[ CAS No. 10406-05-0 ] {[proInfo.proName]}

Name: 10406-05-0|5-Chloro-1H-indole-3-carboxylic acid|98%
Brand: Ambeed
SKU: A128510
Price: 6.0 USD
Availability: InStock
Rating: 95 (35 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 10406-05-0

Structure of 10406-05-0 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 10406-05-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 10406-05-0 ]

SDS Specification

Alternatived Products of [ 10406-05-0 ]

Product Details of [ 10406-05-0 ]

CAS No. :	10406-05-0	MDL No. :	MFCD03410308
Formula :	C₉H₆ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XUDITEOFEQOSAK-UHFFFAOYSA-N
M.W :	195.60	Pubchem ID :	17840246
Synonyms :

Calculated chemistry of [ 10406-05-0 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	50.27
TPSA :	53.09 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) :	-5.63 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.26
Log Po/w (XLOGP3) :	2.62
Log Po/w (WLOGP) :	2.52
Log Po/w (MLOGP) :	1.65
Log Po/w (SILICOS-IT) :	2.5
Consensus Log Po/w :	2.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.15
Solubility :	0.139 mg/ml ; 0.000709 mol/l
Class :	Soluble
Log S (Ali) :	-3.38
Solubility :	0.0806 mg/ml ; 0.000412 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.28
Solubility :	0.103 mg/ml ; 0.000528 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.3

Safety of [ 10406-05-0 ]

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

Application In Synthesis of [ 10406-05-0 ]

* 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 [ 10406-05-0 ]
Downstream synthetic route of [ 10406-05-0 ]

[ 10406-05-0 ] Synthesis Path-Upstream 1~7

1
[ 17422-32-1 ]
[ 407-25-0 ]
[ 10406-05-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: at 0 - 20℃; for 3 h; Stage #2: With sodium hydroxide In waterHeating / reflux	A solution of 5.0 g (33.0 mmol) of commercially available 5-chloro-1H-indole in 50 ml dry DMF was kept at 0° C., while 7.35 g (35.0 mmol) trifluoroacetanhydride was added dropwise. After 3 h stirring at room temperature the mixture was poured into 200 ml water, and the precipitate was filtered with suction and heated with reflux overnight in 200 ml 20percent NaOH. It was extracted twice with dichloromethane, and the aqueous layer was acidified with hydrochloric acid. The crystalline title compound was collected by filtration and dried in vacuo. yield: 6.0 g (93percent)

Reference： [1] Patent: US2004/9976, 2004, A1, . Location in patent: Page/Page column 52
[2] Patent: EP1266897, 2002, A2, . Location in patent: Page 74
[3] Patent: US6410562, 2002, B1,

2
[ 1419517-55-7 ]
[ 10406-05-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: With sodium hydroxide In water for 1 h; Reflux Stage #2: With hydrogenchloride In water	Solid 1-(5-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (hd) (743 mg, 3.0 mmol) was suspended in 10 mL of a 4M aqueous solution of sodium hydroxide. The resulting mixture was stirred at reflux during 1 hour. The solution was extracted with diethyl ether (2x25 mL) and then the aqueous phase was acidified with an aqueous solution of 5M HCl to pH 1. The precipitate was filtered off, washed with water and dried in the presence of P₂O₅ under reduced pressure. Pure 5-chloroindolic acid (2d) (480 mg, 2.45 mmol) was obtained as a beige solid. Yield: 82percent. ¹H NMR (300 MHz, (CD₃)₂CO): δ = 7.20 (dd, J = 2.0 and 8.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 8.10-8.15 (m, 2H), 11.07 (br s, 1H, NH) ppm. ¹³C NMR (75.5 MHz, (CD₃)₂CO): δ = 110.5 (C), 115.3 (CH), 120.6 (C), 122.2 (CH), 124.5 (CH), 128.2 (C), 135.2 (CH), 138.1 (C), 167.3 (CO) ppm.
82%	Stage #1: With sodium hydroxide In water for 1 h; Reflux Stage #2: With hydrogenchloride In water	Solid l-(5-chloro-1H-indol-3-yl)-2,2,2-trifuoroethanone (hd) (743 mg, 3.0 mmol) was suspended in 10 mL of a 4M aqueous solution of sodium hydroxide. The resulting mixture was stirred at reflux during 1 hour. The solution was extracted with diethyl ether (2x25 mL) and then the aqueous phase was acidified with an aqueous solution of 5M HC1 to pH 1. The precipitate was filtered off, washed with water and dried in the presence of P2O5 under reduced pressure. Pure 5- chloroindolic acid (2d) (480 mg, 2.45 mmol) was obtained as a beige solid. Yield: 82percent. 1H NMR (300 MHz, (CD₃)₂CO): δ = 7.20 (dd, J = 2.0 and 8.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 8.10-8.15 (m, 2H), 11.07 (br s, 1H, NH) ppm.¹³C NMR (75.5 MHz, (CD₃)₂CO): δ = 110.5 (C), 115.3 (CH), 120.6 (C), 122.2 (CH), 124.5 (CH), 128.2 (C), 135.2 (CH), 138.1 (C), 167.3 (CO) ppm.

