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Product Details of [ 2075-46-9 ]

CAS No. :2075-46-9 MDL No. :MFCD00159626
Formula : C3H3N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :XORHNJQEWQGXCN-UHFFFAOYSA-N
M.W : 113.08 Pubchem ID :16376
Synonyms :
Chemical Name :4-Nitro-1H-pyrazole

Calculated chemistry of [ 2075-46-9 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 27.41
TPSA : 74.5 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) : -6.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.16
Log Po/w (XLOGP3) : 0.04
Log Po/w (WLOGP) : 0.32
Log Po/w (MLOGP) : -1.62
Log Po/w (SILICOS-IT) : -0.86
Consensus Log Po/w : -0.39

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.96
Solubility : 12.3 mg/ml ; 0.109 mol/l
Class : Very soluble
Log S (Ali) : -1.16
Solubility : 7.87 mg/ml ; 0.0696 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.56
Solubility : 31.2 mg/ml ; 0.276 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.66

Safety of [ 2075-46-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2075-46-9 ]

* 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 [ 2075-46-9 ]
  • Downstream synthetic route of [ 2075-46-9 ]

[ 2075-46-9 ] Synthesis Path-Upstream   1~48

  • 1
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YieldReaction ConditionsOperation in experiment
100% With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 12 h; Under hydrogen (1 atm), to a solution of 4-nitropyrazole (1.13 g, 10 mmol) in methanol (10 mL) was added 10percent Pd—C (0.1 g). The mixture was stirred at 25° C. for 12 hours, and then filtrated, the filtrate was concentrated under reduced pressure to give compound 31-a (860 mg, yield: 100percent), which was used directly for the next step without purification.
100% With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; 5.0g 4-nitropyrazole was dissolved in 160mL of ethanol and 0.8g of 10percent Pd/C was added. The reaction was subjected to hydrogen and reacted overnight at room temperature. TLC was used to monitor reaction completion. By celite was filtered off Pd/C. Ethanol solvent was evaporated to give 3.6g of the pure intermediate 8 as a red solid, quantitative reaction.
99% With palladium 10% on activated carbon; hydrogen In methanol for 16 h; A suspension of 4-nitro-1H-pyrazole (2.05 g, 18.13 mmol), and Pd/C (10percent w/w palladium on activated carbon, 0.96 g, 0.90 mmol) in MeOH (20 mL) was stirred under H2 atmosphere (balloon) for 16 h. The reaction mixture was filtered through Celite, rinsed with MeOH (3x 30 mL) and concentrated, affording 1.50 g of 1H-pyrazol-4- amine (pale pink solid, 99percent yield). HPLC-MS (Method H): Ret, 1.16 min; ESI+-MS m/z: 84 (M+1).
95% With hydrogen In ethanol at 20℃; for 3 h; Compound Ia (15.0 g, 133 mmol) was added to a suspension of palladium on carbon 10percent (7.0 g, 6.65 mmol) in ethanol (100 mL). The mixture was shaken for 3 hours under hydrogen pressure (40 psi) at room temperature. The catalyst was removed by filtration through a pad of Celite.(R). and the solvent was evaporated. Compound Ib was obtained as a burgundy oil (10.5 g, 126 mmol, 95percent) which was used in the following step without purification; GC/MS: m/z = 83 (100percent).
49% With hydrogen In ethanol A mixture of 4-nitro-l/f-pyrazole (1.13 g, 10 mmol), Pd/C (10percent, 57 mg) in ethanol (20 mL) was hydrogenated at 20-30 psi on a parr apparatu overnight. The reaction mixture was filtered through celite, washed with ethanol (10 mL). The filtrate was concentrated to get desired compound 0113-42 (404 mg, 49percent) as a brown solid. LC-MS: 84 [M+l]+; 1H-NMR (400 MHz, DMSO-d6) δ 3.11 (br s, 2H), 6.99 (s, 2H), 11.92 (s, IH).
3.6 g With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; Dissolving 5.0 g of 4-nitropyrazole in 160 mL of ethanol, and then adding 0.8 g of 10 wtpercent Pd/C to the above solution; Hydrogen was introduced into the reaction solution and allowed to react overnight at room temperature; after the TLC detection reaction was completed, the insoluble matter was filtered off with diatomaceous earth; Evaporation of the ethanol solvent gave pure intermediate 2 as a red solid 3.6 g.

