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Product Details of [ 3994-50-1 ]

CAS No. :3994-50-1 MDL No. :MFCD00464261
Formula : C4H5N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :CZVJIVYLYOVBRP-UHFFFAOYSA-N
M.W : 127.10 Pubchem ID :19895
Synonyms :

Calculated chemistry of [ 3994-50-1 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.25
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 32.31
TPSA : 63.64 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.03 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.96
Log Po/w (XLOGP3) : 0.06
Log Po/w (WLOGP) : 0.33
Log Po/w (MLOGP) : -0.35
Log Po/w (SILICOS-IT) : -1.67
Consensus Log Po/w : -0.14

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.01
Solubility : 12.4 mg/ml ; 0.0975 mol/l
Class : Very soluble
Log S (Ali) : -0.95
Solubility : 14.3 mg/ml ; 0.112 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.14
Solubility : 92.5 mg/ml ; 0.728 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.71

Safety of [ 3994-50-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 3994-50-1 ]

* 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.

  • Upstream synthesis route of [ 3994-50-1 ]
  • Downstream synthetic route of [ 3994-50-1 ]

[ 3994-50-1 ] Synthesis Path-Upstream   1~19

  • 1
  • [ 2075-46-9 ]
  • [ 74-88-4 ]
  • [ 3994-50-1 ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate In acetonitrile at 100℃; for 16 h; Inert atmosphere 4-Nitro-1H-pyrazole 12 (10.0 g, 88.4 mmol) was taken in CH3CN (100 mL) in a 250 mL round bottom flask under N2. To it were sequentially added iodomethane (18.8 g, 132.0 mmol) and K2C03 (30.5 g, 221.0 mmol). The reaction mixture was heated at 100°C for 1 6h. The reaction mixture was then poured into ice water (100 g) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was further washed with n-pentane to afford 15 as a light yellow solid (10.8 g, 96percent yield). ‘H NMR (400 MHz, CDC13): 88.11 (s, 1H), 8.05 (s, 1H), 3.96 (s, 3H).
95%
Stage #1: With sodium hydride In acetonitrile; mineral oil at 0 - 20℃; for 1 h; Inert atmosphere
Intermediate P3: 1 -Methyl-4-nitro-1 H-pyrazole To the solution of 4-nitro-1H-pyrazole (200 mg, 1.77 mol) in acetonitrile (2 mL) at 0°C, under argon atmosphere, sodium hydride (106 mg, 2.65 mmol, 60percent solution in mineral oil) was added. Reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture methyl iodide (121 μΙ_, 1.95 mmol) was added during 5 minutes. After 10 minutes water (10 mL) was added. The mixture was poured onto sodium thiosulfate solution (10 mL, 5percent). The mixture was extracted with ethyl acetate (3 15 mL). Organic layers were combined, washed with brine, dried (Na2S04) and evaporated under reduced pressure. Remaining solid was purified by column chromatography (silica gel, eluent: heptane/diethyl ether 100:0 to 20:80, v/v). Resulted creamy solid was dissolved in boiling isopropanol and then cooled to 0°C. Crystallized light-yellow crystals were filtered and dried to obtain title product with the yield of 95percent (214 mg, 1 .68 mmol). 1H NMR (300 MHz, CDCI3) δ 8,18 (s, 1 H), 8,05 (s, 1 H), 3,99 (s, 3H).
93% With sodium hydride In acetonitrile at -5 - 23℃; for 16 h; A 250-mE round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and thermometer was charged with 4-nitro-1H-pyrazole (5 g, 44.22 mmol) and acetonitrile (120 mE) and sodium hydride (2.1 g, 87.50 mmol, 60percent wt) at —5° C. To the reactionwas added iodomethane (7.5 g, 52.8 mmol). The product was stirred for 16 hat 23° C. and quenched with water (20 mE). The product was extracted with ethyl acetate (5x40 mE). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:5 v/v) to afford 1 -methyl-4-nitro- 1H-pyrazole (Intermediate 2-91, 5.2 g, 93percent). LCMS: (ESI) mlz 128 [M+H].
87% With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 16 h; General procedure: To a stirred solution of 4-nitroimidazole or 4-nitropyrazole (1.00 g, 8.84 mmol) in DMF (6.00 mL) at 25°C were added K2CO3 (1.47 g, 10.6 mmol) and alkyl iodide(10.6 mmol). After stirring for 16 h at 25 °C, the reactionmixture was treated with water (15 mL) and EtOAc (20 mL)and transferred to a 125 mL separatory funnel. The organiclayer was collected and the aqueous layer was extracted withEtOAc (25 mL × 2). The combined organic layers werewashed with brine (20 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated, and the residue waspurified by flash column chromatography to provide thecorresponding alkyl azole.
