3-Chloro-1H-pyrazol-4-ylaMine hydrochloride

Step 1: A 4-neck, 500-mL round bottom flask was charged with 3-chloro-1H-pyrazol-4-amine.HCl (15 g, 128 mmol), THF (50 mL), and water (50 mL). Sodium bicarbonate (32.2 g, 383 mmol) was added in portions to control off-gassing, and the mixture was cooled to 5 C. Acryloyl chloride (12.44 mL, 153 mmol) was added at <20 C. and the reaction was stirred for 2 h, after which the reaction was diluted with water (100 mL) and EtOAc (100 mL). The organic layer was concentrated to dryness to afford a white solid, which was suspended in MTBE (50 mL) and stirred for 2 h. The suspension was filtered and the solid was rinsed with MTBE (50 mL) to afford the desired product, N-(3-chloro-1H-pyrazol-4-yl)acrylamide (IIa), as a white solid after drying (14.8 g, 68% yield), mp: 182 C. (decomposition). 1H NMR (400 MHz, DMSO-d6) delta 12.96 (s, 1H), 9.77 (s, 1H), 8.10 (s. 1H), 6.58 (dd, J=17.0, 10.2 Hz, 1H), 6.23 (dd, J=17.0, 2.1 Hz, 1H), 5.73 (dd, 10.2, 2.1 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) delta 162.69, 130.76, 130.14, 126.62, 123.60, 116.53. ESIMS: m/z 172.0 ([M+H]+).A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2×100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2×100 mL) and dried under vacuum at 20 C. to afford a white solid (10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+).10022] A 100 mE, 3-neck flask was charged with N-(3-chloro-1H-pyrazol-4-yl)acetamide (1b) [0021] N-(3-Chloro-1H-pyrazol-4-yl)acetamide (1b) A 100-mL 3-neck round bottom flask was charged with 3-chloro-1H-pyrazol-4-amine.hydrochloride (5.00 g, 32.5 mmol) and water (25 mL). Sodium bicarbonate (10.9 g, 130 mmol) was added slowly over 10 minutes (off-gassing during addition), followed by tetrahydrofuran (25 mL). The mixture was cooled to 5 C. and acetic anhydride (3.48 g, 34.1 mmol) was added over 30 minutes while maintaining the internal temperature at <10 C. The reaction was stirred at 5 C. for 1 hour, at which point thin layer chromatography (TLC) analysis [Eluent: ethyl acetate (EtOAc)] indicated that the starting material had disappeared and a major product was exclusively formed. The reaction mixture was diluted with ethyl acetate (25 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3*25 mL). The combined organic layers were concentrated to afford an off-white solid, which was suspended in methyl tert-butylether (MTBE, 20 mL), stirred for 1 hour, and filtered. The solid was rinsed with methyl tert-butylether (20 mL) and further dried under vacuum at room temperature (about 22 C.) for 4 hours to give a white solid (4.28 g, 83%): mp 162-164 C.; 1H NMR (400 MHz, DMSO-d6) delta 12.90 (bs, 1H), 9.49 (s, 1H), 7.97 (s, 1H), 2.02 (s, 3H); 13C NMR (101 MHz, DMSO-d6) delta 167.81, 130.07, 123.72, 116.73, 22.58; EIMS m/z 159 ([M]+).3-Chloro-1H-pyrazol-4-amine hydrochloride (1a) A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2*100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to '100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to '100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to '100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2*100 mL) and dried under vacuum at 20 C. to afford a white solid (?10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+).3-chloro-N-(-3-chloro-1H-pyrazol-4-yl)propanamide (4a) A 250-mL 3-neck flask was charged with 3-chloro-1H-pyrazol-4-amine.hydrochloride (10.0 g, 64.9 mmol), tetrahydrofuran (50 mL), and water (50 mL). The resulting suspension was cooled to 5 C. and sodium bicarbonate (17.6 g, 210 mmol) was added, followed by dropwise addition of 3-chloropropanoyl chloride (7.33 g, 57.7 mmol) at <5 C. The reaction was stirred at <10 C. for 1 hour, at which point thin layer chromatography (TLC) [Eluent: 1:1 ethyl acetate (EtOAc)/hexane] analysis indicated the starting material was consumed and the desired product was formed. It was diluted with water (50 mL) and ethyl acetate (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a pale brown solid, which was purified by flash column chromatography using ethyl acetate as eluent. The pure fractions were concentrated to afford a white solid (9.20 g, 77%): mp: 138-140 C.; 1H NMR (400 MHz, DMSO-d6) delta 12.91 (s, 1H), 9.68 (s, 1H), 8.03 (d, J=1.7 Hz, 1H), 3.85 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) delta 167.52, 130.05, 123.59, 116.48, 40.75, 37.91; EIMS m/z 207 ([M]+).To a stirred solution of 5-chloro-1H-pyrazol-4-amine, HCl (2 g, 12.99 mmol) and cesium carbonate (8.89 g, 27.3 mmol) in DMF (13 mL) was