Reference: [1] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0252; 0253
[2] ChemMedChem, 2016, p. 1695 - 1699
[3] Patent: CN105418616, 2016, A, . Location in patent: Paragraph 0118; 0119
[4] Organic and Biomolecular Chemistry, 2013, vol. 11, # 3, p. 395 - 399
[5] Patent: WO2017/178510, 2017, A1, . Location in patent: Page/Page column 297
[6] Patent: WO2006/44821, 2006, A1, . Location in patent: Page/Page column 23
[7] Patent: WO2010/75542, 2010, A1, . Location in patent: Page/Page column 73
[8] Chemische Berichte, 1904, vol. 37, p. 3501
[9] Journal of the Chemical Society, 1945, p. 114
[10] Journal of the Chemical Society, 1925, vol. 127, p. 2939
[11] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5780 - 5793
[12] Patent: US6531475, 2003, B1,
[13] Patent: US6514982, 2003, B1,
[14] Patent: WO2007/99326, 2007, A1, . Location in patent: Page/Page column 108-109
[15] Patent: WO2008/8375, 2008, A2, . Location in patent: Page/Page column 83
[16] Patent: WO2009/93012, 2009, A1, . Location in patent: Page/Page column 20; 35
[17] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4350 - 4364
[18] Patent: WO2012/52459, 2012, A1, . Location in patent: Page/Page column 38-39
[19] Patent: WO2012/52458, 2012, A1, . Location in patent: Page/Page column 34
[20] Patent: WO2012/110986, 2012, A1, . Location in patent: Page/Page column 52-53
[21] Patent: WO2014/194242, 2014, A2, . Location in patent: Paragraph 00603-0605
[22] Patent: CN108864057, 2018, A, . Location in patent: Paragraph 0105; 0206-0208
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Reference: [1] Patent: US2015/111938, 2015, A1, . Location in patent: Paragraph 0018; 0019
[2] Patent: US2015/112073, 2015, A1, . Location in patent: Paragraph 0019-0020
[3] Patent: US2015/112074, 2015, A1, . Location in patent: Paragraph 0020; 0021
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Reference: [1] Patent: US2015/112076, 2015, A1, . Location in patent: Paragraph 0008; 0020; 0021
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  • [ 28466-26-4 ]
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 1, p. 82 - 86
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  • [ 33064-36-7 ]
YieldReaction ConditionsOperation in experiment
82% With sodium hexamethyldisilazane In tetrahydrofuran EXAMPLE 119
This example illustrates the preparation of Compound 108 namely, 3-pyridinecarboxylic acid, 5-[(4-amino-1H-pyrazol-1-yl)carbonyl]-2-methoxy-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester.
A solution of 4-nitropyrazole (22.62 g, 200 mmol) in THF (100 mL) was cooled to 0° C., then sodium bis(trimethylsilyl)amide (204.3 mmol) in THF solution was added dropwise.
A solution of Compound 84 (70.75 g, 200 mmol) in THF (100 mL) was then added dropwise at 0° C., then the pot was stirred at 25° C. for 30 minutes.
The reaction mixture was then poured into 5percent hydrochloric acid and extracted with dichloromethane.
The organic layer was dried with MgSO4 and the solvent removed by rotary evaporation.
The residue was purified by silica gel chromatography (5percent ethyl acetate: hexane) to give 70.14 g (82percent) of the pyrazole amide (Compound 101).
Reference: [1] Patent: US5125956, 1992, A,
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1989, vol. 25, # 2, p. 235[2] Khimiya Geterotsiklicheskikh Soedinenii, 1989, # 2, p. 278
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YieldReaction ConditionsOperation in experiment
91%
Stage #1: at 40℃;
Stage #2: at -5℃;
lH-Pyrazol-4-amine (Compound 0113-42)Pyrazole (2.04 g, 30 mmol) was added in portions to concentrated sulfuric acid (15 rnL) at below 4O0C followed by addition of concentrated nitric acid (2.08 g, 33 mmol) at -50C dropwise. After the reaction was completed, the mixture was poured onto ice and extracted with ethyl acetate. The separated organic layer was washed with saturated NaΗCO3 solution, brine, dried and concentrated to give the compound 4-nitro-l/f-pyrazole (3.09 g, 91percent) as a light yellow solid. LC-MS: 114 [M+l]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.59 (br s, 2H), 13.98 (br s, IH).
85.5%
Stage #1: With sulfuric acid; nitric acid In water at 55℃;
Stage #2: With sodium hydroxide In water at 0℃;
2a (5.Og, 73.5mmol) was added in portions to H2SO4 (35mL) while keeping the temperature below 400C, then 70percent HNO3 (5.06mL, 80.6mmol) was added dropwise while maintaining the temperature below 55 0C. The mixture was then heated at 550C for 5h and cooled to 00C. The mixture was neutralized with 50percent NaOH and the resulting slurry was diluted with ethyl acetate. The resulting precipitate was removed by filtration. The filtrate was separated and the organic phase was washed with water and brine, dried over MgSO4 and concentrated in vacuum. The residue was crystallized for ethanol to afford 2b (7.1g, 85.5percent)
74% at 55℃; for 3 h; EXAMPLE 1; SYNTHESIS OF REAGENTS 3-BROMO-7-CHLORO-5-METHYL-lH-PYRAZOLO[4,3-b]PYRiDiNEAND 7-BENZYLOXY-S-BROMO-S-METHYL- lH-PYRAZOLO[4,3-b]PYRIDINE; Step IA; Pyrazole (30.0 g, 441 mmol) was added portionwise to sulfuric acid (220 raL, 97percent) in an ice-bath. The mixture was heated at 55 0C and nitric acid (30 mL, 70percent, 0.5 mol) was added slowly. The reaction mixture was stirred at 55 °C for 3 hours, cooled down, poured into ice-water (600 mL) and neutralized with 6N NaOH solution (pH = 7). The reaction mixture was extracted with ethyl acetate (5x150 mL). The organic phases were combined, washed with water (100 mL) and brine (100 mL), dried with sodium sulfate, filtered and concentrated by vacuum to afford compound Ia as a white solid (37.0 g, 326 mmol, 74percent); GC/MS: m/z = 113 (100percent).
