[ CAS No. 1224724-39-3 ] {[proInfo.proName]}

Name: 1224724-39-3|Methyl 4-bromo-1H-indole-7-carboxylate|95%
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Quality Control of [ 1224724-39-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1224724-39-3 ]

Product Details of [ 1224724-39-3 ]

CAS No. :	1224724-39-3	MDL No. :	MFCD20487964
Formula :	C₁₀H₈BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JTBLJEGYYYHKGQ-UHFFFAOYSA-N
M.W :	254.08	Pubchem ID :	58315919
Synonyms :

Calculated chemistry of [ 1224724-39-3 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.1
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	57.28
TPSA :	42.09 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.41
Log Po/w (XLOGP3) :	2.59
Log Po/w (WLOGP) :	2.72
Log Po/w (MLOGP) :	2.08
Log Po/w (SILICOS-IT) :	3.02
Consensus Log Po/w :	2.57

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.39
Solubility :	0.103 mg/ml ; 0.000407 mol/l
Class :	Soluble
Log S (Ali) :	-3.12
Solubility :	0.192 mg/ml ; 0.000754 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.22
Solubility :	0.0155 mg/ml ; 0.0000608 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.62

Safety of [ 1224724-39-3 ]

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 [ 1224724-39-3 ]

* 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.

Upstream synthesis route of [ 1224724-39-3 ]
Downstream synthetic route of [ 1224724-39-3 ]

[ 1224724-39-3 ] Synthesis Path-Upstream 1~5

1
[ 1224724-39-3 ]
[ 1211594-25-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With water; lithium hydroxide In tetrahydrofuranReflux	To a solution of methyl 4-bromo-1H-indole-7-carboxylate (6 g, 23 mmol, Preparation 1 step B) in THF (300 mL), water (60 mL) and MeOH (60 mL) was added lithium hydroxide (2.83 g, 118 mmol). Then the mixture was heated to reflux overnight. After cooling to rt, the solvent was removed under reduced pressure, the aqueous layer was acidified by addition of 4 N HC1 to about pH 6. The precipitate was filtered, and the solid was dried to provide 4-bromo-]H-indole-7-carboxylic acid (5.5g, 97percent): ‘H NMR (DMSO-d6) 3 11.39 (br, 1H), 7.65-7.63 (d, J= 8.0 Hz, 1H), 7.46-7.44 (m, 1H), 7.33-7.31 (d, J= 8.0 Hz, 1H), 6.49-6.48 (m, 1H).

Reference： [1] Patent: WO2014/210255, 2014, A1, . Location in patent: Page/Page column 101

2
[ 1826-67-1 ]
[ 158580-57-5 ]
[ 1224724-39-3 ]

Yield	Reaction Conditions	Operation in experiment
33%	at -60 - -30℃; for 2 h; Inert atmosphere	To a solution of methyl 4-bromo-2-nitrobenzoate (10 g, 38.4 mmol, 1 eq) in 60 mL of dry THF was added vinylmagnesium bromide (1.0 M in THF, 136 mL, 136 mmol, 3.5 eq) dropwise at -60 °C under nitrogen. The reaction mixture was stirred at -30 °C ~ -40 °C for 2h. Then the mixture was treated with saturated aq. NH4Cl (50 mL), the resulting mixture was extracted with EtOAc (50 mL × 3), the combined organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to afford methyl 4-bromoindole-7-carboxylate (3.2 g, 33percent). 1HNMR (300 MHz, CDCl3): G 9.98 (br, 1H), 7.76- 7.73 (m, 1 H), 7.39- 7.33 (m, 2 H), 6.67 (s, 1 H), 4.00 (s, 3 H). LCMS: (M-H)-: 251.8
31%	Stage #1: at -60 - 20℃; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuran; water	General Procedure I-ETTo a solution of methyl 4-bromo-2-nitrobenzoate (I-XVIIa, 5 g, 19 mmol) in 30 mL of dry THF was added vinylmagnesium bromide (1.0 M in THF, 48 mL, 48 mmol) dropwise at -60° C. under Nitrogen. The reaction mixture was stirred at room temperature overnight. Then the mixture was treated with saturated aq. NH₄Cl, the resulting mixture was extracted with EtOAc (50 mL.x.2), the organic phase was washed with water (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by column chromatography to afford compound I-XVIIb (1.5 g, yield 31percent). ¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.52-7.30 (m, 2H), 6.58 (t, J=2.8 Hz, 1H), 3.91 (s, 3H).

