 C. under a nitrogen atmosphere. The mixture was stirred at 100 C. for 7 hr. The reaction mixture was diluted with saturated aqueous NaHCO3 and then extracted with EtOAc (2*50 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated. The resulting crude product was chromatographed (silica-gel 24 g, MeOH/CHCl3=0/100?1/19) to provide 1.16 g of d10 as a yellow solid. (Yield 87%) d10: 1H-NMR (300 MHz, CDCl3-CD3OD-DCl) delta: 1.17-2.09 (m, 19H), 2.20-2.61 (m, 8H), 2.71-3.50 (m, 3H), 4.17-4.28 (m, 6H), 5.79-5.82 (m, 1H), 6.94-7.84 (m, 4H).
[4-((1R,6S)-8-bicyclo[4.3.1]dec-8-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxalin-2-yl]acetic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With acetic acid; In ethanol; at 100℃; for 8h;Inert atmosphere;
[4-((1S,3R,5R)-(1R,6S,8S)-8-bicyclo[4.3.1]dec-8-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxalin-2-yl]-acetic acid ethyl ester (d2) To a solution of c6 (578 mg, 1.64 mmol) in ethanol (6 mL) was added <strong>[40876-98-0]<strong>[40876-98-0]oxalacetic acid diethyl ester sodium</strong> salt</strong> (977 mg, 4.41 mmol) and acetic acid (0.505 mL, 8.83 mmol) at temperature of about 25 C. under a nitrogen atmosphere. The mixture was stirred at 100 C. for 8 hr. The reaction mixture was diluted with saturated aqueous NaHCO3, then extracted with CHCl3 (2*30 mL). The combined organic phases were washed with saturated aqueous NaCl and dried (MgSO4) and concentrated. The resulting brown solid was chromatographed (silica-gel 45 g, AcOEt/n-hexane=1/3?1/0) to provide 385 mg of compound d2 as a light brown solid. (Yield 49%) d2: 1H-NMR (300 MHz, CDCl3-CD3OD-DCl) delta: 1.18-1.46 (m, 10H), 1.60-1.94 (m, 7H), 2.14-2.58 (m, 8H), 2.82-3.10 (m, 2H), 3.19 (d, J=16.5 Hz, 0.5H), 3.50 (d, J=16.5 Hz, 0.5H), 4.06-4.38 (m, 6H), 5.80-6.26 (m, 1H), 6.93-8.18 (m, 4H); LC/MS: m/z=478.4 [M+H]+ (Calc: 477).
ethyl 2-(4-((1R)-8-(bicyclo[4.3.1]decan-8-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.2%
With acetic acid; In toluene; at 100℃; for 2.5h;Inert atmosphere;
ethyl-2-(4-((1R,3R)-8-(bicyclo[4.3.1]decan-8-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)acetate (d15) To a solution of c6 (700 mg, 1.980 mmol) in toluene (14 mL) was added AcOH (0.249 mL, 4.36 mmol) and diethyl oxalacetate sodium salt (499 mg, 2.376 mmol) at a temperature of about 25 C. under a nitrogen atmosphere. The mixture was stirred at 100 C. for 2.5 hr. After cooling to a temperature of about 25 C. and concentration, the resulting oil was chromatographed (ISCO, 80 g, CHCl3/10% NH3 in MeOH=99/1?95/5) to provide 806 mg of d15 as a brown amorphous solid. (Yield 85.2%) d15: 1H-NMR (300 MHz, CDCl3) delta: 1.24-1.46 (m, 6H), 1.59-1.77 (m, 10H), 2.06 (s, 3H), 2.07-2.31 (m, 8H), 2.60 (s, 2H), 3.93 (s, 2H), 4.21 (q, J=7.1 Hz, 4H), 5.74 (s, 1H), 7.04 (s, 1H), 7.33 (d, J=11.6 Hz, 2H), 7.60 (s, 1H); LC/MS: m/z=493.3 [M+H]+ (Calc: 492.61).
