[ CAS No. 1077-95-8 ] {[proInfo.proName]}

Name: 1077-95-8|5-Chloro-1H-indazole-3-carboxylic acid|97%
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SKU: A128251
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Quality Control of [ 1077-95-8 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1077-95-8 ]

CAS No. :	1077-95-8	MDL No. :	MFCD02326712
Formula :	C₈H₅ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WHAJIAULUPQHHZ-UHFFFAOYSA-N
M.W :	196.59	Pubchem ID :	8027604
Synonyms :

Calculated chemistry of [ 1077-95-8 ]

Physicochemical Properties

Num. heavy atoms :	13
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 :	48.06
TPSA :	65.98 Å²

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) :	-6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.79
Log Po/w (XLOGP3) :	2.04
Log Po/w (WLOGP) :	1.91
Log Po/w (MLOGP) :	1.31
Log Po/w (SILICOS-IT) :	2.0
Consensus Log Po/w :	1.61

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.79
Solubility :	0.319 mg/ml ; 0.00162 mol/l
Class :	Soluble
Log S (Ali) :	-3.05
Solubility :	0.174 mg/ml ; 0.000884 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.9
Solubility :	0.245 mg/ml ; 0.00124 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 1077-95-8 ]

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

Application In Synthesis of [ 1077-95-8 ]

* 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 [ 1077-95-8 ]
Downstream synthetic route of [ 1077-95-8 ]

[ 1077-95-8 ] Synthesis Path-Upstream 1~3

1
[ 17630-76-1 ]
[ 1077-95-8 ]

Yield	Reaction Conditions	Operation in experiment
5.1 g	Stage #1: With sodium hydroxide In water at 50℃; for 1 h; Stage #2: With sulfuric acid; sodium nitrite In water for 1 h; Cooling with ice Stage #3: With hydrogenchloride; tin(II) chloride dihdyrate In water at 20℃;	(a) Step 1 Aqueous sodium hydroxide (1.13 g, 28.3 mmol, 25 mL) was heated to 50°C, and added with 5-chloroisatin (5.00 g, 27.5 mmol). The mixture was stirred at 50°C for 1 hour, and then cooled on ice. Aqueous sodium nitrite (1.90 g, 27.5 mmol, 9 mL) was cooled on ice, and then added dropwise to the reaction mixture. Then, the mixture was added dropwise with concentrated sulfuric acid (5.26 g, 53.6 mmol) in ice-cooled water (44 mL), and the mixture was stirred for 1 hour under ice cooling. Then, the reaction mixture was added dropwise with an ice-cooled solution of tin(II) chloride dihydrate (14.9 g, 66.0 mmol) in concentrated hydrochloric acid (22 mL). The mixture was stirred overnight at room temperature, and then filtered, and the resulting solid was washed with water to obtain a pale brown solid (5.10 g).

Reference： [1] Patent: WO2005/14554, 2005, A1, . Location in patent: Page/Page column 60-61
[2] Patent: EP2565192, 2013, A1, . Location in patent: Paragraph 0356
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6259 - 6272
[4] Patent: WO2015/103317, 2015, A1, . Location in patent: Page/Page column 97

2
[ 1077-95-8 ]
[ 28751-70-4 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere Stage #2: With ammonium hydroxide In tetrahydrofuran at 25℃; for 1 h; Inert atmosphere	To a solution of 5-chloro indazole 3- carboxylic acid¹ 2 (0.8 g, 4.0 mmol) in anhydrous THF (20 mL) was added isobutyl chloroformate (0.64 mL, 4.9 mmol) and N-methylmorpholine (0.7 mL, 6.1 mmol) under argon at 0° C and the mixture was stirred for 2h. Then to this mixture 10 mL of aqueous NH₃ was added and mixture was stirred at 25°C for 1 h. THF was removed under reduced pressure solid was obtained filtered through buchner funnel, solid was washed with diethyl ether and dried under vacuum to afford title compound 3 (0.5 g, 63percent ) as a pale y solid. IR i (film): cm^{" 1} 2925, 2854, 1463; NMR (200 MHz, DMSO-d₆): δ 8.14 (d, ./ Hz, 1 H), 7.80 (bs, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.45-7.39 (m, 2H); MS: 218 (M+Na)⁺.

