[ CAS No. 5442-91-1 ] {[proInfo.proName]}

Name: 5442-91-1|4-(Ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid|98%
Brand: Ambeed
SKU: A847630
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Quality Control of [ 5442-91-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5442-91-1 ]

Product Details of [ 5442-91-1 ]

CAS No. :	5442-91-1	MDL No. :	MFCD00030408
Formula :	C₁₀H₁₃NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DXKYHAPIBYYLJR-UHFFFAOYSA-N
M.W :	211.21	Pubchem ID :	224709
Synonyms :

Calculated chemistry of [ 5442-91-1 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.4
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	53.77
TPSA :	79.39 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) :	-6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.72
Log Po/w (XLOGP3) :	1.55
Log Po/w (WLOGP) :	1.51
Log Po/w (MLOGP) :	0.64
Log Po/w (SILICOS-IT) :	1.99
Consensus Log Po/w :	1.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.11
Solubility :	1.64 mg/ml ; 0.00779 mol/l
Class :	Soluble
Log S (Ali) :	-2.83
Solubility :	0.315 mg/ml ; 0.00149 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.24
Solubility :	1.2 mg/ml ; 0.0057 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.25

Safety of [ 5442-91-1 ]

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 [ 5442-91-1 ]

* 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 [ 5442-91-1 ]
Downstream synthetic route of [ 5442-91-1 ]

[ 5442-91-1 ] Synthesis Path-Upstream 1~5

1
[ 5442-91-1 ]
[ 2199-51-1 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	Inert atmosphere	4-(Ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (7, 5.0 g, 25.0 mmol) was heated in a flask to 200-210 °C with an oil bath for 12 min. The reactant gradually melted with accompanying production of carbon dioxide. The heating was removed when there was no more gas evolving. The reaction was allowed to cool down to r.t. and then dried under vacuum to afford 8 as a pale-gray solid (3.90 g, 98.5 percent), m.p. 75-76 °C (lit. 74-76 °C [17]), yield 90.0 percent (lit. [13]). R_f = 0.73 (eluent: chloroform/methanol, v/v = 10:1).
53%	for 1.5 h; Heating	35,5-dimethyl-4-ethoxycarbonyl--1H- pyrrole-2-carboxylic acid (9.5g, 0.045mol) was heated to a molten state reaction 1.5h, cooled to room temperature, dissolved in dichloromethane, filtered and the filtrate dried over anhydrous sodium sulfate, and concentrated. Column chromatography with petroleum ether: ethyl acetate = 10:1 (V / V) as eluent to give dark red crystals (4.0g, 53percent).

Reference： [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[2] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 7, p. 2117 - 2123
[3] Journal of the American Chemical Society, 1980, vol. 102, # 4, p. 1377 - 1382
[4] Patent: CN102898402, 2016, B, . Location in patent: Paragraph 0299-0301
[5] Justus Liebigs Annalen der Chemie, 1886, vol. 236, p. 296,298[6] Chemische Berichte, 1889, vol. 22, p. 162
[7] Justus Liebigs Annalen der Chemie, 1934, vol. 512, p. 195,209
[8] Patent: US4560700, 1985, A,
[9] Patent: EP190712, 1991, B1,
[10] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 756 - 769

2
[ 5442-91-1 ]
[ 253870-02-9 ]

Reference： [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[2] Patent: CN102898402, 2016, B,

3
[ 5442-91-1 ]
[ 2199-59-9 ]

Reference： [1] Patent: EP1911755, 2008, A1, . Location in patent: Page/Page column 48
[2] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[3] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 756 - 769
[4] Patent: CN102898402, 2016, B,

4
[ 5442-91-1 ]
[ 5434-29-7 ]

Reference： [1] Bioorganic and medicinal chemistry, 2003, vol. 11, # 2, p. 171 - 183

5
[ 5442-91-1 ]
[ 356068-86-5 ]

Reference： [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954

[ 5442-91-1 ] Synthesis Path-Downstream 1~71

1
[ 5442-91-1 ]
[ 1003-90-3 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1954,vol. 589,p. 188,194

