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[ CAS No. 2199-43-1 ]

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Chemical Structure| 2199-43-1
Chemical Structure| 2199-43-1
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Product Details of [ 2199-43-1 ]

CAS No. :2199-43-1MDL No. :MFCD00817049
Formula : C7H9NO2 Boiling Point : 244.6°C at 760 mmHg
Linear Structure Formula :-InChI Key :-
M.W :139.15Pubchem ID :255670
Synonyms :

Computed Properties of [ 2199-43-1 ]

TPSA : 42.1 H-Bond Acceptor Count : 2
XLogP3 : - H-Bond Donor Count : 1
SP3 : 0.29 Rotatable Bond Count : 3

Safety of [ 2199-43-1 ]

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

Application In Synthesis of [ 2199-43-1 ]

  • Upstream synthesis route of [ 2199-43-1 ]
  • Downstream synthetic route of [ 2199-43-1 ]

[ 2199-43-1 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 2199-43-1 ]
  • [ 1072-82-8 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 48 - 54
  • 2
  • [ 2199-43-1 ]
  • [ 6973-60-0 ]
Reference: [1] Bulletin of the Agricultural Chemical Society of Japan, 1959, vol. 23, p. 165,170[2] Journal of the American Chemical Society, 1958, vol. 80, p. 4749
  • 3
  • [ 2199-43-1 ]
  • [ 6636-06-2 ]
Reference: [1] Patent: CN107151255, 2017, A,
  • 4
  • [ 2199-43-1 ]
  • [ 68-12-2 ]
  • [ 7126-50-3 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With trichlorophosphate In dichloromethaneCooling with ice
Stage #2: at 0℃; for 4 h; Reflux
To an ice cold solution of DMF (9.3 mL, 0.121 mmol, 1.12 eq.) in anhydrous DCM (23 mL) was added phosphorus oxychloride (11.1 mL, 0.120 mL, 1.11 eq.) dropwise.
A solution of ethyl pyrrole-2-carboxylate (15 g, 0.108 mmol) in anhydrous DCM (23 mL) was then added slowly to the reaction mixture, which was stirred at 0° C. for 1 h and then heated to reflux for 3 hrs until no more starting material was seen on TLC.
The reaction mixture was allowed to cool to RT, diluted with EtOAc (150 mL) and water (150 mL) and the washed with NaHCO3 (saturated) (2*450 mL).
The aqueous layer was re-extracted with ethyl acetate (3*150 mL) and the combined organic layers were dried over Na2SO4 and concentrated.
The product was then purified by column chromatography using 5percent to 30percent ethyl acetate in hexanes as the eluent to give I-1 as a white solid (11.95 g, 66percent).
1H NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J=7 Hz), 4.39 (2H, q, J=7 Hz), 6.95 (2H, d, J=2 Hz), 9.68 (1H, s).
43%
Stage #1: With trichlorophosphate In dichloromethane at 0℃; for 4 h; Reflux
Stage #2: With water In ethyl acetate at 20℃;
To an ice cooled solution of DMF (24.5 mL, 316.43 mmol) in dichloromethane (70 mL) was added POCl3 (29 mL, 313.63 mmol) followed by dropwise addition of a solution of ethyl pyrrole-2-carboxylate (15b) (40 g, 98percent, 281.71 mmol) in dichloromethane (70 mL). The reaction mixture was stirred at 00C for 1 h and then refluxed for 3 h. The reaction was cooled to room temperature and diluted with ethyl acetate (250 mL); water (300 mL).The aqueous layer was separated and extracted with ethyl acetate (3 x 150 mL). The combined ethyl acetate layers were washed with aqueous 1 M NaHCO3 (3 x 100 mL), dried over MgSO4, filtered and concentrated in vacuum. The residue obtained was purified by column chromatography (silica gel, 450 g eluting with hexanes/ethyl acetate, 1 :0 to 2: 1, Rf = 0.54 with hexanes/ethyl acetate = 2:1) to give ethyl 5-formyl-lH-pyrrole-2-carboxylate (22b) (20.2 g, 43percent) as a yellow solid. 