[ CAS No. 161833-42-7 ] {[proInfo.proName]}

Name: 161833-42-7|Methyl 3-amino-4-bromothiophene-2-carboxylate|95%
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Quality Control of [ 161833-42-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 161833-42-7 ]

Product Details of [ 161833-42-7 ]

CAS No. :	161833-42-7	MDL No. :	MFCD09038329
Formula :	C₆H₆BrNO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LWSWLXPUUCBUPI-UHFFFAOYSA-N
M.W :	236.09	Pubchem ID :	53346568
Synonyms :

Calculated chemistry of [ 161833-42-7 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.7
TPSA :	80.56 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.1
Log Po/w (XLOGP3) :	2.35
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	1.08
Log Po/w (SILICOS-IT) :	2.36
Consensus Log Po/w :	1.95

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.99
Solubility :	0.242 mg/ml ; 0.00103 mol/l
Class :	Soluble
Log S (Ali) :	-3.68
Solubility :	0.0491 mg/ml ; 0.000208 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.24
Solubility :	1.35 mg/ml ; 0.00571 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.44

Safety of [ 161833-42-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 161833-42-7 ]

* 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 [ 161833-42-7 ]
Downstream synthetic route of [ 161833-42-7 ]

[ 161833-42-7 ] Synthesis Path-Upstream 1~1

1
[ 22288-78-4 ]
[ 161833-42-7 ]

Yield	Reaction Conditions	Operation in experiment
37%	at 20℃; for 20 h;	To 3-amino-2-methoxycarbonylthiophene(10 g, 63 mmol)in acetic acid (200 mL) at room temperature was added a solution of bromine (3.25 mL, 63 mmol) in acetic acid (50mL) slowly for 5 min, and the resulting mixture was stirred for 20 h at the same temperature. The reaction mixture was poured into ice cold water and extracted with dichloromethane. The organic layer was washed with water. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (3:1)to give the desired product 5 (5.59 g, 37percent). ¹H NMR (300 MHz, CDCl₃): δ=7.30 (s, 1H), 5.63 (br s, 2H), 3.85 ppm (s, 3H).
33%	at 20℃; for 16.0833 h;	Example 2: Synthesis of 3-[(dimethylamino)diazenyl]-4-bromothiophene-2- carboxamide (compound 2); Step a:Methyl 3-amino-4-bromothiophene-2-carboxylate: To a solution of methyl 3- aminothiophene-2carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3 x 100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33percent), mp 58-60 ⁰C. ¹H NMR (400 MHz, CDCl₃): δ 7.29 (IH, s), 5.63 (2H, br s), 3.85 (3H, s).
33%	at 20℃; for 16.0833 h;	Step a:Methyl 3-amino-4-bromothiophene-2-carboxylate: To a solution of methyl 3-aminothiophene-2-carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3.x.100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33percent), mp 58-60° C. ¹H NMR (400 MHz, CDCl₃): δ 7.29 (1H, s), 5.63 (2H, br s), 3.85 (3H, s).

33.8%	at 20℃; for 24 h;	A mixture of 3-amino-2-thiophenecarboxylate(500 mg, 3.2 mmol) was dissolved in acetic acid (4 mL)Bromine (180 [mu] L, 3.5 mmol) was added dropwise,At room temperature for 24 hAfter the reaction is over,The reaction solution was poured into saturated sodium thiosulfate,And then extracted with methylene chloride,Separation and purification by column chromatography,To give a yellow solid,Yield: 33.8percent
26%	at 20℃;	Commercially available methyl 3-aminothiophene-2-carboxylate (4 g, 25.4 mmol) was dissolved in acetic acid (40 mL), and a solution of bromine (1.31 mL, 25.4 mmol) in acetic acid (4 mL) was dropped onto the mixture. The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane/ethyl acetate = 95/5) to give methyl 3-amino-4-bromothiophene-2-carboxylate (1.53 g, 26 percent).