56% at 0℃; for 6 h; Reflux Pyrazole (8.5 g) and cold concentrated nitric acid (18 cm3, d = 1.4 g/mL) were added to concentrated sulfuric acid (15 cm3) that had been cooled to 0 °C using an ice–salt bath.The reaction mixture was heated under reflux for 3 h. The reaction mixture was cooled toroom temperature, and additional nitrating mixture (6 cm3 of concentrated sulfuric acid and 6 cm3 of nitric acid) was added dropwise. The mixture was heated under reflux for a further 3 h, cooled and left to stand overnight. The obtained solution was poured onto ice (80 g), and the precipitate was filtered under reduced pressure, washed with cold water and cold ethanol, and crystallized from toluene. 4-Nitropyrazole (56 percent yield) was obtained as a white solid.
42% at 60℃; for 4 h; Cooling with ice 4-nitro-1H-pyrazole
Pyrazole (10 g, 147 mmol), was added to concentrated sulfuric acid (100 mL), in portions, while maintaining the internal reaction temperature below 50° C. via an ice water bath.
Concentrated nitric acid (10 mL) was then added, dropwise, maintaining the internal reaction temperature below 50° C. via an ice water bath.
The ice water bath was removed and the reaction was heated to 60° C. and stirred for 4 hours.
The reaction was cooled via an ice water bath and made basic, to ˜pH 8, with 18 N aqueous NaOH solution (150 mL).
The product, which precipitated as a white solid, was collected by filtration, washed with H2O, and dried under high vacuum to afford 4-nitro-1H-pyrazole (7 g, 42percent) as a white solid. 13C NMR (100 MHz, CDCl3): δ 126.4, 137.0.
42% at 0 - 55℃; for 5 h; Example 41c
3,5-Dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole
1H-Pyrazole (10 g, 147 mmol) was added in small portions to concentrated H2SO4 (100 mL), cooled to 0° C. via an ice/water bath, maintaining the internal reaction temperature below 40° C. Concentrated HNO3 (10 mL) was carefully added, dropwise, to the reaction mixture maintaining the internal reaction temperature below 55° C.
The reaction was then heated to 55° C. and stirred for 5 hours.
The mixture was cooled to 0° C. and carefully made basic (pH-8) with aqueous NaOH solution (110 g NaOH in 150 mL H2O) until a white precipitate formed, carefully ensuring the internal temperature of the solution remain below 40° C.
The white solid was collected by filtration and washed with ethyl acetate/hexanes (1/3) then dried en vacuo to afford 4-nitro-1H-pyrazole (7 g, 42percent, isolated yield).
13C NMR (DMSO-d6, 100 MHz) δ 137.0, 126.4.
To 4-nitro-1H-pyrazole (9 g, 80 mmol) in DMF (100 mL) was added cesium carbonate (26 g, 80 mmol) followed by the addition of 4-(chloromethyl)-3,5-dimethylisoxazole (12.3 g, 85 mmol).
The reaction mixture was stirred in DMF (100 mL) at 80° C. for 30 minutes, then cooled, diluted with H2O (150 mL) and extracted with ethyl acetate (3*, 75 mL).
The combined organic layers were dried over sodium sulfate, filtered and concentrated.
The residue was taken up in ethyl acetate (200 mL) and washed with H2O (2*, 100 mL).
The organic layer was dried over sodium sulfate, filtered and concentrated.
The solid product was triturated with ethyl acetate/hexanes (1/9) and collected by filtration.
The product was dried under high vacuum to afford 3,5-dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole (12 g, 67percent) as a light yellow solid. 1H NMR (CDCl3, 400 MHz): δ 2.23 (s, 3H), 2.46 (s, 3H), 5.08 (s, 2H), 8.02 (s, 1H), 8.08 (s, 1H).

Reference: [1] Patent: WO2010/75542, 2010, A1, . Location in patent: Page/Page column 73
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5780 - 5793
[3] Patent: WO2009/154769, 2009, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2006/44821, 2006, A1, . Location in patent: Page/Page column 22
[5] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1517 - 1525
[6] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1621 - 1627
[7] Patent: US9247759, 2016, B2, . Location in patent: Page/Page column 87
[8] Patent: US2016/376263, 2016, A1, . Location in patent: Paragraph 0395; 0396
[9] Justus Liebigs Annalen der Chemie, 1893, vol. 273, p. 252
[10] Chemische Berichte, 1955, vol. 88, p. 1577,1583
[11] Journal of Chemical Research - Part S, 1996, # 5, p. 244 - 245
[12] Patent: WO2008/8375, 2008, A2, . Location in patent: Page/Page column 82-83
[13] Patent: WO2009/93012, 2009, A1, . Location in patent: Page/Page column 19-20; 33
[14] Polyhedron, 2012, vol. 47, # 1, p. 151 - 164
[15] Patent: CN106986860, 2017, A, . Location in patent: Paragraph 0030; 0031; 0032
[16] Patent: CN107098861, 2017, A, . Location in patent: Paragraph 0032; 0034
[17] Patent: CN107118157, 2017, A, . Location in patent: Paragraph 0029
[18] Chemical Biology and Drug Design, 2018, vol. 91, # 2, p. 567 - 574
[19] Patent: CN107880029, 2018, A, . Location in patent: Paragraph 0029
[20] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2382 - 2390
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YieldReaction ConditionsOperation in experiment
72% 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] Catalysis Communications, 2013, vol. 42, p. 35 - 39
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YieldReaction ConditionsOperation in experiment
0.97 g at 25℃; 1-Nitropyrazole (1 g) was slowly added to a round-bottomed flask containing H2SO4 (98percent, 5 mL) and stirred for 20 h at room temperature. The reaction mixture was slowly transferred to a beaker containing ice with stirring. The solution was extracted with ether. The organic layer was dried with Na2SO4 then evaporated to afford 4-nitropyrazole as a colorless solid (0.97 g, 96percent). The solid was recrystallized from ether/hexane to get white crystalline compound. m.p. 163–165 °C; FT-IR (KBr, cm−1) 3186 (N−H), 1526 and 1353 cm−1 (NO2). 1H NMR (DMSO-d6) δ: 8.26 (d, 1, 5-H), 6.76 (d, 1, 3-H). EI-MS: m/z 113 (M). Anal. Calcd for C3H3N3O2: C, 27.54; H, 3.88; N, 32.42. Found: C, 28.31; H, 3.21; N, 31.38.