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 17, p. 7293 - 7316
[2] Patent: EP2548864, 2013, A1, . Location in patent: Paragraph 0172
[3] Patent: WO2013/14102, 2013, A1, . Location in patent: Page/Page column 26; 31; 32

3
[ 10406-06-1 ]
[ 10406-05-0 ]

Reference： [1] Journal of the Korean Chemical Society, 2011, vol. 55, # 2, p. 240 - 242
[2] Journal of the Korean Chemical Society, 2011, vol. 55, # 2, p. 317 - 322

4
[ 17422-32-1 ]
[ 10406-05-0 ]

Reference： [1] Patent: EP2548864, 2013, A1,
[2] Patent: WO2013/14102, 2013, A1,
[3] CrystEngComm, 2013, vol. 15, # 37, p. 7490 - 7497
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 17, p. 7293 - 7316

5
[ 827-01-0 ]
[ 10406-05-0 ]

Reference： [1] CrystEngComm, 2013, vol. 15, # 37, p. 7490 - 7497
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788

6
[ 194490-14-7 ]
[ 10406-05-0 ]

Reference： [1] CrystEngComm, 2013, vol. 15, # 37, p. 7490 - 7497

7
[ 1261024-31-0 ]
[ 10406-05-0 ]

Reference： [1] CrystEngComm, 2013, vol. 15, # 37, p. 7490 - 7497

[ 10406-05-0 ] Synthesis Path-Downstream 1~88

1
[ 10406-05-0 ]
[ 17422-32-1 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1953,vol. 583,p. 150,155

2
[ 10406-05-0 ]
[ 1001910-53-7 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 60℃; for 1.5h;	Description 1 delta-Chloro-IW-indole-S-carbonyl chlA mixture of delta-chloro-IH-indole-S-carboxylic acid (2.50 g, 12.8 mmol) and thionyl chloride (4.7 ml, 63.9 mmol) was stirred at 60 0C for 30 minutes under an atmosphere of argon. A pink slurry formed. On cooling, further thionyl chloride (1.0 ml, 12.8 mmol) was added and reaction mixture was then reheated to 60 0C and stirred for 1 hour under an atmosphere of argon. After this time, the reaction mixture was allowed to cool and concentrated under reduced pressure to give 5-chloro-1H-indole-3-carbonyl chloride. The residue was used immediately without further purification in the next stage.
	With thionyl chloride; at 60℃; for 1.5h;	Description 1 delta-Chloro-IH-indole-S-carbonyl chlA mixture of S-chloro-IH-indole-S-carboxylic acid (2.50 g, 12.8 mmol) and thionyl chloride (4.7 ml, 63.9 mmol) was stirred at 60 0C for 30 minutes under an atmosphere of argon. A pink slurry formed. On cooling, further thionyl chloride (1.0 ml, 12.8 mmol) was added and reaction mixture was then reheated to 60 0C and stirred for 1 hour under an atmosphere of argon. After this time, the reaction mixture was allowed to cool and concentrated under reduced pressure to give 5-chloro-1H-indole-3-carbonyl chloride. The residue was used immediately without further purification in the next stage.