added 3, 5-difluoropyridine (1.794 g, 15.58 mmol) and the mixture heated at 70° C. for 12 h. The mixture was cooled to room temperature and filtered. The solids were washed with copious amount of ethyl acetate. The filtrates was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a brown solid. This solid was dissolved in ethyl acetate and the resulting solution was saturated with hexanes to precipitate 3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine (2.31 g, 10.32 mmol, 79percent yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) delta 8.89-8.82 (m, 1H), 8.45 (d, J=2.5 Hz, 1H), 8.07 (d, J=10.4 Hz, 1H), 7.94 (s, 1H), 4.51 (s, 2H); EIMS (m/z) 213 ([M+1]+).Step 2: Preparation of tert-butyl(3-chloro-1H-pyrazol-4-yl)carbamate Into a 2 L round bottom flask was added Into a 2 L round bottom flask was added Step 2: Preparation of tert-butyl (3-chloro-1H-pyrazol-4-yl)carbamate Into a 2 L round bottom flask was added Into a 2 L round bottom flask was added 3- chioro- lH-pyrazo4-amine hydrochloride (30 g, 195 mmoi) and THF (150 mL). To this mixture were added di-ferr-butyldi carbonate (46.8 g, 214 mmoi) followed by sodium bicarbonate (36 g, 428.7 mmoi) and water (15 mL). The mixture was stirred for 16 h, diluted with water ( 150 mL) and ethyl acetate (150 mL) and transferred to a separatory funnel. This gave three layers; bottom- a white gelatinous precipitate, middle-light yellow aqueous, top-auburn organic. The phases w ere separated collecting the white gelatinous precipitate and the aqueous layer together. Tire aqueous was extracted with ethyl acetate (2 chi 100 mL) and the ethyl acetate extracts were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and rotary evaporated to give crude product. The crude product was purified by- column chromatography (PE:EtOAc = 6: 1 to 3: 1) to get tert-butyl (3 -chioro- lH~pyrazo4~yl) carbamate as a white solid. LCMS: RT 0.66 min. m/z = 218 [M + I s i ' . Tl NMR (400 MHz, CDC13): delta 11.04 (br s, 1 H), 7.91 (br. s, 1 H), 6.28 (br. s, 1 H), 1.52 is. 9 I I).Into a 2 L round bottom flask were added 3-chloro- l/-/-pyrazol-4-amine hydrochloride (C2 ; 100 g, 649 mmol) and tetrahydrofuran (THF; 500 mL). To this mixture were added sequentially di-ferf-butyl dicarbonate (156 g, 714 mmol), sodium bicarbonate ( 120 g, 1429 mmol) and water (50.0 mL). The mixture was stirred for 16 h, diluted with water (500 mL) and ethyl acetate (EtOAc; 500 mL) and transferred to a separatory funnel. This gave three layers : a) bottom layer - white gelatinous precipitate; b) middle layer - light yellow aqueous liquid ; and c) top layer - auburn organic liquid . The phases were separated, collecting the bottom and middle layers (/.e., aqueous phase) together. The aqueous phase was extracted with EtOAc (2 x 200 mL), and the organic extracts were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give a thick auburn-colored oil ( 160 g) . The thick oil was suspended in hexane (1000 mL) and stirred at 55 C for 2 h. This gave a light brown suspension . The mixture was cooled to 0 C, and the solid was collected by vacuum filtration and rinsed with hexane (2 x 10 mL). The sample was air dried to constant mass to afford the title compound as a light brown solid ( 103 g, 72% yield, 80% purity) : mp 137- 138 C; *H N MR (400 MHz, CDCb) d 10.69 (s, 1H), 7.91 (s, 1H), 1.52 (s, 9H).Step 2: Preparation of tert-butyl (3-chloro-1H-pyrazol-4-yl)carbamate Into a 2 L round bottom flask was added Step 1: Preparation of Step 1: Preparation of Into a 2 L three-necked round bottom flask affixed with an overhead stirrer, a temperature probe, an addition funnel, and a nitrogen inlet were added ethanol (600 mL) and 4-nitro-1H-pyrazole (50.6 g, 447 mmol). To this solution was added, in one portion, conc. HCl (368 mL) (note: rapid exotherm from 15 C. to 39 C.) and the resulting mixture was purged with nitrogen for 5 minutes. Palladium on alumina (5% w/w) (2.6 g, Alfa, black solid) was added to the mixture and stirred at room temperature while triethylsilane (208 g, 1789 mmol) was added drop-wise over 4 h. The reaction, which started to slowly exotherm from 35 C. to 55 C. over 2.0 h, was stirred for a total of 16 h and vacuum filtered through a plug of Celite to give a biphasic mixture. The mixture was transferred to a separatory funnel, the bottom aqueous layer was collected and rotary evaporated (60 C., 50 mmHg) to dryness with the aid of acetonitrile (3*350 mL). The resulting yellow solid was suspended in acetonitrile (150 mL) and allowed to stand for 2 h at room