80%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 0.0833333 h;
Stage #2: at 20℃;
To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL) wasadded NaH (0.973 g, 24.32 mmol) and the mixture was stirred at rt for 5 mm. To thissuspension was then added CH3I (1.382 mL, 22.11 mmol) and stirred at rt overnight. The reaction mixture was then diluted with EtOAc (2 x 25 mL) and washed with brine (25 mL). The organic layer was concentrated, followed by purification using normal phase chromatography to yield 1-methyl-4-nitro-1H-pyrazole as white solid (1.9 g, 80percent yield).‘H NMR (400 MHz, CDC13) ö ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).
80%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 0.0833333 h;
Stage #2: at 20℃;
To a solution of 4-nitro-lH-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL) was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at rt for 5 min. To this suspension was then added Mel (1.382 mL, 22.11 mmol) and stirred at rt overnight. The reaction mixture was then diluted with EtOAc and washed with brine. The organic layer was concentrated, followed by purification using normal phase chromatography to yield l-methyl-4-nitro-lH-pyrazole a as white solid (1.9 g, 80percent). NMR (400 MHz, CDC13) 5 ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).
70%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h;
Stage #2: at 0℃; for 2 h;
At 0° C., to a solution of 4-nitropyrazole (3.3 g, 29.2 mmol) in anhydrous THF (30 mL) was added sodium hydride (1.3 g, 32.1 mmol). After the mixture was stirred for 1 hour, iodomethane (2 mL) was added slowly, and the resultant mixture was stirred for further 2 hours. Then the mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL×3), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtrated, the filtrate was concentrated under reduced pressure. The residue was added into a component solvent (20 mL) of petroleum ether and ethyl acetate (20:1), stirred, and there was solid precipitated. After filtration, the solid was dried in vacuum for 8 hours to give white solid 15-b (2.6 g, yield: 70percent), which was used directly for the next step without further purification. LC-MS (ESI): m/z=128 [M+H]+.
65%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 2.5 h;
Stage #2: for 1.5 h;
4-Nitro-1H-pyrazole (1.13 g, 9.99 mmol) was dissolved in 15 mL of dry THF.The reaction flask was placed in an ice bath and cooled, and NaH (600 mg, 25 mmol) was slowly added.Stir to room temperature and stir for 2.5 h, then slowly add methyl iodide (3.84 g, 20 mmol).Stirring was continued for 1.5 h, and the reaction was quenched by slowly adding 15 mL of saturated brine.The reaction solution was concentrated under reduced pressure and ethyl acetate (50 mL×3)Wash with water, saturated brine (50 mL×2), dry over anhydrous sodium sulfate,1-Methyl-4-nitro-1H-pyrazole (826 mg, 65percent) was obtained as a pale yellow solid.
53% With caesium carbonate In acetonitrile at 70℃; for 2 h; MC825_SC14 Step 1-IS08149-051 1 -Methyl-4-nitro-1 H-pyrazole Procedure: To a solution of 4-nitro-1 H-pyrazole (5 g, 44.2 mmol) in dry acetonitrile (100 mL), cesium carbonate (28.8 g, 88.4 mmol) and iodomethane (4.1 mL, 66.3 mmol) are added and heated to 70°C for 2 h. The reaction mixture is concentrated and the residue is taken in ethylacetate, washed with water (2 χ 75mL), brine, dried over MgS04 and concentrated to get the product. Yield: 53 percent (3 g, yellow solid). LCMS: (Method A) 128.0 (M+H), RT. 1.3 min, 99.4 percent (Max), 98.6 percent (254 nm). 1H NMR (400 MHz, DMSO-d6): δ [ppm] 8.83 (s, 1H), 8.22 (s, 1 H), 3.90 (s, 3H).

Reference: [1] Journal of Organic Chemistry, 2016, vol. 81, # 2, p. 689 - 698
[2] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 00076
[3] Patent: WO2014/20531, 2014, A1, . Location in patent: Page/Page column 15
[4] Patent: US2016/185785, 2016, A1, . Location in patent: Paragraph 2154; 2155
[5] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 10, p. 3009 - 3014
[6] Patent: WO2015/116886, 2015, A1, . Location in patent: Page/Page column 207; 250
[7] Patent: WO2015/116882, 2015, A1, . Location in patent: Page/Page column 93; 94
[8] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0179; 0180
[9] Patent: CN108373476, 2018, A, . Location in patent: Paragraph 0237-0241; 0289-0292
[10] Patent: WO2013/124026, 2013, A1, . Location in patent: Page/Page column 106; 107
[11] Acta Chemica Scandinavica, 1990, vol. 44, # 10, p. 1050 - 1057
[12] Patent: WO2012/61418, 2012, A2, . Location in patent: Page/Page column 84
[13] Journal of the American Chemical Society, 2014, vol. 136, # 34, p. 11878 - 11881
[14] Patent: CN106986860, 2017, A, . Location in patent: Paragraph 0030; 0031; 0032
[15] Patent: CN107098861, 2017, A, . Location in patent: Paragraph 0032; 0034
[16] Chemical Biology and Drug Design, 2018, vol. 91, # 2, p. 567 - 574
[17] ChemMedChem, 2018, vol. 13, # 23, p. 2558 - 2566
[18] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2382 - 2390
[19] Patent: US2018/208604, 2018, A1, . Location in patent: Paragraph 0131-0132
  • 2
  • [ 2075-46-9 ]
  • [ 77-78-1 ]
  • [ 3994-50-1 ]
YieldReaction ConditionsOperation in experiment
96.1% With sodium hydroxide In water at 20℃; for 72 h; Step A.