2
[ 5442-91-1 ]
[ 2199-51-1 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	Inert atmosphere;	4-(Ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (7, 5.0 g, 25.0 mmol) was heated in a flask to 200-210 C with an oil bath for 12 min. The reactant gradually melted with accompanying production of carbon dioxide. The heating was removed when there was no more gas evolving. The reaction was allowed to cool down to r.t. and then dried under vacuum to afford 8 as a pale-gray solid (3.90 g, 98.5 %), m.p. 75-76 C (lit. 74-76 C [17]), yield 90.0 % (lit. [13]). Rf = 0.73 (eluent: chloroform/methanol, v/v = 10:1).
98.5%	at 200℃; for 0.0833333h;Inert atmosphere;	1) 5.0 mmol of 3,5-dimethyl-1H-pyrrole-4-ethoxycarbonyl-2-carboxylic acid was added to a round bottom flask equipped with a reflux condenser and a magnetron, and then at 200 C under the protection of nitrogen melt, And a large amount of gas is emitted, and no gas is emitted after 5 minutes of reaction, Cooling to obtain a black solid, column chromatography, eluent system using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1, to obtain a dark red solid 2,4-dimethyl-5-formyl-1H- Pyrrole-3-carboxylic acid (0.78 g), yield 98.5%, mp73-74 C (document: yield 90%, mp73-74 C), The reaction route is shown in Equation 3).
53%	In neat (no solvent); for 1.5h;Heating;	35,5-dimethyl-4-ethoxycarbonyl--1H- pyrrole-2-carboxylic acid (9.5g, 0.045mol) was heated to a molten state reaction 1.5h, cooled to room temperature, dissolved in dichloromethane, filtered and the filtrate dried over anhydrous sodium sulfate, and concentrated. Column chromatography with petroleum ether: ethyl acetate = 10:1 (V / V) as eluent to give dark red crystals (4.0g, 53%).

	With copper; In quinoline;	This acid was dissolved in quinoline, 5 g of powdered copper was added, and the mixture heated to 200 C. during which time carbon dioxide was released. The residue was distilled (0.1 mm/120-140 C.) and the distillate recrystallized (ethyl ether/pentane) to give the title compound, m.p. 74-76 C.
	With copper; In quinoline;	This acid was dissolved in quinoline, 5 g of powdered copper was added, and the mixture heated to 200C during which time carbon dioxide was released. The residue was distilled (0.1 mm Hg; (about 13.3 Pa/120-140 C) and the distillate recrystallized (ethyl ether/pentane) to give the title compound, m.p. 74-76C.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 24h;	n this embodiment, as a modification of the present invention, in the third step, the <strong>[5442-91-1]4-ethoxycarbonyl-3,5-dimethylpyrrole-2-carboxylic acid</strong> obtained in the second step is weighed 50 g (0.24 mol). And dissolved in 100g DMF, a small amount of DIPEA catalyzed, heated to 120 C for 24h, to obtain 2,4-dimethyl-3-pyrrolidine ethyl ester solution, cooled to spare.

Reference： [1]Research on Chemical Intermediates,2015,vol. 41,p. 8941 - 8954
[2]Patent: CN103992308,2016,B .Location in patent: Paragraph 0054; 0069-0072; 0075-0081
[3]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 2117 - 2123
[4]Journal of the American Chemical Society,1980,vol. 102,p. 1377 - 1382
[5]Patent: CN102898402,2016,B .Location in patent: Paragraph 0299-0301
[6]Justus Liebigs Annalen der Chemie,1886,vol. 236,p. 296,298
Chemische Berichte,1889,vol. 22,p. 162
[7]Justus Liebigs Annalen der Chemie,1934,vol. 512,p. 195,209
[8]Patent: US4560700,1985,A
[9]Patent: EP190712,1991,B1
[10]European Journal of Medicinal Chemistry,2016,vol. 122,p. 756 - 769
[11]Patent: CN109627200,2019,A .Location in patent: Page/Page column 4-6

3
[ 5442-91-1 ]
[ 5430-79-5 ]

Yield	Reaction Conditions	Operation in experiment
80.8%	With iodine; potassium iodide; In dichloromethane; water; for 2h;Reflux;	Step 3 5-Iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester; <strong>[5442-91-1]3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester</strong> 6c (3.65 g, 17.3 mmol) was dissolved in the solvent mixture of 100 mL of dichloromethane and 10 mL of water followed by addition of potassium iodide (11.5 g, 69.2 mmol) and iodine (4.39 g, 17.3 mmol). Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature and then 20 mL of water and 10 mL of sodium thiosulfate (2 M) were added. The mixture was extracted with dichloromethane (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6d (4.1 g, yield 80.8%) as an orange solid.