Reference： [1] Patent: WO2017/120429, 2017, A1, . Location in patent: Page/Page column 300
[2] Patent: US2011/152246, 2011, A1, . Location in patent: Page/Page column 187
[3] Organic and Biomolecular Chemistry, 2016, vol. 14, # 18, p. 4185 - 4188

3
[ 1211594-25-0 ]
[ 74-88-4 ]
[ 1224724-39-3 ]

Yield	Reaction Conditions	Operation in experiment
13.8 g	Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: at 0 - 20℃; for 3 h;	To a solution of 4-bromo-1H-indole-7-carboxylic acid (33 g, 137 mmol) in DMF (300 mL), Cs2CO3 (90 g, 276 mmol) was added and stirred at rt for 1 h. Then iodomethane (29.3 g, 206 mmol) was added dropwise at about 0 °C. The reaction mixture was warmed to rt for about 3 h. The mixture was poured into water and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography to provide methyl 4-bromo-]H- indole-7-carboxylate (13.8 g, 20percent): ‘H NMR (CDC13) 3 9.98 (s, 1H), 7.76-7.74 (d, J= 8, 1H), 7.39- 7.34 (m, 2H), 6.68-6.66 (m, 1H), 4.00 (s, 3H).

Reference： [1] Patent: WO2014/210255, 2014, A1, . Location in patent: Page/Page column 95

4
[ 99277-71-1 ]
[ 1224724-39-3 ]

Reference： [1] Patent: US2011/152246, 2011, A1,
[2] Patent: WO2014/210255, 2014, A1,
[3] Patent: WO2017/120429, 2017, A1,

5
[ 1224724-39-3 ]
[ 1211596-82-5 ]

Reference： [1] Patent: WO2014/210255, 2014, A1,

[ 1224724-39-3 ] Synthesis Path-Downstream 1~66

1
[ 1224724-39-3 ]
[ 74-88-4 ]
[ 1219741-47-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;Inert atmosphere;	Example I-XXIIPreparation of Compounds 327General Procedure I-GHTo a mixture of compound I-XVIIb (1.0 g, 4.0 mmol) and NaH (60%, 0.32 g, 8.0 mmol) in 15 mL of dry DMF was added methyl iodide (MeI, 0.8 g, 6.0 mmol) dropwise at 0 C. under nitrogen, and the mixture was stirred at room temperature for 1 hour. The mixture was treated with water and extracted with EtOAc (30 mL). The organic phase was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound I-XXIIa (0.6 g, yield 55%). 1H NMR (400 MHz, CDCl3): delta 7.56 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 6.62 (d, J=3.2 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H).

Reference： [1]Patent: US2011/152246,2011,A1 .Location in patent: Page/Page column 206-207

2
[ 1224724-39-3 ]
[ 76513-69-4 ]
methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		General Procedure I-EUSodium hydride (NaH, 60% dispersion in mineral oil, 0.36 g, 9.0 mmol) was added to a mixture of compound I-XVIIb (1.5 g, 6.0 mmol) in 20 mL of dry THF, the mixture was stirred at 0 C. for 30 min. Then 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, 1.2 g, 7.2 mmol) was added dropwise at 0 C. under Nitrogen. The resulting mixture was stirred at room temperature for 1 hour. Then treated with water, and extracted with EtOAc (50 mL×3), the organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound I-XVIIc (1.6 g, yield 70%). 1H NMR (400 MHz, CDCl3) delta 7.61 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.36 (d, J=4.0 Hz, 1H), 6.76 (d, J=4.0 Hz, 1H), 5.80 (s, 2H), 4.06 (s, 3H), 3.30 (t, J=8.0 Hz, 2H), 0.87 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).
60%		To a solution of <strong>[1224724-39-3]methyl 4-bromo-1H-indole-7-carboxylate</strong> (35 g, 138 mmol, Preparation 1 step B) in anhydrous THF (1500 mL) was added NaH (10 g, 250 mmol) in portions at about 0 C and stirred for 1 h at about 0 C. Then SEMC1 (31.9 mL, 180 mmol) was added in portions at about 0 C. The reaction mixture was allowed to warm up to rt and stirred for about 12 h. Then to the reaction mixture was added saturated aqueous NH4C1 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the residue, which was purified by column chromatography on silica gel to give methyl 4-bromo- ]-((2-(trimethylsilyl)ethoxy)methyl)-]H-indole-7-carboxylate (32 g, 60%): ?H NMR (CDC13) 7.62- 7.60 (d, J= 8.4 Hz, 1H), 7.46-7.44 (d, J= 8.0 Hz, 1H), 7.36-7.35 (d, J= 3.2 Hz, 1H), 6.77-6.76 (d, J=3.6 Hz, 1H), 5.80 (s, 2H), 4.06 (s, 3H), 3.32-3.28 (t, J = 8.0 Hz, 2H), 0.89-0.85 (t, J = 8.0 Hz, 2H),0.00 (s, 9H).

