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Product Details of [ 43120-28-1 ]

CAS No. :43120-28-1 MDL No. :MFCD01138133
Formula : C9H8N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :KWTCVAHCQGKXAZ-UHFFFAOYSA-N
M.W : 176.17 Pubchem ID :657476
Synonyms :

Calculated chemistry of [ 43120-28-1 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.11
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 47.37
TPSA : 54.98 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) : -6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.42
Log Po/w (XLOGP3) : 1.74
Log Po/w (WLOGP) : 1.35
Log Po/w (MLOGP) : 1.04
Log Po/w (SILICOS-IT) : 1.84
Consensus Log Po/w : 1.48

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.41
Solubility : 0.687 mg/ml ; 0.0039 mol/l
Class : Soluble
Log S (Ali) : -2.51
Solubility : 0.543 mg/ml ; 0.00308 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.98
Solubility : 0.183 mg/ml ; 0.00104 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.7

Safety of [ 43120-28-1 ]

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 [ 43120-28-1 ]

* 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 [ 43120-28-1 ]
  • Downstream synthetic route of [ 43120-28-1 ]

[ 43120-28-1 ] Synthesis Path-Upstream   1~24

  • 1
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  • [ 64132-13-4 ]
Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 2009,2010
[2] Patent: US2005/9894, 2005, A1, . Location in patent: Page 18; 27
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YieldReaction ConditionsOperation in experiment
94% at 0℃; for 1.5 h; Reflux [00211] To a solution of IH-indazole-3-carhoxyhc acid (5.0 g, 30.8 mmol) in methanol (50 rnL), thionyl chloride (15 mL) was added dropwise at 0 °C After the addition, the mixture was heated to rcflux and maintained at the temperature for 1.5 hours. Then the reaction mixture was concentrated to give a residue. To the residue was added saturated sodium bicarbonate (50 mnL), and then extracted with ethyl acetate (50 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 1H-indazolc-3-carboxylatc as a white solid (5.1 g 94percent). ‘Fl NMR (300 MHz. d6-DMSO): d 13.91 (s, 1H), 8.06 (d, J= 8.2 Hz, 1H), 7.65 (d. J= 8.4 Hz. 1H), 7.44 (ddd, J= 8.3 Hz, J= 6.9 Hz, J=1.1 Hz, IH), 7.30 (ddd. J= 7.9 Hz. J= 6.9 Hz, J= 0.9 Hz, 1H), 3.92 (s, 3H).
93% at 20℃; Cooling with ice The 1H- indazole-3-carboxylic acid (1.50g, 9.3mmol)Was dissolved in methanol (50 mL)Ice bath was slowly added thionyl chloride (2.20g, 18.6mmol), at room temperature overnight.The solvent was recovered under reduced pressure, and water (30 mL) was added to the residue,And extracted with ethyl acetate (2 x 100 mL)The organic layers were combined, washed with saturated NaCl,Anhydrous Na2SO4 dried,The solvent was recovered to give 1.51 g of a white powder in a yield of 93.0percent
92% at 0℃; for 5 h; Reflux To a stirred solution of indazole-3-carboxylic acid (80.5 grams, 0.497 mmol, obtained in above step) in methanol (2 L) cooled at 0° C. was added thionyl chloride (120 mL, 1.59 mmol) over a period of 1 hour.
The reaction temperature was gradually raised and the reaction mixture was refluxed for 5 hours.
The volatiles were removed and the crude mass was diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain the title compound (80.2 grams).
Yield: 92percent.
1H-NMR (CDCl3): δ 13.2 (bs, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.48 (t, J=7.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 4.09 (s, 3H); Mass (m/z): 177 (M+H)+.
90.1%
Stage #1: at 80℃; for 16 h;
Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
Methyl lH-indazole-3-carboxylate (I): lH-indazole-3-carboxylic acid (2.4 g, 14.8 mmol) was dissolved in 100 mL methanol with 0.20 mL H2SO4 and heated to 80 °C for 16 hours. Methanol was removed on rotary evaporator and the resulting residue was dissolved in 100 mL EtOAc. The organic solution was washed with water, saturatedNaHCC"3 and brine, dried over Na2S04 and concentrated to yield product (2.37g, 13.5 mmol, 90.1percent). Product was identified by GC/MS.
85%
Stage #1: for 0.166667 h; Cooling with ice
Stage #2: at 20℃;
For the synthesis of RC-MC-30, methyl indazole-3-carboxylate was first formed.Acetyl chloride (7mL, excess) was added dropwise to ice-cooled methanol (2OmL) and the solution was stirred at the same temperature for 10 minutes. Commercially available indazole-3-carboxylic acid (2.3g, 14mmol) was then added to the solution in one lot and the mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed under vacuum, then the residual solid was dissolved in CHCl3 (10OmL), and washed with std. NaHCO3 solution. The aqueous layer was extracted with CHCl3 and the combined organic extract was washed with brine and dried over anhydrous Na2SO4. Removal of solvent left the product as a light yellow solid. Yield = 2.05g (85percent); m.p. = 168°-170 0C; IH NMR (400MHz, CDCl3) D 8.25 (d, J = 8.8 Hz, IH), 7.89 (d, J = 8.8 Hz, IH), 7.50 (t, J = 7.8 Hz, IH), 7.37 (t, J = 7.8 Hz, IH), 4.10 (s, 3H).
78%
Stage #1: for 4 h; Reflux
Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
To a solution of indazole 3-carboxylic acid (0.3 g, 1.86 mmol) in MeOH (10 mL) was added sulfuric acid (0.2 mL) and the mixture was stirred under reflux for 4 h. The mixture was then concentrated under reduced pressure and the residue was taken up in EtOAc (20 mL), washed with aq. NaHCO3 (2.x.20 mL), dried over Na2SO4, and concentrated in vacuum. The residue was purified by crystallization (n-hexane/EtOAc) as white crystals; yield 0.25 g 78percent; m.p. 168-170° C.; 1H NMR (400 MHz, CDCl3, TMS, ppm) δ 4.07 (s, 3H), 7.35 (t, 1H, J=15.35 Hz), 7.48 (t, 1H, J=14.45 Hz), 7.59 (d, 1H, J=8.23 Hz), 8.23 (d, 1H J=8.36 Hz), 11.72 (s, 1H).
48% for 10 h; Heating / reflux Step [0120] A 500 mL round-bottomed flask was charged sequentially with A (20 g, 0.12 mole), methanol (350 mL), and H2S04 (50 mL). The mixture was heated at reflux with stirring by magnetic stirrer for 10 hrs. The reaction was monitored by TLC on silica gel plates. [0121] Upon complete consumption of A, the mixture was poured into ice water (1 L) and methyl ester precipitated out as light yellow solid. White crystals of the product B (10 g, 0.057 mole, 48percent yield) were obtained by recrystallization from ethyl acetate.
22.76 g at 60℃; [0017] Sulfuric acid (18 ml) was added to a solution of indazole-3-carboxylic acid (19.3 g, 0.119mol) in methanol andthe solution was stirred at 60°C overnight. The solvent was removed in vacuo and the residue dissolved in ethyl acetate(500ml) and washed with water (200ml). The aqueous layer was extracted with ethyl acetate (2 x100 ml) and the combinedorganic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give (22.76g) of Methyl 1H-indazole-3-carboxylate as a cream coloured solid

Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 14, p. 2457 - 2460
[2] Chemical Communications, 2010, vol. 46, # 33, p. 6165 - 6167
[3] ChemMedChem, 2017, vol. 12, # 19, p. 1578 - 1584
[4] Patent: WO2013/120104, 2013, A2, . Location in patent: Paragraph 00210; 00211
[5] RSC Advances, 2015, vol. 5, # 100, p. 81817 - 81830
[6] Patent: CN106366078, 2017, A, . Location in patent: Paragraph 0136; 0137; 0138
[7] Patent: US2014/187581, 2014, A1, . Location in patent: Paragraph 0122-0124
[8] Patent: WO2012/177782, 2012, A1, . Location in patent: Page/Page column 68
[9] Patent: WO2011/5759, 2011, A2, . Location in patent: Page/Page column 69-70
[10] ChemMedChem, 2018, vol. 13, # 15, p. 1597 - 1607
[11] Patent: US2012/130078, 2012, A1, . Location in patent: Page/Page column 3
[12] Patent: WO2005/120498, 2005, A2, . Location in patent: Page/Page column 18-20
[13] Chemische Berichte, 1919, vol. 52, p. 1345,1348
[14] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[15] Patent: US2006/135764, 2006, A1, . Location in patent: Page/Page column 23
[16] Patent: US2006/183901, 2006, A1, . Location in patent: Page/Page column 10
[17] Physical Chemistry Chemical Physics, 2009, vol. 11, # 2, p. 341 - 348
[18] Patent: US2009/257979, 2009, A1, . Location in patent: Page/Page column 54-55
[19] Patent: US2005/9894, 2005, A1, . Location in patent: Page 18; 27
[20] Patent: WO2005/80389, 2005, A1, . Location in patent: Page/Page column 40-41
[21] Patent: WO2005/103022, 2005, A1, . Location in patent: Page/Page column 134
[22] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 15, p. 4460 - 4472
[23] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6259 - 6272
[24] Patent: EP2950103, 2015, A1, . Location in patent: Paragraph 0017
[25] Patent: WO2018/97945, 2018, A1, . Location in patent: Paragraph 0756
  • 3
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YieldReaction ConditionsOperation in experiment
85%
Stage #1: at 0℃; for 0.166667 h;
Stage #2: at 0 - 20℃;
For the synthesis of RC-MC-30, methyl indazole-3-carboxylate was first formed. Acetyl chloride (7 mL, excess) was added dropwise to ice-cooled methanol (20 mL) and the solution was stirred at the same temperature for 10 minutes. Commercially available indazole-3-carboxylic acid (2.3 g, 14 mmol) was then added to the solution in one lot and the mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed under vacuum, then the residual solid was dissolved in CHCl3 (100 mL), and washed with std. NaHCO3 solution. The aqueous layer was extracted with CHCl3 and the combined organic extract was washed with brine and dried over anhydrous Na2SO4. Removal of solvent left the product as a light yellow solid. Yield=2.05 g (85percent); m.p.=168°-170° C.; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 4.10 (s, 3H).
61% With sodium bicarbonate; sulfuric acid In methanol EXAMPLE 49
Indazole-3-carboxylic Acid Methyl Ester
Concentrated H2SO4 (1 mL) was added to a solution of indazole-3-carboxylic acid (2.0 g, 12 mmol) in MeOH (40 mL).
The reaction mixture was heated at reflux for 3 h, the MeOH was removed under reduced pressure and the residue was partitioned between diethyl ether (100 mL) and H2O (100 mL).
Saturated sodium hydrogen carbonate solution was added (100 mL) and the diethyl ether layer was separated.
The aqueous layer was further extracted with 2*200 mL of diethyl ether.
The combined extracts were dried (MgSO4) and solvent removed under reduced pressure and the solid was recrystallized from cyclohexane/ethyl acetate to afford the title compound (1.29 g, 61percent).
Mp 158-159° C., lit 168-169° C. v.Auwers, Dereser Chem. Ber. 1919, 52, 1343. 1H-NMR (300 MHz, CDCl3) ppm 4.09 (s, 3H), 7.33-7.38 (m, 1H), 7.46-7.52 (m, 1H), 7.71-7.74 (m, 1H), 8.23-8.26 (m, 1H), 12.03 (s, 1H). MS(EI) m/z 176 [M+].
Reference: [1] Patent: US2006/47126, 2006, A1, . Location in patent: Page/Page column 25
[2] Patent: US2003/171403, 2003, A1,
[3] Patent: US2003/187026, 2003, A1,
  • 4
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YieldReaction ConditionsOperation in experiment