Reference： [1]Patent: EP2236500,2010,A1 .Location in patent: Page/Page column 23
[2]Journal of Organic Chemistry,1953,vol. 18,p. 1406,1409
[3]Justus Liebigs Annalen der Chemie,1958,vol. 614,p. 176,195
[4]Farmaco, Edizione Scientifica,1953,vol. 8,p. 156,158

4
[ 2199-51-1 ]
[ 5442-91-1 ]

Reference： [1]Hoppe-Seyler's Zeitschrift fur Physiologische Chemie,1923,vol. 128,p. 230,235, 236

5
[ 2436-79-5 ]
[ 5442-91-1 ]

Yield	Reaction Conditions	Operation in experiment
97.6%	With water; potassium hydroxide; In ethanol; at 50 - 60℃; for 10h;	Compound 6 (0.48 g, 2.0 mmol) was added into a flask equipped with a stirrer, a thermometer, and a condenser; absolute ethanol (3.0 mL) was added into the flask until partially dissolving. Aqueous solution (6.0 mL) of potassium hydroxide (0.28 g, 5.0 mmol) was added under mechanical stirring, being kept at 50-60 C for 10 h with monitoring by TLC (eluent: chloroform/methanol, v/v = 10:1) until reaction completion. The reaction was then stopped by cooling down to r.t. The reaction mixture was poured into ice-water (20 mL) to form an aqueous solution. A small amount of insoluble substance was filtered under vacuum and was washed with water (20 mL). The combined aqueous layers were adjusted with hydrochloride (2 mol/L) to pH 4 to afford some white precipitates, which were collected viafiltering and washing with ice-water to provide 7 (0.41 g, 97.6 %), m.p. 169-170 C (lit. 235-236 C [13]), yield 85.3 % (lit. [13]). Rf = 0.41 (eluent: chloroform/methanol, v/v = 10:1). 1H NMR (DMSO-d6) delta: 1.25 (t, 3H, J = 7.2 Hz, CH3), 2.38 (s, 3H, CH3), 2.43 (s, 3H, CH3), 4.15 (q, 2H, J = 7.2 Hz, CH2), 11.70 (s, 1H, NH-pyrrole), 12.34 (s, 1H, COOH).
97.6%	With potassium hydroxide; In ethanol; water; at 50℃; for 10h;	Add 2.0 mmol of <strong>[2436-79-5]3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester</strong> to a 100 mL three-necked flask equipped with a mechanical stirrer, thermometer, and reflux tube condenser, and add 3 mL of absolute ethanol. Under mechanical stirring, an aqueous potassium hydroxide solution containing 5.0 mmol of potassium hydroxide and a concentration of 0.83 mol / L was added dropwise. During the dropwise addition, the temperature was controlled at 50 C, and the reaction process was monitored by TLC. Mixed solvent of chloroform and methanol, TLC showed that the reaction was complete in 10 h. Stop the reaction, cool the obtained reaction solution to room temperature, then pour the reaction solution into 20 mL of ice water to precipitate a solid, suction filter, wash the filter cake with water, add 2 mol / L hydrochloric acid to the filtrate to adjust to pH 4, and suction filter. The cake was also washed with ice water, The filter cakes from two suction filtrations were collected and dried to obtain 3,5-dimethyl-1H-pyrrole-4-ethoxycarbonyl-2-carboxylic acid (0.41 g) as a white solid, with a yield of 97.6%, mp169- 170 C, the reaction scheme is shown in Equation 2).
92%	With potassium hydroxide; In ethanol; water; for 2.5h;Reflux;	35,5-dimethyl--1H- pyrrole-2,4-dicarboxylic acid diethyl ester (8.0g, 0.033mol) was dissolved in ethanol (108 ml of), potassium hydroxide (2.28g, 0.041mol) in water (28ml ) solution, refluxed for 2.5h, cooled to room temperature, concentrated under reduced pressure to about 40ml, poured into ice water (80ml), add 10% hydrochloric acid was adjusted to pH = 4, filtration, washing the filter cake with water and dried to give a white solid (6.5g, 92%).

