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[ CAS No. 871836-51-0 ] {[proInfo.proName]}

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Chemical Structure| 871836-51-0
Chemical Structure| 871836-51-0
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Product Details of [ 871836-51-0 ]

CAS No. :871836-51-0 MDL No. :MFCD11870058
Formula : C6H4ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :FUXZQGSDRGDYGX-UHFFFAOYSA-N
M.W : 153.57 Pubchem ID :46835637
Synonyms :

Calculated chemistry of [ 871836-51-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.9
TPSA : 41.57 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.21 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.65
Log Po/w (XLOGP3) : 1.44
Log Po/w (WLOGP) : 1.61
Log Po/w (MLOGP) : 0.78
Log Po/w (SILICOS-IT) : 2.24
Consensus Log Po/w : 1.35

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.37
Solubility : 0.662 mg/ml ; 0.00431 mol/l
Class : Soluble
Log S (Ali) : -1.92
Solubility : 1.85 mg/ml ; 0.0121 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.14
Solubility : 0.112 mg/ml ; 0.000728 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.45

Safety of [ 871836-51-0 ]

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

Application In Synthesis of [ 871836-51-0 ]

* 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 [ 871836-51-0 ]
  • Downstream synthetic route of [ 871836-51-0 ]

[ 871836-51-0 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 134031-24-6 ]
  • [ 871836-51-0 ]
YieldReaction ConditionsOperation in experiment
56% With hydrazine hydrate In 1,2-dimethoxyethane at 20 - 75℃; Intermediate 24-Chlora-1 H-pyrazolo[4, 3-c]pyridineTo a solution of Intermediate 1 (1.7 g, 9.7 mmol) in dimethoxyethane (12 ml) at room temperature was added hydrazine monohydrate (1.2 ml, 38.6 mmol) and the resulting mixture was stirred at 75 °C overnight. The mixture was then concentrated to dryness and the crude residue was purified by flash chromatography, eluting with 20 to 100percent ethyl acetate/petroleum ether gradient to give a white solid (0.82 g, 56percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.60 (d, J=6.9 Hz, 1 H), 8.14 (d, J=6.0 Hz, 1 H), 8.32 (s, 1 H); m/z (ES+APCI)+: 154 [M + H]+.
56% With hydrazine hydrate In 1,2-dimethoxyethane at 20 - 75℃; Intermediate 11
4-Chloro-1H-pyrazolo[4,3-c]pyridine
To a solution of Intermediate 11 (1.7 g, 9.7 mmol) in dimethoxyethane (12 ml) at room temperature was added hydrazine monohydrate (1.2 ml, 38.6 mmol) and the resulting mixture was stirred at 75 0C overnight. The mixture was then concentrated to dryness and the crude residue was purified by flash chromatography, eluting with 20 to 100percent ethyl acetate/petroleum ether gradient to give a white solid (0.82 g, 56percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.60 (d, J=6.9 Hz, 1 H), 8.14 (d, J=6.0 Hz, 1 H), 8.32 (s, 1 H); m/z (ES+APCI)+: 154 [M + H]+.
54.4% With hydrazine In 1,2-dimethoxyethane at 80℃; for 2 h; A mixture of 2 4-dichloronicotinaldehyde (800 mg 4.55 mmol) and hydrazine (364 mg 9.09 mmol) in DME (10 mL) was stirred at 80 for 2 h the solvent was concentrated and the residue was purified by column chromatography (DCMMeOH201 800 mL) to provide 4-chloro-1H-pyrazolo [4 3-c] pyridine (400 mg 2.474 mmol 54.4yield) 1HNMR(400 MHz CDCl3) δ 13.85 (m 1H) 8.31 (s 1H) 8.13 (d J5.6 Hz 1H) 7.60 (d J5.6 Hz 1H) ES-LCMS m/z 154.0 (M+H)
4 g With hydrazine hydrate In 1,2-dimethoxyethane at 75℃; B) 4-chloro-1H-pyrazolo[4,3-c]pyridine [1032] To a solution of 2,4-dichloropyridine-3-carbaldehyde (7.0 g) in DME (70 mL) was added hydrazine monohydrate (8.0 g) at room temperature. The reaction mixture was stirred overnight at 75°C, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.0 g). 1H NMR (400 MHz, DMSO-d6) δ 7.60 (1H, d, J = 6.0 Hz), 8.14 (1H, d, J = 6.0 Hz), 8.33 (1H, s), 13.89 (1H, brs).
1.35 g With hydrazine hydrate In 1,2-dimethoxyethane at 0 - 75℃; for 16 h; To a stuffed solution of 2,4—dichloronicotinaldehyde (8.5 g, 48.29 mmol) in DME (60 mL) was added hydrazine hydrate (9.38 mL, 193.18 mmol) at 0 °C slowly and the resultant reaction mixture was heated at 75 °C for 16 h. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched using ice-cold water (200 mL). The aq. layer was then extracted with EtOAc (2x300 mL). The combined organic layers were washed with water (400 mL), brine (100 mL), dried over Na2SO4 and concentrated. The crude compound was purified by silica-gel (230-400) column chromatography, compound eluting at 20percent EtOAc hexane to afford 4-chloro-1H-pyrazolo[4,3-c]pyridine (1.35 g) as a light brown solid.

