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Chemical Structure| 4498-67-3 Chemical Structure| 4498-67-3

Structure of Indazole-3-carboxylic acid
CAS No.: 4498-67-3

Chemical Structure| 4498-67-3

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CAS No.: 4498-67-3

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Product Details of [ 4498-67-3 ]

CAS No. :4498-67-3
Formula : C8H6N2O2
M.W : 162.15
SMILES Code : O=C(C1=NNC2=C1C=CC=C2)O
MDL No. :MFCD00211066
InChI Key :BHXVYTQDWMQVBI-UHFFFAOYSA-N
Pubchem ID :78250

Safety of [ 4498-67-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H319
Precautionary Statements:P305+P351+P338

Computational Chemistry of [ 4498-67-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 9
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 43.05
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

65.98 ?2

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.59
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.41
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.26
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.72
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.38
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.07

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.22
Solubility 0.971 mg/ml ; 0.00599 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.4
Solubility 0.646 mg/ml ; 0.00398 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.27
Solubility 0.863 mg/ml ; 0.00532 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

 High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

 Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

 No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

 No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

 No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

 No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

 No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

 No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.29 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

 0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

 None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

 0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

 0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

 1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.56

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

 No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

 1.44

Application In Synthesis of [ 4498-67-3 ]

* 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.

  • Downstream synthetic route of [ 4498-67-3 ]