ethyl 6-amino-4-(3-methoxyphenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.5h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
ethyl 6-amino-4-(4-chlorophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.3h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
ethyl 6-amino-4-(3-nitrophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.2h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
ethyl 6-amino-4-(3-fluorophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.2h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
ethyl 6-amino-4-(4-isopropylphenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.5h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
ethyl 6-amino-4-(4-fluorophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.3h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
ethyl 6-amino-4-(2-nitrophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.3h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
ethyl 6-amino-4-(4-ethoxyphenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydrazine hydrate; acetic acid; In ethanol; at 120℃; for 1.5h;
General procedure: A mixture of malononitrile(2) (0.01 mol) and aromatic aldehyde (3) (0.01 mol) in EtOH was heated for 1 h. Next, a mixture of the sodium salt of diethyloxaloacetate (0.01 mol) (1)and hydrazine hydrate (4) in AcOH was added. The solution was heatedat 120omicronC for 15-30 min. After cooling, the precipitated solid was filtered,and recrystallized from EtOH.
(E)-5-((4-chlorobenzylidene)amino)-1,3-dimethylpyridin-2(1H)-one[ No CAS ]
[ 40876-98-0 ]
ethyl 2-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dioxopyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With acetic acid; at 110℃; for 1h;
Step 73.2: ethyl 2-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dioxopyrrolidine-3-carboxylate To a stirred solution of (E)-5-((4-chlorobenzylidene)amino)-1,3-dimethylpyridin-2(1H)-one (Step 73.1) (4 g, 15.34 mmol) in AcOH (40 mL) was added <strong>[40876-98-0]diethyl oxaloacetate sodium salt</strong> (6.45 g, 30.7 mmol) and the resulting mixture was heated up and stirred at 110 C. for 1 hr. The reaction was concentrated under reduced pressure, diluted with CH2Cl2 and water and both phases separated. The aqueous layer was extracted twice with CH2Cl2, combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated in Et2O to afford the title product (4.42 g, 8.34 mmol, 54% yield) as beige solid. tR: 0.86 min (LC-MS 2); ESI-MS: 403 [M+H]+, ESI-MS: 401 [M-H]- (LC-MS 2)
54%
In acetic acid; at 110℃; for 1h;
To a stirred solution of (E)-5-((4-chlorobenzylidene)amino)-1,3-dimethylpyridin-2(1H)-one (Step 73.1) (4 g, 15.34 mmol) in AcOH (40 mL) was added <strong>[40876-98-0]diethyl oxaloacetate sodium salt</strong> (6.45 g,30.7 mmol) and the resulting mixture was heated up and stirred at 110 00 for 1 hr. The reactionwas concentrated under reduced pressure, diluted with CH2CI2 and water and both phases separated. The aqueous layer was extracted twice with CH2CI2, combined organic layers were washed with brine, dried over Na2504, filtered and concentrated under reduced pressure. The crude product was triturated in Et20 to afford the title product (4.42 g, 8.34 mmol, 54% yield) as beige solid. tR: 0.86 mm (LC-MS 2); ESl-MS: 403 [M+H], ESl-MS: 401 [M-H] (LC-MS 2).
ethyl 1-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80 g
With acetic acid; at 100℃; for 20.0h;
A solution of 160 g (0.76 mol) of sodium 1,4-diethoxy-1,4-dioxobut-2-en-2-olate and 109 g (0.76 mol) of <strong>[51859-98-4](2-fluorobenzyl)hydrazine</strong> in 1 l of glacial acetic acid was heated at 100 C. for 20 h. After cooling, the mixture was concentrated under reduced pressure. Water and dichloromethane were added to the residue, and the precipitate was filtered off and dried. 80 g (40% of theory) of the target compound were obtained.