Reference: [1] Chemische Berichte, 1955, vol. 88, p. 1586,1590
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[3] Patent: WO2006/40520, 2006, A1, . Location in patent: Page/Page column 122
[4] Patent: WO2007/99326, 2007, A1, . Location in patent: Page/Page column 103-104
[5] Patent: WO2007/99317, 2007, A1, . Location in patent: Page/Page column 101
[6] Patent: WO2007/99335, 2007, A1, . Location in patent: Page/Page column 94-95
[7] Patent: US2009/76075, 2009, A1, . Location in patent: Page/Page column 36
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[9] Patent: WO2007/113548, 2007, A1, . Location in patent: Page/Page column 142
[10] Patent: WO2007/113565, 2007, A1, . Location in patent: Page/Page column 93-94
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Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 24, p. 8382 - 8386
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Reference: [1] Catalysis Communications, 2012, vol. 19, p. 37 - 41
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Reference: [1] Patent: US6514982, 2003, B1,
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 8, p. 926[2] Khimiya Geterotsiklicheskikh Soedinenii, 1986, # 8, p. 1136
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Reference: [1] Chemistry - An Asian Journal, 2015, vol. 10, # 9, p. 1987 - 1996
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 5, p. 530 - 533[2] Khimiya Geterotsiklicheskikh Soedinenii, 1991, vol. 27, # 5, p. 665 - 668
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1989, vol. 25, # 2, p. 235[2] Khimiya Geterotsiklicheskikh Soedinenii, 1989, # 2, p. 278
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1989, vol. 25, # 2, p. 235[2] Khimiya Geterotsiklicheskikh Soedinenii, 1989, # 2, p. 278
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Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1989, vol. 25, # 2, p. 235[2] Khimiya Geterotsiklicheskikh Soedinenii, 1989, # 2, p. 278
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Reference: [1] Justus Liebigs Annalen der Chemie, 1894, vol. 279, p. 228 Anm.50
[2] Justus Liebigs Annalen der Chemie, 1894, vol. 279, p. 228 Anm.50
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Reference: [1] Chemische Berichte, 1955, vol. 88, p. 1586,1590
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Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 24, p. 4656 - 4660
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  • [ 540-51-2 ]
  • [ 42027-81-6 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In ethyl bromide; acetonitrile for 16 h; Reflux [0214j A mixture of 2-bromoethanol (3.75 g, 30.00 mmol), 4-nitropyrazzole (3.39 g, 30.00 mmol) and K2C03 (4.97 g, 36.00 mmol) in acetonitrile (30 mL) was refluxed for 16 h. Then the mixture was filtered and the filtrate was concentrated to dryness to give crude product 2-(4-nitro-1H-pyrazol-1-yl)ethanol as a white solid (4.70 g, yield: 100percent), which was used directly in the next step. ESI-MS (M+H) : 158.0.
94% With potassium carbonate In acetonitrile at 60℃; for 6 h; A solution of 2b (0.8g, 7.08mmol), 2-bromoethan-l-ol (0.97g, 7.76mmol) and K2CO3 (1.46g, 10.56mmol) in acetonitrile (15mL) was heated at 600C for 6h, then the solvent was evaporated and the residue was added water (15mL), extracted with ethyl acetate (10mLx3), dried with MgSO4 and concentrated to give 9a (1.05g, 94percent) as white solid.
61% With potassium carbonate In acetonitrile at 80℃; for 18 h; A solution of 4-nitropyrazole (300 rro, 0.27 mmol, I eq.), 2-bromoethanol (206 4,0.29 mmol, 1.1 eq.) and K2C03 (549 mg, 0.40 mmol, 1.5 eq.) in CH3CN (5mL) was heated to 80 °C for 18 h. The mixiure was allowed to cool and parlitioned between EtOAc (3 x 30 mL) and water (20 mL). The organic layers were dried over MgSO4, evaporated, and the residue purified by MPLC on SiC2 with gradient elution from 30-60percent EtOAc/petrolto give 2-(4-Nitro-IH-pyrazol-1- y[)ethanol as a white solid (256 mg, 61percent).
50% With potassium carbonate In acetonitrile at 95℃; Into a 250 mL round-bottom flask, was placed a solution of compound 28.1 (5 g, 44.22 mmol, 1.00 equiv) in CH3CN (100 mL), 2-bromoethan-1- ol (11 g, 88.02 mmol, 2.00 equiv) and potassium carbonate (18.5 g, 133.85 mmol, 3.00 equiv). The resulting solution was stirred overnight at 95°C in an oil bath. The reaction was then quenched by the addition of water and extracted with 3 x 100 mL of ethyl acetate. Organic layers were combined and concentrated under vacuum. The product crude was purified using flash column chromatography to furnish 3.5 g (50percent) of intermediate 28.2 as yellow oil.