[ 4498-67-3 ] Synthesis Path-Downstream   1~12

  • 1
  • [ 4498-67-3 ]
  • [ 78155-76-7 ]
YieldReaction ConditionsOperation in experiment
80% With sulfuric acid; potassium nitrate; at 0 - 20℃; for 4h; To a suspension of indazole-3-carboxylic acid 16AP (10.5g, 64.8mmol) in concentrated sulfuric acid (125ml) at OC was added KNO3 (64.8mmol, 6.55g). The reaction mixture was warmed up to r.t. After stirring for 4hr at r.t, it was poured into a 525ml of ice/water. Solid was collected by filtration and washed with water to give desired 5-nitro-1 H-indazole-3-carboxylic acid 17AP (10.74g, 80%).
63% With sulfuric acid; nitric acid; at 10 - 20℃; for 1h; At 10 C., indazole-3-carboxylic acid (0.3 g, 0.18) was dissolved in sulfuric acid (4 mL). Then a mixture of conc. sulfuric acid (2 mL) and 64% HNO3 (0.3 mL) was added and the mixture was allowed to warm to room temperature. After 1 h, the mixture was poured onto ice and water (30 mL). The resulting precipitate was filtered off and washed with cold H2O (2×20 mL). The crude product was recrystallized from AcOH to yield 0.17 g (63%). m.p. 189-194 C. 1H NMR (400 MHz, DMSO-d6) delta 14.3 (s, 1H), 9.37 (s, 1H), 8.38 (d, 1H), 7.69 (d, 1H), 6.9 (s, 1H).
With sulfuric acid; potassium nitrate; at 0 - 20℃;Product distribution / selectivity; To a suspension of indazoIe-3-carboxylic acid (compound 53, 3.0 g, 18 mmol) in 18 ml_ of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to give compound 54 (2.9 g) as the major isomer.; Step iTo a suspension of indazole-3-carboxylic acid (3.0 g, 18 rnmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate (90 mL total). The combined organic layer was washed with brine, dried and concentrated to give (54) (2.9 g) as the major product.; Step iTo a suspension of indazoIe-3-carboxylic acid (compound 53, 3.0 g, 18 mmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to give compound 54 (2.9 g) as the major isomer.
  • 2
  • [ 6638-79-5 ]
  • [ 4498-67-3 ]
  • [ 351457-12-0 ]
YieldReaction ConditionsOperation in experiment
81.4% SYNTHETIC PREPARATION 63-Carboxyindazole (10 g, 61.7 mmol) in DMF (100 mL) was treated with carbonyldiimidazole (11 g, 67.84 mmol) at rt with gas evolution for 15 min, after which the reaction mixture was heated up to 65 0C for 2 hours. After cooling to rt, N1O- dimethylhydroxyamine-HCI (4.14 g, 67.8 mmol) was added and the mixture was heated to 65 0C overnight. The reaction was cooled, quenched with water, extracted with CH2CI2 and washed with water. The combined organic phase was dried and concentrated to afford N- methoxy-N-methyl-1 H-indazole-3-carboxamide (10.3 g, 81.4%).
79% lH-indazole-3-carboxylic acid (CX) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65C for 2 h and then allowed to cool to room temperature. Nu,Omicron-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65 C for 3 h. The reaction was concentrated to a paste, taken up in DCM and washed subsequently with water and 2 N HC1. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgS04 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-lH-indazole-3- carboxamide (CXI) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-d6) delta ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56- 7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for CioHiiN302 mlz 206 (M+H).
79% 1H-indazole-3-carboxylic acid (XV) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65 C. for two hours and then allowed to cool to room temperature. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65 C. for 3 hours. The reaction was concentrated to a paste and taken up in DCM, and washed subsequently with water and 2N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVI) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-d6) delta ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
79% Step a ;1H-indazole-3-carboxylic acid (VIII) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at r.t. until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65C for two hours and then allowed to cool to r.t. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65C for 3 hours. The reaction was concentrated to a paste and taken up in DCM, and washed subsequently with water and 2N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) as a white solid (100 g, 487 mmol), 79% yield). 1H NMR (DMSO-d6) delta ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