(3,3,4,4,4-pentafluorobutyl)hydrazine hydrochloride salt[ No CAS ]
[ 40876-98-0 ]
C10H11F5N2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With acetic acid; In benzene; at 90℃; for 4h;
Step 3: Synthesis of ethyl5-oxo- 1 -(3,3 ,4,4,4-pentafluorobutyl)-2,5-dihydro- 1 H-pyrazole-3 -carboxylate. To a prestirred mixture of diethyl oxalacetate sodium salt (1 equiv.) and acetic acid (10 equiv.) in benzene was added (3,3,4,4,4-pentafluorobutyl)hydrazine hydrochloride (1 equiv.). The mixture was heated to 90 C for 4 h. The solvent was removed in vacuo, and the resulting precipitate was rinsed with a minimal amount of diethyl ether, collected by filtration, and dried under vacuum to deliver the desired intermediate, ethyl 5 -oxo- 1 -(3,3 ,4,4,4-pentafluorobutyl)-2,5 -dihydro- 1 H-pyrazole-3 -carboxylate (2.93 g, 24% yield) as a white solid.?H NMR (500 MHz, DMSO-d6) ppm 5.78 (s, 1 H), 4.13 - 4.32 (m, 4 H), 2.64 - 2.83 (m, 2 H), 1.19 - 1.34 (m, 3 H).
(3,3,3-trifluoropropyl)hydrazine hydrochloride salt[ No CAS ]
[ 40876-98-0 ]
ethyl 5-hydroxy-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With acetic acid; In benzene; at 60℃; for 3h;
Step 1: Synthesis of ethyl 5-hydroxy- 1 -(3,3,3 -trifluoropropyl)- 1 H-pyrazole-3 -carboxylate. A mixture of acetic acid (1 equiv.), sodium diethyl oxalacetate (1 equiv.) and (3,3,3 -trifluoropropyl)hydrazine hydrochloride (1 equiv.) in benzene was heated to 60 C for 3 h. Themixture was diluted in ethyl acetate and washed with iN HC1 solution. The organic layer was dried, filtered and evaporated to give a crude oil. The oil was purified via silica gel chromatography (0 to 100% ethyl acetate in hexanes) to deliver the desired intermediate, ethyl5-hydroxy-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylate (1.0 g, 17% yield) as a light yellow solid.?H NMR (500 MHz, CD3OD) ppm 5.86 (s, 1 H), 4.32 (q, 2 H), 4.26 (t, 2 H), 2.66 - 2.80 (m, 2 H), 1.33- 1.38 (m, 3 H).
Sten 1: Synthesis of ethyl 1 -(2-fluorobenzyl)-5 -hydroxy- 1 H-pyrazole-3 -carboxylate.A mixture containing acetic acid (15 equiv.) and diethyl oxalacetate sodium salt (1 equiv.) in benzene was stirred at 25 C for 30 mm. To this mixture was added (2-fluorobenzyl)hydrazine hydrochloride (2 equiv.). The resulting mixture was heated to 100 C for 2 h. The mixture was cooled to 23 C and concentrated under vacuum. The precipitate formed was collected by filtration. The solid was dissolved in ethyl acetate and washed with iN HC1 solution (x3). The organic layer was dried, filtered, and evaporated to give a solid containing the desired product. The solid was rinsed with a minimal amount of a methanol-diethyl ether mixture, dried under vacuum to deliver the desired intermediate, ethyl 1 -(2-fluorobenzyl)-5 -hydroxy-1H-pyrazole-3-carboxylate (11.8 g, 71 % yield) as a cream colored solid.?H NMR (500 MHz, CD3OD) ppm 7.24 - 7.41 (m, 1 H), 7.09 - 7.16 (m, 2 H), 7.02 - 7.07 (m, 1 H), 5.95 (s, 1 H), 5.29 (s, 2 H), 4.33 (q, 2 H), 1.36 (t, 3 H).