93%
Stage #1: for 16 h; Reflux
Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
A solution of 2H-indazole-3-carboxylic acid (5.00 g, 30.8 mmol) and concentrated sulphuric acid (0.16 mL, 3.08 mmol) in methanol (100 mL) was heated to reflux for 16 hours. The reaction mixture was concentrated in vacuo and then partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate solution (aq.), the aqueous phase extracted with ethyl acetate, the combined organic layers washed with brine, dried (magnesium sulfate) and concentrated to give 2.02 g (93percent) of the title compound.
Reference: [1] Patent: US2010/305120, 2010, A1, . Location in patent: Page/Page column 43
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Reference: [1] Patent: WO2015/25025, 2015, A1, . Location in patent: Page/Page column 106; 107
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Reference: [1] Synthesis, 2011, # 19, p. 3089 - 3098
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Reference: [1] Patent: EP1346982, 2003, A1,
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Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 1, p. 219 - 226
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Reference: [1] Heterocycles, 1996, vol. 43, # 12, p. 2701 - 2712
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Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
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Reference: [1] Patent: WO2007/36727, 2007, A1, . Location in patent: Page/Page column 14
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Reference: [1] Heterocycles, 1996, vol. 43, # 12, p. 2701 - 2712
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Reference: [1] Heterocycles, 1996, vol. 43, # 12, p. 2701 - 2712
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Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
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Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
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Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
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Reference: [1] Chemical Communications, 2018, vol. 54, # 60, p. 8411 - 8414
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 11, p. 1912 - 1930
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Reference: [1] Chemische Berichte, 1919, vol. 52, p. 1345,1348
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Reference: [1] Patent: WO2005/120498, 2005, A2, . Location in patent: Page/Page column 22
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Reference: [1] ChemMedChem, 2017, vol. 12, # 19, p. 1578 - 1584
  • 22
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  • [ 78155-74-5 ]
YieldReaction ConditionsOperation in experiment
63% With bromine In N,N-dimethyl-formamide at 20℃; for 41 h; Cooling with ice Reference Example 1 [Step a] To a solution of compound 1 (5.00 g, 28.3 mmol) in N,N-dimethylformamide (30.0 mL) was added dropwise bromine (1.74 mL, 34.1 mmol) under ice-cooling, and the mixture was stirred for 1 day while raising the temperature to room temperature. The reaction solution was ice-cooled again, bromine (1.74 mL, 34.1 mmol) was added, and the mixture was stirred for 17 hr while raising the temperature to room temperature. To the reaction solution were added 10percent aqueous sodium thiosulfate solution and saturated aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The obtained solid was suspended and washed in hexane to give compound 2 (4.51 g, 63.0percent). MS(ESI)m/z: 255, 257(M+1)+.
Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 14, p. 2457 - 2460
[2] Patent: EP3135667, 2017, A1, . Location in patent: Paragraph 0387-0388
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6259 - 6272
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Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 14, p. 2457 - 2460
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  • [ 1185282-01-2 ]
Reference: [1] Patent: US2011/28447, 2011, A1,
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