79% lH-indazole-3-carboxylic acid (CX) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65C for 2 h and then allowed to cool to room temperature. N,0-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65C for 3 h. The reaction was concentrated to a paste, taken up in DCM and washed subsequently with water and 2 N HC1. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgS04 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1 : 1 mixture of DCM-ether, filtered, and dried to produce N-methoxy- N-methyl-lH-indazole-3-carboxamide (CXI) as a white solid (100 g, 487 mmol, 79% yield). NMR (DMSO-de) delta ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 mlz 206 (M+H).
75.4% A solution of 1H-indazole-3-carboxylic acid (1.0 g, 6.17 mmol, 1.0 eq.) and CDI (1.1 g, 6.78 mmol, 1.leq.) in DMF (20 mL) was stirred at 65C for 2h, then cooled down to r.t., N,O-dimethylhydroxylamine hydrochloride (661 mg, 6.78 mmol, 1.1 eq.) was added and the mixture was stirred at 65 C for 12 h. The solvent of the mixture was removed under vacuum and the residue was purified by flash chromatography (elute: EAPE = 1/2) to give N-methoxy-N-methyl -1 H-indazole-3 -carboxamide (950mg, 75.4 % yield) as a yellow solid.
With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide; at 20℃; Example 17; (3-hydroxyphenyI)(l-isobutyl-lfl-indazol-3-yl)methanone; Step A: lH-Indazole-3-carboxylic acid methoxy-methyl-amide[0201]; Indazole-3-carboxylic acid (15 g, 0.0925 mol) was dissolved in DMF (40 niL) at room temperature. Carbonyldiimidazole (17 g, 0.104 mol) was added. A solution of diisopropylethylamine (18 mL, 0.104 mol) and N,O-dimethylhydroxylamine HCl (1Og, 0.104 mol) in DMF (10 mL) was added in portions. The reaction was stirred at room temperature overnight. The reaction was taken up in ethyl acetate and washed repeatedly with 2-N HCl, water, and brine. The organic layer was evaporated to a yellow oil, and passed through a pad of silica gel with hexane/ethyl acetate (1 :2). The resulting solid was washed with ethyl acetate to give the desired product as a white solid (11.4O g, 0.056 mol).
With pyridine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In tetrahydrofuran; at 20℃; for 20h; 7.2 N-Methoxy-N-methyl-1H-indazole-3-carboxamideIn a round-bottomed flask, 4.0 g of 1H-indazole-3-carboxylic acid, 2.6 g of N,O-dimethylhydroxylamine hydrochloride, 9.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 8.4 ml of pyridine are placed in 120 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 20 h. The mixture is concentrated and the residue is taken up in water. The yellow precipitate obtained is washed with water and then dried under reduced pressure. 3.5 g of compound are obtained.1H NMR (DMSO-d6, delta in ppm): 3.5 (s, 3H); 3.8 (s, 3H); 7.25 (m, 1H); 7.45 (m, 1H); 7.65 (d, 1H); 8.05 (d, 1H); 13.65 (s, 1H). M+H=206.
361 mg Step 2: N-Methoxy-N-methyl-lH-indazole-3-carboxamide: To a stirred solution of step 1 intermediate (500 mg, 3.083 mmol) in THF (20 mL) was added N, 0-dimethylhydroxylamine hydrochloride (360 mg, 3.70 mmol). The reaction mixture was cooled to 0 C and added pyridine (2.5 mL). The reaction mixture was stirred at the same temperature for 2 h and then at room temperature for 1 h. To the reaction mixture was added some more pyridine (2 mL) followed by EDCI.HC1 (1.18 g, 6.167 mmol) and further stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 15 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 361 mg of the title product as off white solid. 1H NMR (300 MHz, DMSO-i) delta 3.55 (s, 3H), 3.82 (s, 3H), 7.32 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 6.9 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 13.62 (br s, 1H).
4.6 g Add carbazole-3-carboxylic acid, dimethylhydroxylamine hydrochloride (7.3 g, 75 mmol) to the reaction flask, add 50 mL of THF, cool to 0 C, add pyridine (7.9 g, 0.1 mol), stir for 1 h and then shift After stirring to room temperature for 30 min, EDCI (12.5 g, 65 mmol), pyridine (8.7 g, 0.11 mol).The progress of the reaction was detected by TLC. After the reaction was completed, the solvent was spun dry, ultrasonically added, suction filtered, and washed with a large amount of water.The solid was collected, dissolved in dichloromethane, and filtered to remove insoluble material. The filtrate was extracted with water, and the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then passed through EA/PE (v/v, 1:5) Separation and purification by washing column chromatography to obtain pale yellow solid 5 (4.6 g, two-step combined yield 45%)