	With potassium hydroxide; In ethanol; water;	EXAMPLE 2 Preparation of Ethyl 2,4-Dimethyl-1H-pyrrole-3-carboxylate To a solution of 23,9 g (0.1 mol) of <strong>[2436-79-5]diethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate</strong> in 300 ml of hot ethanol was added a solution of 14 g (0.25 mol) of potassium hydroxide in 350 ml of water. The solution was boiled and the ethanol was allowed to evaporate. After 1.5 hours, the volume was reduced by 350 ml then cooled, filtered, and acidified with 2 N hydrochloric acid. A precipitate formed which was collected, washed with water, and dried to give 19 g of 3,5-dimethyl-4-ethoxycarbonyl-1H-pyrrolecarboxylic acid.
		Example 53 (1) 5-Formyl-2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester (starting material for compound according to Example 53) 2,4-Diethoxycarbonyl-3,5-dimethylpyrrole (2.0 g) was dissolved in ethanol (20 ml), and a 1 N sodium hydroxide solution (20 ml) was added and stirred overnight at 80C. After cooling to room temperature, the reaction mixture was neutralized with a hydrochloric acid solution. The precipitate was collected by filtration, and dried in vacuo. The obtained solid was dissolved in trifluoroacetic acid (20 ml), and stirred for 1 hour at 40C. While cooling with ice, triethyl orthoformate (2.5 ml) was slowly added dropwise to the reaction mixture. The mixture was allowed to room temperature, and then stirred for 2 hours. The resultant was concentrated at reduced pressure. The residue was added to a saturated sodium hydrogencarbonate and stirred, and then the precipitate was collected by filtration. The obtained solid was purified using medium pressure silica gel flash column chromatography (hexane:ethyl acetate = 5:1 to 1:1), and dried in vacuo to afford 5-formyl-2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester (1.21 g, 74 %) as a light yellow solid.
85 g	With sodium hydroxide; In ethanol; water; for 2h;Reflux;	In this embodiment, as a modification of the present invention, in the second step, 120 g (20.5 mol) of <strong>[2436-79-5]diethyl 2,4-dimethylpyrrole-3,5-dicarboxylate</strong> obtained in the first step is obtained. Dissolved in a mixed solution of 425 g of water and 340 g of ethanol, adding 28 g (0.7 mol) of sodium hydroxide, heating to reflux for 2 h, adding hydrochloric acid by cooling, adjusting the pH to 4 to 5, and washing with water to obtain a red-pink solid. 85 g of 4-ethoxycarbonyl-3,5-dimethylpyrrole-2-carboxylic acid was dried.

Reference： [1]Research on Chemical Intermediates,2015,vol. 41,p. 8941 - 8954
[2]Patent: CN103992308,2016,B .Location in patent: Paragraph 0045; 0059-0067
[3]Patent: CN102898402,2016,B .Location in patent: Paragraph 0295-0297
[4]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 2117 - 2123
[5]Justus Liebigs Annalen der Chemie,1886,vol. 236,p. 296,298
Chemische Berichte,1889,vol. 22,p. 162
[6]Patent: US4560700,1985,A
[7]Patent: EP1911755,2008,A1 .Location in patent: Page/Page column 48
[8]European Journal of Medicinal Chemistry,2016,vol. 122,p. 756 - 769
[9]Patent: CN109627200,2019,A .Location in patent: Page/Page column 4-6

6
[ 68999-91-7 ]
[ 5442-91-1 ]

Reference： [1]Journal of the Chemical Society,1958,p. 3779,3782
[2]Journal of the Chemical Society,1958,p. 3779,3782
[3]Journal of Organic Chemistry,2005,vol. 70,p. 10607 - 10610

7
[ 5442-91-1 ]
[ 536-90-3 ]
ethyl 5-[(3-methoxyphenyl)carbamoyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate [ No CAS ]