49.5% With potassium carbonate In acetonitrile at 60℃; for 16 h; 2-Bromoethanol (1.9 g, 15.57 mmol) and potassium carbonate (2.9 g, 21.12 mmol) were added to a solution of 4-nitropyrazole (1.6 g, 14.16 mmol) in acetonitrile (20 mL) in sequence, the mixture was heated to 60° C. and stirred for 16 hours. After cooled to room temperature, the mixture was filtrated, the filtrate was concentrated under reduced pressure to give compound 51-b (1.1 g, yield: 49.5percent), which was used directly for the next step without purification.
43% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 6 h; A stirred solution of 4-nitro-1H-pyrazole 12 (10.0 g, , 88.4 mmol), 2-bromo ethanol (12.0 g, 97.3 mmol) and cesium carbonate (43.0 g, 132.6 mmol) in DMF (130 mL) was heated to 100°C for 6h. After the completion of reaction (TLC monitoring), the reaction mixture was cooled to RT, diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phase washed with water, dried over Na2SO4, concentrated to give 2-(4-nitro-1H-pyrazol-1-yl)ethanol 17 (6.0 g, 43percent yield). ‘I-INMR (400 MHz, DMSO-d6): ö 8.81 (s, 1H), 8.26 (s, 1H), 4.99 (t, 1H), 4.22 (t, 2H) 3.76-3.78 (m, 2H).

Reference: [1] Patent: WO2015/89337, 2015, A1, . Location in patent: Paragraph 0214
[2] Patent: WO2009/154769, 2009, A1, . Location in patent: Page/Page column 41
[3] Patent: WO2016/42341, 2016, A1, . Location in patent: Page/Page column 183; 184
[4] Patent: WO2015/48281, 2015, A1, . Location in patent: Paragraph 00413; 00414
[5] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0342; 0343
[6] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 00080
[7] Patent: WO2007/99326, 2007, A1, . Location in patent: Page/Page column 112
[8] Patent: WO2012/110986, 2012, A1, . Location in patent: Page/Page column 43
[9] Patent: WO2013/17479, 2013, A1, . Location in patent: Page/Page column 48
[10] Patent: US2018/208604, 2018, A1, . Location in patent: Paragraph 0301-0302
  • 23
  • [ 2075-46-9 ]
  • [ 79-08-3 ]
  • [ 6645-69-8 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: With potassium hydroxide In water; acetone at 20℃; for 0.5 h;
Stage #2: at 20℃;
A solution of potassium hydroxide (32.7 g, 0.58 mol) in water (100 mL) was added to a stirred mixture of 4-nitro-lH-pyrazole (30 g, 0.27 mol) in acetone (500 mL) at room temperature. After 30 min, a solution of 2-bromoacetic acid (38.7 g, 0.27 mol) in acetone (100 mL) was added and the reaction was stirred overnight. The solvent was removed in vacuo, the residue was diluted with water then extracted three times with ethyl acetate and the combined organic layer was concentrated in vacuo. The residue was further extracted with dichloromethane and methanol and the combined organic layer was concentrated in vacuo to afford 2-(4-nitro-lH-pyrazol-l-yl)acetic acid (40 g, 88percent).
Reference: [1] Patent: WO2013/174895, 2013, A1, . Location in patent: Page/Page column 70
  • 24
  • [ 2075-46-9 ]
  • [ 96-34-4 ]
  • [ 6715-84-0 ]
YieldReaction ConditionsOperation in experiment
92% With potassium carbonate In acetonitrile at 60℃; for 5 h; Step 1 To a solution of 4-nitro-lH-pyrazole (100 g, 0.88 mol) in ACN (2L) was added K2C03 (183.2 g, 1.33 mol) and methyl 2-chloroacetate (95.6 g, 0.88 mol). The mixture was warmed to 60°C and stirred for 5h. The mixture was then filtered and solvent removed to give methyl 2-(4- nitro-lH-pyrazol-l-yl)acetate as a white solid (150 g, 92percent). 1H NMR (400 MHz CDC13): δ 8.28 (s, 1H), 8.11 (s, 1H), 4.98 (s, 2H), 3.84 (s, 3H),
Reference: [1] Patent: WO2013/14162, 2013, A1, . Location in patent: Page/Page column 99
  • 25
  • [ 2075-46-9 ]
  • [ 96-32-2 ]
  • [ 6715-84-0 ]
Reference: [1] Patent: WO2014/139328, 2014, A1, . Location in patent: Page/Page column 658A
  • 26
  • [ 288-13-1 ]
  • [ 2075-46-9 ]
  • [ 26621-44-3 ]
Reference: [1] Catalysis Communications, 2012, vol. 19, p. 37 - 41
  • 27
  • [ 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
  • 28
  • [ 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
  • 29
  • [ 2075-46-9 ]
  • [ 100-39-0 ]
  • [ 88095-61-8 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere
Stage #2: at 0 - 20℃; for 12 h; Inert atmosphere
a)
1-Benzyl-4-nitro-1H-pyrazole
To a solution of 4-nitro-1H-pyrazole (283 mg, 2.5 mmol) in dry DMF (5 ml) under an argon atmosphere was added NaH (120 mg, 2.75 mmol) in small portions at 0° C.