Reference： [1] Patent: WO2015/15519, 2015, A1, . Location in patent: Page/Page column 17; 18

3
[ 1077-95-8 ]
[ 102735-84-2 ]

Reference： [1] Journal of the American Chemical Society, 1986, vol. 108, # 14, p. 4115 - 4119
[2] Patent: EP2565192, 2013, A1,

[ 1077-95-8 ] Synthesis Path-Downstream 1~58

1
[ 1077-95-8 ]
[ 102735-90-0 ]

Reference： [1]Journal of the American Chemical Society,1986,vol. 108,p. 4115 - 4119
[2]Patent: EP2565192,2013,A1

2
[ 1077-95-8 ]
[ 129295-49-4 ]
5-Chloro-1H-indazole-3-carboxylic acid (1-benzyl-4-methyl-[1,4]diazepan-6-yl)-amide [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 1912 - 1930

4
[ 67-56-1 ]
[ 1077-95-8 ]
[ 1079-46-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sulfuric acid; for 3h;Reflux;	A solution of the above solid (5.10 g) in methanol (75 mL) was added with concentrated sulfuric acid (10 mL), and the mixture was refluxed for 3 hours by heating. The reaction mixture was cooled to room temperature, and then poured into water (225 mL), and the precipitated solid was collected by filtration, and washed with water to obtain methyl 5-chloro-1H-indazole-3-carboxylate (4.39 g, 75%). 1H NMR (300 MHz, DMSO-d6) delta 3.93 (s, 3H), 7.48 (dd, J = 1.5, 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 8.0 (d, J = 1.5 Hz, 1H).
1.28 g	With sulfuric acid; at 75℃;	To the solution of 5 -chioro- lH-indazole-3-carboxylic acid (2 g, 10 mmol, 1.0 eq.) in MeOH (100 mL) was added cone. H2SO4 (3 drops). The mixture was stirred at 75 C overnight. Filtered and the filtrate was concentrated. The residue was partitioned between saturated NaHCCb aqueous solution (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mLX2). The combined organic extracts were dried over Na2S04 and concentrated to afford methyl 5-chloro-lH-indazole-3-carboxylate as a yellow solid (1.28 g, 61%).

Reference： [1]Patent: EP2565192,2013,A1 .Location in patent: Paragraph 0357
[2]European Journal of Organic Chemistry,2007,p. 4909 - 4916
[3]Physical Chemistry Chemical Physics,2009,vol. 11,p. 341 - 348
[4]Patent: WO2015/103317,2015,A1 .Location in patent: Page/Page column 97

5
[ 1077-95-8 ]
[ 102735-84-2 ]

Reference： [1]Journal of the American Chemical Society,1986,vol. 108,p. 4115 - 4119
[2]Patent: EP2565192,2013,A1

