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[ CAS No. 42098-25-9 ] {[proInfo.proName]}

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Chemical Structure| 42098-25-9
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Product Details of [ 42098-25-9 ]

CAS No. :42098-25-9 MDL No. :MFCD21607270
Formula : C4H4ClN3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :POXLZEWCWNUVDW-UHFFFAOYSA-N
M.W : 161.55 Pubchem ID :12344836
Synonyms :

Calculated chemistry of [ 42098-25-9 ]

Physicochemical Properties

Num. heavy atoms : 10
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 : 37.32
TPSA : 63.64 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.12
Log Po/w (XLOGP3) : 1.02
Log Po/w (WLOGP) : 0.98
Log Po/w (MLOGP) : 0.33
Log Po/w (SILICOS-IT) : -0.97
Consensus Log Po/w : 0.49

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.79
Solubility : 2.63 mg/ml ; 0.0163 mol/l
Class : Very soluble
Log S (Ali) : -1.95
Solubility : 1.83 mg/ml ; 0.0113 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.78
Solubility : 26.6 mg/ml ; 0.164 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.87

Safety of [ 42098-25-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 42098-25-9 ]

* 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 [ 42098-25-9 ]
  • Downstream synthetic route of [ 42098-25-9 ]

[ 42098-25-9 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 3994-50-1 ]
  • [ 42098-25-9 ]
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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  • [ 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
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