Reference： [1]Patent: US2011/152246,2011,A1 .Location in patent: Page/Page column 188
[2]Patent: WO2014/210255,2014,A1 .Location in patent: Page/Page column 106

3
[ 99277-71-1 ]
[ 1224724-39-3 ]

Reference： [1]Patent: US2011/152246,2011,A1
[2]Patent: WO2014/210255,2014,A1
[3]Patent: WO2017/120429,2017,A1
[4]Patent: CN110627775,2019,A

4
[ 1826-67-1 ]
[ 158580-57-5 ]
[ 1224724-39-3 ]

Yield	Reaction Conditions	Operation in experiment
33%	In tetrahydrofuran; at -60 - -30℃; for 2h;Inert atmosphere;	To a solution of <strong>[158580-57-5]methyl 4-bromo-2-nitrobenzoate</strong> (10 g, 38.4 mmol, 1 eq) in 60 mL of dry THF was added vinylmagnesium bromide (1.0 M in THF, 136 mL, 136 mmol, 3.5 eq) dropwise at -60 C under nitrogen. The reaction mixture was stirred at -30 C ~ -40 C for 2h. Then the mixture was treated with saturated aq. NH4Cl (50 mL), the resulting mixture was extracted with EtOAc (50 mL × 3), the combined organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to afford methyl 4-bromoindole-7-carboxylate (3.2 g, 33%). 1HNMR (300 MHz, CDCl3): G 9.98 (br, 1H), 7.76- 7.73 (m, 1 H), 7.39- 7.33 (m, 2 H), 6.67 (s, 1 H), 4.00 (s, 3 H). LCMS: (M-H)-: 251.8
31%		General Procedure I-ETTo a solution of <strong>[158580-57-5]methyl 4-bromo-2-nitrobenzoate</strong> (I-XVIIa, 5 g, 19 mmol) in 30 mL of dry THF was added vinylmagnesium bromide (1.0 M in THF, 48 mL, 48 mmol) dropwise at -60 C. under Nitrogen. The reaction mixture was stirred at room temperature overnight. Then the mixture was treated with saturated aq. NH4Cl, the resulting mixture was extracted with EtOAc (50 mL×2), the organic phase was washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to afford compound I-XVIIb (1.5 g, yield 31%). 1H NMR (400 MHz, CDCl3) delta 9.90 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.52-7.30 (m, 2H), 6.58 (t, J=2.8 Hz, 1H), 3.91 (s, 3H).
30%	In tetrahydrofuran; at -60 - -40℃; for 2h;	A solution of compound 267b (2.5 g, 9.614 mmol) in tetrahydrofuran (15 mL) was cooled to -60 C, and vinyl magnesium bromide (1.0 M in tetrahydrofuran, 34 mL, 34 mmol, 3.5 equivalents) was added dropwise to the solution under a nitrogen atmosphere. ). The reaction solution was stirred at -40 C for 2 hours. The reaction solution was then treated with a saturated aqueous ammonium chloride solution (30 mL), and the resulting mixture was extracted with ethyl acetate (80 mL × 3).The combined organic phases were washed with water (60 mL), brine (60 mL),It was dried over anhydrous sodium sulfate and then purified by silica gel chromatography (petroleum ether: ethyl acetate = 97: 3) to obtain a white solid compound 267c, which is methyl 4-bromo-1H-indole-7-carboxylic acid (850 mg, 30% yield).

Reference： [1]Patent: WO2017/120429,2017,A1 .Location in patent: Page/Page column 300
[2]Patent: US2011/152246,2011,A1 .Location in patent: Page/Page column 187
[3]Organic and Biomolecular Chemistry,2016,vol. 14,p. 4185 - 4188
[4]Patent: CN110627775,2019,A .Location in patent: Paragraph 0423-0424; 0427-0428

5
[ 1224724-39-3 ]
4-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1<i>H</i>-indole-7-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2011/152246,2011,A1

6
[ 1224724-39-3 ]
C₁₅H₁₉BrClNO₂Si [ No CAS ]

Reference： [1]Patent: US2011/152246,2011,A1

7
[ 1224724-39-3 ]
[ 1312610-53-9 ]

Reference： [1]Patent: US2011/152246,2011,A1

8
[ 1224724-39-3 ]
[ 1312612-10-4 ]

Reference： [1]Patent: US2011/152246,2011,A1

9
[ 1224724-39-3 ]
[ 1312610-54-0 ]