6
[ 17630-76-1 ]
[ 1077-95-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 General Amide Preparative Procedure B; To a suspension of 5-iodoisatin (Lancaster Synthesis) (2.2 g, 8.0 mmol, 1.0 equiv) or 5-CHLOROISATIN (Lancaster Synthesis) (1.0 equiv. ) in water (20 ml) was added NAOH (0.34 g, 8.48 mmol, 1.06 equiv) and the mixture was warmed to approximately 35 C for 30 minutes to form a solution. The solution was cooled to 5 C and a solution of sodium nitrite (0.62 g, 8.98 mmol, 1.12 equiv) was added dropwise over approximately 30 minutes, keeping the temperature below 10 C. The whole mixture was added dropwise via a cannula to a vigorously stirred solution of concentrated sulphuric acid (1.53 g, 15.6 mmol, 1.95 equiv) in water (20 ml) keeping the temperature below 10 C. The mixture was stirred for 20 minutes and a solution of tin (II) chloride (3.7 g, 19.52 mmol, 2.44 equiv) in concentrated hydrochloric acid (8 ml) was added dropwise. The mixture was stirred at 5 C for 2 hours and the resulting crude 5-iodo or 5-chloro indazole-3-carboxylic acid (a yellow solid) was isolated by filtration and washed several times with water. The yellow solid was then azeotroped with toluene (3 x 100 ml) to remove water prior to the next step. The crude product was dissolved in dichloromethane (36 ml) and split into four 8 ml portions. To the separate solutions of crude 5-iodo or 5-chloro INDAZOLE-3-CARBOXYLIC acid in dichloromethane (8 ML) was added the appropriate AMINE/ANILINE (2.4 mmol, 1.2 equiv), N, N-DIISOPROPYLETHYLAMINE (1.2 ml, 7.2 mmol, 3.6 equiv) and 0- (7-AZABENZOTRIAZOL-1-YL)-NNN, N -TETRAMETHYLURONIUM hexafluorophosphate (0.84 g, 2.20 mmol, 1.1 equiv). The mixture was stirred for a period of 24-72 hours and was then quenched with water (8 ml) and dichloromethane (8 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. By following either preparative Procedure A or Procedure B, compounds of the formula (1) were prepared as described in Examples 3 to 14.
5.1 g		(a) Step 1 Aqueous sodium hydroxide (1.13 g, 28.3 mmol, 25 mL) was heated to 50C, and added with 5-chloroisatin (5.00 g, 27.5 mmol). The mixture was stirred at 50C for 1 hour, and then cooled on ice. Aqueous sodium nitrite (1.90 g, 27.5 mmol, 9 mL) was cooled on ice, and then added dropwise to the reaction mixture. Then, the mixture was added dropwise with concentrated sulfuric acid (5.26 g, 53.6 mmol) in ice-cooled water (44 mL), and the mixture was stirred for 1 hour under ice cooling. Then, the reaction mixture was added dropwise with an ice-cooled solution of tin(II) chloride dihydrate (14.9 g, 66.0 mmol) in concentrated hydrochloric acid (22 mL). The mixture was stirred overnight at room temperature, and then filtered, and the resulting solid was washed with water to obtain a pale brown solid (5.10 g).
		To the solution of NaOH (440 mg, 11 mmol, 1.1 eq.) in H2O (10 mL) was added 5-chloroindoline-2,3-dione (1.81 g, 10 mmol, 1.0 eq). The dark solution was cooled to 0-5 C. A solution of NaNC (828 mg, 12 mmol, 1.2 eq) in H2O (3 mL) was added. The mixture was added to a solution of cone. H2SO4 (2.90 g, 30 mmol, 3.0 eq) in H20 (30 mL) at 0-5 C. The mixture was stirred at 0-5 C for 30 min. A solution of SnCl2 H20 (5.64 g, 25 mmol, 2.5 eq) in cone. HC1 (15 mL) was added and the yellow slurry was stirred at rt for 2.5 h. Filtered and the solid was collected to afford 5-chloro-lH-indazole-3-carboxylic acid as a yellow solid (2 g crude, quant).

Reference： [1]Patent: WO2005/14554,2005,A1 .Location in patent: Page/Page column 60-61
[2]Patent: EP2565192,2013,A1 .Location in patent: Paragraph 0356
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 6259 - 6272
[4]Patent: WO2015/103317,2015,A1 .Location in patent: Page/Page column 97

7
[ 64-18-6 ]
[ 6530-09-2 ]
[ 1077-95-8 ]
[ 865881-70-5 ]

Yield	Reaction Conditions	Operation in experiment
29%		To a solution of the carboxylic acid (16.1 mmol) in N, N dimethylformamide (65 mL) was added HBTU (16. 1 mmol), catalytic amount of dimethylaminopyridine, N, N- diisopropylethylamine (96. 6 mmol) and 4 A activated molecular sieves (2.6 g). The reaction mixture was maintained at room temperature for 2 h under nitrogen and then 3- aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 h, the solvent was removed under reduced pressure. The oily residue was partitioned between saturated, aqueous sodium bicarbonate (25 mL) and dichloromethane (100 mL). The aqueous layer was further extracted with 9/1 dichloromethane/methanol (5 x 100 mL) and the combined organic layers were concentrated. The residue was purified by chromatography [90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/ (70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC, thus providing the product in 30%-70% yield.