Reference： [1]Patent: WO2008/6794,2008,A1 .Location in patent: Page/Page column 18
[2]Patent: WO2008/6795,2008,A2 .Location in patent: Page/Page column 18
[3]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 499 - 503

3
[ 10406-05-0 ]
[ 78-77-3 ]
[ 1001910-66-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;	Description 142-Methylpropyl 5-chloro-1-(2-methylpropyl)-1H-indole-3-carboxylate (D14) <n="24"/>A solution of delta-chloroindole-S-carboxylic acid (2.00 g, 10.26 mmol) in dry DMF (35 ml) was stirred at room temperature under an atmosphere of argon. K2CO3 (2.831 g, 20.52 mmol) was added. 1-bromo-2-methyl propane (4.462 ml, 41.04 mmol) was added to the solution, and the solution heated to 6O0C overnight. The mixture was cooled to room temperature and then diluted with EtOAc (~ 200 ml). The organics were washed with H2O (* 3), dried over MgSO4, filtered and concentrated under reduced pressure to give a pink coloured solid. The residue was chromatographed [SiO2, Hexane:EtOAc 0-25%] to give product (2.217 g, 70 % yield). LCMS Rt = 4.03 min, [MH+] 308, 310.
70%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃;	Description 82-Methylpropyl 5-chloro-1 -(2-methylpropyl)-1 H-indole-3-carboxylate (D8)A solution of <strong>[10406-05-0]5-chloroindole-3-carboxylic acid</strong> (2.00 g, 10.26 mmol) in dry DMF (35 ml) was stirred at room temperature under an atmosphere of argon. K2CO3 (2.831 g, 20.52 mmol) <n="23"/>was added. 1-bromo-2-methyl propane (4.462 ml, 41.04 mmol) was added to the solution, and the solution heated to 60C overnight. The mixture was cooled to room temperature and then diluted with EtOAc (- 200 ml). The organics were washed with H2O (* 3), dried over MgSO4, filtered and concentrated under reduced pressure to give a pink coloured solid. The residue was chromatographed [SiO2, Hexane:EtOAc 0-25%] to give product (2.217 g, 70 % yield). LCMS Rt = 4.03 min, [MH+] 308, 310.

Reference： [1]Patent: WO2008/6794,2008,A1 .Location in patent: Page/Page column 22-23
[2]Patent: WO2008/6795,2008,A2 .Location in patent: Page/Page column 21-22

4
[ 17422-32-1 ]
[ 407-25-0 ]
[ 10406-05-0 ]

Yield	Reaction Conditions	Operation in experiment
93%		A solution of 5.0 g (33.0 mmol) of commercially available 5-chloro-1H-indole in 50 ml dry DMF was kept at 0 C., while 7.35 g (35.0 mmol) trifluoroacetanhydride was added dropwise. After 3 h stirring at room temperature the mixture was poured into 200 ml water, and the precipitate was filtered with suction and heated with reflux overnight in 200 ml 20% NaOH. It was extracted twice with dichloromethane, and the aqueous layer was acidified with hydrochloric acid. The crystalline title compound was collected by filtration and dried in vacuo. yield: 6.0 g (93%)
	In sodium hydroxide; N,N-dimethyl-formamide;	Step A: 5-Chloro-1H-indole-3-carboxylic Acid A solution of 5.0 g (33.0 mmol) of commercially available 5-chloro-1H-indole in 50 ml dry DMF was kept at 0 C., while 7.35 g (35.0 mmol) trifluoroacetanhydride was added dropwise. After 3 h stirring at room temperature the mixture was poured into 200 ml water, and the precipitate was filtered with suction and heated with reflux overnight in 200 ml 20% NaOH. It was extracted twice with dichloromethane, and the aqueous layer was acidified with hydrochloric acid. The crystalline title compoundcompound was collected by filtration and dried in vacuo. yield: 6.0 g (93%)