Reference: [1] Patent: WO2012/38743, 2012, A1, . Location in patent: Page/Page column 82
[2] Patent: WO2010/106333, 2010, A1, . Location in patent: Page/Page column 78-79
[3] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 118
[4] Patent: EP2857400, 2015, A1, . Location in patent: Paragraph 1032
[5] Patent: WO2015/58084, 2015, A1, . Location in patent: Paragraph 0403
  • 2
  • [ 153034-90-3 ]
  • [ 871836-51-0 ]
YieldReaction ConditionsOperation in experiment
70% With hydrazine hydrate In ethanol at 0 - 20℃; To a solution of 2-chloro-4-iodonicotinaldehyde (101) (1.33 g, 5 mmol) in EtOH (10 mL), N2H4H2O (480 uL, 2 eq, 10 mmol) was added slowly at 0 - 5 °C.
The solution was stirred at 10 °C for 1 h.
Then additional amount of N2H4H2O (480 uL, 2 eq, 10 mmol) was added slowly and the resulting mixture was stirred at RT overnight.
The mixture was concentrated in vacuo, brine (20 mL) was added and then extracted with ethyl acetate (3 * 50 mL).
The combined organic layer was washed with brine (20 mL), dried over MgSO4 and filtered.
The filtrate was concentrated in vacuo to afford the crude product.
19% With hydrazine In ethanol at 20℃; for 15 h; Step 2:4-Chloro-lH-pyrazolo[4,3-c]pyridine To a mixture of 2-chloro-4-iodonicotinaldehyde (1.0 g, 3.7 mmol) in ethanol (6.0 mL) was added 3.0 mL of hydrazine (excess). The mixture was stirred at room temperature for 15 h and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with dichloromethane (300 mL). The organic extract was washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and stirred for 5 min. The precipitated solid was isolated by filtration and dried to give the desired intermediate 4-chloro-lH-pyrazolo[4,3-c]pyridine as a grey solid (110 mg, 19percent yield), which was used in the next step without further purification. LCMS(ESI) m/z: 154.1 [M+H+]
Reference: [1] Patent: EP2252293, 2018, B1, . Location in patent: Paragraph 0257; 0258
[2] Patent: WO2012/66061, 2012, A1, . Location in patent: Page/Page column 77
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4370 - 4376
  • 3
  • [ 871836-50-9 ]
  • [ 871836-51-0 ]
Reference: [1] Patent: WO2005/121094, 2005, A1, . Location in patent: Page/Page column 52
  • 4
  • [ 871836-50-9 ]
  • [ 871836-51-0 ]
  • [ 1206979-33-0 ]
Reference: [1] Patent: EP1772454, 2007, A1, . Location in patent: Page/Page column 63
  • 5
  • [ 26452-80-2 ]
  • [ 871836-51-0 ]
Reference: [1] Patent: EP2857400, 2015, A1,
[2] Patent: WO2015/58084, 2015, A1,
[3] Patent: WO2012/38743, 2012, A1,
[4] Patent: WO2010/106333, 2010, A1,
  • 6
  • [ 153034-86-7 ]
  • [ 871836-51-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4370 - 4376
  • 7
  • [ 871836-50-9 ]
  • [ 871836-51-0 ]
  • [ 1206979-33-0 ]
Reference: [1] Patent: EP1772454, 2007, A1, . Location in patent: Page/Page column 63
  • 8
  • [ 871836-51-0 ]
  • [ 1186647-69-7 ]
YieldReaction ConditionsOperation in experiment