  • 3
  • [ 4498-67-3 ]
  • [ 4498-72-0 ]
  • 4
  • [ 109903-35-7 ]
  • [ 4498-67-3 ]
  • [ 660822-40-2 ]
YieldReaction ConditionsOperation in experiment
14% With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 24 - 72h; To a solution of indazole-3-carboxylic acid (Fluka) (405 mg, 2.5 mmol, 1.0 equiv) in dichloromethane (10 [ML)] was added an amine or appropriately substituted aniline (3.0 mmol, 1.2 equiv), [N, N DIISOPROPYLETHYLAMINE] (1.6 ml, 9.0 mmol, 3.6 equiv) [AND 0-(7-AZABENZOTRIAZOL-1-YL)-N, N, N', N'-TETRAMETHYLURONIUM] hexafluorophosphate (1.05 g, 2.75 mmol, 1.1 equiv). The mixture was stirred for a period of 24-72 hours and additional [0-(7-AZABENZOTRIAZOL-1-YL)-N, N, N', N'-] [TETRAMETHYLURONIUM] hexafluorophosphate was added if necessary. The reaction was quenched with water (10 [ML)] and dichloromethane (10 ml). The compounds were purified as described in the examples below, and characterised by liquid chromatography and mass spectrometry using either of the systems described above. Procedure A was followed. Water and dichloromethane were removed by filtration and the solid was triturated with water and dichloromethane. The title compound was dried in vacuo to afford 119 mg [(14%) ;] LCMS 2.92 min, mlz [M+H] [+] 345.
  • 5
  • [ 4498-67-3 ]
  • [ 660823-32-5 ]
  • [ 78155-76-7 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid; potassium nitrate; at 0 - 20℃; To a suspension of indazole-3-carboxylic acid (Fluka) (5 g, [31MMOL)] in concentrated H2SO4 (30 ml) at [0 C] was added [KN03] (3.13 g, 31 mmol). The reaction was allowed to stir overnight at room temperature, then diluted with water and the products extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over [MGS04.] Evaporation to dryness left the product as a yellow solid as a 7: 3 mixture with the 7-nitro isomer ; LCMS 2.58 min, [M/Z] [[M+H]] + 208.EXAMPLE 63; [5- [3-(2-CHLORO-ETHYL)-UREIDO]-LH-INDAZOLE-3-CARBOXYLIC] acid (4- methylsulphamoylmethyl-phenyl)-amide; 63A. PREPARATION OF 5-NITRO-LH-INDAZOLE-3-CARBOXYLIC] acidTo a suspension of indazole-3-carboxylic acid (Fluka) (5 g, [31MMOL)] in concentrated [H2SO4] (30 ml) at [0 C] was added [KNO3] (3.13 g, 31 mmol). The reaction was allowed to stir overnight at room temperature, then diluted with water and the products were extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over [MGS04.] Evaporation to dryness left the product as a yellow solid as a 7: 3 mixture with the 7-nitro isomer ; LCMS 2.58 min, [M/Z] [M+H] + 208.
With sulfuric acid; potassium nitrate; at 0 - 20℃; EXAMPLE 13 PREPARATION OF 5-MORPHOLIN-4-VL-LH-INDAZOLE-3-CARBOXYLIC acid phenylamide 13A. Preparation of 5-Nitro-1H-indazole-3-carboxylic acid; To a suspension of indazole-3-carboxylic acid (Fluka) (5 g, 31MMOL) in concentrated HAIS04 (30 ml) at 0 C was added KN03 (3.13 g, 31 mmol). The reaction was allowed to stir overnight at room temperature, then diluted with water and the products extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over MGS04. Evaporation to dryness left the product as a yellow solid as a 7: 3 mixture with the 7-nitro isomer; LCMS 2.58 min, M/Z [M+H] + 208.
  • 6
  • CH2Cl2-ether [ No CAS ]
  • [ 4498-67-3 ]
  • [ 351457-12-0 ]
YieldReaction ConditionsOperation in experiment
79% With hydrogenchloride; 1,1'-carbonyldiimidazole; In dichloromethane; N,N-dimethyl-formamide; Step a 1H-indazole-3-carboxylic acid (VI) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at 25 C. until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65 C. for two hours and then allowed to cool to 25 C. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65 C. for 3 hours. The reaction was concentrated to a paste and taken up in CH2Cl2, and washed subsequently with water and 2N HCl. The product was visibly coming out of solution. The solid was filtered and rinsed separately with ethyl acetate. The ethyl acetate and CH2Cl2 layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated. The resulting solids were combined, triturated with 1:1 mixture of CH2Cl2-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (VII) as a white solid (79% yield). 1H NMR (DMSO-d6) delta ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
  • 7
  • [ 4498-67-3 ]
  • [ 351457-12-0 ]
  • 8
  • [ 4498-67-3 ]
  • [ 1117-97-1 ]
  • [ 351457-12-0 ]
YieldReaction ConditionsOperation in experiment
56% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 23℃; for 18h; To a stirred solution of compound A (1 g, 6.2 mmol, 1 eq) in CH2CI2 (30 mL) were added compound B (903 mg, 9.25 mmol, 1.5 eq), HOBT (1 g, 7.4 mmol, 1.2 eq) and EDCI (2.4 g, 12.3 mmol,2 eq) at 0 C . DIPEA (4 g, 30.8 mmol, 5 eq) was added to it at 0 C and the resulting mixture was stirred for 18 h at 23 C. The reaction mixture was diluted with CH2CI2 (100 ml) and DCM layer was washed with water (30 ml). DCM layer was removed in vacuo and the crude residue was purified by flash chromatography (Combiflash) using 100- 200 mesh silica gel and eluting with 50% ethyl acetate/hexane to obtain the compound C (700 mg, 56%) as off white solid. (0283) [0273] H NMR (400 MHz, DMSO-ifc) delta 13.60 (s, 1 H) 8.00 (d, J = 8 Hz, 1 H), 7.61 (d, / = 8 Hz, 1 H), 7.41 (t, J = 8 Hz, 1 H), 7.23 (t, J = 8 Hz, 1 H), 3.78 (s, 3 H), 3.45 (s, 3 H); (0284) [0274] LCMS: m/z = 206.2 [M+H], RT = 2.55 minutes; (Program Rl, Column W).
  • 9
  • [ 4498-67-3 ]
  • [ 1081-04-5 ]
  • 10
  • [ 3535-88-4 ]
  • [ 4498-67-3 ]
  • N-(5-tert-butyl-2-methoxyphenyl)-1H-indazole-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 12h; General procedure: In distinct reactors, carboxylic acids (1 equiv) 17-21, 1-hydroxybenzotriazole (1.2 equiv), and suitable amines 22-24(1.2 equiv), were dissolved in dimethylformamide at room temperature. DCC (1.2 equiv) was added, and the mixtures were stirred at room temperature overnight. The precipitate of dicyclohexylurea was filtered off and the filtrate wasadded in cold stirring water and extracted with ethyl acetatex 3. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. Each crude product was purified by flash chromatography on a short pad of silica gel.
  • 11
  • [ 3535-88-4 ]
  • [ 4498-67-3 ]
  • N-(5-tert-butyl-2-hydroxyphenyl)-1H-indazole-3-carboxamide [ No CAS ]
  • 12
  • [ 6274-22-2 ]
  • [ 4498-67-3 ]
  • N-[4-(methylcarbamoyl)phenyl]-1H-indazole-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 100℃; for 10h; General procedure: To a 0.5 M solution of carboxylic acid (1.0 eq.) in DMF, aniline (1.0 or 1.2 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq.), and HOBt.H2O (1.2 eq.) were added. The mixture was stirred at 100C for 10 hours. After cooling, the mixture was poured into water (10 x DMF volume). The resulting precipitate was collected by filtration. The collected powder was washed with water, and dried in vacuoto afford the product.
 

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