1-Methyl-4-nitro-1H-pyrazole
A mixture of 4-nitro-1H-pyrazole (10.0 g, 88.4 mmol, commercially available from Aldrich), 1.0 M aq. NaOH (400.0 mL, 400.0 mmol) and dimethyl sulfate (62 mL, 660 mmol) was stirred at room temperature for 72 h.
The mixture was extracted with DCM (2*300 mL).
The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give 11.2 g (96.1percent yield) of the sub-title compound as a white solid. LCMS calc. for C4H6N3O2 (M+H)+: m/z=128.1. found: 128.1.
87% With sodium hydroxide In water at 20℃; for 3.5 h; Dimethyl sulphate (3.33g, 26.4mmol) was slowly added to a stirred solution of 2b (1.Og, 8.85mmol) in IN NaOH (1OmL) that had been warmed to 3O0C. After being stirred at r.t. for 3.5h, the reaction mixture was extracted with ethyl acetate (10mLx4), combined the organic phase, washed with brine (2OmL), dried over MgSO4, filtered and concentrated. The residue was triturated with petrol and filtered to give 3a (0.98g, 87percent) as a white solid.
76% at 20℃; for 72 h; Example 1
5-chloro-1-methyl-4-nitro-1H-pyrazole
To a 500 mL round bottom flask containing 4-nitro-1-H-pyrazole (5 g, 44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate (31 mL, 330 mmol).
The mixture was stirred at room temperature for 72 h and the mixture was extracted with CH2Cl2 (2*150 mL).
The organic layer was separated and the solvent was distilled off to yield 1-methyl-4-nitro-1H-pyrazole as a white solid (4.30 g, 76percent).
Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL).
The mixture was cooled to -78° C. and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min.
The brown mixture was stirred for 30 min and warmed to -45 C over 30 min.
The mixture was cooled back down to -78° C. and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min.
The mixture was stirred for 2.5 h, warmed from -78 C to -40 C and the reaction was monitored by LCMS.
Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4Cl (150 mL), and ethyl acetate (100 mL) was added.
The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL).
The combined organic layer was washed with water (150 mL), dried over Na2SO4 and the organic solvent was distilled off.
The crude product was purified via flash chromatography (CH2Cl2/7percent MeOH) to yield 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20percent).
1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)
76% at 20℃; for 72 h; Example 1
5-chloro-1-methyl-4-nitro-1H-pyrazole
To a 500 mL round bottom flask containing 4-nitro-1-H-pyrazole (5 g, 44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate (31 mL, 330 mmol).
The mixture was stirred at room temperature for 72 h and the mixture was extracted with CH2Cl2 (2*150 mL).
The organic layer was separated and the solvent was distilled off to yield 1-methyl-4-nitro-1H-pyrazole as a white solid (4.30 g, 76percent).
Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL).
The mixture was cooled to -78° C. and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min.
The brown mixture was stirred for 30 min and warmed to -45° C. over 30 min.
The mixture was cooled back down to -78° C. and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min.
The mixture was stirred for 2.5 h, warmed from -78° C. to -40° C. and the reaction was monitored by LCMS.
Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4Cl (150 mL), and ethyl acetate (100 mL) was added.
The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL).
The combined organic layer was washed with water (150 mL), dried over Na2SO4 and the organic solvent was distilled off.
The crude product was purified via flash chromatography (CH2Cl2/7percent MeOH) to yield 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20percent).
1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)
76% at 20℃; for 72 h; To a 500 mL round bottom flask containing 4-nitro-i-H-pyrazole (5g, 44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate (31 mL, 330 mmol). The mixture was stirred at room temperature for 72 h and the mixture was extracted with CH2C12 (2 x 150 mL). The organic layer was separated and the solvent was distilled off to yield 1- methyl-4-nitro- lH-pyrazole as a white solid (4.30 g, 76percent). Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1- methyl-4-nitro- lH-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL). The mixture was cooled to -78 °C and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min. The brown mixture was stirred for 30 min and warmed to -45 °C over 30 min. The mixture was cooled back down to -78 °C and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min. The mixture was stirred for 2.5 h, warmed from -78 °C to -40 °C and the reaction was monitored by LCMS. Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4C1 (150 mL), and ethyl acetate (100 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (150 mL), dried over Na2S04 and the organic solvent was distilled off. The crude product was purified via flash chromatography (CH2C12/ 7percent MeOH) to yield 5-chloro-l-methyl-4-nitro- lH-pyrazole as a white solid (1.40 g, 20percent). 1H NMR (400 MHz, CDC13) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z = 162.0 (M+l)
50% at 35℃; for 48 h; Example 25Synthesis of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineThe compound was synthesized according to Method A.A mixture of 0.996 g (8.82 mmol) of 4-nitropyrazole (J. Med. Chem. 2005, 48, 5780-5793) and 1.33 g (10.6 mmol) of dimethyl sulphate in 10 mL of 1 M NaOH was heated at 35° C. for 48 hrs. The reaction mixture was cooled to RT and the precipitate was filtered, washed with water, and dried to give 0.561 g (50percent yield) of 1-methyl-4-nitro-1H-pyrazole: 1H NMR (DMSO-d6) δ8.83 (s, 1H), 8.22 (s, 1H), 3.91 (s, 3H).A mixture of 0.144 g (1.14 mmol) 1-methyl-4-nitro-1H-pyrazole, 0.017 g (0.07 mmol) platinum oxide, and ethyl acetate (5 mL) in ethanol (15 mL) was stirred under 2 atmospheres of hydrogen for 14 hrs. The catalyst was removed by filtration through a pad of celite and the solvent was removed to give 0.080 mg (73percent yield) of 4-amino-1-methyl-1H-pyrazole as a purple residue, which was used in the next step without further purification: 1H NMR (DMSO-d6) δ6.98 (s, 1H), 6.88 (s, 1H), 3.76 (br s, 2H), 3.65 (s, 3H).A mixture of 0.405 g (4.27 mmol) of 4-amino-1-methylpyrazole and 0.695 g (1.90 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (5 mL) was heated at 125° C. for 15 min. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration, washed with water, and dried. Chromatography on alumina, eluting with hexanes/EtOAc (1:1) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.145 g (18percent yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 225-226° C.; 1H NMR (DMSO-d6) (rotamers) δ10.00 (s, 1H), 9.73 (s, 0.2H), 8.60 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 0.2H), 7.92 (t, JHF=52.8 Hz, 1H), 7.86-7.80 (m, 2.6H), 7.68 (t, JHF=52.6 Hz, 0.2H), 7.59 (s, 1H), 7.52-7.42 (m, 2.9H), 3.85-3.82 (m, 8.4H), 3.75-3.73 (m, 4.8H); Anal. Calcd. for C19H19F2N9O 0.06EtOAc 0.24H2O: C, 52.9; H, 4.6; N, 28.8. Found: C, 52.9; H, 4.5; N, 28.6percent.

Reference: [1] Patent: US2015/57265, 2015, A1, . Location in patent: Paragraph 0713
[2] Patent: WO2009/154769, 2009, A1, . Location in patent: Page/Page column 37
[3] Russian Journal of General Chemistry, 2001, vol. 71, # 1, p. 137 - 142
[4] Patent: US2011/251176, 2011, A1, . Location in patent: Page/Page column 103
[5] Patent: US2013/79321, 2013, A1, . Location in patent: Paragraph 0178
[6] Patent: WO2015/140189, 2015, A1, . Location in patent: Page/Page column 59
[7] Patent: US2011/9405, 2011, A1, . Location in patent: Page/Page column 49
[8] Patent: WO2006/40520, 2006, A1, . Location in patent: Page/Page column 122
[9] Patent: WO2007/99326, 2007, A1, . Location in patent: Page/Page column 109
[10] Patent: WO2007/99317, 2007, A1, . Location in patent: Page/Page column 113
[11] Patent: WO2007/99335, 2007, A1, . Location in patent: Page/Page column 100-101
[12] Patent: US2009/76075, 2009, A1, . Location in patent: Page/Page column 42
[13] Patent: WO2007/113548, 2007, A1, . Location in patent: Page/Page column 158
[14] Patent: WO2007/113565, 2007, A1, . Location in patent: Page/Page column 100-101
  • 3
  • [ 39806-90-1 ]
  • [ 3994-50-1 ]
YieldReaction ConditionsOperation in experiment
64% With nitric acid In tetrahydrofuran; water at 20℃; for 3.5 h; General procedure: To iodopyrazole (1 mmol) dissolved in THF (10 mL), Fuajasite (250 mg) was added. Nitric acid (d 1.52 g/cm3, 10 mL) was added slowly and the mixture was stirred at room temperature for required time. The catalyst was recovered by filtration and the filtrate was extracted repeatedly with dichloromethane. The solvent was removed under vacuum to obtain nitropyrazole.