1H NMR (300 MHz, OMSO-d6): δ 13.04 (bs, IH), 9.71 (s, IH), 6.97 (d, J= 3.9 Hz, IH), 6.88 (d, J = 3.9 Hz, IH), 4.30 (q, J= 7.1 Hz, 2H), 1.31 (t, J= 7.1 Hz, 3H); MS (ES ): 166.1 (M - H)".
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9350 - 9359
[2] Tetrahedron Letters, 2008, vol. 49, # 51, p. 7337 - 7340
[3] Chemistry - A European Journal, 2017, vol. 23, # 7, p. 1484 - 1489
[4] Patent: US9458138, 2016, B1, . Location in patent: Page/Page column 42
[5] Journal of Organic Chemistry, 2002, vol. 67, # 10, p. 3479 - 3486
[6] Organic and Biomolecular Chemistry, 2003, vol. 1, # 12, p. 2103 - 2110
[7] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 16, p. 2153 - 2157
[8] Patent: WO2011/14817, 2011, A1, . Location in patent: Page/Page column 90
  • 5
  • [ 2199-43-1 ]
  • [ 68-12-2 ]
  • [ 7126-50-3 ]
  • [ 7126-57-0 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With trichlorophosphate In 1,2-dichloro-ethane at 0 - 40℃; for 0.5 h;
Stage #2: at 0 - 40℃; for 1.5 h;
A-6
5-Formyl-1H-pyrrole-2-carboxylic acid
To a solution of dimethylformamide (21 mL, 0.27 mol) in 75 mL of dichloroethane was added a solution of phosphorus oxychloride (25 mL, 0.27 mol) in 75 mL of dichloroethane at 0 oC.
The mixture was stirred at room temperature for 30 minutes and cooled to 0 oC.
To the mixture was added a solution of ethyl pyrrole-2-carboxylate (25 g, 0.18 mol) in 50 mL of dichloroethane dropwise.
The resulting mixture was stirred at room temperature for 30 minutes and then at 40 oC for 1 hour.
The mixture was poured into ice and basified to pH 11 with 5 N sodium hydroxide solution.
The mixture was extracted with ethyl acetate and the extract washed with water and brine and dried over anhydrous sodium sulfate.
The two products were separated by column chromatography (1:3 ethyl acetate:hexane) to give 15 g (50percent yield) of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester and 2 g (7percent yield) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H-NMR (300 MHz, dimethylsulfoxide) δ 13.02 (br s, 1H, NH), 9.69 (s, 1H, CHO), 6.95 (d, 1H), 6.86 (d, 1H), 4.27 (q, 2H, CH3), 1.28 (t, 3H, CH3). MS m/z 167 [M+].
50%
Stage #1: With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5 h;
Stage #2: at 0 - 40℃; for 1.5 h;
To a solution of dimethylformamide (21 mL, 0.27 mol) in 75 mL of dichloroethane was added a solution of phosphorus oxychloride (25 mL, 0.27 mol) in 75 mL of dichloroethane at 0 oC.
The mixture was stirred at room temperature for 30 minutes and cooled to 0 oC.
To the mixture was added a solution of ethyl pyrrole-2-carboxylate (25 g, 0.18 mol) in 50 mL of dichloroethane dropwise.
The resulting mixture was stirred at room temperature for 30 minutes and then at 40 oC. for 1 hour.
The mixture was poured into ice and basified to pH 11 with 5 N sodium hydroxide solution.
The mixture was extracted with ethyl acetate and the extract washed with water, brine and dried over anhydrous sodium sulfate.