Reference： [1]Patent: US2004/9976,2004,A1 .Location in patent: Page/Page column 52
[2]Patent: EP1266897,2002,A2 .Location in patent: Page 74
[3]Patent: US6410562,2002,B1

5
[ 10406-05-0 ]
[ 64-17-5 ]
[ 91349-03-0 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sulfuric acid; for 16h;Heating / reflux;	To a suspension of 5.23 g (26.74 mmol) <strong>[10406-05-0]5-chloro-1H-indole-3-carboxylic acid</strong> in 140 ml dry ethanol were added 10 ml concentrated sulfuric acid, and the mixture was heated with reflux for 16 h. It was concentrated under reduced pressure, and the residue was treated with ethanol/hexane to give the crystalline title ester, which was filtered and dried in vacuo. yield: 3.84 g (64%); MS 224 (M++1)

Reference： [1]Patent: US2004/9976,2004,A1 .Location in patent: Page/Page column 52
[2]Patent: EP1266897,2002,A2 .Location in patent: Page 74

6
[ 117497-27-5 ]
[ 10406-05-0 ]
[ 2942-58-7 ]
[ 124185-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N-methyl-acetamide; dichloromethane; ethyl acetate;	3A. 2R,4S,5S-6-cyclohexyl-5-(5'-chloroindol-3'-yl-carbonylamino)-2-(2'-methylpropyl)-gamma-hexanolactone To 10 ml of methylene chloride at 0 C. was added 20 mg (0.1 mmol) of <strong>[10406-05-0]5-chloroindole-3-carboxylic acid</strong>, 30 mg (0.1 mmol) of 2R,4S,5S-6-cyclohexyl-5-amino-2-(2'-methylpropyl)-gamma-hexanolactone hydrochloride, 15 mul (0.1 mmol) of diethyl cyanophosphate and 42 mul (0.3 mmol) of triethylamine. Dimethylformamide (1 ml) was added and the reaction mixture allowed to stir at room temperature overnight. The reaction was concentrated to dryness and redissolved in ethyl acetate which was washed successively with water (2x), a saturated sodium bicarbonate solution (2x) and a brine solution. The solution was dried over sodium sulfate and concentrated to an oil, 51 mg.

Reference： [1]Patent: US4923864,1990,A

7
[ 10406-05-0 ]
[ 96-32-2 ]
[ 1404530-50-2 ]