temperature followed by 1 h at 0 C. in the refrigerator. The solids were filtered and washed with acetonitrile (100 mL) to afford the titled compound Into a 2 L three-necked round bottom flask affixed with an overhead stirrer, a temperature probe, an addition funnel, and a nitrogen inlet were added ethanol (600 mL) and 4-nitro-1H-pyrazole (50.6 g, 447 mmol). To this solution was added, in one portion, conc. HCl (368 mL) (note: rapid exotherm from 15 C. to 39 C.) and the resulting mixture was purged with nitrogen for 5 minutes. Palladium on alumina (5% w/w) (2.6 g, Alfa, black solid) was added to the mixture and stirred at room temperature while triethylsilane (208 g, 1789 mmol) was added drop-wise over 4 h. The reaction, which started to slowly exotherm from 35 C. to 55 C. over 2.0 h, was stirred for a total of 16 h and vacuum filtered through a plug of Celite to give a biphasic mixture. The mixture was transferred to a separatory funnel, the bottom aqueous layer was collected and rotary evaporated (60 C., 50 mmHg) to dryness with the aid of acetonitrile (3×350 mL). The resulting yellow solid was suspended in acetonitrile (150 mL) and allowed to stand for 2 h at room temperature followed by 1 h at 0 C. in the refrigerator. The solids were filtered and washed with acetonitrile (100 mL) to afford the titled compound Step 1: Preparation of Into a 2 L three-necked round-bottom flask affixed with an overhead stirrer, a temperature probe, an addition funnel and a nitrogen inlet were added ethanoi (500 mL) and 4-nitro- 1 H-pyrazole (40 g, 354 mmoi). To this solution was added, in one portion, cone. HC1 (290 mL) (note: rapid exotherm observed from 15 C to 39 C) and the resulting mixture was purged with nitrogen for 5 minutes. Palladium on alumina (5% w/w) (2.1 g) was added to the mixture and stirred at room temperature while triethylsiiane (208 g, 1789 mmoi) was added dropwise over 2 h. The reaction, which started to slowly exotherm from 35 C to 45 C over 1 h, was stirred for a total of 16 h and vacuum filtered through a plug of celite to give a biphasic mixture. The mixture was transferred to a separatory funnel. The bottom aqueous layer was collected and rotary evaporated to dryness with the aid of acetonitrile (3 chi 100 mL). The resulting yellow solid was suspended in acetonitriie (100 mL) and allowed to stand for 0.5 h at room temperature followed by 1 h at 0 C. The solids were filtered and washed with acetonitriie (50 mL) to afford 3-chloro-lH-pyrazol-4-amine hydrochloride as a white solid, which was used to next step without purification, LCMS: RT 0.1 min, m/z = 1 18 [M + H]+ H NMR (400 MHz, DMSO-d6): delta 10.49 (br. s, 2 H), 8.02 (s, 0.59 H), 7.74 (s, 0.31 H), 5.12 (br. s, 1 H).A 2 liter (L) three-necked round bottom flask was affixed with an overhead stirrer, a temperature probe, an addition funnel, and a nitrogen inlet. Into this three-necked flask were added ethanol (600 milliliters (mL)) and 4-nitro-l/-/-pyrazole (Cl ; 50.6 grams (g), 447 millimoles (mmol)). To this solution was added, in one portion, concentrated hydrochloric acid (HCI; 368 mL) (note : rapid exotherm from 15 C to 39 C), and the resulting mixture was purged with nitrogen (Na) for 5 minutes (min) . Palladium on alumina (5% w/w) (2.6 g) was added, and the mixture was stirred at room temperature while triethylsilane (208 g, 1789 mmol) was added drop-wise over 4 hours (h) . The reaction mixture, which started to self-heat slowly from 35 C to 55 C over 2 h, was stirred for a total of 16 h. The mixture was vacuum filtered through a plug of Celite, and a biphasic mixture was collected. The biphasic mixture was transferred to a separatory funnel, and the bottom aqueous layer was collected and rotary evaporated (60 C, 50 mmHg) to dryness with the aid of acetonitrile (3 x 350 mL) . The resulting yellow solid was suspended in acetonitrile (150 mL) and allowed to stand for 2 h at room temperature followed by 1 h at 0 C in the refrigerator. The solids were filtered and washed with acetonitrile (100 mL) to afford the title compound as a white solid (84 g, 97% yield, 80% purity) : mp 190- 193 C; *H N MR (400 MHz, DMSO-de) d 10.46 - 10.24 (br s, 2H), 8.03 (s, 0.54H), 7.75 (s, 0.46H), 5.95 (br s, 1H) ; 13C-NMR ( 101 MHz, DMSO- da) d 128.24, 125.97, 116.71.

Molecular Weight:154.00
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:2
Exact Mass:152.9860526
Monoisotopic Mass:152.9860526
Topological Polar Surface Area:54.7
Heavy Atom Count:8
Complexity:67.2
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes