[ CAS No. 2199-59-9 ]

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2D
Chemical Structure| 2199-59-9
Chemical Structure| 2199-59-9
Structure of 2199-59-9

Quality Control of [ 2199-59-9 ]

Purity: {[proInfo.showProBatch.pb_purity]}

Related Doc. of [ 2199-59-9 ]

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Product Details of [ 2199-59-9 ]

CAS No. :2199-59-9MDL No. :MFCD00030352
Formula :C10H13NO3Boiling Point :-
Linear Structure Formula :(CH3)2(C2H5O2C)C4NH(COH)InChI Key :-
M.W :195.22Pubchem ID :-
Synonyms :

Computed Properties of [ 2199-59-9 ]

TPSA : 59.2 H-Bond Acceptor Count : 3
XLogP3 : 1.5 H-Bond Donor Count : 1
SP3 : 0.40 Rotatable Bond Count : 4

Safety of [ 2199-59-9 ]

Signal Word:WarningClassN/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2199-59-9 ]

  • Upstream synthesis route of [ 2199-59-9 ]

[ 2199-59-9 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 2199-51-1 ]
  • [ 2199-59-9 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring.
Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes.
The maximum temperature reached was 18° C.
The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring.
The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring.
The temperature increased to 22° C.
The mixture was allowed to stand for 30 minutes and the layers allowed to separate.
The temperature reached a maximum of 40° C.
The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition.
After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour.
The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
100% With hydrogenchloride In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring.
Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes.
The maximum temperature reached was 18° C.
The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring.
The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring.
The temperature increased to 22° C.
The mixture was allowed to stand for 30 minutes and the layers allowed to separate.
The temperature reached a maximum of 40° C.
The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition.
After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour.
The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
100% With hydrogenchloride In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring.
Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes.
The maximum temperature reached was 18° C.
The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring.
The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring.
The temperature increased to 22° C.
The mixture was allowed to stand for 30 minutes and the layers allowed to separate.
The temperature reached a maximum of 40° C.
The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition.
After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour.
The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
100% With hydrogenchloride In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring.
Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes.
The maximum temperature reached was 18° C.
The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring.
The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring.
The temperature increased to 22° C.
The mixture was allowed to stand for 30 minutes and the layers allowed to separate.
The temperature reached a maximum of 40° C.
The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition.
After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour.
The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 μM+1].
100% With hydrogenchloride In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring.
Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes.
The maximum temperature reached was 18° C.
The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring.
The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring.
The temperature increased to 22° C.
The mixture was allowed to stand for 30 minutes and the layers allowed to separate.
The temperature reached a maximum of 40° C.
The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition.
After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour.
The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
100% With hydrogenchloride In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring.
Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes.
The maximum temperature reached was 18° C.
The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring.
The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring.
The temperature increased to 22° C.
The mixture was allowed to stand for 30 minutes and the layers allowed to separate.
The temperature reached a maximum of 40° C.
The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition.
After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour.
The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
90%
Stage #1: With trichlorophosphate In dichloromethane at 10 - 20℃; for 0.83 h;
Stage #2: at 5℃; for 1.50 h; Heating / reflux
Step Ie. Ethyl 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylate (Compound 107)To a solution of DMF (2 g, 27 mmol) at 100C was added POCl3 (2.6 mL) in 10 mL of dichloromethane through the dropping funnel over a period of 30 min. After addition, the mixture was stirred for 20 min at room temperature. Dichloromethane (10 mL) was added into the mixture. When the internal temperature lowed to 5°C, a solution of compound 506 in dichloromethane (10 mL) was added through a dropping funnel to the stirred, cooled mixture over a period of 1 h, then the mixture was stirred at the reflux temperature for 30 min, the mixture was then cooled to30°C, a solution of sodium acetate (17 g, 125 mmol) in water (100 ml) was added. The reaction mixture was again refluxed for 30 min. then cooled to room temperature, the aqueous layer was extracted with dichloromethane (4x100 mL). The combined organic layer were washed with brine, dried and evaporated to give gray solid product 107 (4.42 g,90percent). LCMS: m/z 196(M+1), 1H NMR(DMSO-^6) δl.35 (t, J3H), 2.23 (s, 3H), 2.48 (s, 3H), 4.12 (q, 2H), 9.60 (s, IH), 10.58 (s, IH).