Yield	Reaction Conditions	Operation in experiment
65%		Preparation 3.1 5-Chloro-1-(2-methoxy-2-oxoethyl)-1H-indole-3-carboxylic acid (IV-A): R3=OMe; R4=Cl 110 ml of a solution containing 10 g (51 mmol) of (commercial) <strong>[10406-05-0]5-chloro-1H-indole-3-carboxylic acid</strong> in DMF are added dropwise to a mixture of 4.50 g (112 mmol) of NaH (60% in oil) in 400 ml of DMF at -10 C., and the mixture is left to stir for 1 h. The reaction mixture is cooled to -20 C. and then 4.86 ml (51 mmol) of methyl bromoacetate are added dropwise. The temperature is brought back up to AT over a period of 5 hours and then the reaction medium is stirred at AT for 15 h. The reaction medium is added to 1 l of an EtOAc/1N HCl mixture, the organic phase is collected and the aqueous phase is extracted with EtOAc. The organic phases are combined, washed with water and with brine, and then dried over Na2SO4 and evaporated to dryness to obtain 8.9 g of the expected compound in the form of a white powder. Yield=65% 1H NMR: DMSO-d6 (250 MHz): delta (ppm): 3.70 (3H, s); 7.26 (1H, d); 7.57 (1H, d); 7.98 (1H,s); 8.12 (1H, s); 12.3 (1H, br).
		110 ml of a solution containing 10 g of <strong>[10406-05-0]5-chloro-1H-indole-3-carboxylic acid</strong> (commercial) in DMF is added dropwise to a mixture of 4.50 g of NaH (60% in oil) in 400 ml of DMF at -10 C. After it returns to RT, it is stirred for 1 hour. The reaction mixture is cooled to -20 C. 4.86 ml of methyl bromoacetate is added dropwise, it is returned to RT for a period of 5 hours and is stirred for 15 hours. The reaction mixture is added to 1 L of EtOAc/1N HCl mixture, the organic phase is collected and the aqueous phase is extracted with EtOAc. The organic phases are combined, washed with water and with brine, then dried over Na2SO4 and evaporated to dryness. 8.9 g of the expected compound is obtained in the form of a white powder.1H NMR: DMSO-d6 (250 MHz): delta (ppm): 3.70 (3H, s); 7.26 (1H, d); 7.57 (1H, d); 7.98 (1H, s); 8.12 (1H, s); 12.3 (1H, br).
		3. Preparations of the compounds of formula (IV).Preparation 3.15-Chloro-1 -(2-methoxy-2-oxoethyl)-1 /-/-indole-3-carboxylic acid.(IV): X = CH; R4 = CI; R5 = H; Z = Me.1 10 ml of a solution containing 10 g of 5-chloro-1 /-/-indole-3-carboxylic acid (commercial) in DMF is added dropwise to a mixture of 4.50 g of NaH (60% in oil) in 400 ml of DMF at -10C. After it returns to RT, it is stirred for 1 hour. The reaction mixture is cooled to -20C. 4.86 ml of methyl bromoacetate is added dropwise, it is returned to RT for a period of 5 hours and is stirred for 15 hours. The reaction mixture is added to 1 L of EtOAc/1 N HCI mixture, the organic phase is collected and the aqueous phase is extracted with EtOAc. The organic phases are combined, washed with water and with brine, then dried over Na2S04 and evaporated to dryness. 8.9 g of the expected compound is obtained in the form of a white powder.1H NMR: DMSO-de (250 MHz): delta (ppm): 3.70 (3H, s); 7.26 (1 H, d); 7.57 (1 H, d); 7.98 (1 H, s); 8.12 (1 H, s); 12.3 (1 H, br).

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316
[2]Patent: US2015/274703,2015,A1 .Location in patent: Paragraph 0251; 0252; 0253; 0254
[3]Patent: US2012/277205,2012,A1 .Location in patent: Page/Page column 26
[4]Patent: WO2012/146318,2012,A1 .Location in patent: Page/Page column 57

8
[ 10406-05-0 ]
[ 1404529-08-3 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316

9
[ 10406-05-0 ]
[ 1404529-48-1 ]

Reference： [1]Patent: US2012/277205,2012,A1

10
[ 10406-05-0 ]
[ 1279867-21-8 ]

Reference： [1]Patent: US2012/277205,2012,A1

11
[ 10406-05-0 ]
[ 1280292-76-3 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1

12
[ 10406-05-0 ]
[ 1404529-53-8 ]

Reference： [1]Patent: US2012/277205,2012,A1

13
[ 10406-05-0 ]
[ 1404531-66-3 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316

14
[ 10406-05-0 ]
[ 1404531-68-5 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316

15
[ 10406-05-0 ]
[ 1404531-75-4 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316

16
[ 10406-05-0 ]
[ 1404529-04-9 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1

17
[ 10406-05-0 ]
[ 1404531-69-6 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316

18
[ 10406-05-0 ]
[ 1404531-74-3 ]

Reference： [1]Patent: US2012/277205,2012,A1
[2]Patent: WO2012/146318,2012,A1
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316

19
[ 10406-05-0 ]
N-[5-(4-butyryl-5-methyl-1H-pyrazol-1-yl)pyrazin-2-yl]-5-chloro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2012/277205,2012,A1

20
[ 10406-05-0 ]
N-[6-(4-butyryl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-{2-[4-(2-methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2012/277205,2012,A1

21
[ 10406-05-0 ]
N-[6-(4-butyryl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-(2-oxo-2-{4-[2-(trifluoromethoxy)ethyl]piperazin-1-yl}ethyl)-1H-indole-3-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2012/277205,2012,A1

22
[ 10406-05-0 ]
N-[6-(4-butyryl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-{2-oxo-2-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]ethyl}-1H-indole-3-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2012/277205,2012,A1

23
[ 17422-32-1 ]
[ 10406-05-0 ]

Reference： [1]Patent: EP2548864,2013,A1
[2]Patent: WO2013/14102,2013,A1
[3]CrystEngComm,2013,vol. 15,p. 7490 - 7497
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316

24
[ 1419517-55-7 ]
[ 10406-05-0 ]

Yield	Reaction Conditions	Operation in experiment
82%		Solid 1-(5-chloro-1H-indol-3-yl)-2,2,2-trifluoroethanone (hd) (743 mg, 3.0 mmol) was suspended in 10 mL of a 4M aqueous solution of sodium hydroxide. The resulting mixture was stirred at reflux during 1 hour. The solution was extracted with diethyl ether (2x25 mL) and then the aqueous phase was acidified with an aqueous solution of 5M HCl to pH 1. The precipitate was filtered off, washed with water and dried in the presence of P2O5 under reduced pressure. Pure 5-chloroindolic acid (2d) (480 mg, 2.45 mmol) was obtained as a beige solid. Yield: 82%. 1H NMR (300 MHz, (CD3)2CO): delta = 7.20 (dd, J = 2.0 and 8.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 8.10-8.15 (m, 2H), 11.07 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, (CD3)2CO): delta = 110.5 (C), 115.3 (CH), 120.6 (C), 122.2 (CH), 124.5 (CH), 128.2 (C), 135.2 (CH), 138.1 (C), 167.3 (CO) ppm.
82%		Solid l-(5-chloro-1H-indol-3-yl)-2,2,2-trifuoroethanone (hd) (743 mg, 3.0 mmol) was suspended in 10 mL of a 4M aqueous solution of sodium hydroxide. The resulting mixture was stirred at reflux during 1 hour. The solution was extracted with diethyl ether (2x25 mL) and then the aqueous phase was acidified with an aqueous solution of 5M HC1 to pH 1. The precipitate was filtered off, washed with water and dried in the presence of P2O5 under reduced pressure. Pure 5- chloroindolic acid (2d) (480 mg, 2.45 mmol) was obtained as a beige solid. Yield: 82%. 1H NMR (300 MHz, (CD3)2CO): delta = 7.20 (dd, J = 2.0 and 8.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 8.10-8.15 (m, 2H), 11.07 (br s, 1H, NH) ppm.13C NMR (75.5 MHz, (CD3)2CO): delta = 110.5 (C), 115.3 (CH), 120.6 (C), 122.2 (CH), 124.5 (CH), 128.2 (C), 135.2 (CH), 138.1 (C), 167.3 (CO) ppm.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7293 - 7316
[2]Patent: EP2548864,2013,A1 .Location in patent: Paragraph 0172
[3]Patent: WO2013/14102,2013,A1 .Location in patent: Page/Page column 26; 31; 32