71%
A mixture containing acetic acid (15 equiv.) and diethyl oxalacetate sodium salt (1 equiv.) in benzene was stirred at 25 C for 30 min. To this mixture was added(2-fluorobenzyl)hydrazine hydrochloride (2 equiv.). The resulting mixture was heated to 100 C for 2 h. The mixture was cooled to 23 C and concentrated under vacuum. The precipitate formed was collected by filtration. The solid was dissolved in ethyl acetate and washed with IN HC1 solution (x3). The organic layer was dried, filtered, and evaporated to give a solid containing the desired product. The solid was rinsed with a minimal amount of a methanol-diethyl ether mixture, dried under vacuum to deliver the desired intermediate, ethyll-(2-fluorobenzyl)-5-hydroxy-lH-pyrazole-3-carboxylate (11.8 g, 71 % yield) as a cream colored solid. 'H NMR (500 MHz, CD3OD) delta ppm 7.24 - 7.41 (m, 1 H), 7.09 - 7.16 (m, 2 H), 7.02 - 7.07 (m, 1 H), 5.95 (s, 1 H), 5.29 (s, 2 H), 4.33 (q, 2 H), 1.36 (t, 3 H)
To a solution of diethyl oxalacetate sodium salt (100 g, 476 mmol) in ethanol (250.00 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (113 g, 952 mmol) and the reaction was stirred at room temperature for 30 min. Acetic acid (54.5 mL, 952 mmol) was added slowly over a period of 3 h and stirred at room temperature for 24 h. The volatile components were evaporated under reduced pressure and the oily residue was purified by silica gel chromatography (750 g REDISEP column, eluting with 30% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 104A (43 g, 30.8%). MS(ES): m/z=244 [M+H]+; 1H NMR (400 MHz, CDCl3) delta ppm 7.84 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.18 (q, J=5.4 Hz, 2H), 3.35 (s, 3H), 3.04 (s, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H).
A mixture containing acetic acid (15 equiv.) and diethyl oxalacetate sodium salt (1 equiv.) in benzene was stirred at 25 C for 30 mm. To this mixture was added (2-fluorobenzyl)hydrazine hydrochloride (2 equiv.). The resulting mixture was heated to 100 C for 2 h. The mixture was cooled to 23 C and concentrated under vacuum. The precipitate formed was collected by filtration. The solid was dissolved in ethyl acetate and washed with iN HC1 solution (x3). The organic layer was dried, filtered, and evaporated to give a solid containing the desired product. The solid was rinsed with a minimal amount of a methanol-diethyl ether mixture, dried under vacuum to deliver the desired intermediate, ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate (11.8 g, 71 % yield) as a cream colored solid.?H NMR (500 MHz, CD3OD) oe ppm 7.24 - 7.41 (m, 1 H), 7.09 - 7.16 (m, 2 H), 7.02 - 7.07 (m, 1 H), 5.95 (s, 1 H), 5.29 (s, 2 H), 4.33 (q, 2 H), 1.36 (t, 3 H).
diethyl 6-(4-tert-butylphenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
In acetic acid; at 20℃; for 26h;Reflux;
A mixture of0.01 mol of <strong>[40876-98-0]diethyl oxalylacetate sodium salt</strong>, 0.01 molof aromatic aldehyde, and 0.01 mol of urea was heatedat reflux in 10 mL of acetic acid for 2 h. The mixturewas kept for 24 h at room temperature, the precipitatewas filtered off and recrystallized from ethanol. Yield2.32 g (62%), mp 214-216. IR spectrum, nu, cm-1:3300, 3210 (NH), 1750, 1710 (COOC2H5), 1650(C=C). 1 NMR spectrum, delta, ppm: 1.05 t (3,CH3CH2OCO, J 6.5 Hz), 1.23 s [9, (3)3], 1.26 t(3, CH3CH2OCO, J 6.5 Hz), 3.97 q (2,CH3CH2OCO, J 6.5 Hz), 4.20 q (2, CH3CH2OCO, J6.5 Hz), 5.08 d (1H, CH6, J 1.8 Hz), 7.07-7.33 m (4,Ar), 8.11 d (1H, NH1, J 1.8 Hz), 9.70 br.s (1, NH3).Found, %: 64.04, 64.29; 6.92, 7.09; N 7.35, 7.60.20H26N2O5. Calculated, %: 64.16; 7.00; N 7.48.
diethyl 6-(2,4-dimethoxyphenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
In acetic acid; at 20℃; for 26h;Reflux;
General procedure: A mixture of0.01 mol of <strong>[40876-98-0]diethyl oxalylacetate sodium salt</strong>, 0.01 molof aromatic aldehyde, and 0.01 mol of urea was heatedat reflux in 10 mL of acetic acid for 2 h. The mixturewas kept for 24 h at room temperature, the precipitatewas filtered off and recrystallized from ethanol.