Reference: [1] Patent: US2003/216410, 2003, A1
[2] Patent: US2003/130280, 2003, A1
[3] Patent: US2003/100555, 2003, A1
[4] Patent: US2002/32204, 2002, A1
[5] Patent: US2002/156292, 2002, A1
[6] Patent: US2004/209937, 2004, A1
[7] Patent: WO2008/33743, 2008, A1. Location in patent: Page/Page column 53; 56
[8] Journal of the American Chemical Society, 1936, vol. 58, p. 1086,1088
  • 2
  • [ 2199-51-1 ]
  • [ 68-12-2 ]
  • [ 2199-59-9 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With trichlorophosphate In dichloromethane for 1.50 h; Reflux
Stage #2: With sodium hydroxide In dichloromethane; water for 0.50 h; Reflux
Anhydrous DMF (2.0 mL, 24.4 mmol) in a dry flask was precooled to 0 °C with a salt-ice bath, into which a solution of POCl3 (3.60 mL, 39.1 mmol) in anhydrous dichloromethane (8.2 mL) was added slowly dropwise. The temperature should be kept below 3 °C during the whole addition process. The reaction mixture was stirred for 0.5 h using an ice-bath before dropwise addition of solution of ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate (8) in anhydrous dichloromethane (10.0 mL, 2.27 mol/L). The mixture was heated under reflux for 1.5 h before evaporating the excess dichloromethane from the system. Aqueous sodium hydroxide (52.0 mL, 2.81 mol/L) was then added before further reflux for 0.5 h. While cooling to r.t., a large amount of pale-gray solid appeared from the system. The solid was filtrated and washed with a small amount of cold water, and dried under vacuum to afford 9 (4.5 g, 100 percent), m.p. 163-164 °C (lit. 166-167 °C [19]), yield 91.5 percent (lit. [13]). Rf = 0.71 (eluent: chloroform/methanol, v/v = 10:1). 1H NMR (400 MHz, CDCl3) δ: 10.71 (s, 1H, CHO), 9.61 (s, 1H, pyrrole-1-H), 4.31 (q, 2H, CH3CH2O), 2.58 (m, 6H, 2 x 9 (CH3)), 1.38 (t, 3H, J = 8.0 Hz, CH3CH2O).
92%
Stage #1: at 0 - 50℃;
Step (iii): Preparation of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester (IV):Into a 5-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel, air condenser and a nitrogen bubbler was charged dimethyl formamide (1.05 L). The solvent was cooled to 0° C. To this chilled solvent, phosphorous oxychloride (0.434 L) was charged at below 5° C. After addition, the temperature of the reaction mixture was slowly brought to 25-30° C. Then a solution of 2,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester (III) (0.7 Kg; 4.2 mole) dissolved in dimethyl formamide (1.05 L) was added drop-wise into the flask at 25-30° C. After addition, the temperature of the reaction mixture was brought to 50° C and maintained for 2-3 hours. The reaction was monitored by TLC. After maintenance, the reaction mixture was cooled to 25-30° C and quenched in a carboy containing ice-water. The pH of the solution was then adjusted to 12-13 using aq. KOH solution. After pH adjustment, the solution was stirred at 25-30° C and filtered and washed with water. The product was dried in a hot air oven at 60° C. Dry Weight: 0.753 Kg Yield: 92percent HPLC purity: >99.9percent
92%
Stage #1: at 0 - 50℃; for h;
Stage #2: With potassium hydroxide In water at 25 - 30℃;
Into a 5-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel, air condenser and a nitrogen bubbler was charged dimethyl formamide (1.05 L).
The solvent was cooled to 0o C.
To this chilled solvent, phosphorous oxychloride (0.434 L) was charged at below 5oC.
