[ CAS No. 290825-52-4 ] {[proInfo.proName]}

Name: 290825-52-4|Dimethyl 2-(2-nitro-4-(trifluoromethyl)phenyl)malonate|98%
Brand: Ambeed
SKU: A433223
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2D 3D

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Quality Control of [ 290825-52-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 290825-52-4 ]

CAS No. :	290825-52-4	MDL No. :	MFCD03617804
Formula :	C₁₂H₁₀F₃NO₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MBAQGFLNQDHQCE-UHFFFAOYSA-N
M.W :	321.21	Pubchem ID :	2763558
Synonyms :

Safety of [ 290825-52-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 290825-52-4 ]

* 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 [ 290825-52-4 ]

[ 290825-52-4 ] Synthesis Path-Downstream 1~22

1
[ 290825-52-4 ]
[ 13544-07-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium chloride In water; dimethyl sulfoxide at 120℃; for 16 - 20h;	2.2 Step 2: (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester 2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120° C. (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105° C. 1H NMR (CDCl3) 8.3 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.12 (s, 2H), 3.60 (s, 3H). MS (FAB) m/z: 275.2 (M++1).
	With lithium chloride In water; dimethyl sulfoxide at 100℃; for 3h; Heating / reflux;	6-Trifluoromethyl-2-oxindole The diester was dissolved in a mixture of 6.4 g of lithium chloride and 2.7 ML of water in 100 ML of dimethylsulfoxide and heated to 100° C. for 3 hours.. The reaction was cooled and poured into a mixture of ethyl acetate and brine.. The organic phase was washed with brine, dried with sodium sulfate, concentrated and chromatographed on silica gel (10% ethyl acetate in hexane).. The fractions containing product were evaporated to give 25.7 g of methyl 2-nitro-4-trifluoromethylphenylacetate.
	With dimethyl sulfoxide; sodium chloride In water at 120℃;	2.2 Step 2: (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester.2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120 0C (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105 0C. 1H NMR (CDCl3) 8.3 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 4.12 (s, 2 H), 3.60 (s, 3 H). MS (FAB) m/z: 275.2 (M+ + 1).

With water; lithium chloride In dimethyl sulfoxide at 100℃; for 3h;

6-Trifluoromethyl-2-oxindole The diester was dissolved in a mixture of 6.4 g of lithium chloride and 2.7 mL of water in 100 mL of dimethylsulfoxide and heated to 100° C. for 3 hours. The reaction was cooled and poured into a mixture of ethyl acetate and brine. The organic phase was washed with brine, dried with sodium sulfate, concentrated and chromatographed on silica gel (10% ethyl acetate in hexane). The fractions containing product were evaporated to give 25.7 g of methyl 2-nitro-4-trifluoromethylphenylacetate.

Reference： [1]Current Patent Assignee: UNIVERSITY OF KANSAS - US2006/47126, 2006, A1 Location in patent: Page/Page column 26
[2]Current Patent Assignee: PFIZER INC - US6350754, 2002, B2 Location in patent: Page column 22
[3]Current Patent Assignee: UNIVERSITY OF KANSAS - WO2011/5759, 2011, A2 Location in patent: Page/Page column 71
[4]Current Patent Assignee: PFIZER INC - US6878733, 2005, B1 Location in patent: Page/Page column 171