diethyl 6-(4-fluorophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
In acetic acid; at 20℃; for 26h;Reflux;
General procedure: A mixture of0.01 mol of <strong>[40876-98-0]diethyl oxalylacetate sodium salt</strong>, 0.01 molof aromatic aldehyde, and 0.01 mol of urea was heatedat reflux in 10 mL of acetic acid for 2 h. The mixturewas kept for 24 h at room temperature, the precipitatewas filtered off and recrystallized from ethanol.
diethyl 6-(3-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
In acetic acid; at 20℃; for 26h;Reflux;
General procedure: A mixture of0.01 mol of <strong>[40876-98-0]diethyl oxalylacetate sodium salt</strong>, 0.01 molof aromatic aldehyde, and 0.01 mol of urea was heatedat reflux in 10 mL of acetic acid for 2 h. The mixturewas kept for 24 h at room temperature, the precipitatewas filtered off and recrystallized from ethanol.
diethyl 6-(2,5-dimethoxyphenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
In acetic acid; at 20℃; for 26h;Reflux;
General procedure: A mixture of0.01 mol of <strong>[40876-98-0]diethyl oxalylacetate sodium salt</strong>, 0.01 molof aromatic aldehyde, and 0.01 mol of urea was heatedat reflux in 10 mL of acetic acid for 2 h. The mixturewas kept for 24 h at room temperature, the precipitatewas filtered off and recrystallized from ethanol.
General procedure: A mixture of malononitrile (3) (0.01 mol), isatin (4) (0.01 mol) and Et3N (1mL) in EtOH (10 mL) was stirred at room temperature for 0.5 h. Next, a mixture of diethyl oxalacetate sodium salt (1) (0.01 mol) and hydrazine hydrate (4) (0.01 mol) in AcOH (10 mL) was added. After reaction completion, the resulting precipitate was collected by filtration and the crude product was recrystallized from EtOH.
General procedure: A mixture of malononitrile (3) (0.01 mol), isatin (4) (0.01 mol) and Et3N (1mL) in EtOH (10 mL) was stirred at room temperature for 0.5 h. Next, a mixture of diethyl oxalacetate sodium salt (1) (0.01 mol) and hydrazine hydrate (4) (0.01 mol) in AcOH (10 mL) was added. After reaction completion, the resulting precipitate was collected by filtration and the crude product was recrystallized from EtOH.
General procedure: A mixture of malononitrile (3) (0.01 mol), isatin (4) (0.01 mol) and Et3N (1mL) in EtOH (10 mL) was stirred at room temperature for 0.5 h. Next, a mixture of diethyl oxalacetate sodium salt (1) (0.01 mol) and hydrazine hydrate (4) (0.01 mol) in AcOH (10 mL) was added. After reaction completion, the resulting precipitate was collected by filtration and the crude product was recrystallized from EtOH.
ethyl 6'-amino-5'-cyano-2-oxo-5-nitro-2'H-spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
General procedure: A mixture of malononitrile (3) (0.01 mol), isatin (4) (0.01 mol) and Et3N (1mL) in EtOH (10 mL) was stirred at room temperature for 0.5 h. Next, a mixture of diethyl oxalacetate sodium salt (1) (0.01 mol) and hydrazine hydrate (4) (0.01 mol) in AcOH (10 mL) was added. After reaction completion, the resulting precipitate was collected by filtration and the crude product was recrystallized from EtOH.
ethyl 6'-amino-5'-cyano-2-oxo-5-fluoro-2'H-spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: A mixture of malononitrile (3) (0.01 mol), isatin (4) (0.01 mol) and Et3N (1mL) in EtOH (10 mL) was stirred at room temperature for 0.5 h. Next, a mixture of diethyl oxalacetate sodium salt (1) (0.01 mol) and hydrazine hydrate (4) (0.01 mol) in AcOH (10 mL) was added. After reaction completion, the resulting precipitate was collected by filtration and the crude product was recrystallized from EtOH.