After addition, the temperature of the reaction mixture was slowly brought to 25-30oC. Then a solution of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (III) (0.7 Kg; 4.2 mole) dissolved in dimethyl formamide (1.05 L) was added drop-wise into the flask at 25-30oC.
After addition, the temperature of the reaction mixture was brought to 50oC. and maintained for 2-3 hours.
The reaction was monitored by TLC. After maintenance, the reaction mixture was cooled to 25-30oC. and quenched in a carboy containing ice-water.
The pH of the solution was then adjusted to 12-13 using aq. KOH solution.
After pH adjustment, the solution was stirred at 25-30oC. and filtered and washed with water.
The product was dried in a hot air oven at 60oC. Dry Weight: 0.753 Kg Yield: 92percent HPLC purity: >99.9percent
90%
Stage #1: With trichlorophosphate In dichloromethane at 10 - 20℃; for 0.83 h;
Stage #2: at 5℃; for 1.50 h; Heating / reflux
To a solution of DMF (2 g, 27 mmol) at 100C was added POCl3 (2.6 mL) in 10 mL of dichloromethane through the dropping funnel over a period of 30 min. After addition, the mixture was stirred for 20 min at room temperature. Dichloromethane(10 mL) was added into the mixture. When the internal temperature lowed to 5°C, a solution of compound 506 in dichloromethane (10 mL) was added through a dropping funnel to the stirred, cooled mixture over a period of 1 h, then the mixture was stirred at the reflux temperature for 30 min, the mixture was then cooled to30°C, a solution of sodium acetate (17 g, 125 mmol) in water (100 ml) was added.The reaction mixture was again refluxed for 30 min. then cooled to room temperature, the aqueous layer was extracted with dichloromethane (4x100 mL). The combined organic layer were washed with brine, dried and evaporated to give gray solid product 107 (4.42 g,90percent). LCMS: m/z 196(M+1), 1H NMR(DMSO-J6) δl.35 (t, J3H), 2.23 (s, 3H), 2.48 (s, 3H), 4.12 (q, 2H), 9.60 (s, IH), 10.58 (s, IH).
84%
Stage #1: With trichlorophosphate In dichloromethane at 5℃; for 0.50 h;
Stage #2: for 1.50 h; Reflux
DMF (1.0ml) dropwise POCl 3 (1.88ml) in dichloromethane (4ml) solution, ice water bath temperature was cooled to 5 ° C, dropwise with stirring Bi 30min, was added dropwise 2,4-dimethyl -1H- pyrrole 3-carboxylate (2.0g, 12mmol) in dichloromethane (5ml) was dropwise Bi reflux 1.5h, concentrated under reduced pressure to dryness. Was added sodium hydroxide (3.1g) in water (27 ml of) the solution was stirred at reflux for 0.5h, cooled to room temperature, filtered, the filter cake was washed with water to give a tan solid (2.25g, 97percent). Recrystallized from ethanol to give white crystals (1.97g, 84percent).
76%
Stage #1: With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.25 h;
Stage #2: at 20 - 40℃; for 2.25 h;
Stage #3: With sodium hydrogencarbonate In 1,2-dichloro-ethane at 40℃; for 1.00 h;
Under ice bath conditions, 0.25 mL (2.625 mmol) of phosphorus oxychloride was slowly dropped into 0.20 mL (2.63 mmol) of DMF in dichloroethane solution.After the reaction mixture was stirred at room temperature for 15 min, 400 mg (2.39 mmol) of 2,4-dimethyl-H-pyrrole-3-carboxylic acid ethyl ester dichloroethane solution was slowly added dropwise, stirred at room temperature for 15 min and then heated to 40 ° C. After 2 h of reaction, cool to room temperature and add 12 mL of 1 M sodium bicarbonate solution.Heated at 40 ° C for 1 h, extracted with DCM, dried over anhydrous Na 2 SO 4 ,Column chromatography purification (PE: EA =8:1) gave 357 mg of light yellow solid, yield 76percent.

Reference: [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[2] Synlett, 2010, # 17, p. 2561 - 2564
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2009, vol. 52, # 9, p. 360 - 365
[4] Patent: WO2009/157011, 2009, A1. Location in patent: Page/Page column 28
[5] Patent: US2011/92717, 2011, A1. Location in patent: Page/Page column 14
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 139 - 146
[7] Patent: WO2008/33747, 2008, A2. Location in patent: Page/Page column 201
[8] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841
[9] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1723 - 1729
[10] Patent: CN102898402, 2016, B. Location in patent: Paragraph 0303-0305
[11] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[12] Patent: CN108191835, 2018, A. Location in patent: Paragraph 0028-0029
[13] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 807 - 812
[14] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 756 - 769
[15] Journal of the American Chemical Society, 2018, vol. 140, # 18, p. 5882 - 5885
  • 3
  • [ 86770-31-2 ]
  • [ 122-51-0 ]
  • [ 2199-59-9 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: at 40℃; for 0.08 h;
Stage #2: at -5 - 20℃; for 1.00 h;
[0167] 3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (80.1 g, 0.3 mol) and 400 mL of trifluoroacetic acid were stirred for 5 minutes in a 2 L 3-neck round bottom flask equipped with mechanical stirring and warmed to 40° C. in an oil bath. The mixture was then cooled to -5° C. and triethyl orthoformate (67.0 g, 0.45 mol) was added all at once. The temperature increased to 15° C. The mixture was stirred for about 1 minute, removed from the cold bath and then stirred for 1 hour. The trifluoroacetic acid was removed by rotary evaporation and the residue put in the refrigerator where it solidified. The solid was dissolved by warming and poured into 500 g of ice. The mixture was extracted with 800 mL of dichloromethane to give a red solution and a brown precipitate, both of which were saved. The precipitate was isolated and washed with 150 mL of saturated sodium bicarbonate solution. The dichloromethane phase was washed with 150 mL of sodium bicarbonate and both bicarbonate solutions discarded. The dichloromethane solution was washed with 3 times with 100 mL of water each time. The dichloromethane solution was evaporated to dryness and the dark residue recrystallized twice from hot ethyl acetate after decolorizing with Darco to give golden yellow needles. The brown precipitate was recrystallized from 350 mL of hot ethyl acetate after decolorizing with Darco to give a yellow-red solid. All the recrystallized solids were combined and recrystallized from 500 mL of hot ethanol to give 37.4 g (63.9percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellow needles (mp 165.6-166.3° C., lit. 163-164° C.). The evaporated residues from the ethyl acetate and ethanol mother liquors were recrystallized from 500 mL of ethanol to give 10.1 g (17.1percent) of a second crop of dirty yellow needles.
63.9%
Stage #1: at 40℃; for 0.08 h;
Stage #2: at -5 - 15℃;
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (80.1 g, 0.3 mol) and 400 mL trifluoroacetic acid were stirred for 5 minutes in a 2 L 3-neck round bottom flask equipped with mechanical stirring and warmed to 40° C. in an oil bath.
The mixture was then cooled to -5° C. and triethyl orthoformate (67.0 g, 0.45 mol) was added all at once.
The temperature increased to 15° C.
The mixture was stirred for about 1 minute, removed from the cold bath and then stirred for 1 hour.
The trifluoroacetic acid was removed by rotary evaporation and the residue put in the refrigerator where it solidified.
The solid was dissolved by warming and poured into 500 g of ice.
The mixture was extracted with 800 mL of dichloromethane to give a red solution and a brown precipitate, both of which were saved.
The precipitate was isolated and washed with 150 mL of saturated sodium bicarbonate solution.
The dichloromethane phase was also washed with 150 mL of sodium bicarbonate.
The dichloromethane solution was then washed 3 more times with 100 mL of water.
The dichloromethane solution was evaporated to dryness.
The dark residue which remained was recrystallized twice from ethyl acetate containing Darco carbon black to give golden yellow needles.
The brown precipitate was recrystallized from 350 mL ethyl acetate likewise containing Darco to give a yellow-red solid.
All the recrystallized solids were combined and recrystallized from 500 mL of ethanol to give 37.4 g (63.9percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellow needles (mp 165.6-166.3° C., lit. 163-164° C.).
The residue obtained after evaporationg of the ethyl acetate and ethanol mother liquors were combined and recrystallized from 500 mL of ethanol to give a second crop (10.1 g) or product as dirty yellow needles.
63.9%
Stage #1: at 40℃; for 0.08 h;
Stage #2: at -5 - 15℃; for 1.00 h;
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (80.1 g, 0.3 mol) and 400 mL of trifluoroacetic acid were stirred for 5 minutes in a 2 L 3-neck round bottom flask equipped with mechanical stirring and warmed to 40° C. in an oil bath.
The mixture was then cooled to -5° C. and triethyl orthoformate (67.0 g, 0.45 mol) was added all at once.
The temperature increased to 15° C.
The mixture was stirred for about 1 minute, removed from the cold bath and then stirred for 1 hour.
The trifluoroacetic acid was removed by rotary evaporation and the residue put in the refrigerator where it solidified.
The solid was dissolved by warming and poured into 500 g of ice.