Reference: [1] Synthetic Communications, 2012, vol. 42, # 23, p. 3463 - 3471
[2] Russian Chemical Bulletin, 1996, vol. 45, # 11, p. 2581 - 2584
[3] Catalysis Communications, 2013, vol. 42, p. 35 - 39
  • 4
  • [ 930-36-9 ]
  • [ 3994-50-1 ]
YieldReaction ConditionsOperation in experiment
74.01% at 35℃; for 6 h; Take 2.7g (0.024mol) of N-nitropyrazole,1g (0.012mol) 1-methylpyrazole spare,8 mL of 98percent concentrated sulfuric acid was added to a 100 mL four-port flask equipped with a mechanical stirrer, a thermometer, and an addition funnel.Add 1-methylpyrazole dropwise to concentrated sulfuric acid at 20°C using a constant pressure dropping funnel.After the feed is completed, the water bath is heated to 35° C. and N-nitropyrazole is added in 10 portions at this temperature.Every time 0.0024mol is added,Constant temperature reaction 6h,While hot, pour the reaction mixture into a beaker with ice cubes and stir it.A white, fine crystalline solid precipitates outAfter the ice melts,Suction filtrationObtained white solid I and filtrate;The filtrate was extracted with ether,Combine solvents,Remove the solvent by vortexing under reduced pressureGet white solid II,The white solid I and white solid II were combined and recrystallized from ethanol to give the desired product.Using the test method in Example 1 to characterize the structure of the target product,The test results obtained are similar to those in Example 1.The target product obtained in Example 3 was proved to be 1-methyl-4-nitropyrazole,The purity of the product is 99.2percent.The product has a melting point of 90-91°C and a yield of 74.01percent
Reference: [1] Patent: CN107629003, 2018, A, . Location in patent: Paragraph 0055; 0070-0074; 0076; 0077 0079; 0080
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 5, p. 778 - 784[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 5, p. 1071 - 1077
  • 5
  • [ 930-36-9 ]
  • [ 1173911-09-5 ]
  • [ 3994-50-1 ]
Reference: [1] Catalysis Communications, 2012, vol. 19, p. 37 - 41
  • 6
  • [ 930-36-9 ]
  • [ 54210-32-1 ]
  • [ 3994-50-1 ]
Reference: [1] Catalysis Communications, 2012, vol. 19, p. 37 - 41
  • 7
  • [ 60-34-4 ]
  • [ 181294-57-5 ]
  • [ 3994-50-1 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 24, p. 8382 - 8386
[2] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 7, p. 1997 - 2002
  • 8
  • [ 34461-00-2 ]
  • [ 60-34-4 ]
  • [ 3994-50-1 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 7, p. 2906 - 2915
  • 9
  • [ 92534-69-5 ]
  • [ 3994-50-1 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, vol. 19, # 12, p. 1326 - 1330[2] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 12, p. 1676 - 1679
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Reference: [1] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 7, p. 1997 - 2002
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1990, vol. 26, # 10, p. 1196[2] Khimiya Geterotsiklicheskikh Soedinenii, 1990, # 10, p. 1430 - 1431
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1990, vol. 26, # 10, p. 1196[4] Khimiya Geterotsiklicheskikh Soedinenii, 1990, # 10, p. 1430 - 1431
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Reference: [1] Russian Chemical Bulletin, 2012, vol. 61, # 1, p. 209 - 210[2] Izv. Akad. Nauk, Ser. Khim., 2012, # 1, p. 206 - 207
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1987, vol. 23, # 10, p. 1081 - 1083[2] Khimiya Geterotsiklicheskikh Soedinenii, 1987, # 10, p. 1350 - 1352
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YieldReaction ConditionsOperation in experiment
99% With hydrogen In methanol at 70℃; Example 317
3-amino-6-bromo-N-(1-methyl-1H-pyrazol-4-yl)picolinamide 317
1-Methyl-4-nitro-1H-pyrazole (1.62 g, 12.7 mmol) was dissolved in methanol (250 mL) and hydrogenated on H-Cube at 60 bar hydrogen pressure and 70° C. to give 1-methyl-1H-pyrazol-4-amine (1.23 g, 99percent).
To a 100 mL round bottom flask containing 1-methyl-1H-pyrazol-4-amine (700 mg, 7.0 mmol), 3-amino-6-bromopicolinic acid (1.86 g, 8.5 mmol) and PyBop (4.12 g, 8.0 mmol) was added methylene chloride (30 mL) and diisopropylethylamine (3.8 mL, 21.6 mmol).
The reaction mixture was stirred for 24 hr at room temperature and the reaction was monitored by LCMS.
Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, heptane/ethyl acetate 0percent to 100percent to afford a yellow solid.
A fraction of it was purified via reverse phase HPLC to afford 317. 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.02 (br, 2H), 3.81 (s, 3H). MS (ESI) m/z: 296.0/298.0 [M+H+].
99% With 50% palladium on charcoal; hydrogen In methanol A par flask was charged with 1-methyl-4-nitro-1H-pyrazole 15 (5.3 g, 41.0 mmol) and methanol (70 mL) followed by addition of Pd-C (50percent w/w, 2.70 g). The flask was evacuated under vacuum and then purged with hydrogen. The reaction was stirred under hydrogen atmosphere (30 psi). The reaction was monitored by TLC. It was then filtered through sintered funnel with a pad of celite, washed with methanol and concentrated under reduced pressure to afford precursor-05 as a brown colored gummy solid (4.0 g, 99percent yield) that was used as such for the next step without any further purification. ‘H NMR (400 MHz, CDC13): 6 7.12 (s, 1H), 6.97 (s, IH), 3.78 (s, 3H), 2.87 (br s, 2H).