25
[ 10406-05-0 ]
[ 1270503-43-9 ]
[ 1419517-23-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	To a stirred solution of indolic amine (1d) (93 mg, 0.3 mmol) and <strong>[10406-05-0]5-chloro-1H-indole-3-carboxylic acid</strong> (2d) (65 mg, 0.33 mmol) in 5 mL of dry CH2Cl2, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 5 mg, 0.33 mmol) was added at room temperature. The resulting mixture was stirred overnight. CH2Cl2 was evaporated then EtOAc (20 mL) and a 1M aqueous solution of hydrochloric acid (20 mL) were added. After extraction, organic phase was washed with hydrochloric acid aqueous solution, 5% Na2CO3 aqueous solution, brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum. Purification of the crude product by column chromatography using EtOAc-pentane (from 10/90 to 80/20) yielded the pure bis-indole 6a (110 mg, 0.226 mmol) as a beige foam. Yield: 75%. IR (neat): 3410, 3290, 2975, 2930, 1685, 1625, 1535, 1450, 1365, 1160, 895, 795 cm-1. 1H NMR (300 MHz, CDCl3): delta = 1.36 (s, 9H), 3.56-3.60 (m, 2H), 5.22-5.28 (m, 1H), 5.38-5.43 (m, 1H), 6.88-7.20 (m, 6H), 7.46-7.52 (m, 2H), 8.13 (s, 1H), 8.99 (s, 1H), 9.58 (s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): delta = 28.0 (3C), 44.6, 47.9, 79.8, 110.4, 112.4, 112.6, 113.7, 118.1, 120.1, 122.1, 122.8, 123.5, 124.9, 126.4, 126.7, 126.9, 128.8, 134.7, 134.8, 157.7, 165.8 ppm. LRMS (ESI): m/z (%) = 509 (39) [(M+Na)+], 237 (100).
75%	With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 20℃;	To a stirred solution of indolic amine (Id) (93 mg, 0.3 mmol) and 5-chloro-lH-indole-3- carboxylic acid (2d) (65 mg, 0.33 mmol) in 5 mL of dry CH2C12, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI, 5 mg, 0.33 mmol) was added at room temperature. The resulting mixture was stirred overnight. CH2C12 was evaporated then EtOAc (20 mL) and a 1M aqueous solution of hydrochloric acid (20 mL) were added. After extraction, organic phase was washed with hydrochloric acid aqueous solution, 5% Na2C03 aqueous solution, brine, dried over anhydrous MgS04, filtered and concentrated under vacuum. Purification of the crude product by column chromatography using EtOAc-pentane (from 10/90 to 80/20) yielded the pure bis-indole 6a (110 mg, 0.226 mmol) as a beige foam. Yield: 75%.IR (neat): 3410, 3290, 2975, 2930, 1685, 1625, 1535, 1450, 1365, 1160, 895, 795 cm"1. 1H NMR (300 MHz, CDC13): delta = 1.36 (s, 9H), 3.56-3.60 (m, 2H), 5.22-5.28 (m, 1H), 5.38-5.43 (m, 1H),6.88- 7.20 (m, 6H), 7.46-7.52 (m, 2H), 8.13 (s, 1H), 8.99 (s, 1H), 9.58 (s, 1H) ppm. 13C NMR (75.5 MHz, CDC13): delta = 28.0 (3C), 44.6, 47.9, 79.8, 110.4, 112.4, 112.6, 113.7, 118.1, 120.1, 122.1, 122.8, 123.5, 124.9, 126.4, 126.7, 126.9, 128.8, 134.7, 134.8, 157.7, 165.8 ppm. LRMS (ESI): m/z (%) = 509 (39) [(M+Na)+], 237 (100).

Reference： [1]Patent: EP2548864,2013,A1 .Location in patent: Paragraph 0288; 0289
[2]Patent: WO2013/14102,2013,A1 .Location in patent: Page/Page column 51; 57

26
[ 827-01-0 ]
[ 10406-05-0 ]

Reference： [1]CrystEngComm,2013,vol. 15,p. 7490 - 7497
[2]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5781 - 5788

27
[ 1261024-31-0 ]
[ 10406-05-0 ]

Reference： [1]CrystEngComm,2013,vol. 15,p. 7490 - 7497

28
[ 10406-05-0 ]
[ 1404532-62-2 ]