The reaction mixture was stirred at rt for 1 hour, cooled again to 0° C. before benzyl bromide (300 μl, 2.5 mmol) was added and stirred at rt for 12 h.
The mixture was diluted with water, extracted with ethyl acetate and the product was purified by chromatography on silica gel using heptane/ethyl acetate as eluent.
The title compound was obtained as light yellow oil (484 mg, 95percent). MS ISP (m/e): 226.3 (100) [(M+Na)+].
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5714 - 5727
[2] Patent: US2010/120874, 2010, A1, . Location in patent: Page/Page column 27-28
  • 30
  • [ 2075-46-9 ]
  • [ 620-05-3 ]
  • [ 88095-61-8 ]
YieldReaction ConditionsOperation in experiment
98% 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.
Reference: [1] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 10, p. 3009 - 3014
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2382 - 2390
  • 31
  • [ 2075-46-9 ]
  • [ 74-88-4 ]
  • [ 69843-13-6 ]
Reference: [1] Patent: WO2011/134831, 2011, A1, . Location in patent: Page/Page column 36
  • 32
  • [ 2075-46-9 ]
  • [ 6482-24-2 ]
  • [ 948570-74-9 ]
Reference: [1] Patent: WO2014/7951, 2014, A2, . Location in patent: Page/Page column 241
  • 33
  • [ 2075-46-9 ]
  • [ 540-51-2 ]
  • [ 948571-47-9 ]
Reference: [1] Patent: WO2012/143320, 2012, A1, . Location in patent: Page/Page column 39
  • 34
  • [ 2075-46-9 ]
  • [ 6482-24-2 ]
  • [ 948570-75-0 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In acetonitrile at 80℃; for 4 h; [0223j To a mixture of 4-nitro-1H-pyrazole (113 mg, 1 mmol, 1.0 eq) in CH3CN (5 mL), 1-bromo-2-methoxyethane (138 mg, 1 mmol, 1.0 equiv) and K2C03 (276 mg, 2 mmol, 2.0 equiv) was added. The mixture was stirred at 80 °C for 4 h. After diluted with EtOAc (100 mL), the mixture was washed with water (50 mL x 2). The organic layer was concentrated and purified by silica gel column (petroleum ether/EtOAc = 10 : 1) to give 1-(2-methoxyethyl)-4-nitro-1H- pyrazole (170 mg, yield: 100percent) as a colorless oil. ESI-MS (M+H): 172.1. ‘H NMR (400 MHz, CDC13) (5: 8.23 (s, 1H), 8.07 (s, 1H), 4.31 (t, J= 5.2 Hz, 2H), 3.74 (t, J= 5.2 Hz, 2H), 3.35 (s, 3H).
97% With potassium carbonate In acetonitrile at 90℃; for 5 h; To a solution of 4-nitro-1H-pyrazole 12 (1.70 g, 15.03 mmol) in CH3CN (50 mL) was added K2C03 (3.11 g, 22.53 mmol) followed by addition of 1-bromo-2- methoxy-ethane (2.5 g, 18.0 mmol) at room temperature. The reaction mixture was heated to 90°C for 5 h. After completion of reaction (monitored by TLC), the solvent was evaporated, added water and extracted with EtOAc (3 x 200 mL). the combined organics was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2.50 g (97percent yield) of the title compound 16 as colorless liquid. 1H NMR (400 MHz, DMDO-d6): 3 8.85 (s, 1H), 8.27 (s, 1H), 4.36-4.33 (t, 2H), 3.77-3.72 (t, 2H), 3.23 (s, 3H). MS: 172.11 (M+H).
76% With potassium carbonate In acetonitrile at 60℃; for 6 h; A mixture of 4-nitro-1H-pyrazole (1 equiv), 1-bromo-2-methoxyethane (1.05 equiv), potassium carbonate (1.5 equiv) and acetonitrile (0.44 M) was stirred and heated to 60° C. for 6 h. The resultant mixture was evaporated and the residue was purified by flash chromatography (2.5percent MeOH in DCM) to afford the desired product as a yellow solid (76percent yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.25 (s, 1H), 8.08 (s, 1H), 4.34-4.31 (t, J=4.8 Hz, 2H), 3.77-3.74 (t, J=4.8 Hz, 2H), 3.37 (s, 3H)
Reference: [1] Patent: WO2015/89337, 2015, A1, . Location in patent: Paragraph 0223
[2] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 00078
[3] Patent: US2014/200206, 2014, A1, . Location in patent: Paragraph 0339
[4] Patent: WO2007/99326, 2007, A1, . Location in patent: Page/Page column 104
  • 35
  • [ 2075-46-9 ]
  • [ 109-86-4 ]
  • [ 948570-75-0 ]
YieldReaction ConditionsOperation in experiment
76.1% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 3 h; At 0° C., DEAD (4.1 g, 19.91 mmol) was added slowly to a solution of 4-nitropyrazole (1.5 g, 13.27 mmol), 2-methoxyethanol (1.5 g, 19.91 mmol) and PPh3 (5.2 g, 19.91 mmol) in anhydrous TH-IF (25 mL). The mixture was warmed to room temperature and stirred for 3 hours, then concentrated under reduced pressure, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give white solid 70-b (1.72 g, yield: 76.1percent). LC-MS (ESI): m/z=198 [M+H
Reference: [1] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0436; 0437
  • 36
  • [ 2075-46-9 ]
  • [ 627-42-9 ]
  • [ 948570-75-0 ]
YieldReaction ConditionsOperation in experiment
49.5% With potassium carbonate In acetonitrile for 18 h; Reflux 4-Nitropyrazole (2.0 g, 17.68 mmol),The solution obtained by dissolving 2-chloroethyl methyl ether (2.01 g, 21.26 mmol) and potassium carbonate (4.88 g, 35.31 mmol) in 40 mL of acetonitrile was refluxed for 18 h.Spin dry,A silica gel column (PE/EA = 4:1) gave 1.5 g of a pale yellow solid.Yield: 49.5percent.