92% With palladium 10% on activated carbon; hydrogen In ethanol at 25℃; for 18 h; Under hydrogen (1 atm), to a solution of compound 15-b (1.0 g, 7.87 mmol) in ethanol (15 mL) was added 10percent Pd—C (0.2 g). The mixture was stirred at 25° C. for 18 hours, and then filtrated, the filtrate was concentrated under reduced pressure, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=1:1) to give red oil 15-a (700 mg, yield: 92percent).
83.7% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; Inert atmosphere Pd / C (10percent, 500 mg) was added to the column1-methyl-4-nitro-1H-pyrazole (1.90 g, 14.9 mmol)And methanol (25 mL)Hydrogen at room temperature overnight.Diatomaceous earth filter, dichloromethane washing filter cake,The filtrate was concentrated under reduced pressure, (Eluent: ethyl acetate / methanol (v / v) = 18/1) to give 1.35 g of a black solid, yield:83.7percent.
80% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 6 h; Step 1: 1-Methyl-1H-pyrazol-4-amine[2226]To 10 mL of methanol were added 1-methyl-4-nitro-1H-pyrazole (500 mg, 3.93 mmol) and Pd/C (10, 50 mg) . The mixture was stirred at rt for 6 hours under hydrogen atomosphere at ordinary pressure, then filtered. The filtrate was concentrated to give red liquid (305 mg, 80) .[2227]1H NMR (600 MHz, CDCl3) : δ ppm 7.18 (s, 1H) , 7.14 (s, 1H) , 3.78 (s, 3H) and MS-ESI: m/z 98.20 [M+H]+.
73% With hydrogen In ethanol; ethyl acetate at 20℃; for 14 h; Example 25Synthesis of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineThe compound was synthesized according to Method A.A mixture of 0.996 g (8.82 mmol) of 4-nitropyrazole (J. Med. Chem. 2005, 48, 5780-5793) and 1.33 g (10.6 mmol) of dimethyl sulphate in 10 mL of 1 M NaOH was heated at 35° C. for 48 hrs. The reaction mixture was cooled to RT and the precipitate was filtered, washed with water, and dried to give 0.561 g (50percent yield) of 1-methyl-4-nitro-1H-pyrazole: 1H NMR (DMSO-d6) δ8.83 (s, 1H), 8.22 (s, 1H), 3.91 (s, 3H).A mixture of 0.144 g (1.14 mmol) 1-methyl-4-nitro-1H-pyrazole, 0.017 g (0.07 mmol) platinum oxide, and ethyl acetate (5 mL) in ethanol (15 mL) was stirred under 2 atmospheres of hydrogen for 14 hrs. The catalyst was removed by filtration through a pad of celite and the solvent was removed to give 0.080 mg (73percent yield) of 4-amino-1-methyl-1H-pyrazole as a purple residue, which was used in the next step without further purification: 1H NMR (DMSO-d6) δ6.98 (s, 1H), 6.88 (s, 1H), 3.76 (br s, 2H), 3.65 (s, 3H).A mixture of 0.405 g (4.27 mmol) of 4-amino-1-methylpyrazole and 0.695 g (1.90 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (5 mL) was heated at 125° C. for 15 min. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration, washed with water, and dried. Chromatography on alumina, eluting with hexanes/EtOAc (1:1) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.145 g (18percent yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 225-226° C.; 1H NMR (DMSO-d6) (rotamers) δ10.00 (s, 1H), 9.73 (s, 0.2H), 8.60 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 0.2H), 7.92 (t, JHF=52.8 Hz, 1H), 7.86-7.80 (m, 2.6H), 7.68 (t, JHF=52.6 Hz, 0.2H), 7.59 (s, 1H), 7.52-7.42 (m, 2.9H), 3.85-3.82 (m, 8.4H), 3.75-3.73 (m, 4.8H); Anal. Calcd. for C19H19F2N9O 0.06EtOAc 0.24H2O: C, 52.9; H, 4.6; N, 28.8. Found: C, 52.9; H, 4.5; N, 28.6percent.