2
[ 121-17-5 ]
[ 108-59-8 ]
[ 290825-52-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol for 3 - 6h; Heating / reflux;	2.1 Step 1: 2-(2-nitro-4-trifluoromethylphenyl)-malonic Acid dimethyl ester Dimethyl malonate (59.7 g, 0.44 mol) was added dropwise to a stirred solution of potassium tert-butoxide (51 g, 0.44 mol) in dry t-butanol (500 mL). To the resultant suspension, a warm solution of 2-chloro-5-trifluoromethylnitrobenzene (50 g, 0.22 mol) in t-butanol (100 mL) was added and the mixture was refluxed for 6 h (reaction monitored by TLC). After completion of the reaction, most of the t-butanol was distilled off under vacuum, and chilled water was then added to the reaction mixture. The pH was adjusted to neutral with dilute hydrochloric acid, which resulted in the precipitation of the product. The mixture was stirred for 30 minutes and the product was filtered off (68 g, 95%). This material was used without further purification in the next step. A small amount was crystallized (EtOAc/hexane, 4:6) for analysis, to yield a yellow crystalline material, mp 65-67° C. 1H NMR (CDCl3) 8.30 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 5.37 (s, 1H), 3.80 (s, 6H). MS (FAB) m/z: 322.1 (M++1).
	With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol Reflux;	2.1 Step 1 : 2-(2-nitro-4-trifluoromethylphenyl)-malonic Acid dimethyl ester. Dimethyl malonate (59.7 g, 0.44 mol) was added dropwise to a stirred solution of potassium tert-butoxide (51 g, 0.44 mol) in dry t-butanol (500 mL). To the resultant suspension, a warm solution of 2-chloro-5-trifluoromethylnitrobenzene (50 g, 0.22 mol) in t-butanol (100 mL) was added and the mixture was refluxed for 6 h (reaction monitored by TLC). After completion of the reaction, most of the t-butanol was distilled off under vacuum, and chilled water was then added to the reaction mixture. The pH was adjusted to neutral with dilute hydrochloric acid, which resulted in the precipitation of the product. The mixture was stirred for 30 minutes and the product was filtered off (68 g, 95%). This material was used without further purification in the next step. A small amount was crystallized (EtOAc/hexane, 4:6) for analysis, to yield a yellow crystalline material, mp 65-67 0C. 1U NMR (CDCl3) 8.30 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 5.37 (s, 1 H), 3.80 (s, 6 H). MS (FAB) m/z: 322.1 (M+ + 1).

Reference： [1]Current Patent Assignee: UNIVERSITY OF KANSAS - US2006/47126, 2006, A1 Location in patent: Page/Page column 26
[2]Current Patent Assignee: UNIVERSITY OF KANSAS - WO2011/5759, 2011, A2 Location in patent: Page/Page column 70-71

3
[ 65754-26-9 ]
ammonium chloride [ No CAS ]
[ 95-92-1 ]
[ 290825-52-4 ]

Yield	Reaction Conditions	Operation in experiment
	In hexane; dimethyl sulfoxide; ethyl acetate	1 6-Trifluoromethyl-2-oxindole 6-Trifluoromethyl-2-oxindole Dimethylsulfoxide (330 mL) was added to 7.9 g of sodium hydride followed by dropwise addition of 43.6 g diethyloxalate. The mixture was heated to 100° C. for 1.0 hour and cooled to room temperature. 2-Nitro-4-trifluoromethyltoluene (31.3 g) was added, the reaction stirred for 30 minutes at room temperature and then heated to 100° C. for 1 hour. The reaction was cooled and poured into a mixture of saturated aqueous ammonium chloride, ethyl acetate and hexane. The organic layer was washed with saturated ammonium chloride, water and brine, dried, and concentrated to give dimethyl 2-(2-nitro4-trifluoromethylphenyl)malonate.
	In hexane; dimethyl sulfoxide; ethyl acetate	6-Trifluoromethyl-2-oxindole 6-Trifluoromethyl-2-oxindole Dimethylsulfoxide (330 mL) was added to 7.9 g of sodium hydride followed by dropwise addition of 43.6 g diethyloxalate. The mixture was heated to 100° C. for 1.0 hour and cooled to room temperature. 2-Nitro-4-trifluoromethyltoluene (31.3 g) was added, the reaction stirred for 30 minutes at room temperature and then heated to 100° C. for 1 hour. The reaction was cooled and poured into a mixture of saturated aqueous ammonium chloride, ethyl acetate and hexane. The organic layer was washed with saturated ammonium chloride, water and brine, dried, and concentrated to give dimethyl 2-(2-nitro-4-trifluoromethylphenyl)malonate.
	In hexane; dimethyl sulfoxide; ethyl acetate	1 6-Trifluoromethyl-2-oxindole 6-Trifluoromethyl-2-oxindole Dimethylsulfoxide (330 mL) was added to 7.9 g of sodium hydride followed by dropwise addition of 43.6 g diethyloxalate. The mixture was heated to 100° C. for 1.0 hour and cooled to room temperature. 2-Nitro-4-trifluoromethyltoluene (31.3 g) was added, the reaction stirred for 30 minutes at room temperature and then heated to 100° C. for 1 hour. The reaction was cooled and poured into a mixture of saturated aqueous ammonium chloride, ethyl acetate and hexane. The organic layer was washed with saturated ammonium chloride, water and brine, dried, and concentrated to give dimethyl 2-(2-nitro-4-trifluoromethylphenyl)malonate.