Reference: [1] Patent: CN104583195, 2018, B, . Location in patent: Paragraph 0633; 0634; 0635; 0636; 0637
  • 37
  • [ 2075-46-9 ]
  • [ 1895-39-2 ]
  • [ 956477-64-8 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333 h;
Stage #2: for 0.5 h;
Cs2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-1H-pyrazole(5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 mm, solid sodium2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 mm. The reaction was complete after 10 mm of additional heating. The mixture wasadded to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phasechromatography eluting with a gradient of hexanes/EtOAc yielded 1 -(difluoromethyl)-4- nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97percent yield) as a clear, colorless oil. ‘H NMR(500MHz, CDC13) ö 8.58 (s, 1H), 8.22 (s, 1H), 7.39-7.05 (t,J= 60Hz, 1H).
97%
Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333 h;
Stage #2: at 120℃; for 0.5 h;
CS2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-lH-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 min. The reaction was complete after 10 min of additional heating. The mixture was added to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phase chromatography eluting with a gradient of hexanes/EtOAc yielded 1 -(difluoromethyl)-4- nitro-lH-pyrazole (6.99 g, 42.9 mmol, 97percent yield) as a clear, colorless oil. 'H NMR (500MHz, CDCI3) δ 8.58 (s, 1H), 8.22 (s, 1H), 7.39 - 7.05 (t, J= 60 Hz, 1H).
41% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 100℃; [00559] Intermediate 56a: I -(diluoromethyl)-4-nitro-pyrazole[00560] Sodium chiorodifluoroacetate (2.7g, 17.6gmmol) was added to a solution of 4- nitropyrazole (1 .OOg, 8.84mmol) and NaHCO3 (1 .49g, 1 7.6gmmol) in DMF (8mL) and the solution heated to 100°C overnight. More NaHCO3 (1.49g, 17.6gmmol) and 4-nitropyrazole (1.OOg, 8.84mmol) were added and stirring was continued overnight. More NaHCO3 (1 .49g, 1 7.6gmmol) and 4-nitropyrazole (1 .Og, 8.84mmol) were added and stirring was continued overnight. The solutionwas then cooled to room temperature and the mixture was diluted with water (5OmL) and EtOAc (5OmL). The insoluble precipitate was filtered off and the organic layer separated. The aqueous was extracted with EtOAc (3 x 5OmL) and the combined organic layers were washed with brine (5OmL), dried over Na2504 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50percent EtOAc in heptane to give 1-(difluoromethyl)-4-nitro-pyrazole (0.58g,3.S9mmol, 41percent yield) as a pale yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 8.59 (1H, 5), 8.24 (1H, 5), 7.23 (1H, t, J= 60.0Hz). MS Method 2: RT: 1.16 mi mlz 164.0 [M+H]
Reference: [1] Patent: WO2015/116886, 2015, A1, . Location in patent: Page/Page column 200
[2] Patent: WO2015/116882, 2015, A1, . Location in patent: Page/Page column 84; 88
[3] Patent: WO2016/51193, 2016, A1, . Location in patent: Paragraph 00558; 00559; 00560
[4] Patent: WO2017/74832, 2017, A1, . Location in patent: Page/Page column 202
  • 38
  • [ 2075-46-9 ]
  • [ 65094-22-6 ]
  • [ 956477-64-8 ]
YieldReaction ConditionsOperation in experiment
68% With potassium fluoride In acetonitrile at 20℃; for 12 h; Schlenk technique; Inert atmosphere; Green chemistry General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
Reference: [1] Tetrahedron Letters, 2018, vol. 59, # 28, p. 2752 - 2754
  • 39
  • [ 2075-46-9 ]
  • [ 75-45-6 ]
  • [ 956477-64-8 ]
Reference: [1] Patent: WO2010/10184, 2010, A1, . Location in patent: Page/Page column 60
  • 40
  • [ 2075-46-9 ]
  • [ 141699-55-0 ]
  • [ 1314987-79-5 ]
YieldReaction ConditionsOperation in experiment
85% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 16 h; Inert atmosphere [0229j DIAD (3.92 mL, 19.9 mmmol, 1.5 equiv) was added dropwise to a stirred solution of 4-nitro-1H-pyrazole (1.5 g, 13.27 mmol), 1-Boc-3-Hydroxyazetidine (2.3 g, 13.27 mmol, 1 equiv) and triphenyiphosphine (5.22 g, 19.9 mmol, 1.5 equiv) in THF (30 mL) placed an ice-bath under N2. The mixture was stirred at 0 °C for 10 mm and allowed to warm to rt and stirred for 16 h. After diluted with EA (100 mL), the mixture was washed with water (40 mL), brine (30 mL x 2). The combined organic layer was dried, concentrated. The crude was purified through silica gel column chromatography (petroleum ether/EtOAc = 1/10) to give tert-butyl 3-(4-nitro-1H- pyrazol-1-yl)azetidine-1-carboxylate as light yellow solid (3 g, yield: 85percent). ESI-MS (M+H-56) : 213.1. ‘H NMR (400 MHz, CDC13)(5: 8.28 (s, 1H), 8.16 (s, 1H), 5.07-5.04 (m, 1H), 4.44-4.40 (m, 2H), 4.34-4.30 (m, 2H), 1.47 (s, 9H).