Reference： [1]Patent: WO2005/92890,2005,A2 .Location in patent: Page/Page column 110-111

8
[ 1152841-39-8 ]
[ 1077-95-8 ]
[ 1422979-60-9 ]

Yield	Reaction Conditions	Operation in experiment
18.4%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;	<strong>[1077-95-8]5-chloro-1H-indazole-3-carboxylic acid</strong> (49.1 mg, 0.25 mmol) and crude 3-((4-amino-1H-pyrazol-1-yl)methyl)benzonitrile (59.5 mg, 0.30 mmol) were weighed into a reaction vial, and then dichloromethane (0.50 mL) and MF (0.5 mL) were added. HOBt hydrate (57.4 mg, 0.375 mmol) was then added followed by EDCl (71.9 mg, 0.375 mmol). The reaction was stirred at room temperature until no further reaction was observed in LC-MS. The mixture was dissolved in enough DMF and then purified by reverse-phase HPLC to give the desired product (17.3 mg, 18.4%). 1H NMR (400 MHz, DMSO) delta 13.93 (s, 1H), 10.71 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.75 (s, 1H), 7.73 - 7.68 (m, J= 8.4 Hz, 2H), 7.60 - 7.54 (m, J = 4.9, 1.9 Hz, 2H), 7.46 (dd, J= 8.9, 2.0 Hz, 1H), 5.40 (s, 2H). MS: m/z = 377.0 (M+H) +

Reference： [1]Patent: WO2013/24011,2013,A1 .Location in patent: Page/Page column 66

9
[ 1077-95-8 ]
C₂₁H₁₉ClN₄O₃*(x)ClH [ No CAS ]

Reference： [1]Patent: EP2565192,2013,A1

10
[ 1077-95-8 ]
C₂₁H₁₈Cl₂N₄O₃*(x)ClH [ No CAS ]

Reference： [1]Patent: EP2565192,2013,A1

11
[ 1077-95-8 ]
[ 1346151-81-2 ]

Reference： [1]Patent: EP2565192,2013,A1

12
[ 1077-95-8 ]
[ 1346150-27-3 ]

Reference： [1]Patent: EP2565192,2013,A1

13
[ 1077-95-8 ]
[ 1346151-94-7 ]

Reference： [1]Patent: EP2565192,2013,A1

14
[ 1077-95-8 ]
[ 1346150-33-1 ]

Reference： [1]Patent: EP2565192,2013,A1

15
[ 1077-95-8 ]
[ 1346152-00-8 ]

Reference： [1]Patent: EP2565192,2013,A1

16
[ 1077-95-8 ]
[ 1346150-36-4 ]

Reference： [1]Patent: EP2565192,2013,A1

17
[ 64-17-5 ]
[ 1077-95-8 ]
[ 1081-05-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6259 - 6272

18
[ 1077-95-8 ]
[ 1448314-59-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6259 - 6272

19
[ 1077-95-8 ]
methyl 5-chloro-1-methyl-1H-indazole-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/111457,2014,A1

20
[ 1077-95-8 ]
[ 74-88-4 ]
methyl 5-chloro-1-methyl-1H-indazole-3-carboxylate [ No CAS ]
[ 1257122-43-2 ]