General procedure: A mixture of malononitrile (3) (0.01 mol), isatin (4) (0.01 mol) and Et3N (1mL) in EtOH (10 mL) was stirred at room temperature for 0.5 h. Next, a mixture of diethyl oxalacetate sodium salt (1) (0.01 mol) and hydrazine hydrate (4) (0.01 mol) in AcOH (10 mL) was added. After reaction completion, the resulting precipitate was collected by filtration and the crude product was recrystallized from EtOH.
Add sodium diethyl oxalacetate (34.55 g, 156,2 rnmol) to 1-120 (170 mE). Add sodium hydroxide (2N, 117.1 mL, 234.3 nmol) followed by 2-methyithiopseudoureasulfate (15 g, 156.2 mmol) and stir the mixture for 2 hours at ambient temperature. Cool to 0 C and add HCI aq. (12N, 19.57 mE, 234.3 rnmol) drop-wise. Isolate the white precipitate via filtration, wash the filter cake with water and methyl tert-butyl ether, then air dry to provide the title product as a white solid (I 1.1g. 75%). MS (n/z): 187 (M+i).
With toluene-4-sulfonic acid; In toluene;Dean-Stark; Reflux;
Step 1: Under Dean-Stark trap, the solution of <strong>[59557-90-3]4-bromo-3,5-dimethylaniline</strong> (7.5 g, 37.5 mmol), diethyl oxaloacetate sodium salt (7.88 g, 37.5 mmol) and p-toluenesulfonic acid (6.46g, 37. 5 mmol) in toluene (75 mL) was heated to reflux for overnight. The solvent was slowly removed under vacuum, and the crude product was then dissolved in Ph20 (20 mL). The resulting dark brown mixture was heated to 250 C for lh. After lh, 200 mL H20 was added to the reaction mixture, and the suspension was filtered. The solid collected was then washed with Et20, dried overnight to yield 13-C without further purification (10 g, 83% yield). ?H NMR (400 MHz, DMSO-d6) 11.80 (s, 1H), 7.78 (s, 1H), 6.57 (s, 1H), 4.41 (q,J= 7.1 Hz, 2H), 2.98 (s, 3H), 2.45 (s, 3H), 1.36 (t, J= 7.1 Hz, 3H). LCMS (M+H): 324.15, 326.15.
UnderDean-Stark trap, the solution of <strong>[59557-90-3]4-bromo-3,5-dimethylaniline</strong> (7.5 g, 37.5mmol), diethyl oxaloacetate sodium salt (7.88 g, 37.5 mmol) andp-toluenesulfonic acid (6.46 g, 37. 5 mmol) in toluene (75 mL) was heated toreflux for overnight. The solvent was slowly removed under vacuum, and thecrude product was then dissolved in Ph2O (20 mL). The resulting darkbrown mixture was heated to 250 C for 1h. After 1h, 200 mL H2O wasadded to the reaction mixture, and the suspension was filtered. The solidcollected was then washed with Et2O, dried overnight to yield 11 without further purification (10 g,83% yield). 1H NMR (400 MHz,DMSO-d6) delta 11.80 (s,1H), 7.78 (s, 1H), 6.57 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.98 (s, 3H),2.45 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (M+H)+: 324.15,326.15.
3,3-dimethylbutylhydrazine monophosphate[ No CAS ]
[ 40876-98-0 ]
1-(3,3-dimethylbutyl)-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.2%
With triethylamine; In ethanol; at 30 - 40℃; for 6h;
(3)The product (75.0 g),Diethyl sodium oxalate acetate (132.5 g)In ethanol (375.0 g) was added triethylamine (88.6 g)Was added dropwise at 30 C. over 1 hour.After stirring at 40 C. for 5 hours,The temperature was raised to 60 C., water (1125.0 g)Was added dropwise over 10 minutes. After confirming dissolution,Concentrated hydrochloric acid (117.0 g) was added dropwise,After cooling to 25 C., the precipitated crystals were collected by filtration,One time with ethanol: water = 1: 3 (180.0 g)And washed twice with acetonitrile (105.0 g).The obtained crystals were dried under reduced pressure,1- (3,3-dimethylbutyl) -5-oxo-4,5-dihydro-1 H-pyrazole-3-carboxylic acidEthyl ester (71.69 g, yield 85.2%)As crystals.
ethyl 2-cyclopropyl-6-hydroxypyrimidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With ethanol; potassium carbonate; at 80℃; for 4h;
To a solution of diethyl oxalacetate sodium salt (20.0 g, 106.28 mmol) in EtOH (200 mL) were added K2CO3 (36.7 g, 265.70 mmol) and cyclopropanecarboximidamide (8.9 g, 106.28 mmol). The resulting solution was stirred at 80 C for 4 h before being concentrated. The residue was purified by chromatography B to afford the title compound (10.0 g, 45%) as a yellow solid. MS (ESI) calculated for (CIOH12N203) [M+H]+, 209.1; found, 209.0.
A mixture of methylhydrazine sulfate (7.2 g, 50.0 mmol), diethyl oxalacetate sodium salt (10.5 g, 50.0 mmol) in acetic acid (50 ml_) and ethanol (100 ml_) was stirred at 80 C for 7 h. Ethanol was removed under reduced pressure and the residue was poured into water. The aqueous layers were extracted with ethyl acetate (200 ml_ x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1 /1 ) to give ethyl 5-hydroxy-1 -methyl- 7/-/-pyrazole-3-carboxylate (5.20 g, 30.6 mmol, 61 %) as a light-yellow solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 1 1 .40 (s, 1 H), 5.76 (s, 1 H), 4.20 (q, J = 7.0 Hz, 2H), 3.59 (s, 3H), 1 .25 (t, J = 7.0 Hz, 3H); LCMS (ESI) m/z: 171 .1 [M+H]+.
(cyclohexylmethyl)hydrazine dihydrochloride[ No CAS ]
[ 40876-98-0 ]
[ 1487461-37-9 ]
Yield
Reaction Conditions
Operation in experiment
57%
With acetic acid; In toluene;
Step 1 (Cyclohexylmethyl)hydrazine hydrochloride was used for the starting material and reacted and treated according to the method of Reference Example 36 Step (i) described in Patent Literature 1 to give ethyl 1-(cyclohexylmethyl)-5-hydroxy-1H-pyrazol-3-carboxylate (2.16 g, 57%) as a solid. 1H-NMR (300MHz, CDCl3) delta: 0.90-1.06 (2H, m), 1.08-1.27 (3H, m), 1.29-1.42 (3H, m), 1.51-1.77 (5H, m), 1.77-1.98 (1H, m), 3.54 (0.7H, s), 3.61 (0.7H, d, J = 7.3 Hz), 3.87 (1.3H, d, J = 7.5 Hz), 4.30-4.43 (2H, m), 5.96 (0.6H, s).
ethyl 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With ammonia; In ethanol;Reflux;
General procedure: A mixture of compound 1 (1 equiv) and aldehyde (1 equiv) together with an equimolar amount of amine in ethanol was refluxed towards completion (0.5 - 2 hours). Iced-water was added to the mixture after cooling and HCl was then added dropwise to pH 1. Filter the solid while appear. Traces aldehyde in the crude product was washed with water and ether to give (4a-k). Ethyl 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (4a) White solid; 60%; m.p. 106-109oC. IR (ATR) n/cm-1: 3344 (OH), 2986 (NH, amide), 1782 (C=O, ester), 1687 (C=C), 1670 (-N-C=O, amide), 1302 (C-N); 1H-NMR (400 MHz, CDCl3): delta 4.91-4.85 (2H, s, CH2), 4.39-4.32 (2H, q, J= 7.2 Hz, CH2), 1.38-1.31 (3H, t, J= 7.1 Hz, CH3); 13C-NMR (100 MHz, CDCl3,): delta 166.54 (COH), 164.23 (C=O) 151.29 (C=O), 116.09 (quat. C), 66.26 (OCH2), 62.09 (CH2), 14.34 (CH3); Anal. Calcd. for C7H9NO4: C, 49.12; H, 5.30; N, 8.18; O, 37.39. Found: C, 49.30; H, 4.65; N, 7.04; O, 39.01; GCMS m/z(EI, + ve): found 172.00 ([M]+), C7H9NO4 calculated 172.06
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