Reference： [1]Patent: US2011/152246,2011,A1

10
[ 1224724-39-3 ]
[ 1312610-55-1 ]

Reference： [1]Patent: US2011/152246,2011,A1

11
[ 1224724-39-3 ]
[ 1312608-64-2 ]

Reference： [1]Patent: US2011/152246,2011,A1

12
[ 1224724-39-3 ]
[ 1312610-77-7 ]

Reference： [1]Patent: US2011/152246,2011,A1

13
[ 1224724-39-3 ]
C₁₀H₇BrClNO [ No CAS ]

Reference： [1]Patent: US2011/152246,2011,A1

14
[ 1224724-39-3 ]
[ 1312610-78-8 ]

Reference： [1]Patent: US2011/152246,2011,A1

15
[ 1224724-39-3 ]
[ 1312610-79-9 ]

Reference： [1]Patent: US2011/152246,2011,A1

16
[ 1224724-39-3 ]
[ 98-59-9 ]
methyl 4-bromo-1-tosyl-1H-indole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		To a solution of methyl 4-bromo- 1H-indole-7-carboxylate (130 g, 512 mmol) in anhydrous THF (1500 mL) was added NaH (18.4 g, 767 mmol) in portions at about 0 C and stirred for about 1 h at 0C. Then TsC1 (117 g, 614 mmol) was added in portions at about 0 C. The reaction mixture was warmed to rt for about 2 h. The reaction mixture was poured into ice water and extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography to provide methyl 4-bromo-]-tosyl-]H-indole-7-carboxylate (150 g, 72%): ?H NMR (CDC13) 3 7.60-7.58 (d, J= 8.4, 2H), 7.54-7.53 (d, J= 3.6, 1H), 7.46-7.44 (d, J= 8, 1H), 7.37-7.35 (d, J= 8.4, 1H), 7.21-7.18 (d, J= 8.4, 2H), 6.77-6.76 (m, 1H), 3.93 (s, 3H), 2.35 (s, 3H).

Reference： [1]Patent: WO2014/210255,2014,A1 .Location in patent: Page/Page column 95

17
[ 1211594-25-0 ]
[ 74-88-4 ]
[ 1224724-39-3 ]

Yield	Reaction Conditions	Operation in experiment
13.8 g		To a solution of <strong>[1211594-25-0]4-bromo-1H-indole-7-carboxylic acid</strong> (33 g, 137 mmol) in DMF (300 mL), Cs2CO3 (90 g, 276 mmol) was added and stirred at rt for 1 h. Then iodomethane (29.3 g, 206 mmol) was added dropwise at about 0 C. The reaction mixture was warmed to rt for about 3 h. The mixture was poured into water and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography to provide methyl 4-bromo-]H- indole-7-carboxylate (13.8 g, 20%): ?H NMR (CDC13) 3 9.98 (s, 1H), 7.76-7.74 (d, J= 8, 1H), 7.39- 7.34 (m, 2H), 6.68-6.66 (m, 1H), 4.00 (s, 3H).

Reference： [1]Patent: WO2014/210255,2014,A1 .Location in patent: Page/Page column 95

18
[ 1224724-39-3 ]
[ 68-12-2 ]
methyl 4-bromo-3-formyl-1H-indole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With trichlorophosphate; at 0 - 90℃; for 3.33333h;	POC13 (2.4 mL, 26 mmol) was added into DMF (60 mL) solution dropwise at 0 C and stirred for about 30 mm. Then a solution of <strong>[1224724-39-3]methyl 4-bromo-1H-indole-7-carboxylate</strong> (5 g, 13 mmol, Preparation 1, step B) in DMF (60 mL) was added dropwise into the above reaction mixture at about 0 C and stirred for about 20 mm. The resulting reaction mixture was heated to about 90 OC for about3 h. After cooling to rt, the mixture was poured into ice water and basified by addition of aqueous NaOH solution to pH = 8 to 9. The aqueous mixture was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2504, filtered and concentrated under reduced pressure to get a residue, which was purified by column chromatography on silica gel to provide methyl 4-bromo-3-formyl-]H-indole-7-carboxylate (3.5 g, 95%): ?H NMR (DMSO-d6): 3 12.33 (br, 1H), 10.69 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.76-7.74 (d, J = 8.0 Hz, 1H), 7.61-7.59 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H).

Reference： [1]Patent: WO2014/210255,2014,A1 .Location in patent: Page/Page column 284

19
[ 1224724-39-3 ]
methyl 4-bromo-2-iodo-1-tosyl-1H-indole-7-carboxylate [ No CAS ]