Yield	Reaction Conditions	Operation in experiment
		5-Chloro-3-indazolecarboxylic acid (1.34 g, 6.82 mmol) was dissolved in dry DMF (50 mL), then the r.m. was cooled to 0 C under N2 atmosphere. NaH (0.6 g, 15 mmol) was added in portions, and the r.m. stirred for 20 min at 0 C. Methyl iodide (0.9 mL, 15 mrnol) was added dropwise, and the r.m. allowed to reach r.t. and stirred for 4 h. After this time the reaction was quenched with water, adjusted to pH = 6 with IN HC1 sol. DCM was added and the organic layer was separated and dried over MgSC>4, filtered and the solvent was evaporated. The crude material showed to be a mixture of intermediate 59 and intermediate 60 (800 mg; LC-MS ratio ester/acid: 34/53), and was subsequently dissolved in MeOH (60 mL). Sulfuric acid (3 mL) was added, and the r.m. was heated at 60 C for 4 h. The solvent was then evaporated. DCM was added and the reaction mixture was basified with sat.NaHCC sol. The organic layer was separated and dried over MgS04, filtered and the solvent evaporated under reduced pressure, to afford intermediate 59 (0.4 g, 26% over two steps).
		5-Chloro-3-indazolecarboxylic acid (1.34 g, 6.82 mmol) was dissolved in dry DMF (50 mL), then the r.m. was cooled to 0 C. under N2 atmosphere. NaH (0.6 g, 15 mmol) was added in portions, and the r.m. stirred for 20 min at 0 C. Methyl iodide (0.9 mL, 15 mmol) was added dropwise, and the r.m. allowed to reach r.t. and stirred for 4 h. After this time the reaction was quenched with water, adjusted to pH=6 with 1N HCl sol. DCM was added and the organic layer was separated and dried over MgSO4, filtered and the solvent was evaporated. The crude material showed to be a mixture of intermediate 59 and intermediate 60 (800 mg; LC-MS ratio ester/acid: 34/53), and was subsequently dissolved in MeOH (60 mL). Sulfuric acid (3 mL) was added, and the r.m. was heated at 60 C. for 4 h. The solvent was then evaporated. DCM was added and the reaction mixture was basified with sat. NaHCO3 sol. The organic layer was separated and dried over MgSO4, filtered and the solvent evaporated under reduced pressure, to afford intermediate 59 (0.4 g, 26% over two steps).

Reference： [1]Patent: WO2014/111457,2014,A1 .Location in patent: Page/Page column 78; 79
[2]Patent: US2018/319797,2018,A1 .Location in patent: Paragraph 0674-0675

21
[ 1077-95-8 ]
5-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

22
[ 1077-95-8 ]
5-chloro-1-methyl-1H-indazole-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

23
[ 1077-95-8 ]
5-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-1-methyl-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

24
[ 1077-95-8 ]
5-chloro-3-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2-yl)-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

25
[ 1077-95-8 ]
5-chloro-1-ethyl-1H-indazole-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

26
[ 1077-95-8 ]
5-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-1-ethyl-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

27
[ 1077-95-8 ]
1-benzyl-5-chloro-1H-indazole-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

28
[ 1077-95-8 ]
1-benzyl-5-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2015/15519,2015,A1

29
[ 1077-95-8 ]
[ 28751-70-4 ]

Yield	Reaction Conditions	Operation in experiment
63%		To a solution of 5-chloro indazole 3- carboxylic acid1 2 (0.8 g, 4.0 mmol) in anhydrous THF (20 mL) was added isobutyl chloroformate (0.64 mL, 4.9 mmol) and N-methylmorpholine (0.7 mL, 6.1 mmol) under argon at 0 C and the mixture was stirred for 2h. Then to this mixture 10 mL of aqueous NH3 was added and mixture was stirred at 25C for 1 h. THF was removed under reduced pressure solid was obtained filtered through buchner funnel, solid was washed with diethyl ether and dried under vacuum to afford title compound 3 (0.5 g, 63% ) as a pale y solid. IR i (film): cm" 1 2925, 2854, 1463; NMR (200 MHz, DMSO-d6): delta 8.14 (d, ./ Hz, 1 H), 7.80 (bs, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.45-7.39 (m, 2H); MS: 218 (M+Na)+.

Reference： [1]Patent: WO2015/15519,2015,A1 .Location in patent: Page/Page column 17; 18

30
[ 1077-95-8 ]
[ 29646-35-3 ]