92% With iodine; potassium hydroxide In 1,4-dioxane at 75℃; for 4 h; A solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine (1.5 g, 9.77 mmol, 1.00 equiv), 1,4-dioxane(25 mL), potassium hydroxide (2.0 g, 35.65 mmol, 3.60 equiv), and iodine (4.95 g, 19.50 mmol,2.00 equiv) was stuffed for 4 h at 75 °C. The reaction was quenched by saturated aqueous sodium thiosulfate pentahydrate and the solids were collected by filtration. This resulted in 2.5 g (92percent) of the title compound as a light yellow solid. LC-MS (ES, mlz): 280 [M+H].
85% With N-iodo-succinimide In N,N-dimethyl-formamide at 100℃; To a solution of 4-chloro-lH-pyrazolo[4,3-c]pyridine (5.5 g, 36 mmol) in DMF (50 mL) was added NIS (6.9 g, 69 mmol). The resulted mixture was stirred at 100 °C overnight. Then the mixture was cooled and diluted with water, the precipitate was collected by filtration and dried to to give 4-chloro-3-iodo-lH-pyrazolo[4,3-c]pyridine (8.5 g, 85percent) as a light yellow solid.
72% With iodine; potassium hydroxide In 1,4-dioxane at 75℃; for 4 h; To a mixture of 4-chloro-1H-pyrazolo [4, 3-c] pyridine (5.8 g, 38 mmol, synthesized according to WO 2010106333A1 and WO 2012038743A1) and KOH (8 g, 142 mmol) in dioxane (100 mL) at room temperature was added iodine (19 g, 76 mmol) . The reaction mixture was stirred at 75 for 4 h and then allowed to cool to room temperature. The solution was diluted with saturated Na2S2O3(aq) and the resulting precipitate was filtered and dried to give a yellow solid (4.1 g) . The filtrate was left standing for 3 days and filtration of the resulting precipitate yielded a further 3.55 g of the product. Combined yield (7.65 g, 72) .1H NMR (400 MHz, CDCl3) δ ppm 7.65 (d, J 6.0 Hz, 1H) , 8.13 (d, J 6.0 Hz, 1H) , 14.22 (s, 1H) . m/z (ESI)+: 280 [M+H]+
62% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 3 h; A solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine (102) (30 mg, 0.196 mmol) and NIS (66 mg 1.5 eq, 0.249mmol) in DMF (1 mL) was heated to 80 °C for 3 h. The mixture was concentrated in vacuo, brine (10 mL) was addedand then extracted with ethyl acetate (3 3 30 mL). The combined organic layer was washed with brine (10 mL), driedover MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product, 4-chloro-3-iodo-1Hpyrazolo[4,3-c]pyridine (103) (34 mg, 62percent yield) as a white solid. ESI-MS m/z : 277.85 [M - H]- .The product obtainedwas used directly in the next step without purification.
61% With iodine; potassium hydroxide In 1,4-dioxane at 75℃; for 4 h; Intermediate 34-Chloro-3-iodo-1 H-pyrazolo[4, 3-c]pyridiTo a mixture of Intermediate 2 (5.8 g, 38 mmol) and KOH (8 g, 142 mmol) in dioxane (100 ml) at room temperature was added iodine (19 g, 76 mmol). The reaction mixture was stirred at 75 °C for 4 h, and then allowed to cool to room temperature. The solution was diluted with saturated Na2S203 (aq), and the resulting precipitate was filtered and dried to give a yellow solid (4.1 g). The filtrate was left standing for 3 days and filtration of the resulting precipitate yielded a further 2.35 g of the product. Combined yield (6.45 g, 61percent). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.64 (d, J=6.0 Hz, 1 H), 8.11 (d, J=6.0 Hz, 1 H); m/z (ES+APCI)+: 280 [M + H]+.