Reference： [1]Current Patent Assignee: PFIZER INC - US6486185, 2002, B1
[2]Current Patent Assignee: PFIZER INC - US2003/69421, 2003, A1 Current Patent Assignee: PFIZER INC - US6051593, 2000, A
[3]Current Patent Assignee: PFIZER INC - US6114371, 2000, A

4
[ 290825-52-4 ]
[ 1735-91-7 ]

Yield	Reaction Conditions	Operation in experiment
		To prepare 6-trifluoromethyloxindole, first a 2L flask with a stir bar was charged with 45.8 ml (400 mmol) of dimethylmalonate and 500 ml of anhydrous DMSO. Next, 15.6 grams (391 mmol) of NaH was added in portions over 10 minutes to the vigorously stiring solution under an atmosphere of N2. That solution was heated to 1000C and stirred for lhour and then allowed to cool to ambient temperature. Next, 26 ml (186 mmol) of 4-fluoro-3-nitrobenzotrifluoride (CASNo. 367-86-2) was added using a syringe in one portion, which resulted in the previously colorless solution becoming dark brown/red. That colored solution was again heated to 1000C5 stirred for 1 hour and allowed to cool to ambient temperature. The solution was then poured into 1.3 L of saturated NH4Cl solution. The resulting mixture was Extracted with ethyl acetate followed by drying (using MgSO4) and concentration in vacuo, resulting in a red/orange oil that crystallized on standing overnight. Some of the excess dimethylmalonate was <n="51"/>removed by decanting from the crystallized solid product. The crystallized solid product was then pulverized using a mortar and pestle, suspended in hexanes and filtered to remove the remaining dimethylmalonate.[0138] The resulting 2-(2-Nitro-4-trifluoromethyl-phenyl)-malonic acid dimethyl ester (56.1 g) was suspended in 200 ml of 6N HCl and stirred at reflux overnight. That solution was cooled, diluted with 500 ml of water, and filtered. The filtered solids were pulverized using mortar and pestil and suspended in water and filtered again, washing with copious water to remove traces of HCl. After drying in vacuo, the resuting solid (2-Nitro-4-trifluoromethyl-phenyl)-acetic acid was dissolved in 200 ml of AcOH to which was then added 5.4 grams of Palladium (10%) on Carbon. The resulting suspension was placed under one atmosphere of hydrogen (60 psi, Parr apparatus) for 4 hours. The suspenson was filtered through celite, washed with MeOH and CH2CI2, and concentrated in vacuo. Recrystallization from ethyl acetate/hexanes gave 27.19 g from the first crop, and 1.1 g from a second crop for a total yield of 28.29 g (76%, 3 steps) of 6-trifluoromethyloxindole (CASNo. 1735-89-3) as white prisms.

Reference： [1]Patent: WO2007/106564,2007,A2 .Location in patent: Page/Page column 49-50