5.3 g With di-tert-butyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 35℃; A)
tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate
To a solution of 4-nitro-1H-pyrazole (2.0 g), tert-butyl 3-hydroxyazetidine-1-carboxylate (3.1 g) and triphenylphosphine (5.6 g) in tetrahydrofuran (20 mL) was added di-tert-butyl (E)-diazene-1,2-dicarboxylate (5.3 g) at room temperature, and the mixture was stirred overnight at room temperature.
The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.3 g).
1H NMR(300 MHz, CDCl3)δ1.47 (9H, s), 4.28-4.37 (2H, m), 4.38-4.47 (2H, m), 5.05 (1H, tt, J = 7.9, 5.1 Hz), 8.16 (1H, s), 8.27 (1H, s).
Reference: [1] Patent: WO2015/89337, 2015, A1, . Location in patent: Paragraph 0229
[2] Tetrahedron Letters, 2008, vol. 49, # 18, p. 2996 - 2998
[3] Patent: EP2832734, 2015, A1, . Location in patent: Paragraph 0520
  • 41
  • [ 2075-46-9 ]
  • [ 605655-08-1 ]
  • [ 1314987-79-5 ]
YieldReaction ConditionsOperation in experiment
41% With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h; Compound 54-c (4.9 g, 15 mmol) and cesium carbonate (6.5 g, 2 mmol) were added to a solution of 4-nitropyrazole (1.13 g, 10 mmol) in DMF (15 mL) in sequence, and then the mixture was heated to 120° C. and stirred for 12 hours. After cooled to room temperature, the mixture was treated with water (60 mL), extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 54-b (1.1 g, yield: 41percent). LC-MS (ESI): m/z=291 [M+Na]+.
Reference: [1] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0353; 0356
  • 42
  • [ 2075-46-9 ]
  • [ 109384-19-2 ]
  • [ 1029413-55-5 ]
Reference: [1] Patent: WO2014/26242, 2014, A1, . Location in patent: Page/Page column 164
  • 43
  • [ 2075-46-9 ]
  • [ 67-72-1 ]
  • [ 3994-50-1 ]
  • [ 42098-25-9 ]
Reference: [1] Patent: US2014/88117, 2014, A1, . Location in patent: Page/Page column
  • 44
  • [ 2075-46-9 ]
  • [ 103286-54-0 ]
Reference: [1] Journal of the American Chemical Society, 2018, vol. 140, # 18, p. 6014 - 6026
  • 45
  • [ 2075-46-9 ]
  • [ 63680-90-0 ]
YieldReaction ConditionsOperation in experiment
97% With hydrogenchloride; triethylsilane; Pd/Al In ethanol at 15 - 39℃; for 4 h; Inert atmosphere Step 1:
Preparation of 3-chloro-1H-pyrazol-4-amine hydrochloride
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 (5percent 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 3-chloro-1H-pyrazol-4-amine hydrochloride (84 g, 97percent yield, 80percent purity) as a white solid: mp 190-193° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.46-10.24 (bs, 2H), 8.03 (s, 0.54H), 7.75 (s, 0.46H), 5.95 (bs, 1H)); 13C-NMR (101 MHz, DMSO) δ 128.24, 125.97, 116.71.
Reference: [1] Patent: US2016/60245, 2016, A1, . Location in patent: Paragraph 0290; 0291
[2] Patent: US2012/110702, 2012, A1, . Location in patent: Page/Page column 17.1
[3] Patent: US2012/220453, 2012, A1, . Location in patent: Paragraph 0192; 0193
[4] Patent: US2013/109566, 2013, A1, . Location in patent: Paragraph 0250; 0251
[5] Patent: US2013/288893, 2013, A1, . Location in patent: Paragraph 0289-0290
[6] Patent: WO2017/87905, 2017, A1, . Location in patent: Page/Page column 116
  • 46
  • [ 2075-46-9 ]
  • [ 28466-26-4 ]
  • [ 63680-90-0 ]
Reference: [1] Patent: US2015/111938, 2015, A1, . Location in patent: Paragraph 0018; 0019
[2] Patent: US2015/112073, 2015, A1, . Location in patent: Paragraph 0019-0020
[3] Patent: US2015/112074, 2015, A1, . Location in patent: Paragraph 0020; 0021
  • 47
  • [ 2075-46-9 ]
  • [ 63680-90-0 ]
  • [ 4331-28-6 ]
Reference: [1] Patent: US2015/112075, 2015, A1, . Location in patent: Paragraph 0019; 0020
  • 48
  • [ 2075-46-9 ]
  • [ 63680-90-0 ]
  • [ 4331-28-6 ]
Reference: [1] Patent: US2015/112075, 2015, A1, . Location in patent: Paragraph 0019; 0020
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