Reference： [1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 9, p. 1406 - 1414
[2] Patent: WO2010/29577, 2010, A2, . Location in patent: Page/Page column 28-29
[3] Patent: US2010/68178, 2010, A1, . Location in patent: Page/Page column 12
[4] Patent: CN106167497, 2016, A, . Location in patent: Paragraph 0162; 0163; 0164
[5] Patent: EP2708540, 2014, A1, . Location in patent: Paragraph 0137

[ 161833-42-7 ] Synthesis Path-Downstream 1~68

1
[ 161833-42-7 ]
[ 124-40-3 ]
[ 1215310-57-8 ]

Yield	Reaction Conditions	Operation in experiment
81%		Step b:Methyl 3-[dimethyIamino)diazenyl]-4-bromothiophene-2-carboxylate: To a solution of <strong>[161833-42-7]methyl 3-amino-4-bromothiophene-2-carboxylate</strong> (0.5 g, 2.11 mmol) and cone. HCl (0.85 mL, 8.47 mmol) in H2O (5 mL) was added NaNO2 (160 mg, 2.33 mmol) in portions for 5 min at 00C. After stirring 0.5 h at (0-50C), the reaction mixture was added to the solution Of K2CO3 (1.1 g, 8.04 mmol) and dimethylamine (0.85 mL, 40%, 7.6 mmol) in H2O (6 mL) at O0C. The mixture was stirred at 0-100C for 1 h and poured into ice cold water. The solution was extracted with chloroform (3 x 30 mL). The combined CHCl3 layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (90:10) as eluents to give the product as a pale orange color oil (0.5 g, 81%). 1H NMR (400 MHz, CDCl3): delta 7.38 (IH, s), 3.80 (3H, s), 3.53 (3H, br s), 3.28 (3H, br s).
81%		Step b:Methyl 3-[dimethylamino)diazenyl]-4-bromothiophene-2-carboxylate:; To a solution of <strong>[161833-42-7]methyl 3-amino-4-bromothiophene-2-carboxylate</strong> (0.5 g, 2.11 mmol) and cone. HCl (0.85 mL, 8.47 mmol) in H2O (5 mL) was added NaNO2 (160 mg, 2.33 mmol) in portions for 5 min at 0 C. After stirring 0.5 h at (0-5 C.), the reaction mixture was added to the solution of K2CO3 (1.1 g, 8.04 mmol) and dimethylamine (0.85 mL, 40%, 7.6 mmol) in H2O (6 mL) at 0 C. The mixture was stirred at 0-10 C. for 1 h and poured into ice cold water. The solution was extracted with chloroform (3×30 mL). The combined CHCl3 layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (90:10) as eluents to give the product as a pale orange color oil (0.5 g, 81%). 1H NMR (400 MHz, CDCl3): delta 7.38 (1H, s), 3.80 (3H, s), 3.53 (3H, br s), 3.28 (3H, br s).

Reference： [1]Patent: WO2010/29577,2010,A2 .Location in patent: Page/Page column 29
[2]Patent: US2010/68178,2010,A1 .Location in patent: Page/Page column 12

2
[ 22288-78-4 ]
[ 161833-42-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With bromine; acetic acid; at 60℃; for 0.75h;	General procedure: To a solution of compound 73 (1.0 eq) in HOAc (15.0 mL) was added Br2 (3.0 eq). The reaction was heated to 60 C. and allowed to stir approximately 45 minutes. The excess Br2 was neutralized with excess of Na2 S203, and the crude product was extracted (3 *25 mL) of DCM. The combined organic layers were dried over Mg504 and concentrated in vacuo, affording crude compound 74 as a light yellow solid. The products were used in the next step without purification. The scale of the reaction was calculated based on a theoretical yield of 1 g of 74.
37%	With bromine; acetic acid; at 20℃; for 20h;	To 3-amino-2-methoxycarbonylthiophene(10 g, 63 mmol)in acetic acid (200 mL) at room temperature was added a solution of bromine (3.25 mL, 63 mmol) in acetic acid (50mL) slowly for 5 min, and the resulting mixture was stirred for 20 h at the same temperature. The reaction mixture was poured into ice cold water and extracted with dichloromethane. The organic layer was washed with water. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (3:1)to give the desired product 5 (5.59 g, 37%). 1H NMR (300 MHz, CDCl3): delta=7.30 (s, 1H), 5.63 (br s, 2H), 3.85 ppm (s, 3H).
33%	With bromine; acetic acid; at 20℃; for 16.0833h;	Example 2: Synthesis of 3-[(dimethylamino)diazenyl]-4-bromothiophene-2- carboxamide (compound 2); Step a:Methyl 3-amino-4-bromothiophene-2-carboxylate: To a solution of methyl 3- aminothiophene-2carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3 x 100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33%), mp 58-60 0C. 1H NMR (400 MHz, CDCl3): delta 7.29 (IH, s), 5.63 (2H, br s), 3.85 (3H, s).