5
[ 367-86-2 ]
[ 290825-52-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: malonic acid dimethyl ester With sodium hydride In dimethyl sulfoxide at 100℃; for 1h; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In dimethyl sulfoxide at 20 - 100℃; for 1h;	1 To prepare 6-trifluoromethyloxindole, first a 2L flask with a stir bar was charged with 45.8 ml (400 mmol) of dimethylmalonate and 500 ml of anhydrous DMSO. Next, 15.6 grams (391 mmol) of NaH was added in portions over 10 minutes to the vigorously stiring solution under an atmosphere of N2. That solution was heated to 1000C and stirred for lhour and then allowed to cool to ambient temperature. Next, 26 ml (186 mmol) of 4-fluoro-3-nitrobenzotrifluoride (CASNo. 367-86-2) was added using a syringe in one portion, which resulted in the previously colorless solution becoming dark brown/red. That colored solution was again heated to 1000C5 stirred for 1 hour and allowed to cool to ambient temperature. The solution was then poured into 1.3 L of saturated NH4Cl solution. The resulting mixture was Extracted with ethyl acetate followed by drying (using MgSO4) and concentration in vacuo, resulting in a red/orange oil that crystallized on standing overnight. Some of the excess dimethylmalonate was removed by decanting from the crystallized solid product. The crystallized solid product was then pulverized using a mortar and pestle, suspended in hexanes and filtered to remove the remaining dimethylmalonate.[0138] The resulting 2-(2-Nitro-4-trifluoromethyl-phenyl)-malonic acid dimethyl ester (56.1 g) was suspended in 200 ml of 6N HCl and stirred at reflux overnight. That solution was cooled, diluted with 500 ml of water, and filtered. The filtered solids were pulverized using mortar and pestil and suspended in water and filtered again, washing with copious water to remove traces of HCl. After drying in vacuo, the resuting solid (2-Nitro-4-trifluoromethyl-phenyl)-acetic acid was dissolved in 200 ml of AcOH to which was then added 5.4 grams of Palladium (10%) on Carbon. The resulting suspension was placed under one atmosphere of hydrogen (60 psi, Parr apparatus) for 4 hours. The suspenson was filtered through celite, washed with MeOH and CH2CI2, and concentrated in vacuo. Recrystallization from ethyl acetate/hexanes gave 27.19 g from the first crop, and 1.1 g from a second crop for a total yield of 28.29 g (76%, 3 steps) of 6-trifluoromethyloxindole (CASNo. 1735-89-3) as white prisms.

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2007/106564, 2007, A2 Location in patent: Page/Page column 49-50

6
[ 65754-26-9 ]
[ 95-92-1 ]
[ 290825-52-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: oxalic acid diethyl ester With sodium hydride In dimethyl sulfoxide at 100℃; for 1h; Heating / reflux; Stage #2: 2-methyl-5-trifluoromethylnitrobenzene In dimethyl sulfoxide at 100℃; for 0.5h; Heating / reflux;	6-Trifluoromethyl-2-oxindole 6-Trifluoromethyl-2-oxindole Dimethylsulfoxide (330 ML) was added to 7.9 g of sodium hydride followed by dropwise addition of 43.6 g diethyloxalate.. The mixture was heated to 100° C. for 1.0 hour and cooled to room temperature. 2-Nitro-4- trifluoromethyltoluene (31.3 g) was added, the reaction stirred for 30 minutes at room temperature and then heated to 100° C. for 1 hour.. The reaction was cooled and poured into a mixture of saturated aqueous ammonium chloride, ethyl acetate and hexane.. The organic layer was washed with saturated ammonium chloride, water and brine, dried, and concentrated to give dimethyl 2-(2-nitro-4-trifluoromethylphenyl)malonate.
	Stage #1: oxalic acid diethyl ester With sodium hydride In dimethyl sulfoxide at 100℃; for 1h; Stage #2: 2-methyl-5-trifluoromethylnitrobenzene In dimethyl sulfoxide at 20 - 100℃; for 1.5h;	6-Trifluoromethyl-2-oxindole 6-Trifluoromethyl-2-oxindole Dimethylsulfoxide (330 mL) was added to 7.9 g of sodium hydride followed by dropwise addition of 43.6 g diethyloxalate. The mixture was heated to 100° C. for 1.0 hour and cooled to room temperature. 2-Nitro-4-trifluoromethyltoluene (31.3 g) was added, the reaction stirred for 30 minutes at room temperature and then heated to 100° C. for 1 hour. The reaction was cooled and poured into a mixture of saturated aqueous ammonium chloride, ethyl acetate and hexane. The organic layer was washed with saturated ammonium chloride, water and brine, dried, and concentrated to give dimethyl 2-(2-nitro-4-trifluoromethylphenyl)malonate.

Reference： [1]Current Patent Assignee: PFIZER INC - US6350754, 2002, B2 Location in patent: Page column 22
[2]Current Patent Assignee: PFIZER INC - US6878733, 2005, B1 Location in patent: Page/Page column 171

7
[ 290825-52-4 ]
[ 877766-69-3 ]