Reference: [1] Patent: US2011/251176, 2011, A1, . Location in patent: Page/Page column 160-161
[2] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 00077
[3] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0179; 0181
[4] Patent: CN106432246, 2017, A, . Location in patent: Paragraph 0453; 0806; 0807; 0808
[5] Patent: WO2015/161830, 2015, A1, . Location in patent: Paragraph 00770
[6] Patent: US2011/9405, 2011, A1, . Location in patent: Page/Page column 49
[7] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 997 - 1000
[8] Patent: US5252538, 1993, A,
[9] Patent: WO2006/40520, 2006, A1, . Location in patent: Page/Page column 123
[10] Patent: WO2007/99326, 2007, A1, . Location in patent: Page/Page column 109-110
[11] Patent: WO2007/99317, 2007, A1, . Location in patent: Page/Page column 113
[12] Patent: WO2007/99335, 2007, A1, . Location in patent: Page/Page column 101
[13] Patent: US2009/76075, 2009, A1, . Location in patent: Page/Page column 42
[14] Patent: WO2012/62704, 2012, A1, . Location in patent: Page/Page column 48
[15] Patent: WO2014/20531, 2014, A1, . Location in patent: Page/Page column 38-39
[16] Journal of the American Chemical Society, 2014, vol. 136, # 34, p. 11878 - 11881
[17] Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 10013 - 10030
[18] Patent: CN106986860, 2017, A, . Location in patent: Paragraph 0030; 0031; 0032
[19] Patent: CN107098861, 2017, A, . Location in patent: Paragraph 0032; 0034
[20] Chemical Biology and Drug Design, 2018, vol. 91, # 2, p. 567 - 574
[21] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2382 - 2390
[22] Patent: US2018/208604, 2018, A1, . Location in patent: Paragraph 0133-0134
[23] Patent: WO2007/113548, 2007, A1, . Location in patent: Page/Page column 158
[24] Patent: WO2007/113565, 2007, A1, . Location in patent: Page/Page column 101
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Reference: [1] Russian Chemical Bulletin, 2012, vol. 61, # 1, p. 209 - 210[2] Izv. Akad. Nauk, Ser. Khim., 2012, # 1, p. 206 - 207
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Reference: [1] Russian Chemical Bulletin, 2012, vol. 61, # 1, p. 209 - 210[2] Izv. Akad. Nauk, Ser. Khim., 2012, # 1, p. 206 - 207
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Reference: [1] Russian Chemical Bulletin, 2012, vol. 61, # 1, p. 209 - 210[2] Izv. Akad. Nauk, Ser. Khim., 2012, # 1, p. 206 - 207
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YieldReaction ConditionsOperation in experiment
93% With hexachloroethane; lithium hexamethyldisilazane In tetrahydrofuran; dichloromethane at 25℃; for 1 h; Example 1 7-(Azetidin-l-yl)-3-methyl-l-(l-methyl-5-(4-(trifluoromethyl)phenyl)-lH- pyrazol-4-yl)-lH-pyrazolo[4, -d]pyrimidine (a) 5-Chloro-l-methyl-4-nitro-lH-pyrazole Lithium bis(trimethylsilyl)amide (1.0 M, 65 mL, 65 mmol) in THF is added dropwise into a solution of l-methyl-4-nitro-lH-pyrazole (5.50 g, 43.3 mmol) and hexachloroethane (10.54 g, 44.5 mmol) in methylene chloride (120 mL) at 25 °C. The reaction mixture is stirred at 25 °C for 60 min, and then quenched with water (1 mL). The mixture is evaperated to dryness. The residue is washed with water (50 mL), sat. NaHCC>3 two times (2x30 mL) and brine (30 mL) successively, and then dried under vacuum to give 6.50 g of product (93percent yield). MS (ESI) mJz 162.0 [M+H]+. NMR (500 MHz, CDC ) δ 8.15 (s, 1H), 3.92 (s, 3H).
78.7%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78 - -45℃; for 1.33333 h;
Stage #2: With hexachloroethane In tetrahydrofuran at -78 - 40℃; for 2.75 h;
Step B.
5-Chloro-1-methyl-4-nitro-1H-pyrazole
To 1 L three-neck flask 1-methyl-4-nitro-1H-pyrazole (10.8 g, 85.0 mmol) and THF (30 mL) were added.
The mixture was cooled to -78° C. and 1.0 M lithium hexamethyldisilazide in THF (222 mL) was added dropwise via an addition funnel over 20 min.
The brown mixture was stirred for 30 min. and then allowed to warm to -45° C. over 30 min.
The mixture was cooled back down to -78° C. and hexachloroethane (26.4 g, 111 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min.
The mixture was stirred for 2.5 h and then allowed to warm from -78° C. to 40° C. and the reaction was monitored by LCMS.
Upon the completion of the reaction, the reaction was quenched with a solution of NH4Cl (450 mL) and then EtOAc (300 mL) was added.
The organic phase was separated and the aqueous layer was extracted with EtOAc.
The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure give an oil residue, which was further purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexane (50-100percent).
The purification gave 10.8 g (78.7percent yield) of the sub-title compound as a white solid. LCMS calc. for C4H5ClN3O2(M+H)+: m/z=162.0. found: 162.0.