The mixture was extracted with 800 mL of dichloromethane to give a red solution and a brown precipitate, both of which were saved.
The precipitate was isolated and washed with 150 mL of saturated sodium bicarbonate solution.
The dichloromethane phase was washed with 150 mL of sodium bicarbonate and both bicarbonate solutions discarded.
The dichloromethane solution was washed with 3 times with 100 mL of water each time.
The dichloromethane solution was evaporated to dryness and the dark residue recrystallized twice from hot ethyl acetate after decolorizing with Darco to give golden yellow needles.
The brown precipitate was recrystallized from 350 mL of hot ethyl acetate after decolorizing with Darco to give a yellow-red solid.
All the recrystallized solids were combined and recrystallized from 500 mL of hot ethanol to give 37.4 g (63.9percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellow needles (mp 165.6-166.3° C., lit. 163-164° C.).
The evaporated residues from the ethyl acetate and ethanol mother liquors were recrystallized from 500 mL of ethanol to give 10.1 g (17.1percent) of a second crop of dirty yellow needles.
63.9 % With sodium hydrogencarbonate; trifluoroacetic acid In ethanol; water Step 2
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (80.1 g, 0.3 mol) and 400 mL of trifluoroacetic acid were stirred for 5 minutes in a 2 L 3-neck round bottom flask equipped with mechanical stirring and warmed to 40° C. in an oil bath.
The mixture was then cooled to -5 ° C. and triethyl orthoformate (67.0 g, 0.45 mol) was added all at once.
The temperature increased to 15 ° C.
The mixture was stirred for about 1 minute, removed from the cold bath and then stirred for 1 hour.
The trifluoroacetic acid was removed by rotary evaporation and the residue put in the refrigerator where it solidified.
The solid was dissolved by warming and poured into 500 g of ice.
The mixture was extracted with 800 mL of dichloromethane to give a red solution and a brown precipitate, both of which were saved.
The precipitate was isolated and washed with 150 mL of saturated sodium bicarbonate solution.
The dichloromethane phase was washed with 150 mL of sodium bicarbonate and both bicarbonate solutions discarded.
The dichloromethane solution was washed with 3 times with 100 mL of water each time.
The dichloromethane solution was evaporated to dryness and the dark residue recrystallized twice from hot ethyl acetate after decolorizing with Darco to give golden yellow needles.
The brown precipitate was recrystallized from 350 mL of hot ethyl acetate after decolorizing with Darco to give a yellow-red solid.
All the recrystallized solids were combined and recrystallized from 500 mL of hot ethanol to give 37.4 g (63.9 percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellow needles (mp 165.6 -166.3 ° C, lit. 163 -164 ° C).
The evaporated residues from the ethyl acetate and ethanol mother liquors were recrystallized from 500 mL of ethanol to give 10.1 g (17.1 percent) of a second crop of dirty yellow needles.
63.9% With sodium hydrogencarbonate; trifluoroacetic acid In ethanol; water 3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (80.1 g, 0.3 mol) and 400 mL of trifluoroacetic acid were stirred for 5 minutes in a 2 L 3-neck round bottom flask equipped with mechanical stirring and warmed to 40° C. in an oil bath.
The mixture was then cooled to -5° C. and triethyl orthoformate (67.0 g, 0.45 mol) was added all at once.
The temperature increased to 15° C.
The mixture was stirred for about 1 minute, removed from the cold bath and then stirred for 1 hour.
The trifluoroacetic acid was removed by rotary evaporation and the residue put in the refrigerator where it solidified The solid was dissolved by warming and poured into 500 g of ice.
The mixture was extracted with 800 mL of dichloromethane to give a red solution and a brown precipitate, both of which were saved.
The precipitate was isolated and washed with 150 mL of saturated sodium bicarbonate solution.
The dichloromethane phase was washed with 150 mL of sodium bicarbonate and both bicarbonate solutions discarded.
The dichloromethane solution was washed with 3 times with 100 mL of water each time.
The dichloromethane solution was evaporated to dryness and the dark residue recrystallized twice from hot ethyl acetate after decolorizing with Darco to give golden yellow needles.
The brown precipitate was recrystallized from 350 mL of hot ethyl acetate after decolorizing with Darco to give a yellow-red solid.
All the recrystallized solids were combined and recrystallized from 500 mL of hot ethanol to give 37.4 g (63.9percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellow needles (mp 165.6-166.3° C., lit. 163-164° C.).
The evaporated residues from the ethyl acetate and ethanol mother liquors were recrystallized from 500 mL of ethanol to give 10.1 g (17. 1percent) of a second crop of dirty yellow needles.

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[2] Patent: US2004/266843, 2004, A1. Location in patent: Page 10; 11
[3] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 10, p. 1439 - 1441
[4] Patent: US6878733, 2005, B1. Location in patent: Page/Page column 181-182
[5] Patent: US2004/204407, 2004, A1. Location in patent: Page/Page column 14-15
[6] Patent: US2003/69297, 2003, A1
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[2] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 756 - 769
[3] Patent: CN102898402, 2016, B
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[2] Patent: CN108191835, 2018, A
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[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 518
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