The two products were separated by column chromatography (1:3 ethyl acetate:hexane) to give 15 g (50percent yield) of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester and 2 g (7percent yield) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H-NMR (5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester) (300 MHz, dimethylsulfoxide) δ 13.02 (br s, 1H, NH), 9.69 (s, 1H, CHO), 6.95 (d, 1H), 6.86 (d, 1H), 4.27 (q, 2H, CH3), 1.28 (t, 3H, CH3). MS m/z 167 [M+].
50%
Stage #1: With trichlorophosphate In 1,1-dichloroethane at 0 - 20℃; for 0.5 h;
Stage #2: at 0 - 40℃; for 1.5 h;
Stage #3: With sodium hydroxide In water at 0℃;
[0179] To a solution of dimethylformamide (21 mL, 0.27 mol) in 75 mL of dichloroethane was added a solution of phosphorus oxychloride (25 mL, 0.27 mol) in 75 mL of dichloroethane at 0° C. The mixture was stirred at room temperature for 30 minutes and cooled to 0° C. To the mixture was added a solution of ethyl pyrrole-2-carboxylate (25 g, 0.18 mol) in 50 mL of dichloroethane dropwise. The resulting mixture was stirred at room temperature for 30 minutes and then at 40° C. for 1 hour. The mixture was poured into ice and basified to pH 11 with 5 N sodium hydroxide solution. The mixture was extracted with ethyl acetate and the extract washed with water and brine and dried over anhydrous sodium sulfate. The two products were separated by column chromatography (1:3 ethyl acetate:hexane) to give 15 g (50percent yield) of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester and 2 g (7percent yield) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H-NMR (300 MHz, dimethylsulfoxide) δ 13.02 (br s, 1H, NH), 9.69 (s, 1H, CHO), 6.95 (d, 1H), 6.86 (d, 1H), 4.27 (q, 2H, CH3), 1.28 (t, 3H, CH3). MS M/Z 167 [M+].
42% at 30℃; Inert atmosphere; Cooling with ice To an ice-cooled solution of ethyl 1H-pyrrole-2-carboxylate2 (10 g, 72 mmol) in dry DMF (129.3 mL), freshly distilled phosphorus oxychloride (POCl3, 20.1 mL, 216 mmol) was added dropwise under argon atmosphere. After the completion of the addition, the cooling bath was removed and the reaction mixture was stirredat 30 °C for 21 h. Then, the mixture was gradually added to ice-water, the pH was adjusted to pH=7 with 25 percent aq. NH3 and the aqueous solution was extracted with DCM (3×). The combined organic layers were washed with saturated aqueous NaHCO3 (1×) and brine (1×), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The resulting oily residue was purified by silica gel flash column chromatography (DCM/MeOH 98:2) to afford 4 (5 g, red-browns olid, 42 percent) and ethyl 5-formyl-1H-pyrrole-2-carboxylate (5.5 g, red-brown solid, 46 percent).For compound 4: Rf (toluene/EtOAc 8:2) 0.13. mp 103-104 °C. IR (KBr): max 3175, 2881, 1705, 1651, 1269 cm-1. 1H NMR (CDCl3, 400 MHz): 10.10 (br s, 1H), 9.85 (s, 1H), 7.58 (dd, J = 3.3 Hz,J = 1.5 Hz, 1H), 7.33-7.32 (m, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz,3H). 13C NMR (CDCl3, 100 MHz): 185.82, 161.12, 128.61, 127.69, 125.26, 114.28,61.31, 14.45. MS (ESI+) (m/z): 168.53 [M+H]+. HRMS-ESI (m/z): [M+Na]+ calcd for C8H9NO3: 190.04746, found: 109.04756.

Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 25, p. 7245 - 7257
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6911 - 6923
[3] Patent: US2004/204407, 2004, A1, . Location in patent: Page/Page column 16
[4] Patent: US2004/204407, 2004, A1, . Location in patent: Page/Page column 21
[5] Patent: US2004/266843, 2004, A1, . Location in patent: Page 12
[6] Tetrahedron, 2016, vol. 72, # 19, p. 2376 - 2385
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  • [ 2199-43-1 ]
  • [ 7126-50-3 ]
YieldReaction ConditionsOperation in experiment
42% With trichlorophosphate In hexane; water; ethyl acetate; 1,2-dichloro-ethane; N,N-dimethyl-formamide a)
5-Formyl-1H-pyrrole-2-carboxylic Acid Ethyl Ester
To DMF (1.3 mL, 17 mmol) cooled to 5-10° C. was added phosphorous oxychloride (1.5 mL) dropwise and the mixture was diluted with 1,2-dichloroethane (5 mL).
The flask was then cooled to -10° C. and ethyl pyrrole-2-carboxylate (2.00 g, 14.4 mmol) in 1,2-dichloroethane (5 mL) was added dropwise over 5 min.
The mixture was heated to reflux for 15 min, cooled to RT and ethyl acetate (15 mL), water (20 mL), and satd aq sodium bicarbonate (70 mL) were added.
The layers were separated and the aqueous layer was extracted with diethyl ether (3*20 mL).
The combined organic layers were washed with saturated sodium carbonate (50 mL), dried (Na2SO4) and the solvents were removed in vacuo.
The resulting solid was purified by column chromatography on silica gel (300 g), eluding with 30percent ethyl acetate in hexane to yield 1.0 g (42percent) of the title compound as a pale yellow crystalline solid. 1H-NMR (400 MHz, CDCl3): δ 9.89 (br s, 1H), 9.67 (s, 1H), 6.95 (d, 1H, J=4.1 Hz), 6.94 (d, 1H, J=4.1 Hz), 4.38 (q, 2H, J=7.1 Hz), 1.39 (t, 3H, J=7.1).
Reference: [1] Patent: US2005/131022, 2005, A1,
  • 7
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  • [ 7126-50-3 ]
Reference: [1] Patent: US2004/209886, 2004, A1,
  • 8
  • [ 2199-43-1 ]
  • [ 3724-43-4 ]
  • [ 7126-50-3 ]
Reference: [1] Organic Process Research and Development, 2018,
  • 9
  • [ 74-90-8 ]
  • [ 2199-43-1 ]
  • [ 7126-50-3 ]
Reference: [1] Helvetica Chimica Acta, 1930, vol. 13, p. 349,353
  • 10
  • [ 2199-43-1 ]
  • [ 75-36-5 ]
  • [ 119647-69-7 ]
YieldReaction ConditionsOperation in experiment
76%
Stage #1: With aluminum (III) chloride In 1,2-dichloro-ethane at 20℃; for 1.25 h;
Ethyl 4-acetylpyrrole-2-carboxylate. In a two-neck round bottom flask with an argon inlet, 4.0 g of ethyl pyrrole 2-carboxylate (28.8 mmol) is dissolved in 100 ml of 1,2-dichloroethane. Subsequently, 8.0 g of AlCl3 is added slowly. A solution of 4.4 ml of acetyl chloride (62 mmol) in 50 ml of 1,2-dichloroethane was then added dropwise over a period of 15 min. After stirring the reaction mixture at room temperature for one hour, it is carefully poured onto 200 g of crushed ice. After hydrolysis, the mixture is transferred into a separatory funnel and the organic phase is separated off. The aqueous phase is extracted with dichloromethane (2.x.200 ml), and the combined organic phases are washed with a saturated solution of aqueous sodium bicarbonate (1.x.100 ml) and with water (1.x.100 ml) before being dried over magnesium sulfate. The solvent is then removed under vacuum. Chromatographic workup (silica gel; 1percent methanol in dichloromethane as eluent) yielded the product as a pale brown powder (4.0 g, 76percent yield).
Reference: [1] Heterocycles, 1988, vol. 27, # 8, p. 1855 - 1860
[2] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 48 - 54
[3] Patent: US2003/229131, 2003, A1, . Location in patent: Page 24
  • 11
  • [ 2199-43-1 ]
  • [ 108-24-7 ]
  • [ 119647-69-7 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 48 - 54
  • 12
  • [ 2199-43-1 ]
  • [ 108-24-7 ]
  • [ 119647-69-7 ]
  • [ 119647-70-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 48 - 54
  • 13
  • [ 2199-43-1 ]
  • [ 75-36-5 ]
  • [ 119647-69-7 ]
  • [ 119647-70-0 ]
Reference: [1] Heterocycles, 1988, vol. 27, # 8, p. 1855 - 1860
[2] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 48 - 54
[3] Heterocycles, 1988, vol. 27, # 8, p. 1855 - 1860
[4] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 48 - 54
  • 14
  • [ 2199-43-1 ]
  • [ 433267-55-1 ]
Reference: [1] Synthesis, 2002, # 2, p. 274 - 278
  • 15
  • [ 2199-43-1 ]
  • [ 433267-55-1 ]
  • [ 516465-86-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 657 - 661
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 3165 - 3186
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