61% With iodine; potassium hydroxide In 1,4-dioxane at 75℃; for 4 h; Intermediate 12
4-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine
To a mixture of Intermediate 11 (5.8 g, 38 mmol) and KOH (8 g, 142 mmol) in dioxane (100 ml) at room temperature was added iodine (19g, 76 mmol). The reaction mixture was stirred at 750C for 4 h, and then allowed to cool to room temperature. The solution was diluted with saturated Na2S2O3 (aq), and the resulting precipitate was filtered and dried to give a yellow solid (4.1 g). The filtrate was left standing for 3 days and filtration of the resulting precipitate yielded a further 2.35 g of the product. Combined yield (6.45 g, 61percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64 (d, J=6.0 Hz, 1 H), 8.11 (d, J=6.0 Hz, 1 H); m/z (ES+APCI)+: 280 [M + H]+.
6.3 g With iodine; potassium hydroxide In 1,2-dimethoxyethane at 75℃; for 4 h; C) 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine [1033] To a mixture of 4-chloro-1H-pyrazolo[4,3-c]pyridine (4.0 g) and potassium hydroxide (4.4 g) in DME (50 mL) was added iodine (13.3 g) at room temperature. The reaction mixture was stirred at 75°C for 4 hr. The reaction mixture was added to aqueous sodium thiosulfate solution, and the mixture was left stand overnight, and the resulting solid was collected by filtration to give the title compound (6.3 g). MS(ESI+): [M+H]+ 279.9. MS(ESI+), found: 280.1.
1.57 g With iodine; potassium hydroxide In 1,4-dioxane at 75℃; for 4 h; A solution of 4-chloro-lH-pyrazolo[4,3-c]pyridine (750.0 mg, 4.902 mmol, 1.0 eq), KOH (988.0 mg, 17.647 mmol, 4.0 eq) and 12 (2.49 g, 9.804 mmoL, 2.0 eq) in 1,4- dioxane (20.0 mL) was stirred at 75 °C for 4 h, then cooled and quenched by sat. aq. Na2S03 and the precipitate was collected by filtration to provide 4-chloro-3-iodo-lH- pyrazolo[4,3-c]pyridine (1.57 g).

Reference: [1] Patent: WO2015/25025, 2015, A1, . Location in patent: Page/Page column 171; 328; 333
[2] Patent: WO2016/210165, 2016, A1, . Location in patent: Page/Page column 67
[3] Patent: WO2017/215600, 2017, A1, . Location in patent: Page/Page column 32-33
[4] Patent: EP2252293, 2018, B1, . Location in patent: Paragraph 0257; 0259
[5] Patent: WO2012/38743, 2012, A1, . Location in patent: Page/Page column 82
[6] Patent: WO2010/106333, 2010, A1, . Location in patent: Page/Page column 78-79
[7] Patent: EP2857400, 2015, A1, . Location in patent: Paragraph 1033
[8] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00619
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  • [ 871836-51-0 ]
  • [ 1246349-97-2 ]
Reference: [1] Patent: WO2017/215600, 2017, A1,
[2] Patent: WO2012/38743, 2012, A1,
  • 10
  • [ 871836-51-0 ]
  • [ 1246349-97-2 ]
Reference: [1] Patent: WO2010/106333, 2010, A1,
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