54%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere
Stage #2: With hexachloroethane In tetrahydrofuran at -78 - 20℃; for 3 h;
1-Methyl-4-nitro-1H-pyrazole (1 g, 7.87 mmol) was dissolved in 12 mL of dry THF.Cool to -78 ° C under a nitrogen atmosphere, and slowly add 6 mL of LDA at a concentration of 2 mol/L.Stirring was continued for 1 h at -78 ° C under a nitrogen atmosphere;Hexachloroethane (2.42 g, 10.2 mmol) was dissolved in 12 mL of anhydrous THF and slowly added dropwise to the above reaction mixture.Stir at -78 °C for 2 h, then warm to room temperature and continue stirring for 1 h, then quenched with saturated aqueous ammonium chloride.The organic phase was washed with an aqueous solution of ammonium chloride (20 mL×1) and ethyl acetate (10 mL×3).The combined organic layers were dried with anhydrous sodium sSeparated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1).1-Methyl-4-nitro-5-chloro-1H-pyrazole (691 mg, 54percent) was obtained as a yellow solid.
20%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.833333 h;
Stage #2: With hexachloroethane In tetrahydrofuran at -78 - -45℃; for 2.75 h;
Example 1
5-chloro-1-methyl-4-nitro-1H-pyrazole
To a 500 mL round bottom flask containing 4-nitro-1-H-pyrazole (5 g, 44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate (31 mL, 330 mmol).
The mixture was stirred at room temperature for 72 h and the mixture was extracted with CH2Cl2 (2*150 mL).
The organic layer was separated and the solvent was distilled off to yield 1-methyl-4-nitro-1H-pyrazole as a white solid (4.30 g, 76percent).
Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL).
The mixture was cooled to -78° C. and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min.
The brown mixture was stirred for 30 min and warmed to -45 C over 30 min.
The mixture was cooled back down to -78° C. and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min.
The mixture was stirred for 2.5 h, warmed from -78 C to -40 C and the reaction was monitored by LCMS.
Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4Cl (150 mL), and ethyl acetate (100 mL) was added.
The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL).
The combined organic layer was washed with water (150 mL), dried over Na2SO4 and the organic solvent was distilled off.
The crude product was purified via flash chromatography (CH2Cl2/7percent MeOH) to yield 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20percent).
1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)
20% With hexachloroethane; ammonium chloride; lithium hexamethyldisilazane In tetrahydrofuran at -78 - -45℃; for 0.0583333 h; Example 1 5-chloro-1-methyl-4-nitro-1H-pyrazole [0177] 4-nitro-1-H-pyrazole (5 g, 44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate (31 mL, 330 mmol). The mixture was stirred at room temperature for 72 h and the mixture was extracted with CH2Cl2 (2×150 mL). The organic layer was separated and the solvent was distilled off to yield 1-methyl-4-nitro-1H-pyrazole as a white solid (4.30 g, 76percent). [0179] Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL). The mixture was cooled to −78° C. and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min. The brown mixture was stirred for 30 min and warmed to −45° C. over 30 min. The mixture was cooled back down to −78° C. and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min. The mixture was stirred for 2.5 h, warmed from −78° C. to −40° C. and the reaction was monitored by LCMS. Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4Cl (150 mL), and ethyl acetate (100 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (150 mL), dried over Na2SO4 and the organic solvent was distilled off. The crude product was purified via flash chromatography (CH2Cl2/7percent MeOH) to yield 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20percent). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)
20%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78 - -45℃; for 1.66667 h;
Stage #2: With hexachloroethane In tetrahydrofuran at -78 - -40℃; for 2.5 h;
To a 500 mL round bottom flask containing 4-nitro-i-H-pyrazole (5g, 44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate (31 mL, 330 mmol). The mixture was stirred at room temperature for 72 h and the mixture was extracted with CH2C12 (2 x 150 mL). The organic layer was separated and the solvent was distilled off to yield 1- methyl-4-nitro- lH-pyrazole as a white solid (4.30 g, 76percent). Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1- methyl-4-nitro- lH-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL). The mixture was cooled to -78 °C and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min. The brown mixture was stirred for 30 min and warmed to -45 °C over 30 min. The mixture was cooled back down to -78 °C and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min. The mixture was stirred for 2.5 h, warmed from -78 °C to -40 °C and the reaction was monitored by LCMS. Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4C1 (150 mL), and ethyl acetate (100 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (150 mL), dried over Na2S04 and the organic solvent was distilled off. The crude product was purified via flash chromatography (CH2C12/ 7percent MeOH) to yield 5-chloro-l-methyl-4-nitro- lH-pyrazole as a white solid (1.40 g, 20percent). 1H NMR (400 MHz, CDC13) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z = 162.0 (M+l)

Reference: [1] Patent: WO2016/90380, 2016, A1, . Location in patent: Paragraph 0021
[2] Patent: US2015/57265, 2015, A1, . Location in patent: Paragraph 0714
[3] Patent: CN108373476, 2018, A, . Location in patent: Paragraph 0237-0239; 0242; 0243; 0290; 0294
[4] Patent: US2011/251176, 2011, A1, . Location in patent: Page/Page column 103
[5] Patent: US2013/79321, 2013, A1, . Location in patent: Paragraph 0177; 0178; 0179
[6] Patent: WO2015/140189, 2015, A1, . Location in patent: Page/Page column 59
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Reference: [1] Patent: US2014/88117, 2014, A1, . Location in patent: Page/Page column
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