33%	With bromine; acetic acid; at 20℃; for 16.0833h;	Step a:Methyl 3-amino-4-bromothiophene-2-carboxylate: To a solution of methyl 3-aminothiophene-2-carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33%), mp 58-60 C. 1H NMR (400 MHz, CDCl3): delta 7.29 (1H, s), 5.63 (2H, br s), 3.85 (3H, s).
33.8%	With bromine; acetic acid; at 20℃; for 24h;	A mixture of 3-amino-2-thiophenecarboxylate(500 mg, 3.2 mmol) was dissolved in acetic acid (4 mL)Bromine (180 [mu] L, 3.5 mmol) was added dropwise,At room temperature for 24 hAfter the reaction is over,The reaction solution was poured into saturated sodium thiosulfate,And then extracted with methylene chloride,Separation and purification by column chromatography,To give a yellow solid,Yield: 33.8%
26%	With bromine; acetic acid; at 20℃;	Commercially available methyl 3-aminothiophene-2-carboxylate (4 g, 25.4 mmol) was dissolved in acetic acid (40 mL), and a solution of bromine (1.31 mL, 25.4 mmol) in acetic acid (4 mL) was dropped onto the mixture. The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane/ethyl acetate = 95/5) to give methyl 3-amino-4-bromothiophene-2-carboxylate (1.53 g, 26 %).

Reference： [1]Patent: WO2018/237084,2018,A1 .Location in patent: Paragraph 002139; 002644
[2]Bulletin of the Korean Chemical Society,2016,vol. 37,p. 1406 - 1414
[3]Patent: WO2010/29577,2010,A2 .Location in patent: Page/Page column 28-29
[4]Patent: US2010/68178,2010,A1 .Location in patent: Page/Page column 12
[5]Patent: CN106167497,2016,A .Location in patent: Paragraph 0162; 0163; 0164
[6]ChemMedChem,2018,vol. 13,p. 2455 - 2463
[7]Patent: EP2708540,2014,A1 .Location in patent: Paragraph 0137

3
[ 161833-42-7 ]
[ 1215310-40-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With ammonium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 20.0833h;	Step c:3-[(Dimethylamino)diazenyl]-4-bromothiophene-2-carboxamide: To an ice cold (0-5 0C) solution of ammonium hydroxide (10 mL) was added a solution of methyl 3- [(dimethylamino)diazenyl]-4-bromothiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3 x 50 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform- methanol (98:2) as eluents to give the product as an off-white solid (250 mg, 53%), mp 194-196 0C. 1H NMR (400 MHz, DMSO-dbeta): delta 7.85 (IH, s), 7.75 (IH, br s), 7.56 (IH, br s), 3.56 (3H, br s), 3.21 (3H, br s); LC-MS (positive ion mode): m/z 111, 279 (M+H)+.

Reference： [1]Patent: WO2010/29577,2010,A2 .Location in patent: Page/Page column 29

4
[ 161833-42-7 ]
[ 215927-34-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With lithium hydroxide monohydrate; In methanol; water; at 80℃; for 4h;	To <strong>[161833-42-7]3-amino-4-bromo-2-methoxycarbonylthiophene</strong> (5, 4.00g , 16.9 mmol) in methanol (17.5mL) at room temperature was added a solution of lithium hudroxide monohydrate(1.06 g, 25.3 mmol) in distilled water (70 mL), and the resulting mixture was stirred for 4 h at 80 oC. After completion of the reaction, the reaction mixture was adjusted to pH 3-4 by adding 1N hydrochloric acid and was partitioned between ethyl acetate and water. The aqueous layer extracted with ethyl acetate once more and the combined organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo to give the desired product 20 (3.60 g, 97%). 1H NMR (300 MHz, DMSO-d6): delta=7.80 (s, 1H), 6.29 ppm (br s, 2H).
43%		Methyl 3-amino-4-bromothiophene-2-carboxylate (0.48 g, 2.03 mmol) was dissolved in methanol (10 mL), and a 1 mol/L sodium hydroxide aqueous solution (10.2 mL, 10.2 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1 mol/L hydrochloric acid, concentrated under reduced pressure, suspended in 1,2-dimethoxyethane (20 mL), and filtered through Celite. The filtrate was concentrated under reduced pressure to give 3-amino-4-bromothiophene-2-carboxylic acid (193 mg, 43 %).

Reference： [1]Bulletin of the Korean Chemical Society,2016,vol. 37,p. 1406 - 1414
[2]Patent: EP2708540,2014,A1 .Location in patent: Paragraph 0138

5
[ 161833-42-7 ]
[ 1410974-59-2 ]

Reference： [1]Patent: EP2708540,2014,A1

6
[ 161833-42-7 ]
[ 215927-51-8 ]

Reference： [1]Patent: EP2708540,2014,A1

7
[ 161833-42-7 ]
[ 1410974-64-9 ]

Reference： [1]Patent: EP2708540,2014,A1

8
[ 161833-42-7 ]
[ 1410974-61-6 ]

Reference： [1]Patent: EP2708540,2014,A1

9
[ 161833-42-7 ]
[ 1410974-66-1 ]

Reference： [1]Patent: EP2708540,2014,A1

10
[ 5337-03-1 ]
[ 161833-42-7 ]
C₁₂H₁₄BrNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With 4-methyl-morpholine; isopropyl chloroformate; In acetonitrile; at 10 - 35℃;Cooling with ice;	At normal temperature, N-methyl morpholine (4.55 mE, 41.34 mmol) and isopropyl chioroformate (3.3 mE, 23.77 mmol) were added to a solution of purchased compound 149-f (2.69 g, 20.67 mmol) in acetonitrile (70 mE). The mixture was cooled with an ice-water bath, and a solution of purchased compound 149-g (4.88 g, 20.67 mmol)inacetonitrile (20 mE) was slowly added. The reaction solution was stirred at room temperature overnight, and then the reaction was quenched by adding water, and the reaction solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 149-c(1.1 g, 16%).

Reference： [1]Patent: US2016/214994,2016,A1 .Location in patent: Paragraph 0539; 0541

11
[ 161833-42-7 ]
C₁₇H₁₇BrN₄O₂S [ No CAS ]

Reference： [1]Patent: US2016/214994,2016,A1

12
[ 161833-42-7 ]
C₁₁H₁₁BrN₂O₂S [ No CAS ]

Reference： [1]Patent: US2016/214994,2016,A1

13
[ 161833-42-7 ]
C₁₁H₁₀BrClN₂OS [ No CAS ]

Reference： [1]Patent: US2016/214994,2016,A1

14
[ 161833-42-7 ]
C₁₈H₁₉BrN₄O₄S₂ [ No CAS ]

Reference： [1]Patent: US2016/214994,2016,A1

15
[ 161833-42-7 ]
C₂₈H₃₉N₇O₄S₂ [ No CAS ]

Reference： [1]Patent: US2016/214994,2016,A1

16
[ 161833-42-7 ]
[ 1765-93-1 ]
[ 156274-32-7 ]